leptin and Diabetes-Mellitus--Type-1

Leptin monotherapy is sufficient to restore euglycemia in insulinopenic type 1 diabetes (T1D), yet the underlying mechanism remains poorly understood. Accumulating evidence demonstrates that the brain mediates the leptin action on euglycemia restoration. Here, we first review evidence supporting that symptoms in T1D resemble an uncontrolled response to fasting. Then, we discuss recent research progress on brain neurons and their neurotransmitters that potentially mediate the leptin action. Finally, peripheral effective pathways, which are normally involved in fasting responses and associated with leptin action on euglycemia restoration in T1D, will also be discussed. This summary complements several previous excellent reviews on this topic (Meek and Morton, 2016; Perry et al., 2016; Fujikawa and Coppari, 2015). A deep understanding of neurocircuitry and the peripheral effective pathways that mediate the leptin action on euglycemia restoration will likely lead to novel targets for an insulin-independent therapeutics against T1D.

Topics: Animals; Blood Glucose; Brain; Diabetes Mellitus, Type 1; Fasting; Homeostasis; Humans; Leptin

In this review we discuss the mechanisms for the pleotropic effects of leptin replacement therapy to reverse liver and muscle insulin resistance in lipodystrophic individuals, as well as insulin-independent effects of leptin replacement therapy to suppress white adipose tissue lipolysis, hepatic gluconeogenesis and fasting hyperglycaemia in rodent models of poorly controlled diabetes. On the basis of these studies we conclude with a view of the potential therapeutic applications of leptin replacement therapy in humans. This review summarises a presentation given at the 'Is leptin coming back?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Thomas Meek and Gregory Morton, DOI: 10.1007/s00125-016-3898-3 , and by Christoffer Clemmensen and colleagues, DOI: 10.1007/s00125-016-3906-7 ) and an overview by the Session Chair, Ulf Smith (DOI: 10.1007/s00125-016-3894-7 ).

Topics: Animals; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Humans; Insulin Resistance; Leptin

The adipokine leptin realizes signal transduction via four different leptin receptor (OB-R) isoforms. The amount of functionally active OB-R, however, is affected by constitutive shedding of the extracellular domain. The product of the cleavage process, the so-called soluble leptin receptor (sOB-R), is the main binding protein for leptin in human blood and modulates its bioavailability. Concentrations of sOB-R are differentially regulated in metabolic disorders, such as type 1 diabetes mellitus or obesity, and can, therefore, enhance or reduce leptin sensitivity. Lipotoxicity and apoptosis increase OB-R cleavage via ADAM10-dependent mechanisms. In contrast, although increased sOB-R concentrations seem to directly inhibit leptin effects, reduced amounts of sOB-R may reflect decreased membrane expression of OB-R. These findings, in part, explain alterations of leptin sensitivity that are associated with changes in serum sOB-R concentrations seen in metabolic disorders.

Topics: ADAM10 Protein; Animals; Apoptosis; Diabetes Mellitus, Type 1; Humans; Leptin; Obesity; Receptors, Leptin

The adipose tissue is an endocrine organ that produces a variety of protein hormones. One of them is leptin, which regulates several critical functions at the central nervous system such as caloric intake, basal energy expenditure, reproduction, glucose and lipid metabolism and osteogenesis. Acting at a local level, leptin modulates the immune system and promotes liver fibrogenesis. The most promising therapeutic implications of leptin will possibly be in type 1 diabetes mellitus (DM1). Its supplementation in animal models of DM1 prevents hyperglycemia and ketoacidosis. These actions depend on the activation of leptin receptors in the central nervous system and the suppression of glucagon signaling in the liver.

Topics: Adipose Tissue; Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Leptin; Mice; Rats; Receptors, Leptin

Metreleptin is an analogue of the human hormone leptin being developed by Amylin Pharmaceuticals (a subsidiary of Bristol-Myers Squibb) for the subcutaneous treatment of metabolic disorders including lipodystrophy. The compound is expected to improve insulin sensitivity, hypertriglyceridaemia and hyperglycaemia in patients with lipodystrophy who are unresponsive to conventional treatment. Metreleptin has been approved in Japan as a leptin therapy for the treatment of lipodystrophy. Amylin has also completed a submission for regulatory approval to the US FDA for metreleptin in the treatment of diabetes mellitus and/or hypertriglyceridaemia in patients with rare forms of lipodystrophy. Clinical development of the drug is also underway in the USA for the treatment of type 1 diabetes. Amgen was previously assessing the use of metreleptin as a treatment for amenorrhoea; however, it appears that development in this indication has been discontinued. This article summarizes the milestones in the development of metreleptin leading to this first approval for lipodystrophy.

Topics: Animals; Clinical Trials as Topic; Clinical Trials, Phase I as Topic; Diabetes Mellitus, Type 1; Double-Blind Method; Drosophila Proteins; GTPase-Activating Proteins; Humans; Leptin; Lipodystrophy

Topics: Allylamine; Animals; Blood Glucose; Bromocriptine; Cardiovascular Diseases; Colesevelam Hydrochloride; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Gastrins; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Islet Amyloid Polypeptide; Leptin; Metformin; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds; Thiazolidinediones; United States

The discovery of the adipocyte hormone leptin completely changed our view of energy metabolism. In addition, the discovery of leptin rapidly progressed to clinical development. After a decade of clinical studies, leptin appears not to be the magic bullet therapy for obesity; however, it has a robust role in rare human conditions characterized by its deficiency. Recent exciting work from the Unger laboratory suggests that leptin therapy may also have a potential role for the treatment of Type 1 diabetes. In this review we discuss the positive evidence why such an approach is worthwhile. In order to achieve this broad goal, we reviewed available literature and provided our interpretation of the evidence presented in the original research papers. The potential cautionary aspects of this novel approach will be discussed in an accompanying article.

Topics: Adipocytes; Animals; Diabetes Mellitus, Type 1; Energy Metabolism; Humans; Leptin; Lipid Metabolism; Lipodystrophy; Mutation; Obesity; Receptor, Insulin

Most of the drugs available to treat type 2 diabetes mellitus (T2DM) act either in the pancreas by increasing insulin secretion or in tissues such as the liver or muscle by improving insulin sensitivity. However, recent studies have shown that the brain also plays a critical role in the regulation of glucose homeostasis. For example, central leptin administration reduces hyperglycemia and improves the survival of mice with type 1 diabetes mellitus (T1DM). In addition, several pieces of evidence show that the brain can control the insulin sensitivity in different tissues and the pancreatic secretion of insulin and glucagon. Therefore, the brain emerges as a promising new target of drugs aiming to treat both T1DM and T2DM. An exciting finding is that there is a partial overlap between neuronal populations that regulate energy balance and glucose homeostasis. Therefore, obesity and T2DM may have similar origins that are related to dysfunctions in the central nervous system. Likewise, future drugs that target the brain to treat T2DM may have beneficial effects in reducing body weight, and vice versa. In this review, the recent data showing how the brain is able to have an important regulatory effect over blood glucose levels as well as the possible neuronal circuitries involved in the control of glucose homeostasis will be summarized. The opportunities and challenges of using synthetic drugs or natural compounds that act in the central nervous system to treat diabetes mellitus will also be discussed.

Topics: Animals; Central Nervous System; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucose; Homeostasis; Humans; Insulin; Leptin; Lipodystrophy; Signal Transduction

In the past decade several novel findings point to the critical role of the skeleton in several homeostatic processes, including energy balance. The connection begins in the bone marrow with lineage allocation of mesenchymal stem cells to adipocytes or osteoblasts. Osteoblasts and adipocytes produce factors affecting insulin homeostasis. The hormonally active adipose tissue can regulate bone metabolism. In this review authors discuss targets taking critical part in the bone-fat network: leptin, osteocalcin, PPAR γ2 and the Wnt/beta catenin pathway. Leptin regulates energy metabolism through controlling appetite. Mutation of the leptin gene resulting leptin resistance leads to high leptin levels, enormous appetite and pathologic obesity. Leptin also can influence the bone mass. The main effects of the thiazolidinedions - PPARγ agonists - are mediated through receptors located in adipocytes. However, beside their positive effects, they also suppress osteoblastogenesis and increase the risk for pathologic fractures. Osteocalcin, a known marker of bone formation, produced by osteoblasts decreases fat mass, promotes adiponectin production and insulin sensitivity, increases the number of pancreatic β-cells and increases insulin secretion. Thus, the skeletal system can regulate glucose metabolism and this substantially changed our view on this issue. Novel molecules can now be tested as targets in order to enhance bone formation and possibly prevent fractures.

Topics: Animals; Bone and Bones; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Leptin; Lipid Peroxidation; Osteocalcin; Osteogenesis; Oxidative Stress; PPAR gamma; Signal Transduction; Wnt1 Protein

Diabetes mellitus complicates 1-2% of all pregnancies but is associated with high perinatal morbidity and mortality. Gestational diabetes affects up to 4% of pregnancies and is associated with fetal macrosomia (large for dates). Fetal growth is a complex process influenced by determinants such as genetics, maternal factors, uterine environment and maternal and fetal hormones. Infants of pre-gestational diabetic mothers have an additional influence of maternal fluctuations in glycaemia. The purpose of this paper is to review maternal and fetal growth factors, including insulin, in the aetiology of macrosomia in diabetic pregnancy. Placental Growth Hormone is the major growth hormone secreted during human pregnancy. Leptin may have a role in satiety. Resistin was originally proposed as the link between obesity and diabetes but is now thought to have a more complex role. These hormones and their actions on human in-utero growth are reviewed in depth with particular reference to both pre-gestational (type 1 and type 2 diabetes) and gestational diabetes. Previously increased fetal weight in infants of diabetic mothers was thought to be as a result of maternal hyperglycaemia. It is now evident that control of fetal growth, in normal as well as diabetic pregnancies, is far more complex than previously thought.

Topics: Adult; Birth Weight; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Fetal Macrosomia; Fetus; Growth Hormone; Humans; Hyperglycemia; Infant; Insulin; Leptin; Placental Hormones; Pregnancy; Pregnancy in Diabetics; Resistin

Although its role in energy homeostasis is firmly established, the evidence accumulated over a decade linking the adipocyte leptin-hypothalamus axis in the pathogenesis of diabetes mellitus has received little attention in the contemporary thinking. In this context various lines of evidence are collated here to show that (1) under the direction of leptin two independent relays emanating from the hypothalamus restrain insulin secretion from the pancreas and mobilize peripheral organs--liver, skeletal muscle and brown adipose tissue--to upregulate glucose disposal, and (2), leptin insufficiency in the hypothalamus produced by either leptinopenia or restriction of leptin transport across the blood brain barrier due to hyperleptinemia of obesity and aging, initiate antecedent pathophysiological sequalae of diabetes type 1 and 2. Further, we document here the efficacy of leptin replenishment in vivo, especially by supplying it to the hypothalamus with the aid of gene therapy, in preventing the antecedent pathophysiological sequalae--hyperinsulinemia, insulin resistance and hyperglycemia--in various animal models and clinical paradigms of diabetes type 1 and 2 with or without attendant obesity. Overall, the new insights on the long-lasting antidiabetic potential of two independent hypothalamic relays engendered by central leptin gene therapy and the preclinical safety indicators in rodents warrant further validation in subhuman primates and humans.

Topics: Animals; Appetite Regulation; Body Weight; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucose; Humans; Hypothalamus; Insulin; Leptin; Obesity; Signal Transduction

Atherosclerosis and related forms of cardiovascular disease (CVD) are associated with several genetic and environmental risk factors, including hypercholesterolemia, diabetes mellitus (DM), hypertension, obesity and smoking. Human DM is a multi-system disorder that results from progressive failure of insulin production and insulin resistance. Most diabetic patients die from complications of atherosclerosis and CVD, and DM is also associated with increased risk of restenosis post-angioplasty. Furthermore, the incidence of DM, particularly type 2-DM, is expected to increase significantly during the next decades owing to the unhealthy effects of modern life-style habits (e.g., obesity and lack of physical exercise). Thus, it is of utmost importance to develop novel preventive and therapeutic strategies to reduce the social and health-care burden of CVD and DM. Although a number of physiological alterations thought to promote atherosclerosis have been identified in diabetic patients, the precise molecular mechanisms that link DM and atherosclerosis are largely unknown. Thus, the aim of this review is to discuss current murine models of combined DM and atherosclerosis and to explore how these experimental systems are being utilized to gain mechanistic insights into diabetes-induced neointimal lesion development, as well as their potential use in evaluating the efficacy of new therapies. Our discussion includes models generated by streptozotocin treatment and those resulting from naturally occurring or targeted mutations in the mouse.

Topics: Animals; Atherosclerosis; Constriction, Pathologic; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Glucose; Insulin; Leptin; Mice; Recurrence; Tunica Intima

The incidence of type 1 and type 2 diabetes mellitus in the pediatric population has increased over the past decade. The practitioner is often faced with the challenge of differentiating between type 1 and type 2 diabetes at the time of initial diagnosis because of the overlap of clinical and laboratory characteristics between these two entities. Adipokines are proteins secreted by the adipose tissue. Leptin and adiponectin are two adipokines that have been extensively studied in vitro, in animal studies, and in human subjects with type 1 and type 2 diabetes. Leptin and adiponectin play a significant role in the regulation of lipid and carbohydrate metabolism. Adiponectin increases insulin sensitivity in both the liver and skeletal muscle. Leptin decreases appetite, increases energy expenditure, suppresses insulin synthesis and secretion and increases insulin sensitivity. Changes in the secretion or sensitivity to leptin and adiponectin may contribute to the development of type 1 and type 2 diabetes. Adiponectin is higher in adult and pediatric patients with type 1 diabetes compared to those with type 2 diabetes. Data regarding leptin levels are contradictory. Most studies report decreased serum leptin at the time of diagnosis in type 1 diabetes compared to type 2 diabetes subjects and non-diabetic controls. This paper will review basic research and clinical evidence supporting the role of adiponectin and leptin in the development of type 1 and type 2 diabetes and discuss their potential use as tools in the differential diagnosis of pediatric diabetes.

Topics: Adiponectin; Child; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diagnostic Techniques, Endocrine; Humans; Immune System; Insulin Resistance; Leptin; Metabolic Networks and Pathways; Models, Biological; Obesity

Topics: Adiponectin; Autoantibodies; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Intercellular Signaling Peptides and Proteins; Leptin

Eating disorders are an important health concern among adolescents. Young women frequently present with signs and symptoms of anorexia nervosa and bulimia nervosa. These disorders represent clinically significant illnesses with serious and sometimes permanent medical complications, including a number of endocrine conditions, that, in general, result from the body s adaptive response to malnutrition. Examples include disorders of metabolism, cortisol and leptin regulation, fluid and electrolyte homeostasis, thyroid function, glucose regulation, growth and development, and reproductive function with the development of amenorrhea as well as the risk of osteoporosis.

Topics: Adolescent; Adult; Amenorrhea; Anorexia Nervosa; Bulimia; Diabetes Mellitus, Type 1; Diagnosis, Differential; Endocrine System Diseases; Feeding and Eating Disorders; Female; Humans; Hydrocortisone; Leptin; Osteoporosis; Thyroid Hormones; Water-Electrolyte Balance

Leptin, the protein encoded by the Ob gene in the adipose cell, is produced by the placenta during pregnancy. This review describes recent findings regarding the putative functions of leptin during pregnancy.. and methods. We searched the literature consulting Medline database.. Placental leptin production makes a substantial contribution to maternal circulating levels during pregnancy. Leptin has been detected in fetal plasma as early as week 18 of gestation, and umbilical leptin concentrations are closely related to birth weight. This has led to the hypothesis that fetal fat mass mainly determines fetal circulating leptin. Placental leptin production is increased in choriocarcinoma, preeclampsia and type 1 diabetes. Estrogens, hypoxia and insulin have been suggested as positive regulators of placental leptin production.. Maternal leptinemia might act as a sensor of energy balance during pregnancy. The presence of both leptin and leptin receptors in the placenta suggests that leptin can act by autocrine or endocrine pathways in the human placenta. The roles of fetal leptin and consequences of increased placental leptin production in pathological pregnancies have yet to be elucidated.

Topics: Birth Weight; Choriocarcinoma; Diabetes Mellitus, Type 1; Female; Fetal Blood; Gestational Age; Humans; Infant, Newborn; Leptin; MEDLINE; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Umbilical Cord

The article summarizes the endocrinology axis in relation to leptin in the obesity. There is a glucocorticoid hypothesis in the obesity origin. Human plasma leptin levels are elevated in Cushing's syndrome and there is a robust leptin secretory responses to dexamethasone. Obesity impacts on reproductive function in man and women. Leptin levels are higher in women than in men and a critical blood leptin level is necessary to trigger reproductive ability in women. The relationship between body mass index and circulating leptin varies during the course of spontaneous cycles in women, the best correlation occurring during the luteal phase when progesterone and leptin concentrations are highest. Obesity is associated with a decrease in growth hormone (GH) and reversible with weight loss. The influence of body composition on GH secretion in the obesity may be mediated through leptin, acting as a peripheral signal from adipose tissue. Thyroid dysfunction appear not associated with alterations in serum leptin levels. There is a significant relationship between insulin and leptin, but it is not immediate, since type 2 diabetics show similar leptin levels to those of nondiabetic humans of the same body mass index.

Topics: Adult; Animals; Body Mass Index; Cushing Syndrome; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Human Growth Hormone; Humans; Hyperinsulinism; Hypertension; Hypothalamo-Hypophyseal System; Insulin; Leptin; Male; Menstrual Cycle; Mice; Mice, Obese; Middle Aged; Obesity; Pituitary-Adrenal System; Progesterone; Rats; Reproduction; Sex Factors

Subcutaneous insulin substitution is not physiological. Despite the many attempts using intensified insulin regimens to render current insulin substitution protocols more physiological, a nondiabetic circulating insulin profile cannot be simulated in patients with type 1 diabetes. Despite many efforts, the pharmacological treatment of type 1 diabetes consists of an unphysiological attempt to substitute only one of the hormones which are lost after beta-cell destruction, namely insulin. It is therefore mandatory to search for additional means to achieve physiological regulation of glucose homeostasis and overall metabolic status. Peptides which are being developed as additional new therapeutic compounds for type 1 diabetes include, for example, IGF-I, leptin, C-peptide and amylin. In addition, the application of insulin analogues has already been introduced into clinical practice. However, so far none of these pharmaceutical compounds has been shown to offer real clinical benefits and substantially improve metabolic control in patients with type 1 diabetes. The results of long-term clinical trials using the peptide compounds listed above for the treatment of type 1 diabetes are still not available.

Topics: Adolescent; Amyloid; Blood Glucose; C-Peptide; Child; Diabetes Mellitus, Type 1; Humans; Insulin; Insulin-Like Growth Factor I; Islet Amyloid Polypeptide; Leptin; Proteins

The discovery of leptin has generated an extraordinary interest in the field of obesity but also in the understanding of the relationship between metabolic status and the neuroendocrine system. Following the initial demonstration that leptin administration to fasting mice can 'protect' neuroendocrine secretions and prevent the changes that are associated with fasting, the concept has emerged that a normal leptin secretion is a prerequisite for normal neuroendocrine secretions. Several unfavorable metabolic situations are associated with low plasma leptin, increased secretion of hypothalmic neuropeptide Y (NPY), and hypogonadism, and a causal relationship has been evoked. Severe dietary restriction in juvenile female rats is associated with low plasma leptin and sexual immaturity. Cessation of food restriction leads to immediate increase in plasma leptin followed 4 days later by vaginal opening. If food restriction is maintained, central leptin infusion can induce sexual maturation, thus demonstrating that leptin can act as a signal for the onset of puberty. In untreated type-I diabetic rats, hypogonadism is associated with very low plasma leptin and increased hypothalmic NYP synthesis and oestrous cyclicity. Fasting rapidly inhibits growth hormone (GH) secretion in association with low plasma leptin and elevated hypothalmic NPY. Central infusion of leptin to fasting rats was able to completely prevent the collapse of GH secretion and to maintain a normal low NPY synthesis. In summary, normally elevated plasma levels appear to be a prerequisite for normal GH and gonadotropin secretion in the rat. Degradation of metabolic conditions results in a rapid reduction of circulating leptin that could represent the signal for several alterations of neuroendocrine secretions. At the level of the hypothalamus, leptin could act on NPY neurons to transduce part or all of this 'metabolic' message. The possibility that changing plasma levels for leptin also affect peripheral endocrine targets, such as pituitary, ovary, adrenal or pancreas, is likely since these endocrine organs express functional long-term leptin receptors.

Topics: Animals; Diabetes Mellitus, Type 1; Female; Food Deprivation; Growth Hormone; Leptin; Neuropeptide Y; Proteins; Rats; Sexual Maturation

To report changes in body composition and biochemical parameters in patients with type 1 diabetes mellitus (T1D) after switching from multiple daily injection (MDI) to continuous subcutaneous insulin infusion (CSII).. 31 patients switched over from MDI to CSII. Body composition, biochemical parameters, glycaemic variability (GV) and level of physical activity were evaluated before and 6 months on CSII.. In both sexes, we found an increase in skeletal muscle mass (SMM), (p = 0.008; 0.008). In men, there was mainly a decrease in visceral fat area (VFA), (p = 0.028) and in women there was decrease of total body fat (TBF), (p = 0.020) and non-significant decrease of VFA (p = 0.098). SMM inversely correlated with VFA in men (p = -0.001) and with TBF in women (p = -0.005 ). GV was decreased generally and correlated inversely with TBF in men only (p = -0.026). Physical activity was increased and correlated inversely with VFA in men (p = -0.002) and in women (p = -0.006).. Using CSII in T1D leads to a significant increase of SMM in both sexes to a decrease of VFA in men and to a non-significant decrease of VFA in women. Changes in adipose tissue and SMM were also related to increased physical activity and to decreased GV.

Topics: Adipose Tissue; Adult; Aged; Blood Glucose; Body Composition; Body Fat Distribution; Body Weight; Diabetes Mellitus, Type 1; Female; Ghrelin; Glycated Hemoglobin; Humans; Injections, Subcutaneous; Insulin; Insulin Infusion Systems; Leptin; Male; Middle Aged; Muscle, Skeletal; Organ Size; Waist Circumference

To investigate long-term consequences of diabetes during pregnancy, we determined adiponectin and leptin levels in adolescents born by women with type 1 diabetic (T1D) or non-diabetic mothers, and determined associations between adiponectin and leptin levels in adolescence and the magnitude of intrauterine hyperglycemia.. We measured serum adiponectin and leptin and calculated leptin to adiponectin ratio (LAR) in 271 offspring of T1D women (index offspring) (13-20years), and 297 matched control offspring. Anthropometry included total body fat (TBF) by dual-energy X-ray absorptiometry and an oral glucose tolerance test.. Adiponectin levels were lower in index females (-8.0% (95% CI; -13.9, -1.6)), but not in index males (0.4% (95% CI; -7.3, 8.6)). Leptin levels were approximately 30% higher in index than control offspring, irrespective of gender. In males, this was seen despite similar TBF in index and control offspring. LAR was increased in index offspring (both males and females) compared with control offspring. There were no association between offspring adiponectin and maternal HbA1c levels in pregnancy. Leptin and LAR seemed to be associated with third trimester HbA1c levels in females in unadjusted, but not adjusted analyses.. Male and female offspring of women with T1D demonstrated increased serum leptin and LAR, whereas serum adiponectin was reduced in females only. These results suggest that abnormal regulation of adipokines is a consequence of being born to mothers with T1D. No direct association between maternal glycemic control and adiponectin and leptin levels or LAR in the adolescence was found.. NCT01559181.

Topics: Adipokines; Adiponectin; Adolescent; Case-Control Studies; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Leptin; Male; Mothers; Pregnancy; Pregnancy in Diabetics; Sex Factors; Young Adult

To investigate the efficacy of combined therapy of insulin and rosiglitazone on metabolic and inflammatory parameters, insulin sensitivity, and adipocytokine levels in patients with type 1 diabetes mellitus (type 1 DM).. A total of 61 adults with type 1 DM were randomly and prospectively assigned in open-label fashion to take insulin and rosiglitazone 4 mg/day (n = 30) or insulin alone (n = 31) for a period of 18 weeks while undergoing insulin therapy without acute metabolic complications.. Combination therapy did not significantly improve metabolic and inflammatory parameters, insulin sensitivity, and adiponectin levels. While leptin and resistin levels decreased in both groups (group 1: resistin 6.96 ± 3.06 to 4.99 ± 2.64, P = 0.006; leptin 25.8 ± 17.6 to 20.1 ± 12.55, P = 0.006; group 2: resistin 7.16 ± 2.30 to 5.57 ± 2.48, P = 0.031; leptin 16.72 ± 16.1 to 14.0 ± 13.4, P = 0.007) Hgb and fibrinogen levels decreased only in group 1 (Hgb 13.72 ± 1.98 to 13.16 ± 1.98, P = 0.015, and fibrinogen 4.00 ± 1.08 to 3.46 ± 0.90, P = 0.002). Patients in both groups showed weight gain and the incidence of hypoglycemia was not lower.. The diverse favorable effects of TZDs were not fully experienced in patients with type 1 DM. These results are suggesting that insulin sensitizing and anti-inflammatory characteristics of TZDs were likely to be more pronounced in patients who were not totally devoid of endogenous insulin secretion.

Topics: Adipokines; Adiponectin; Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Fibrinogen; Humans; Hyperglycemia; Hypoglycemic Agents; Inflammation; Insulin; Insulin Secretion; Leptin; Male; Middle Aged; Prognosis; Prospective Studies; Resistin; Rosiglitazone; Thiazolidinediones; Young Adult

Sixteen postmenarcheal Type 1 diabetic adolescent girls were randomized into training (involving aerobic and strength exercises) and nontraining groups. Body composition (skinfold thickness), aerobic fitness (PWC170), plasma lipids, serum apolipoproteins, lipoprotein(a), leptin, and adiponectin were assessed before and after the 6-month period. After the 6-month period, fat mass and leptin increased significantly in the nontraining group but not in the training group. Conversely, in the latter group, fat-free mass increased (P < .01). Moreover, PWC170 improved and apolipoproteinB:apolipoproteinA-1 ratio decreased with physical training (P < .05). Thus, physical training reduces cardiovascular risks and the increase of insulin resistance risk factors in diabetic adolescent girls.

Topics: Adiponectin; Adolescent; Apolipoprotein A-I; Apolipoproteins B; Diabetes Mellitus, Type 1; Female; Humans; Leptin; Oxygen Consumption; Physical Education and Training; Physical Fitness; Quality of Life; Risk; Skinfold Thickness

Overweight and obesity are overrepresented in adolescents with type 1 diabetes mellitus (T1DM). Exogenous insulin administration often poorly reproduces normal insulin patterns and may less effectively regulate leptin and ghrelin, two hormones involved in the control of appetite and adiposity.. The objective of the study was to determine whether insulin regimens that better replicate normal insulin patterns and augment postprandial nutrient disposal may help normalize leptin and ghrelin and improve body weight regulation.. Ten young women with T1DM were studied in this 2-wk prospective, balanced crossover-design study at the University of California, Davis.. Participants received either a single injection of regular + NPH insulin (R+N) or two mealtime injections of Lispro insulin in randomized order on 2 separate days. Meal composition and total insulin administered were the same on both treatment days.. Plasma glucose, insulin, leptin, and ghrelin concentrations were monitored over the 10-h study period.. Lispro produced two distinct mealtime peaks of insulin, compared with one prolonged rise with R+N. Lispro reduced postprandial hyperglycemia and total glucose area under the curve. Leptin increased more on the Lispro (2.7 +/- 0.7 vs. 0.7 +/- 0.5 ng/ml, P = 0.02). Ghrelin was more suppressed after lunch with Lispro (P = 0.004).. Injection of Lispro insulin with meals produces more physiological insulin patterns, better glucose control, and improved leptin and ghrelin regulation than R+N. More closely mimicking normal insulin, leptin, and ghrelin responses to meals with fast-acting insulin may have implications for body weight regulation in T1DM.

Topics: Adolescent; Adult; Area Under Curve; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 1; Female; Ghrelin; Humans; Insulin; Insulin Lispro; Insulin, Isophane; Leptin; Obesity; Peptide Hormones; Postprandial Period; Prospective Studies

To evaluate the effects of improved glycaemic control on the abdominal visceral and subcutaneous fat in type 1 diabetes.. Sixteen subjects were enrolled for this 6-month study. The goal was to achieve normal haemoglobin A1c (HbA1c <5.6% in our laboratory). T1-weighted magnetic resonance imaging was used to measure the abdominal subcutaneous and visceral fat areas at the L2-L3 disk level. Activity and energy intake were assessed using a weekly recall and food diary respectively. Plasma leptin, ghrelin and adiponectin levels were measured at baseline and at 6 months.. Twelve subjects completed the study. HbA1c was 10.4 +/- 2.2% at baseline, and abdominal visceral to subcutaneous fat ratio was 0.29 +/- 0.15. HbA1c dropped to 8.0 +/- 1.4% at 6 months (p = 0.009). There was a +1.85 kg weight change in 6 months (p = 0.30), whereas the visceral to subcutaneous fat ratios changed to 0.36 +/- 0.18 (p = 0.22). Daily metabolic equivalents (METs) of activity at 6 months correlated with a decrease in the visceral to subcutaneous fat ratios (r = -0.80, p = 0.01). Ghrelin level changes correlated negatively with the changes in the visceral to subcutaneous fat ratio (p < 0.01).. The visceral to subcutaneous fat changes had a negative correlation with the physical activity METs at 6 months but not with HbA1c changes in this study. The correlation between the changes in ghrelin and the visceral to subcutaneous fat ratios is intriguing, but a larger study may be needed to confirm this finding.

Topics: Adiponectin; Adult; Body Composition; Cholesterol, HDL; Diabetes Mellitus, Type 1; Eating; Female; Ghrelin; Glycated Hemoglobin; Hemoglobins; Humans; Hypoglycemic Agents; Insulin; Intra-Abdominal Fat; Leptin; Magnetic Resonance Imaging; Male; Peptide Hormones; Physical Exertion; Pilot Projects; Prospective Studies; Subcutaneous Fat; Weight Gain

This study aimed at investigating leptin levels in male diabetes type I patients who were on insulin treatment and also healthy sedentary males. The study included 10 male type I diabetes patients and 17 healthy sedentary males. Leptin levels of type I diabetes patients and healthy sedentary males with body mass index (BMI) over 25 kg/m2 were evaluated separately. The relation between serum leptin, max VO2, blood lactic acid levels before and after exercise, and effort durations of participants were investigated. At the end of the tests, no difference was found between leptin levels, max VO2 values, lactic acid values before exercise, and test durations of male type I diabetes patients and healthy sedentary males (p > .05), whereas lactic acid levels after exercise were found to be lower in healthy sedentary males (p < .05). Leptin levels in the group with BMI above 25 kg/m2 were higher than those in the group with BMI below 25 kg/m2 (p < .001). It was also seen that max VO2 values and test durations were higher in the group with BMI below 25 kg/m2 (p < .05). In conclusion, leptin levels of male type I diabetes patients are close to those of healthy sedentary males. The increase in leptin levels in both groups is in proportion to the BMI of individuals.

Topics: Adult; Diabetes Mellitus, Type 1; Energy Metabolism; Exercise; Humans; Lactic Acid; Leptin; Male; Oxygen Consumption; Pulmonary Gas Exchange

Several reports suggest that insulin may have a role in the regulation of serum leptin levels, and this is related to the fact that serum leptin levels generally indicate the amount of body fat. Studies show that leptin levels are low in newly diagnosed patients with Type-1 diabetes (T1 DM) and increase after institution of insulin therapy. This study was designed to test whether serum leptin levels are higher in patients receiving intensive insulin therapy (IIT) compared to conventional insulin therapy (CIT). Young patients with T1 DM were studied, 23 on IIT and 23 on CIT. The patients were matched for age (19+/-3 and 20+/-5 yr, respectively), duration of diabetes (8+/-5 and 10+/-6 yr, respectively) and BMI (24+/-4 and 23+/-3 kg/m2, respectively). Leptin levels were higher in IIT compared to CIT (13+/-12 vs 7+/-7 ng/ml, respectively, p<0.05). The results of this study demonstrate that patients on IIT have higher leptin levels than patients on CIT. This increase in leptin level in IIT patients is independent of changes in bw and is probably due to the stimulatory effect of insulin on leptin production.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Drug Administration Schedule; Female; Humans; Hypoglycemic Agents; Insulin; Leptin; Male

Leptin, the gene product of adipose tissue that signals caloric plentitude via central nervous system receptors, may also have diverse peripheral metabolic actions. Of paramount interest has been the potential interaction(s) between leptin and insulin. Insofar as insulin alters leptin secretion/action (or vice versa), dysregulation of this system could contribute to disease states such as diabetes. The purpose of this study was to examine the effect of exogenous insulin on serum leptin in children with newly-diagnosed Type 1 diabetes. Since these patients are hypoinsulinemic (insulin-depleted) at diagnosis, they present an ideal opportunity to examine the effect of insulin repletion on serum leptin. Seventeen patients were enrolled. At baseline (prior to insulin therapy), leptin levels were 4.3 +/- 1.1 ng/ml; they were not statistically related to the baseline serum insulin or illness severity. There was no significant change in serum leptin before, shortly (1-6 days) or several weeks (3-26 weeks) after insulin treatment even when the data was corrected for changes in BMI, hemoglobin A1C, and daily insulin dose. Since repletion of the insulin deficiency that is present in non-acidotic, ambulatory patients with new onset Type 1 diabetes did not alter serum leptin, these results argue against an effect of insulin on serum leptin in the absence of the acute diabetic ketoacidosis. Because as the recuperative months following the diagnosis of new onset Type 1 diabetes are marked by weight gain, the absence of a rise in serum leptin might also indicate either an adaptive (weight permissive) or pathologic (impaired secretory) deficit.

Topics: Adolescent; Blood Glucose; Body Mass Index; Child; Child, Preschool; Diabetes Mellitus, Type 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Leptin; Time Factors

Serum leptin levels reflect the amount of body fat. However, several reports suggest that insulin may also regulate serum leptin levels. This study was aimed at testing whether leptin levels are low in newly diagnosed patients with type 1 diabetes and increase after institution of insulin therapy. Nineteen children with new-onset type 1 diabetes were studied. Serum leptin levels were measured at presentation before insulin therapy was initiated (day 0), 1 day after insulin therapy (day 1), 3-5 days after insulin therapy (day 3-5), and at 3 months of follow-up (3 months). The control group consisted of 19 healthy children matched for age and body mass index. On day 0 leptin levels were lower in the patients compared with those in controls (3.3 +/- 0.2 vs. 6.2 +/- 0.9 ng/mL; P < 0.005). After insulin therapy, leptin levels increased significantly by day 1 without significant weight change and became comparable to control values by days 3-5. Before insulin therapy, leptin did not correlate with weight, body mass index, or hemoglobin A1c. After insulin therapy, leptin levels on days 3-5 correlated with insulin dose (r = 0.43; P = 0.03). The results of this study demonstrate that children with new-onset type 1 diabetes have low leptin levels before insulin therapy. Leptin levels increase within 24 h of insulin therapy and become comparable to nondiabetic levels by 3-5 days. This rapid increase in leptin after 24 h of insulinization is independent of changes in body weight and is postulated to be due to a stimulatory effect of insulin on leptin production, nutritional replenishment, or both factors together.

Topics: Adipose Tissue; Child; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Leptin; Male; Proteins; Time Factors

To explore further the effects of the human amylin analog pramlintide on overall glycemic control and postprandial responses of circulating glucose, glucagon, and metabolic intermediates in type 1 diabetes mellitus, 14 male type 1 diabetic patients were examined in a double-blind, placebo-controlled, crossover study. Pramlintide (30 microg four times daily) or placebo were administered for 4 weeks, after which a daytime blood profile (8:30 AM to 4:30 PM) was performed. Serum fructosamine was decreased after pramlintide (314+/-14 micromol/L) compared with placebo (350+/-14 micromol/L, P = .008). On the profile day, the mean plasma glucose (8.3+/-0.7 v 10.2+/-0.8 mmol/L, P = .04) and postprandial concentrations (incremental areas under the curve [AUCs] from 0 to 120 minutes) were significantly decreased during pramlintide administration (P < .01 for both) despite comparable circulating insulin levels (359+/-41 v 340+/-35 pmol/L). Mean blood glycerol values were reduced (0.029+/-0.004 v 0.040+/-0.004 mmol/L, P = .01) and blood alanine levels were elevated (0.274+/-0.012 v 0.246+/-0.008 mmol/L, P = .03) after pramlintide versus placebo. Blood lactate concentrations did not differ during the two regimens. During pramlintide administration, the AUC (0 to 120 minutes) for plasma glucagon after breakfast was diminished (P = .02), and a similar trend was observed following lunch. In addition, peak plasma glucagon concentrations 60 minutes after breakfast (45.8+/-7.3 v 72.4+/-8.0 ng/L, P = .005) and lunch (47.6+/-9.0 v 60.9+/-8.2 ng/L, P = .02) were both decreased following pramlintide. These data indicate that pramlintide (30 microg four times daily) is capable of improving metabolic control in type 1 diabetics. This may relate, in part, to suppression of glucagon concentrations. Longer-term studies are required to ascertain whether these findings are sustained over time.

Topics: Adult; Amyloid; Blood Glucose; Circadian Rhythm; Cross-Over Studies; Diabetes Mellitus, Type 1; Double-Blind Method; Eating; Glucagon; Human Growth Hormone; Humans; Hypoglycemic Agents; Insulin; Islet Amyloid Polypeptide; Leptin; Male; Middle Aged; Osmolar Concentration; Proteins; Time Factors

Topics: Adolescent; Child; Diabetes Mellitus, Type 1; Female; Humans; Leptin; Longitudinal Studies; Male; Obesity

The study aimed to determine the relationship between glucose, C-peptide, brain-derived neurotrophic factor (BDNF), and leptin between mother and fetus and neonatal weight.. In the prospective observational cohort study, we included 66 women with type-1 diabetes mellitus (T1DM). According to the z-score for neonatal weight, patients were divided into healthy-weight neonates (. A strong correlation was confirmed between maternal and umbilical vein glucose concentration and maternal glucose and C-peptide in umbilical vein blood. A negative correlation was found between the concentration of BDNF in the umbilical vein and glucose in maternal blood. A strong correlation was seen between BMI and maternal blood leptin concentration, neonatal fat body mass, and umbilical vein blood leptin concentration. Higher BMI elevated BDNF, and TSH increase the odds for overweight neonates in the first trimester of pregnancy. Maternal higher leptin concentration in the first trimester decrease the odds of overweight neonates.. Maternal glucose concentrations affect the fetus's glucose, C-peptide, and BDNF concentrations. Leptin levels increase in maternal blood due to increased body mass index, and in the neonate, fat body mass is responsible for increased leptin concentrations.

Topics: Body Mass Index; Brain-Derived Neurotrophic Factor; C-Peptide; Cesarean Section; Diabetes Mellitus, Type 1; Female; Fetal Blood; Glucose; Humans; Infant, Newborn; Leptin; Overweight; Pregnancy; Prospective Studies; Thyrotropin; Umbilical Veins

Adiponectin/leptin ratio (ALR) is a promising novel marker of cardio-metabolic risk in patients with metabolic syndrome. Our aim was to study the association of adiponectin-leptin ratio with markers of obesity and adiposity and also to assess its usefulness as a marker of increased cardiometabolic risk (CMR) in Indian children and youth with type 1 diabetes mellitus.. This observational study included 79 children and youth with type 1 diabetes (T1DM) (10-21 years) having disease duration>6 months. Demographic data and laboratory findings were obtained from patients' records. Patients with ALR<1 were categorised as having increased CMR and those with ALR>1 were categorised as having no CMR.. ALR showed a significant negative correlation with body mass index (BMI), waist and hip circumference and body fat percentage (p<0.05). Body fat percentage was the single most important predictor of ALR. Children and youth with increased CMR had higher weight, BMI, waist and hip circumferences and body fat percentage as compared to those with no CMR (p<0.05). In T1DM children with dyslipidemia, ALR was significantly lower as compared to those without dyslipidemia (p<0.05).. ALR may be a useful marker for adiposity and increased cardiometabolic risk in Indian children and youth with type 1 diabetes mellitus.

Topics: Adiponectin; Adolescent; Body Mass Index; Cardiovascular Diseases; Child; Diabetes Mellitus, Type 1; Humans; Leptin; Obesity; Waist Circumference

Vitamin D has been variably implicated in risk of developing type 1 diabetes based on cohorts of at-risk individuals. Emergent type 1 diabetes in childhood is putatively preceded by altered growth.. We explored whether polymorphisms in vitamin D metabolism genes modify risk of type 1 diabetes via effects on growth in a prospective, population-based cohort of infants.. The Cambridge Baby Growth Study enrolled newborns from Cambridgeshire, UK, for follow-up in infancy. In 612 infants, we genotyped single nucleotide polymorphisms in vitamin D metabolism genes that relate with type 1 diabetes: rs10741657 and rs12794714 in CYP2R1, rs12785878 in DHCR7, and rs10877012 in CYP27B1. Multivariate linear regression analyses tested associations between genotypes and anthropometric indices (weight, length, and skinfold thickness) or growth-related hormones (C-peptide, IGF-1, and leptin) in infancy.. Birth weight showed borderline associations with the diabetes risk-increasing alleles in CYP2R1, rs10741657 (β = -.11, P = .02) and rs12794714 (β = -.09, P = .04). The risk-increasing allele rs12794714 was also associated with higher IGF-1 levels at age 24 months (β = .30, P = .01). At age 3 months, the risk-increasing allele rs12785878 in DHCR7, known to negatively associate with 25-hydroxyvitamin D levels, showed a positive association with leptin levels (β = .23, P = .009), which was pronounced in girls (P = .004) vs boys (P = .7).. The vitamin D metabolism genes DHCR7 and CYP2R1 might influence infancy leptin and IGF-1 levels respectively. These findings open the possibility for a developmental role of vitamin D that is mediated by growth-related hormones with implications for the onset of type 1 diabetes autoimmunity.

Topics: Child, Preschool; Cholestanetriol 26-Monooxygenase; Cytochrome P450 Family 2; Diabetes Mellitus, Type 1; Female; Genetic Predisposition to Disease; Genotype; Humans; Infant; Infant, Newborn; Insulin-Like Growth Factor I; Leptin; Male; Polymorphism, Single Nucleotide; Prospective Studies; Vitamin D; Vitamin D Deficiency; Vitamins

Topics: Adolescent; Body Mass Index; Diabetes Mellitus, Type 1; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Metformin

The purpose of our study was tomeasure the level of leptin and biologically active leptin (bioLEP) in children with type 1 diabetes, depending on the duration of diabetes and its degree of metabolic control.. The study included 94 children (58 boys and 36 girls). In a group of children with diabetes, 40 patients were newly diagnosed with type 1 diabetes, 40 children who have diabetes for more than a year (20 with good metabolic control and 20 with poor metabolic control). The control group consisted of 14 healthy children. The serum level of leptin and bioLEP was measured using a sandwich enzyme-linked immunosorbent assay. To our knowledge, this is the first study to describe bioLEP levels among diabetic children with different forms of disease control.. Lower levels of leptin were found in children with diabetes compared to healthy children. Furthermore, we found a statistically higher concentration of leptin in the group of children with newly diagnosed diabetes compared to children from the diabetic group with poor metabolic control and lower than healthy children (11.19 vs. 7.84 and 20.94 ng/mL). Moreover, children in the metabolically well-controlled group had statistically lower levels of this hormone (5.11 ng/mL) than healthy children. Leptin concentrations differed significantly between underweight, overweight, and obese children.. In our study, the level of bioLEP differed significantly between children in the newly diagnosed diabetes group and children in the long-term, poorly controlled diabetes group and healthy controls. Despite many studies published in recent years, many aspects of leptin secretion, action, and mechanisms of its influence on carbohydrate and fat metabolism are still to be clarified. In our opinion, studies evaluating the status of bioLEP in diabetes can also contribute to a better understanding of the mechanisms regulating metabolism.

Topics: Autoimmune Diseases; Child; Diabetes Mellitus, Type 1; Female; Humans; Leptin; Lipid Metabolism; Male; Pediatric Obesity

The role of adipokines in causing inflammation and insulin resistance in normal weight and obese patients is generally well studied. However, there are often conflicting results regarding their levels in type 1 diabetes mellitus (T1DM) patients and their relationship to micro- and macrovascular disease. We therefore investigated which serum adipokine levels are independently associated with markers of early atherosclerosis and microvascular complications in patients with T1DM.. A cross-sectional study was performed in the Diabetes Outpatient Clinic of Hippokrateion General Hospital, Thessaloniki, Greece. Sixty T1DM patients (30 females, mean age 38.8 ± 10.6 years, mean diabetes duration 17.4 ± 9.9 years) were included. Plasma adiponectin, leptin, and resistin, carotid artery intima media thickness (cIMT), and arterial stiffness (pulse wave velocity, PWV/SpygmoCor CP System and Mobil-O-Graph 24 h PWA) were assessed.. Serum adipokine levels demonstrate similar bivariate associations with anthropometric variables in patients with T1DM to those in normal weight subjects. Although microvascular complications are associated with serum adipokine levels by bivariate analysis, only resistin, an inflammatory marker, is independently associated with arterial stiffness in patients with T1DM.

Topics: Adipokines; Adiponectin; Adult; Atherosclerosis; Carotid Intima-Media Thickness; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Female; Humans; Leptin; Male; Middle Aged; Obesity; Pulse Wave Analysis; Resistin

Leptin, a hormone secreted by adipocytes, exhibits therapeutic potential for the treatment of type 1 diabetes (T1D). Protein tyrosine phosphatase 1B (PTP1B) is a key enzyme that negatively regulates leptin receptor signaling. Here, the role of PTP1B in the treatment of T1D was investigated using PTP1B-deficient (knockout [KO]) mice and a PTP1B inhibitor. T1D wild-type (WT) mice induced by streptozotocin showed marked hyperglycemia compared with non-T1D WT mice. KO mice displayed significantly improved glucose metabolism equivalent to non-T1D WT mice, whereas peripheral or central administration of leptin partially improved glucose metabolism in T1D WT mice. Peripheral combination therapy of leptin and a PTP1B inhibitor in T1D WT mice improved glucose metabolism to the same level as non-T1D WT mice. Leptin was shown to act on the arcuate nucleus in the hypothalamus to suppress gluconeogenesis in liver and enhance glucose uptake in both brown adipose tissue and soleus muscle through the sympathetic nervous system. These effects were enhanced by PTP1B deficiency. Thus, treatment of T1D with leptin, PTP1B deficiency, or a PTP1B inhibitor was shown to enhance leptin activity in the hypothalamus to improve glucose metabolism. These findings suggest a potential alternative therapy for T1D.

Topics: Animals; Diabetes Mellitus, Type 1; Glucose; Homeostasis; Leptin; Mice; Mice, Knockout; Protein Tyrosine Phosphatase, Non-Receptor Type 1

Diabetes comprises a serious disease with significant growth in the number of cases in recent years. Here, we cover the gap in information between leptin (LEP) and type 1 diabetes in the Iranian population.. To recognise LEP G2548A and LEP receptor Q223R polymorphisms in Iranian people and their association with type 1 diabetes susceptibility.. Characteristics such as fasting blood sugar (FBS) were measured in 80 control non-diabetic individuals and 89 diabetic patients. Moreover, LEP G2548A and LEP receptor Q223R polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism technique.. The frequency of the A allele was nearly three times greater in diabetes patients than in the control group. In addition, in the diabetes group, the AA genotype was five times greater than in the control group (. The LEP G2548A polymorphism could be related to type 1 diabetes susceptibility, but not LEPR Q223R polymorphism in the Iranian population. Importantly, further studies are essential to examine the impact of LEP G2548A and LEPR Q223R polymorphisms in the endocrinology area.

Topics: Diabetes Mellitus, Type 1; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Iran; Leptin; Polymorphism, Single Nucleotide

We investigated whether peripheral combination treatment of a sodium-glucose cotransporter 2 (SGLT2) inhibitor and leptin improves glucose metabolism in insulin-dependent diabetes mellitus (IDDM) model mice. Twelve-week-old male C57BL6 mice were intraperitoneally administered a high dose of streptozotocin to produce IDDM. IDDM mice were then divided into five groups: SGLT2 inhibitor treatment alone, leptin treatment alone, leptin and SGLT2 inhibitor co-treatment, untreated IDDM mice, and healthy mice groups. The blood glucose (BG) level at the end of the dark cycle was measured, and a glucose tolerance test (GTT) was performed and compared between the five groups. Leptin was peripherally administered at 20 μg/day using an osmotic pump, and an SGLT2 inhibitor, ipragliflozin, was orally administered at 3 mg/kg/day. Monotherapy with SGLT2 inhibitor or leptin significantly improved glucose metabolism in mice as evaluated by BG and GTT compared with the untreated group, whereas the co-treatment group with SGLT2 inhibitor and leptin further improved glucose metabolism as compared with the monotherapy group. Notably, glucose metabolism in the co-treatment group improved to the same level as that in the healthy mice group. Thus, peripheral combination treatment with leptin and SGLT2 inhibitor improved glucose metabolism in IDDM mice without the use of insulin.

Topics: Administration, Oral; Animals; Diabetes Mellitus, Type 1; Disease Models, Animal; Drug Therapy, Combination; Glucose; Glucosides; Infusions, Intravenous; Leptin; Male; Mice, Inbred C57BL; Sodium-Glucose Transporter 2 Inhibitors; Thiophenes

Type 1 diabetes (T1D) is characterized by hyperphagia, hyperglycemia and activation of the hypothalamic-pituitary-adrenal (HPA) axis. We have reported previously that daily leptin injections help to alleviate these symptoms. Therefore, we hypothesized that leptin gene therapy could help to normalize the neuroendocrine dysfunction seen in T1D. Adult male Sprague Dawley rats were injected i.v. with a lentiviral vector containing the leptin gene or green fluorescent protein. Ten days later, they were injected with the vehicle or streptozotocin (STZ). HPA function was assessed by measuring norepinephrine (NE) levels in the paraventricular nucleus (PVN) and serum corticosterone (CS). Treatment with the leptin lentiviral vector (Lepvv) increased leptin and insulin levels in non-diabetic rats, but not in diabetic animals. There was a significant reduction in blood glucose levels in diabetic rats due to Lepvv treatment. Both NE levels in the PVN and serum CS were reduced in diabetic rats treated with Lepvv. Results from this study provide evidence that leptin gene therapy in STZ-induced diabetic rats was able to partially normalize some of the neuroendocrine abnormalities, but studies with higher doses of the Lepvv are needed to develop this into a viable option for treating T1D.

Topics: Animals; Corticosterone; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Genetic Therapy; Genetic Vectors; Injections, Intravenous; Lentivirus; Leptin; Male; Norepinephrine; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley

Central leptin action rescues type 1 diabetic (T1D) hyperglycemia; however, the underlying mechanism and the identity of mediating neurons remain elusive. Here, we show that leptin receptor (LepR)-expressing neurons in arcuate (LepR

Topics: Agouti-Related Protein; AMP-Activated Protein Kinases; Animals; Blood Glucose; Brain; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; GABAergic Neurons; Hyperglycemia; Infusions, Intraventricular; Leptin; Male; Mice, Transgenic; Neurons; Receptors, Leptin; Signal Transduction

Familial partial lipodystrophy type 3 (FPLD3) is a very rare autosomal dominant genetic disorder which is caused by mutations in the peroxisome proliferator activated receptor gamma (. This case highlights the importance of early recognition of FPLD syndromes otherwise frequently observed as difficult-to-classify and manages diabetes cases, in order to prevent cardiovascular complications. Metreleptin may be an effective treatment for FPLD3.

Topics: Diabetes Mellitus, Type 1; Diagnostic Errors; Female; Glycated Hemoglobin; Humans; Insulin Resistance; Leptin; Lipodystrophy, Familial Partial; Liver; Middle Aged; Mutation; Triglycerides

The possibility to use leptin therapeutically for lowering glucose levels in patients with type 1 diabetes has attracted interest. However, earlier animal models of type 1 diabetes are severely catabolic with very low endogenous leptin levels, unlike most patients with diabetes. Here, we aim to test glucose-lowering effects of leptin in novel, more human-like murine models. We examined the glucose-lowering potential of leptin in diabetic models of two types: streptozotocin-treated mice and mice treated with the insulin receptor antagonist S961. To prevent hypoleptinemia, we used combinations of thermoneutral temperature and high-fat feeding. Leptin fully normalized hyperglycemia in standard chow-fed streptozotocin-treated diabetic mice. However, more humanized physiological conditions (high-fat diets or thermoneutral temperatures) that increased adiposity - and thus also leptin levels - in the diabetic mice abrogated the effects of leptin, i.e., the mice developed leptin resistance also in this respect. The glucose-lowering effect of leptin was not dependent on the presence of the uncoupling protein-1 and was not associated with alterations in plasma insulin, insulin-like growth factor 1, food intake or corticosterone but fully correlated with decreased plasma glucagon levels and gluconeogenesis. An important implication of these observations is that the therapeutic potential of leptin as an additional treatment in patients with type 1 diabetes is probably limited. This is because such patients are treated with insulin and do not display low leptin levels. Thus, the potential for a glucose-lowering effect of leptin would already have been attained with standard insulin therapy, and further effects on blood glucose level through additional leptin cannot be anticipated.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Blood Glucose; Corticosterone; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Eating; Glucagon; Gluconeogenesis; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Mice; Mice, Knockout; Oxygen Consumption; Peptides; Pyruvic Acid; Receptor, Insulin; Transcriptome; Uncoupling Protein 1

Joint damage in patients with diabetes mellitus (DM) is a common complication and is associated with the induction of metabolic inflammation against the background of increased catabolic processes in various joint structures. The aim of our work was to study the level of insulin, leptin, osteocalcin, as well as biochemical markers of connective tissue metabolism in patients with diabetes-associated osteoarthritis. We examined 77 patients who were divided into groups by type of diabetes, the presence and severity of diabetic arthropathy. The content of insulin and leptin, osteocalcin in the blood serum was determined by the enzyme immunoassay, the level of glycosaminoglycans, hydroxyproline, hyaluronidase, collagenase according to traditional biochemical methods. Among the examined patients, diabetic arthropathy was diagnosed in more than 70%. Patients with diabetic arthropathy significantly increased levels of insulin (with type 1 diabetes by 38.5%, with type 2 diabetes by 55.6%) and leptin (with type 1 diabetes by 43.8%, with type 2 diabetes by 53.7,%), the level of osteocalcin (only with type 1 diabetes by 53.9%) There is a direct correlation between the severity of joint damage and the level of insulin and leptin. The severity of arthopathy in patients with type 2 diabetes is directly correlated with indicators of insulin resistance. In patients with diabetes-associated osteoarthritis, indicators that characterize catabolic processes in the connective tissue (hydroxyproline free and collagenase (p<0.001) are increased. The chances of detecting arthropathy with type 1 diabetes increase 3.8 times with an increase in insulin levels, with an increase in leptin 1.3 times, in patients with type 2 diabetes, 2.6 and 1.2 times, respectively. For this sample, it was found that the development of arthropathy does not depend on the type of diabetes. In women with type 2 diabetes, the chances of developing arthropathy are six times higher. 4 times than men. An increase in insulin and leptin levels can serve as a marker for the presence and progression of arthropathy in patients with diabetes. Patients with arthropathies have increased levels of hydroxyproline and collagenase, which reflects an increase in catabolic processes in the connective tissue, which may be one of the mechanisms for the development of joint structures in patients with diabetes.

Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Osteoarthritis

Extracellular beta-amyloid (Aβ), intra-neuronal hyper-phosphorylated tau protein, and chronic inflammation are neuropathological hallmarks of Alzheimer's Disease (AD). A link between AD, insulin dysfunction, and tumor necrosis factor-alpha (TNF-α) in promoting both tau and Aβ pathologies in vivo has been proposed.. MA-[D-Leu-4]-OB3 was given, with or without insulin, to streptozotocin (STZ)-treated male Swiss Webster mice, and to male diet-induced obese (DIO) mice. Brains were excised, and coronal sections were imaged with fluoro jade-C (FJC), thioflavin-S, or hematoxylin and eosin (H&E). Serum TNF-α and IGF-1 were measured by ELISA. Histopathological changes in the cerebral cortex (CC) and hippocampus (HC) were correlated with changes in glycemic regulation, episodic memory, and serum levels of TNF-α and IGF-1.. In STZ-treated mice, blood glucose and serum TNF-α and IGF-1 were reduced by insulin alone, and normalized when MA-[D-Leu-4]-OB3 was given in combination with insulin. Improvement in episodic memory was inversely correlated with the number of FJC-positive cells in the CC and HC and serum TNF-α and IGF-1. FJC, thioflavin-S and H&E staining indicated no Aβ deposition. Similar results were observed in DIO mice treated with MA-[D-Leu-4]-OB3.. The mechanism by which MA-[D-Leu-4]-OB3 improves episodic memory in mouse models of TIDM and T2DM appears to be related to improved insulin sensitivity and reduced TNF-α-induced neurodegeneration.. MA-[D-Leu-4]-OB3 may have application to human pre-clinical and clinical AD and AD-like dementia by interrupting the cascade of insulin resistance, neuro-inflammation, and neurodegeneration, that characterizes these diseases.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease Models, Animal; Humans; Insulin Resistance; Leptin; Male; Memory, Episodic; Mice; Neuroprotective Agents; Peptides; Tumor Necrosis Factor-alpha

Evaluation of serum concentration of leptin, adiponectin, resistin, and MCP-1 in pregnant patients with different types of diabetes mellitus (DM) considering preconception planning and method of DM correction in 11-14th and 30-34th weeks of pregnancy.. Longitudinal, prospective study included 130 pregnant women divided into the following comparison groups: type 1 DM (T1DM, n = 40), type 2 DM (T2DM, n = 35), GDM (n = 40), and the control group (n = 15). The ELISA method defined the levels of leptin, resistin, adiponectin, and MCP-1 concentration in serum, which was assessed in 11-14th and 30-34th weeks of pregnancy. Statistical analysis was accomplished using SPSS 23.0 and "Prism 8-GraphPad" software.. The leptin level in the 1st trimester was the highest in T2DM insulin group compared to the control due to gestational age, hence in the 3rd trimester in all groups its serum concentrations appeared higher than in healthy patients (p = 0.0001). In the 1st trimester leptin levels directly correlated with women's BMI, newborns' weight and macrosomia rate, in the 3rd trimester - with OGTT levels, HbA1c, gestational hypertension, and preeclampsia rates. Resistin levels in the 1st and 3rd trimesters were increased in almost all DM groups compared to the control group (p = 0.0001). The study established direct positive correlation between resistin and HbA1c, birth weight, and preeclampsia. In the 1st trimester, adiponectin demonstrated the lowest levels in T2DM insulin compared to T1DM and the control group (p = 0.0001) while in the 3rd trimester, adiponectin levels declined alongside gestational age in DM patients and all the groups compared to the control group (p < 0.05). Adiponectin negatively correlated with BMI, OGTT levels, and preeclampsia rate. MCP-1 levels in T2DM appeared higher than in T1DM patients and the control group in the 1st trimester, whereas in the 3rd trimester MCP-1 declined, correlating with BMI, preeclampsia and OGTT levels.. High rate of adverse perinatal outcomes in diabetic pregnancy might be developed due to more severe metabolic failures and further disturbances of adipokines expression.

Topics: Adipokines; Adiponectin; Chemokine CCL2; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Humans; Infant, Newborn; Leptin; Pregnancy; Prospective Studies; Resistin

We aimed to test whether the serum adipokines leptin and adiponectin are more strongly associated with body fat percentage (BF%) than body mass index (BMI) in adolescents with type 1 diabetes (T1D) and overweight/obesity.. We studied all participants in the T1D Exchange Metformin Study (n=122, median age 12.9 years, range 12-19.5; 32% males; 77% non-Hispanic whites, 100% overweight or obesity; median diabetes duration 6.7 years, range 1.4-15) with a baseline serum sample where we measured leptin and adiponectin concentrations. Anthropometric, clinical, laboratory and dual-energy X-ray absorptiometry (DEXA) scan measurements were analyzed. We compared correlation coefficients between variables of interest.. BF% by DEXA was significantly correlated with BMI Z-score (r=0.38, p<0.0001), BMI per cent of the 95th percentile (BMI%95) (r=0.45, p<0.0001), waist circumference (r=0.46, p<0.0001), leptin (r=0.58, p<0.00001) and leptin/adiponectin ratio (r=0.36, p<0.0001), while it was not significantly correlated with absolute body weight, adiponectin or insulin dose (total or basal). BF% was significantly more strongly correlated with leptin than with BMI Z-score in the overall group (p=0.022). However, there were sex-based differences. Among the significant correlations in the overall group, BF% was most strongly associated with leptin (r=0.75) in boys (n=39) but with waist circumference (r=0.58) in girls (n=83) (all p<0.0001).. Serum leptin could be used as a surrogate convenient marker of adiposity in overweight/obese adolescent boys with T1D, equivalent to BMI Z-score or BMI%95. In girls, waist circumference was the best performing marker overall, and was also strongly correlated with %BF in boys.

Topics: Adiposity; Adolescent; Adult; Child; Diabetes Mellitus, Type 1; Female; Humans; Leptin; Male; Obesity; Overweight; Sex Characteristics; Young Adult

Recent studies have shown that sclerostin, which is a negative regulator of bone formation, could play an important role in the crosstalk between bone and glucose metabolism. The role of sclerostin and its link with glucose homeostasis in type 1 diabetes mellitus (T1D) has not been yet studied extensively in children. The aim of this study was to assess sclerostin and its relationship between other bone and fat related factors as well as glucose metabolism in children and adolescents with T1D in comparison to their healthy peers.. Forty patients with T1D, 18 girls, mean age 12.3 ± 4.7 yrs, and 28 healthy as controls (13.1 ± 4.2 yrs), sex and Tanner stage-matched were included into the study. Fasting blood samples for measurement of sclerostin, osteocalcin (OC), leptin, adiponectin, vitamin D, fasting glucose, lipid profile, HbA1c, and C-peptide were taken at 8.00 AM.. Sclerostin levels were significantly higher in patients with T1D than in the control group (p = 0.04) without significant differences between genders. Pearson correlation coefficients revealed a positive association between serum sclerostin levels and leptin OC (r = 0.59, p < 0.001) and a negative correlation between serum sclerostin levels and leptin (r = -0.32, p = 0.02) in all of the subjects and no significant correlations between sclerostin and adiponectin, 25(OH)D3, nor lipids. In the group of T1D patients a strong positive association between serum sclerostin levels and OC (r = 0.62, p < 0.001), and a negative association between serum sclerostin levels and HbA1c and leptin levels (r = -0.33, p = 0.04; r = -0.33, p = 0.03, respectively) were found. These associations were significant also after adjusting the analysis to the age, SDS-BMI and Tanner staging. In the healthy group after adjustment to age, SDS-BMI and Tanner stage, a negative correlation between sclerostin and C-peptide (r = -0.79, p = 0.02) was found.. Our data suggest a possible relationship between sclerostin and glucose metabolism in children and adolescents with T1D. It would be worth to investigate if an increase in sclerostin levels could present as a potential cause of the reduction of bone formation in T1D. Both bone-derived OC as well as fat-derived leptin seems to possibly modulate the participation of sclerostin in metabolic regulation in T1D.

Topics: Adaptor Proteins, Signal Transducing; Adolescent; Child; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Leptin; Male; Osteocalcin

The aim of the current study is to investigate the effect of leptin on cytoskeleton structures in both in vivo and in vitro model of diabetes.. For in vivo studies, leptin in different doses (240, and 480 mg/kg) was injected to the diabetic rats after 1-week of streptozotocin (STZ, 55 mg/kg) treatment. Leptin levels were analysed in serum, liver, and pancreas samples. Hepatic and pancreatic F- and G-actin expressions were determined by Western blotting. For in vitro studies, hepatic and pancreatic primary cell lines were obtained from the control rats. To these cultures, STZ (15 and 30 mM), leptin (50, 60 and 100 ng/mL), and their combinations were applied for 1, 3, and 4 weeks. After the treatment period, F-actin was visualised by the Alexa-fluor fluorescent dye.. Streptozotocin decreased the G-actin in both tissues in vivo. However, leptin caused a dose-dependent increase in G-actin levels while F-actin decreased in both tissues. Moreover, leptin caused the perimembranous condensation of actin filaments and amelioration of F-actin structures in vivo. A dose-dependent corruption of F-actin filament structures was observed in leptin-treated primary cells in vitro, while STZ also caused corruption of these filaments. Co-exposure of STZ and leptin caused the amelioration of F-actin filaments, while the peri- membranous condensation was also observed as was in vivo study.. Leptin therapy could be a candidate for diabetes, but it should not be ruled out as being important the severity of diabetes and leptin doses.

Topics: Actins; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 1; Leptin; Liver; Male; Pancreas; Rats, Wistar

Our goal was to determine the efficacy of autologous mesenchymal stem cell transplant for treatment in patients with type 1 diabetes mellitus.. We examined 5 patients (4 male, 1 female; age 20-42 y) with type 1 diabetes mellitus who received autologous mesenchymal stem cell transplant (cells were obtained from the patient's iliac crest and cultured for 3-4 weeks) performed by intravenous infusion. The quantity of autologous mesenchymal stem cells infused was 95 to 97 × 106. We analyzed daily insulin dosages and leptin and glycated hemoglobin levels in patients before and 1, 2, and 3 months after their autologous mesenchymal stem cell transplant procedure.. In patients with type 1 diabetes mellitus, autologous mesenchymal stem cell transplant led to a decrease in daily insulin dosage levels, from 63 ± 8.83 to 50.2 ± 12.1 U (P = .064) after 1 month, with significantly increased leptin levels and trend to decreased glycated hemoglobin levels, from 6.86 to 10.77 ng/mL (P = .016) and 9.11% to 8.74% (P = .84) after 3 months, respectively.. Daily insulin dosage level decreased within 1 month and leptin levels increased significantly within 3 months after autologous mesenchymal stem cell transplant in patients with type 1 diabetes mellitus.

Topics: Adult; Biomarkers; Cells, Cultured; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Leptin; Male; Mesenchymal Stem Cell Transplantation; Prospective Studies; Time Factors; Transplantation, Autologous; Treatment Outcome; Young Adult

Loss of white adipose tissue (WAT), associated with type 1 diabetes (DM1), contributes to increased chronic systemic inflammation.. The aim of this study was to investigate the effects of leucine supplementation and resistance training (RT) in attenuating WAT loss and improving inflammatory parameters and glucose metabolism in DM1 rats.. Thirty-two male Wistar rats were distributed into four groups: DA (sedentary and supplemented with non-essential amino acids (NEAA)), DL (sedentary and supplemented with leucine), DTA (submitted to RT and supplemented with NEAA) and DTL (submitted to RT and supplemented with leucine). DM1 was induced by streptozotocin (STZ). An 8-week period of RT consisted of climbing a ladder with a progressively increased load, and supplementation was offered in the feed.. Glycemia, polyphagia and polydipsia were lower in DL, DTA and DTL groups compared with the DA group by approximately 20% ( p<.0001), 28% ( p=.004) and 64% ( p<.0001), respectively. Weight of total WAT and retroperitoneal adipose tissue (RPAT) were higher by approximately 21% ( p=.01) and 54% ( p=.0004), respectively, in DL, DTA and DTL groups compared with DA. However, gene expression of adiponectin and leptin in RPAT was only increased by RT (DTA and DTL) compared with DA and DL by approximately 93% ( p<.0001) and 78% ( p=.0002), respectively. Similarly, the levels of adiponectin in the serum, tissue IL-10 (RPAT) and serum IL-10 were only increased in DTA and DTL compared with DA and DL by approximately 31% ( p=.03), 45% ( p=.0009) and 35% ( p=.003), respectively.. Both interventions, isolated or together, reduced hyperglycemia and excessive loss of WAT, but RT was the main factor responsible for attenuating inflammation.

Topics: Adiponectin; Adipose Tissue, White; Adiposity; Animals; Anti-Inflammatory Agents, Non-Steroidal; Combined Modality Therapy; Diabetes Mellitus, Type 1; Dietary Supplements; Gene Expression Regulation; Hyperglycemia; Inflammation Mediators; Insulin Resistance; Intra-Abdominal Fat; Leptin; Leucine; Male; Random Allocation; Rats, Wistar; Resistance Training; Weight Loss

Metabolic abnormalities in congenital generalized lipodystrophy (CGL) are associated with microvascular complications. However, the evaluation of different types of neuropathy in these patients, including the commitment of cardiovascular autonomic modulation, is scarce. The objective of the present study was to determine the prevalence of cardiovascular autonomic neuropathy (CAN) in patients with CGL compared with individuals with type 1 diabetes and healthy subjects.. Ten patients with CGL, 20 patients with type 1 diabetes and 20 healthy subjects were included in the study. Controls were paired 1:2 for age, gender, BMI and pubertal stage. Heart rate variability (HRV) was analyzed using cardiovascular autonomic reflex tests, including postural hypotension test, Valsalva (VAL), respiratory (E/I) and orthostatic (30/15) coefficients, and spectral analysis of the HRV, determining very low (VLF), low (LF) and high (HF) frequencies components. The diagnosis of CAN was defined as the presence of at least two altered tests.. CAN was detected in 40% of the CGL patients, 5% in type 1 diabetes patients and was absent in healthy individuals (p < 0.05). We observed a significant reduction in the E/I, VLF, LF and HF in CGL cases vs. type 1 diabetes and healthy individuals and lower levels of 30/15 and VAL in CGL vs. healthy individuals. A significant positive correlation was observed between leptin and 30/15 coefficient (r = 0.396; p = 0.036) after adjusting for insulin resistance and triglycerides. Autonomic cardiovascular tests were associated with HbA1c, HOMA-IR, triglycerides and albumin/creatinine ratio in CGL cases.. We observed a high prevalence of CAN in young patients with CGL, suggesting that insulin resistance, hypertriglyceridemia and hypoleptinemia, may have been involved in early CAN development. Additional studies are needed to evaluate the role of leptinemia in the physiopathogenesis of the condition.

Topics: Adolescent; Adult; Autonomic Nervous System; Autonomic Nervous System Diseases; Biomarkers; Blood Glucose; Brazil; Cardiovascular Diseases; Cardiovascular System; Case-Control Studies; Child; Creatinine; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Glycated Hemoglobin; Heart Rate; Humans; Insulin; Insulin Resistance; Leptin; Lipodystrophy, Congenital Generalized; Male; Prevalence; Serum Albumin, Human; Triglycerides

Type 1 diabetes mellitus (T1DM) is associated with a disturbance of carbohydrate and lipid metabolism.. To determine whether T1DM alters maternal and neonatal fatty acid (FA) levels.. Observational study.. Academic hospital.. Sixty pregnant women (30 women with T1DM with good glycemic control and 30 healthy women) were included in the study. Maternal blood, umbilical vein, and artery blood samples were collected immediately upon delivery. Following lipid extraction, the FA profiles of the total FA pool of maternal serum and umbilical vein and artery serum were determined by gas chromatography.. Total FA concentration in maternal serum did not differ between the study groups; it was significantly higher in umbilical vein serum of the T1DM group compared with that in the control group [median (interquartile range)]: T1DM 2126.2 (1446.4 to 3181.3) and control 1073.8 (657.5 to 2226.0; P < 0.001), and in umbilical artery vein serum: T1DM 1805.7 (1393.1 to 2125.0) and control 990.0 (643.3 to 1668.0; P < 0.001). Composition of FAs in umbilical vein serum showed significantly higher concentrations of saturated, monounsaturated, and polyunsaturated FAs (SFAs, MUFAs, and PUFAs, respectively) in the T1DM group than compared with those in the control group (P = 0.001). Furthermore, cord blood levels of leptin (P < 0.001), C-peptide (P < 0.001), and insulin resistance (P = 0.015) were higher in the T1DM group compared with controls.. The neonates born to mothers with T1DM had higher concentrations of total FAs, SFAs and MUFAs, as well as PUFAs, compared with control newborns.

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 1; Fatty Acids; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Female; Fetal Blood; Humans; Infant, Newborn; Insulin Resistance; Leptin; Pregnancy; Pregnancy in Diabetics; Umbilical Arteries; Umbilical Veins; Young Adult

Leptin, a hormone released from fat cells in adipose tissues, was recently found to be capable of normalizing glucose metabolism in animals. Clinical data on patients with lipodystrophy indicates that leptin may have a positive effect on glucose metabolism in individuals with diabetes. There are growing expectations that leptin can improve the current insulin treatment for patients with type 1 diabetes. We investigated this possibility through in silico experiments based on a mathematical model of diabetes, which is currently the only mode of research that eliminates human risk. A model of the brain-centered glucoregulatory system, in which leptin plays a central role, was constructed and integrated within a conventional model of insulin/glucose dynamics. The model has been validated using experimental data from animal studies. The in silico combination experiments showed excellent therapeutic performance over insulin monotherapy.

Topics: Animals; Blood Glucose; Brain; Computer Simulation; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Leptin; Models, Biological

Cardiopulmonary fitness is decreased in type 1 diabetes for reasons that are incompletely understood. In this study, leptin was associated with exercise capacity independent of insulin sensitivity (IS) and body mass index (BMI), suggesting that leptin may relate to cardiopulmonary fitness by mechanisms beyond IS and/or obesity.

Topics: Adiposity; Adolescent; Adult; Biomarkers; Body Mass Index; Cardiorespiratory Fitness; Child; Colorado; Diabetes Mellitus, Type 1; Exercise Tolerance; Female; Humans; Insulin Resistance; Leptin; Male; Overweight; Oxygen Consumption; Pediatric Obesity; Sex Characteristics; Young Adult

(1) Background: We aimed to examine if 25-hydroxyvitamin D (25(OH)D) was related to the peripheral immunological and inflammatory signature both at birth, and in newly diagnosed patients with childhood type 1 diabetes (T1D) and their healthy controls; (2) Methods: The birth cohort consisted of 470 patients and 500 healthy controls. Dried blood samples were collected from the neonates in the period 1981-1999. The newly diagnosed cohort consisted of 460 patients and 453 siblings. Serum samples were collected in the period 1997-2005. A variety of peripheral immune mediators were measured and compared to total 25(OH)D levels (25(OH)D₂ + 25(OH)D₃). For each immune mediator, the relative change (RC) in the mean level was modeled by robust log-normal regression and correction for multiple testing was performed; (3) Results: Two associations were identified; there was a negative association between 25(OH)D (10 nmol/L increase) and leptin (RC (95% confidence interval (CI)), 0.98 (0.96; 1.00)), and a positive association between 25(OH)D (10 nmol/L increase) and the chemokine, chemokine (c-x-c motif) ligand (CXCL) 8 (RC (95% CI), 1.07 (1.01; 1.13)); (4) Conclusion: CXCL8 and leptin have significant associations with levels of 25(OH)D in the newly diagnosed cohort. These results do not indicate a strong influence of 25(OH)D on the peripheral immunological or inflammatory signature.

Topics: Case-Control Studies; Child; Child, Preschool; Cohort Studies; Denmark; Diabetes Mellitus, Type 1; Female; Humans; Immunologic Factors; Infant, Newborn; Interleukin-8; Leptin; Male; Vitamin D; White People

Compared to O-BP, we found elevated plasma leptin and resistin levels in O-T1DM, decreased gene expression of all adipokines in O-GDM, decreased. In conclusion, offspring of women with diabetes in pregnancy exhibit increased

Topics: Adiponectin; Adult Children; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetes, Gestational; DNA Methylation; Epigenesis, Genetic; Female; Follow-Up Studies; Gene Expression Regulation; Genetic Predisposition to Disease; Humans; Leptin; Maternal Exposure; Pregnancy; Resistin; Subcutaneous Fat

Diabetes is a serious disease affects human health. Diabetes in advanced stages is accompanied by general weakness and alteration in fats and carbohydrates metabolism. Recently there are some scientific trends about the usage of camel milk (CM) in the treatment of diabetes and its associated alterations. CM contains vital active particles with insulin like action that cure diabetes and its complications but how these effects occur, still unclear.. Seventy-five adult male rats of the albino type divided into five equal groups. Group 1 served as a negative control (C). Group 2 was supplemented with camel milk (CM). Diabetes was induced in the remaining groups (3, 4 and 5). Group 3 served as positive diabetic control (D). Group 4 served as diabetic and administered metformin (D+MET). Group 5 served as diabetes and supplemented with camel milk (D+CM). Camel milk was supplemented for two consecutive months. Serum glucose, leptin, insulin, liver, kidney, antioxidants, MDA and lipid profiles were assayed. Tissues from liver and adipose tissues were examined using RT-PCR analysis for the changes in mRNA expression of genes of carbohydrates and lipid metabolism. Pancreas and liver were used for immunohistochemical examination using specific antibodies.. Camel milk supplementation ameliorated serum biochemical measurements that altered after diabetes induction. CM supplementation up-regulated mRNA expression of. CM administration is of medical importance and helps physicians in the treatment of diabetes mellitus.

Topics: Animals; Blood Glucose; Camelus; Diabetes Mellitus, Type 1; Humans; Hypoglycemic Agents; Insulin; Insulin Receptor Substrate Proteins; Intracellular Signaling Peptides and Proteins; Kidney; Leptin; Liver; Male; Milk; Phosphoenolpyruvate Carboxykinase (GTP); Rats

Despite the dramatic increase in the prevalence of diabetes, techniques for in situ studies of the underlying pancreatic biochemistry are lacking. Such methods would facilitate obtaining mechanistic understanding of diabetes pathophysiology and aid in prognostic and/or diagnostic assessments. In this report we demonstrate how a multivariate imaging approach (orthogonal projections to latent structures - discriminant analysis) can be applied to generate full vibrational microspectroscopic profiles of pancreatic tissues. These profiles enable extraction of known and previously unrecorded biochemical alterations in models of diabetes, and allow for classification of the investigated tissue with regards to tissue type, strain and stage of disease progression. Most significantly, the approach provided evidence for dramatic alterations of the pancreatic biochemistry at the initial onset of immune-infiltration in the Non Obese Diabetic model for type 1 diabetes. Further, it enabled detection of a previously undocumented accumulation of collagen fibrils in the leptin deficient ob/ob mouse islets. By generating high quality spectral profiles through the tissue capsule of hydrated human pancreata and by in vivo Raman imaging of pancreatic islets transplanted to the anterior chamber of the eye, we provide critical feasibility studies for the translation of this technique to diagnostic assessments of pancreatic biochemistry in vivo.

Topics: Animals; Diabetes Mellitus, Type 1; Disease Models, Animal; Disease Progression; Female; Humans; Leptin; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Pancreas; Spectrum Analysis

The incidence of pre-eclampsia, a multisystem disorder of pregnancy, is fourfold higher in type 1 diabetic than non-diabetic women; it is also increased in women with features of the metabolic syndrome and insulin resistance. In a prospective study of pregnant women with type 1 diabetes, we measured plasma levels of adipokines known to be associated with insulin resistance: leptin, fatty acid binding protein 4 (FABP4), adiponectin (total and high molecular weight [HMW]; also known as high molecular mass), retinol binding protein 4 (RBP4) and resistin and evaluated associations with the subsequent development of pre-eclampsia.. From an established prospective cohort of pregnant type 1 diabetic women, we studied 23 who developed pre-eclampsia and 24 who remained normotensive; for reference values we included 19 healthy non-diabetic normotensive pregnant women. Plasma adipokines were measured (by ELISA) in stored samples from three study visits (Visit 1- Visit 3) at different gestational ages (mean ± SD): Visit 1, 12.4 ± 1.8 weeks; Visit 2, 21.7 ± 1.4 weeks; and Visit 3, 31.4 ± 1.5 weeks. All the women were free of microalbuminuria and hypertension at enrolment. All study visits preceded the clinical onset of pre-eclampsia.. In all groups, leptin, the ratio of leptin to total or HMW adiponectin, FABP4 concentration, ratio of FABP4 to total or HMW adiponectin and resistin level increased, while total and HMW adiponectin decreased, with gestational age. At Visit 1: (1) in diabetic women with vs without subsequent pre-eclampsia, leptin, ratio of leptin to total or HMW adiponectin, and ratio of FABP4 to total or HMW adiponectin, were increased (p < 0.05), while total adiponectin was decreased (p < 0.05); and (2) in normotensive diabetic vs non-diabetic women, total adiponectin was elevated (p < 0.05). At Visits 2 and 3: (1) the primary findings in the two diabetic groups persisted, and FABP4 also increased in women with subsequent pre-eclampsia (p < 0.05); and (2) there were no differences between the two normotensive groups. By logistic regression analyses after covariate adjustment (HbA. As early as the first trimester in type 1 diabetic women, adipokine profiles that suggest insulin resistance are associated with subsequent pre-eclampsia, possibly reflecting maternal characteristics that precede pregnancy. These associations persist in the second and third trimesters, and are independent of BMI. Insulin resistance may predispose women with type 1 diabetes to pre-eclampsia.

Topics: Adipokines; Adiponectin; Adult; Diabetes Mellitus, Type 1; Fatty Acid-Binding Proteins; Female; Humans; Leptin; Pre-Eclampsia; Pregnancy; Prospective Studies; Resistin; Retinol-Binding Proteins, Plasma; Young Adult

Insulin replacement is the cornerstone of type 1 diabetes (T1D) treatment; however, glycemic control remains a challenge. Leptin has been shown to effectively restore euglycemia in rodent models of T1D; however, the mechanism or mechanisms by which leptin exerts glycemic control are unclear. In this issue of the JCI, Perry and colleagues provide evidence that suppression of lipolysis is a key facet of leptin-mediated restoration of euglycemia. However, more work remains to be done to fully understand the antidiabetic mechanisms of leptin.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Humans; Insulin; Leptin; Lipolysis

Our objective was to determine leptin levels in patients with type 1 diabetes mellitus after fetal pancreatic stem cell transplant.. Seven patients, aged 20 to 42 years, with type 1 diabetes mellitus received a fetal pancreatic stem cell transplant by intravenous infusion. The quantity of fetal stem cells infused was ≥ 5 × 10⁶, and the cells were of 12 to 14 weeks of gestation. We analyzed the levels of leptin, C-peptide, and antibodies to the islets of Langerhans before and 3 months after the transplant procedure.. Fetal pancreatic stem cell transplant led to significant increases in leptin and C-peptide levels, from 4.63 ± 1.17 ng/mL and 0.09 ± 0.02 ng/mL to 7.71 ± 1.45 ng/mL (P < .05) and 0.22 ± 0.05 ng/mL (P < .005), respectively, without an increase in antibodies to the islets of Langerhans, which measured 0.64 ± 0.13 U/mL before transplant and 0.57 ± 0.18 U/mL 3 months later (P > .05).. Leptin levels increase significantly within 3 months of fetal pancreatic stem cell transplant in patients with type 1 diabetes mellitus.

Topics: Adult; Biomarkers; C-Peptide; Diabetes Mellitus, Type 1; Female; Fetal Stem Cells; Humans; Leptin; Male; Pancreas Transplantation; Time Factors; Treatment Outcome; Up-Regulation; Young Adult

Reduced testosterone, a recognized comorbidity of reduced insulin sensitivity (IS) and type 2 diabetes (T2D), has also been reported in adult males with type 1 diabetes (T1D). However, there are limited data on how early reduced testosterone occurs, and whether it is related to the reduced IS in T1D. Leptin, a modulator of the HPG-axis, may also influence testosterone in T1D. We hypothesized that IS and leptin would be associated with total testosterone (TT), and free androgen index (FAI) in adolescent males with T1D.. T1D (n = 35), T2D (n = 13), lean (n = 13) and obese (n = 9) adolescent males had IS measured by hyperinsulinemic-euglycemic clamps (glucose infusion rate [GIR]), in addition to leptin, sex hormone binding globulin (SHBG), TT, and FAI. The cohort was stratified into those with T1D (n = 35) and those without (n = 35).. TT and SHBG were lower in T2D boys vs. lean controls, and GIR and leptin correlated with FAI and TT in non-T1D participants. However, despite being insulin resistant, adolescent males with T1D had normal TT and FAI, unrelated to GIR. In T1D, leptin was inversely associated with TT (p = 0.005) and FAI (p = 0.01), independent of puberty, hemoglobin A1c (HbA1c), diabetes duration, body mass index (BMI) z-score and GIR.. Leptin accounted for a significant proportion of the variability of testosterone in T1D. However, despite reduced IS, there was no association between IS and testosterone in T1D adolescents. These observations suggest that the mechanisms affecting testosterone may differ between adolescent males with and without T1D.

Topics: Adolescent; Child; Cohort Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucose Clamp Technique; Humans; Insulin Resistance; Leptin; Male; Obesity; Testosterone

To explore racial differences in adiponectin, and leptin and their relationship with islet autoimmunity in children with new-onset type 1 diabetes (T1D).. Medical records were reviewed from a cohort of new-onset clinically diagnosed T1D subjects matched by race, age, gender, and year of diagnosis. Sera were available for 156 subjects (77 African American (AA), 79 Caucasian (C), 48% male, age of 11.1 ± 3.8 yr) and assayed for adiponectin and leptin prior to (D0), 3, 5 d, and 2-4 months (M3) after insulin therapy and islet autoantibodies to GAD, IA2, insulin, and ICA were measured at onset.. Adiponectin levels increased significantly following insulin therapy by day 5 (D5) (D0: 13.7 ± 7.2 vs. D5: 21.3 ± 9.9 µg/mL, p < 0.0001), but no further significant increase from D5 to M3. At DO, AA had lower adiponectin levels (10.5 vs. 15.7 µg/mL, p = 0.01), were more often overweight than C (55 vs. 18%, BMI ≥ 85th‰) and fewer had positive autoantibodies (72 vs. 87%, p = 0.05). Racial differences in adipocytokines disappeared after adjustment for BMI. At M3, subjects with more number of positive autoantibodies had higher adiponectin levels (p = 0.043) and adiponectin/leptin ratio (ALR) (p = 0.01), and lower leptin levels (p = 0.016).. Adiponectin levels increased acutely with insulin therapy. Significantly lower adiponectin levels in AA were related to greater adiposity and not race. These pilot data showing those with the fewest autoantibodies had the lowest adiponectin levels, supporting the concept that insulin-resistant subjects may present with clinical T1D at earlier stages of β-cell damage.

Topics: Adiponectin; Adiposity; Adolescent; Autoantibodies; Autoimmunity; Child; Child, Preschool; Cohort Studies; Diabetes Mellitus, Type 1; Female; Humans; Hypoglycemic Agents; Infant; Insulin; Insulin Resistance; Leptin; Male; Pennsylvania; Pilot Projects

Recombinant methionyl human leptin (metreleptin) therapy was shown to improve hyperglycaemia, dyslipidaemia and insulin sensitivity in patients with lipodystrophic syndromes, but its effects on insulin secretion remain controversial. We used dynamic intravenous (i.v.) clamp procedures to measure insulin secretion, adjusted to insulin sensitivity, at baseline and after 1 year of metreleptin therapy, in 16 consecutive patients with lipodystrophy, diabetes and leptin deficiency. Patients, with a mean [± standard error of the mean (s.e.m.)] age of 39.2 (±4) years, presented with familial partial lipodystrophy (n = 11, 10 women) or congenital generalized lipodystrophy (n = 5, four women). Their mean (± s.e.m.) BMI (23.9 ± 0.7 kg/m(2) ), glycated haemoglobin levels (8.5 ± 0.4%) and serum triglycerides levels (4.6 ± 0.9 mmol/l) significantly decreased within 1 month of metreleptin therapy, then remained stable. Insulin sensitivity (from hyperglycaemic or euglycaemic-hyperinsulinaemic clamps, n = 4 and n = 12, respectively), insulin secretion during graded glucose infusion (n = 12), and acute insulin response to i.v. glucose adjusted to insulin sensitivity (disposition index, n = 12), significantly increased after 1 year of metreleptin therapy. The increase in disposition index was related to a decrease in percentage of total and trunk body fat. Metreleptin therapy improves not only insulin sensitivity, but also insulin secretion in patients with diabetes attributable to genetic lipodystrophies.

Topics: Adult; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Hypolipidemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Lamin Type A; Leptin; Lipodystrophy; Male; Mutation; Syndrome; Triglycerides

Leptin and adiponectin are adipokines presenting a wide range of impacts, including glycemic balance regulations. Insulin is one of the main regulators of adipose tissue function. In type 1 diabetes mellitus (T1DM) endogenous insulin secretion is replaced by the exogenous supply, which is not regulated naturally. The aim of the study was to establish serum leptin and adiponectin levels, and their relations to body fat mass and disease course in children with T1DM.. The study included 75 children with T1DM and the control group of 20 healthy coevals. All children had estimated serum leptin and adiponectin concentrations, lipid profile, and bioelectrical impedance analysis.. Serum leptin concentrations in children with T1DM were not significantly different from the control group (p=0.067, mean values±SD: 3.11±2.98 vs. 5.29±5.06μg/l, respectively), and related positively to body fat mass in both groups. Adiponectin serum concentrations were significantly higher in children with T1DM than in the control group (p<0.001; mean values: 18.82±9.31 vs. 12.10±5.53μg/ml, respectively), and were not related to the body fat content in the study group. Both, leptin and adiponectin, showed no relation to any of the analyzed parameters of the disease course.. Differences observed between children with T1DM and their healthy coevals, when similar in terms of age, body weight, and body fat mass, seem not to depend directly on the disease duration, its metabolic control or insulin supply.

Topics: Adiponectin; Adiposity; Case-Control Studies; Child; Cholesterol; Diabetes Mellitus, Type 1; Disease Progression; Female; Humans; Leptin; Male; Triglycerides

Leptin can reverse hyperglycemia in rodent models of type 1 diabetes. However, these models have used chemical or immune mediated β-cell destruction where insulin depletion is incomplete. Thus it is unknown which actions of leptin are entirely insulin independent, versus those which require insulin. To directly assess this we maximized blockage of insulin action using an insulin receptor antagonist in combination with streptozotocin-diabetic mice; leptin treatment was still able to reduce blood glucose. Next, we leptin-treated adult insulin knockout (InsKO) mice. Remarkably, leptin-treated InsKO mice were viable for up to 3 weeks without insulin therapy. Leptin treatment reduced plasma corticosterone, glucagon, β-hydroxybutyrate, triglycerides, cholesterol, fatty acids and glycerol. However, leptin-treated InsKO mice exhibited overt fed hyperglycemia and severe fasting hypoglycemia. Therefore, leptin can normalize many metabolic parameters in the complete absence of insulin, but blood glucose levels are volatile and the length of survival finite.

Topics: 3-Hydroxybutyric Acid; Animals; Blood Glucose; Cholesterol; Corticosterone; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Fatty Acids; Glucagon; Glycerol; Hyperglycemia; Hypoglycemia; Insulin; Leptin; Mice; Mice, Knockout; Peptides; Receptor, Insulin; Triglycerides

Central leptin action is sufficient to restore euglycemia in insulinopenic type 1 diabetes (T1D); however, the underlying mechanism remains poorly understood. To examine the role of intracellular signal transducer and activator of transcription 3 (STAT3) pathways, we used LepRs/s mice with disrupted leptin-phosphorylated STAT3 signaling to test the effect of central leptin on euglycemia restoration. These mice developed streptozocin-induced T1D, which was surprisingly not associated with hyperglucagonemia, a typical manifestation in T1D. Further, leptin action on euglycemia restoration was abrogated in these mice, which was associated with refractory hypercorticosteronemia. To examine the role of fast-acting neurotransmitters glutamate and γ-aminobutyric acid (GABA), two major neurotransmitters in the brain, from leptin receptor (LepR) neurons, we used mice with disrupted release of glutamate, GABA, or both from LepR neurons. Surprisingly, all mice responded normally to leptin-mediated euglycemia restoration, which was associated with expected correction from hyperglucagonemia and hyperphagia. In contrast, mice with loss of glutamate and GABA appeared to develop an additive obesity effect over those with loss of single neurotransmitter release. Thus, our study reveals that STAT3 signaling, but not fast-acting neurotransmitter release, is required for leptin action on euglycemia restoration and that hyperglucagonemia is not required for T1D.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Infusions, Intraventricular; Leptin; Male; Mice; Mice, Transgenic; Neurons; Neurotransmitter Agents; Signal Transduction; STAT3 Transcription Factor; Vesicular Glutamate Transport Protein 2; Vesicular Inhibitory Amino Acid Transport Proteins

Adiponectin and leptin are proteins secreted by the adipose tissue and have an influence on insulin sensitivity and on inflammatory markers. Altered levels could play a part in the pathogenesis of type 1 diabetes mellitus. We determined adiponectin and leptin levels over a nine-year period in children with type 1 diabetes mellitus (T1D) in relation to the increasing incidence of T1D, and studied the impact of patient status, age, gender and body mass index (BMI). Data were derived from a population-based registry of diabetic children (DanDiabKids) from 1997 to 2005. Children with newly diagnosed T1D (n = 482) were included, and healthy siblings (n = 479) were chosen as a control group. Leptin levels were significantly higher in recent years (in both patients and siblings), whereas for adiponectin, the levels were lower in recent years in the patient group. Leptin levels were lower in children with T1D (RR 0.74, p = 0.003) and in males (RR 0.52, p < 0.001) and increasing with age in both groups. For adiponectin, there was a negative association between level and age in patients. Both adipokines showed a significant correlation with BMI and lower levels in children with blood samples taken within the first 2 days after initiation of insulin treatment. There has been a change in leptin and adiponectin levels in children with or without T1D from 1997 to 2005. This is not explained by changes in BMI and may reflect changes in other factors like diet or physical activity.

Topics: Adiponectin; Adolescent; Age Factors; Age of Onset; Body Mass Index; Child; Child, Preschool; Diabetes Mellitus, Type 1; Female; Humans; Infant; Insulin; Insulin Resistance; Leptin; Male; Time Factors

The aim of this study was to explore the changes in the adipokines leptin and adiponectin in obese patients with type 1 diabetes mellitus (T1DM) who underwent seven days of fasting and 21 days of low-calorie diet (LCD). The plasma leptin and adiponectin concentrations were measured in 14 obese patients with T1DM at baseline, immediately after 7 days of fasting, and after 21 days of LCD. 13 non-obese patients with T1DM were studied only after an overnight fasting. Bioimpedance technique was used for determination of body composition. Obese T1DM patients lost 6.0 kg (6.0; 6.8) (median, 25 %; 75 %) and decreased their fat tissue after fasting and LCD. Plasma leptin in obese T1DM was significantly higher than in non-obese T1DM patients: 9.10 (5.06; 25.89) vs. 1.71 (1.12; 7.08) microg . l(-1) and transiently decreased immediately after fasting: 3.45 microg . l(-1) (1.47; 7.00), (P<0.05). Adiponectin/leptin ratio in obese T1DM was significantly lower than in non-obese T1DM patients: 0.67 (0.57; 1.49) vs. 3.50 (2.46; 6.30) . 10(3) and transiently increased immediately after fasting: 2.22 (1.26; 3.24) . 10(3), (P<0.05). We conclude that obese patients with T1DM are characterized by hyperleptinemia that is reduced by prolonged fasting, but only slightly affected by low calorie diet.

Topics: Adiponectin; Adipose Tissue; Adult; Body Composition; Caloric Restriction; Diabetes Mellitus, Type 1; Fasting; Fatty Acids, Nonesterified; Female; Glucose; Glucose Clamp Technique; Humans; Leptin; Male; Middle Aged; Obesity; Weight Loss; Young Adult

To evaluate circulating adipokines in people with ketosis-prone diabetes, a heterogeneous disorder characterized by unprovoked ketoacidosis in people with previously unrecognized diabetes.. Patients presenting with ketoacidosis with no previous diabetes diagnosis were compared with patients with previously established Type 1 diabetes. Baseline assessments of autoimmune status (A+/A-), and β-cell function (B+/B-), as well as leptin and adiponectin levels during a standardized mixed-meal tolerance test of 120 min, were performed. In all, 20 patients with heterogeneous ketosis-prone diabetes and 12 patients with Type 1 diabetes were evaluated at baseline, 12 and 24 months.. At baseline, during a mixed-meal tolerance test, glucose and adiponectin concentrations were lower in patients with ketosis-prone diabetes than in those with Type 1 diabetes (P = 0.0023 and P < 0.0001, respectively), whereas C-peptide concentrations were higher, with no significant difference in leptin concentrations. Within 12 months, 11 patients with ketosis-prone diabetes (all A-/B+) were discontinued from insulin treatment (ketosis-prone diabetes - insulin group), while nine patients (four A-B-, four A+B- and one A-B+) were maintained on insulin (ketosis-prone diabetes + insulin group). Fasting C-peptide levels increased significantly over 24 months in the ketosis-prone diabetes - insulin group (P = 0.01), while HbA1c levels decreased (P < 0.0001). Overall, the ketosis-prone diabetes - insulin group had a higher BMI (P = 0.018), yet a lower fasting glucose concentration (P = 0.003) compared with the ketosis-prone diabetes + insulin group. Over 24 months, the mixed-meal tolerance test area-under-the-curve of C-peptide increased in the ketosis-prone diabetes - insulin group, with no change in ketosis-prone diabetes + insulin (P < 0.0001). At 24 months, in spite of the higher BMI in the ketosis-prone diabetes - insulin group, mixed-meal tolerance test glucose and leptin concentrations were significantly lower (P < 0.0001 and P = 0.017, respectively), while adiponectin levels were higher (P = 0.023) compared with the ketosis-prone diabetes + insulin group.. In spite of the higher BMI in the ketosis-prone diabetes - insulin group, lower leptin and higher adiponectin levels may contribute to improved β-cell function and insulin sensitivity, as evidenced by lower glucose and higher C-peptide levels. This allows insulin therapy to be withdrawn.

Topics: Adiponectin; Adolescent; Adult; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Insulin Resistance; Insulin-Secreting Cells; Leptin; Male; Middle Aged; Postprandial Period; Prospective Studies; Time Factors; Young Adult

Autoimmune thyroid diseases (AITDs), predominately Graves׳ disease and Hashimoto׳s thyroiditis, comprise the most common autoimmune diseases in humans. Both have the production of anti-thyroid antibody as an important aspect and both are much more prevalent in females, being at least 10 times more common than in males. Using these two clues, a hypothesis for the initiation of thyroid autoimmunity is proposed that helps to make the case that the thyroid is one of the most sensitive sites for autoimmunity and helps account for the prevalence and the observed sex differences in AITDs and associated diseases, such as type 1 diabetes and Latent Autoimmune Diabetes in Adults (LADA). The primary mechanisms proposed involve the underlying state of inflammation as a result of the adipokines, especially leptin, TNF-α, and IL-6, and the receptors able to recognize pathogen-associated molecular patterns (PAMP׳s) and damage-associated molecular patterns (DAMP׳s) through Toll-like receptors (TLR) and others receptors present on thyrocytes. The adipokines are produced by adipose tissue, but have hormone-like and immune modulating properties. As the levels of leptin are significantly higher in females, an explanation for the sex difference in thyroid autoimmunity emerges. The ability of the thyrocytes to participate in innate immunity through the TLR provides an adjuvant-like signal and allows for the action of other agents, such as environmental factors, viruses, bacteria, and even stress to provide the initiation step to break tolerance to thyroid self-antigens. Seeing the thyroid as one of the most sensitive sites for autoimmunity, means that for many autoimmune disorders, if autoimmunity is present, it is likely to also be present in the thyroid - and that that condition in the thyroid was probably earlier. The evidence is seen in multiple autoimmune syndrome.

Topics: Adipokines; Animals; Autoantibodies; Autoantigens; Autoimmunity; Diabetes Mellitus, Type 1; Female; Graves Disease; Hashimoto Disease; Humans; Immunity, Innate; Inflammation; Leptin; Male; Mice; Prevalence; Receptors, Pattern Recognition; Sex Factors; Thyroid Gland

Recent evidence has highlighted the role of histamine in inflammation. Since this monoamine has also been strongly implicated in the pathogenesis of type-1 diabetes, we assessed its effect in the nonobese diabetic (NOD) mouse model. To this end, we used mice (inactivated) knocked out for the gene encoding histidine decarboxylase, the unique histamine-forming enzyme, backcrossed on a NOD genetic background. We found that the lack of endogenous histamine in NOD HDC(-/-) mice decreased the incidence of diabetes in relation to their wild-type counterpart. Whereas the proportion of regulatory T and myeloid-derived suppressive cells was similar in both strains, histamine deficiency was associated with increased levels of immature macrophages, as compared with wild-type NOD mice. Concerning the cytokine pattern, we found a decrease in circulating IL-12 and IFN-γ in HDC(-/-) mice, while IL-6 or leptin remained unchanged, suggesting that histamine primarily modulates the inflammatory environment. Paradoxically, exogenous histamine given to NOD HDC(-/-) mice provided also protection against T1D. Our study supports the notion that histamine is involved in the pathogenesis of diabetes, thus providing additional evidence for its role in the regulation of the immune response.

Topics: Animals; Cytokines; Diabetes Mellitus, Type 1; Histamine; Histidine Decarboxylase; Interferon-gamma; Interleukin-12; Interleukin-6; Leptin; Mice; Mice, Inbred NOD; Mice, Knockout; T-Lymphocytes, Regulatory

Previous research indicated that coeliac disease (CD) is associated with type 1 diabetes mellitus (T1DM). However, the gut-brain axis peptide hormones secretion has not been evaluated so far in patients with CD prior to treatment initiation or under treatment, irrespective of patients having concomitant T1DM or not. The aim of the study was therefore to evaluate these gut hormones at the preprandial levels of patients with CD before and under treatment.. Of forty-seven CD children, 12 untreated (UCD), 22 treated with gluten-free diet (TCD) and 13 treated CD with coexisting T1DM (DCD), and 18 healthy controls (HC) were enrolled. Preprandial glucagon-like-peptide-1 (GLP-1), glucose-dependent-insulinotropic-polypeptide (GIP), active amylin, acylated ghrelin (AG), leptin, pancreatic polypeptide (PP) and peptide-tyrosine-tyrosine (PYY) were determined with hormone-map-array technology.. We found in patients with CD compared with HC that the concentration of (i) GLP-1 was reduced remarkably in all patients with CD (P = 0.008), (ii) GIP was lower in patients with UCD (P = 0.008), (iii) amylin was remarkably reduced (P < 0.01) in all patients with CD, (iv) AG was significantly decreased in patients with DCD (P < 0.01), while (v) leptin, PP and PYY were not significantly different. GIP, GLP-1 and amylin levels correlated positively with insulin concentrations (P < 0.001, P = 0.004 and P < 0.01, respectively) in all patients. Amylin and GIP levels were strongly associated with triglycerides concentrations (P < 0.001, for both peptides) in children with CD.. Our study revealed a different secretion pattern of gut-brain axis hormones in children with CD compared with HC. The alterations in the axis were more pronounced in children with both CD and T1DM.

Topics: Adolescent; Case-Control Studies; Celiac Disease; Child; Child, Preschool; Diabetes Mellitus, Type 1; Diet, Gluten-Free; Female; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Incretins; Islet Amyloid Polypeptide; Leptin; Male; Pancreatic Polypeptide; Peptide YY

Visceral fat and related adipokines, such as leptin and adiponectin, have been recently suggested to play a role in type 1 diabetes. Nevertheless epicardial fat, the visceral fat of the heart, has been poorly explored in type 1 diabetes. In this study we sought to measure epicardial fat thickness, plasma leptin and adiponectin levels in type 1 diabetic subjects.. 15 subjects with type 1 diabetes (age 52.8 ± 12, 10 females, 5 males, BMI 27.8 ± 5.2) and 15 non-diabetic controls underwent echocardiographic epicardial fat thickness measurement and blood tests for adipokines and Hemoglobin A1c (HbA1c). There were no differences in BMI, age, sex, blood pressure, inflammatory markers and adiponectin between subjects with diabetes and controls. Daily insulin requirement of subjects with type 1 diabetes was 0.54 ± 0.2 UI/kg and HbA1c was 7.6 ± 1.0 reflecting acceptable glycemic control. Patients with Type 1 diabetes showed significantly higher epicardial fat thickness (7.2 ± 2.1 vs 4.9 ± 2.5 mm p < 0.01) and plasma leptin levels (25.9 ± 19 vs 18 ± 12 ng/ml p < 0.01) than controls. Leptin resulted in the best independent correlate of epicardial fat thickness (R(2) = 0.48, p = 0.04, β = 2.45).. Our study provides two major findings of novelty: 1) subjects with type 1 diabetes have higher epicardial fat and serum leptin levels than non-diabetic subjects, 2) epicardial fat thickness and serum leptin levels are the best independent correlates of each other in patients with type 1 diabetes independently of BMI, HbA1c, daily insulin requirement. The mechanisms that link epicardial fat to leptin levels in type 1 diabetes remain to be elucidated.

Topics: Adiponectin; Adiposity; Adult; Blood Glucose; Body Mass Index; C-Reactive Protein; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Echocardiography; Female; Glycated Hemoglobin; Heart; Humans; Insulin; Intra-Abdominal Fat; Leptin; Male; Middle Aged; Obesity; Pericardium

The role of glucagon in the pathological condition of diabetes is gaining interest, and it has been recently reported that its action is essential for hyperglycemia to occur. Glucagon levels, which are elevated in some diabetic models, are reduced following leptin therapy. Likewise, hyperglycemia is corrected in type 1 diabetic mice treated with leptin, although the mechanisms have not been fully determined. A direct inhibitory effect of leptin on mouse and human α-cells has been demonstrated at the levels of electrical activity, calcium signaling, and glucagon secretion. In the present study we employed the Cre-loxP strategy to generate Lepr(flox/flox) Gcg-cre mice, which specifically lack leptin receptors in glucagon-secreting α-cells, to determine whether leptin resistance in α-cells contributes to hyperglucagonemia, and also whether leptin action in α-cells is required to improve glycemia in type 1 diabetes with leptin therapy. Immunohistochemical analysis of pancreas sections revealed Cre-mediated recombination in ∼ 43% of the α-cells. We observed that in vivo Lepr(flox/flox) Gcg-cre mice display normal glucose and lipid homeostasis. In addition, leptin administration in streptozotocin-induced diabetic Lepr(flox/flox) Gcg-cre mice restored euglycemia similarly to control mice. These findings suggest that loss of leptin receptor signaling in close to one-half of α-cells does not alter glucose metabolism in vivo, nor is it sufficient to prevent the therapeutic action of leptin in type 1 diabetes.

Topics: Animals; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Female; Gene Deletion; Glucagon-Secreting Cells; Glucose; Homeostasis; Leptin; Lipid Metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Receptors, Leptin; Signal Transduction

Type 1 diabetes is associated with subfertility in humans. The current treatment for type 1 diabetes, insulin monotherapy, is suboptimal to fully stabilize glycemia, potentially leading to this subfertility. Recent work has demonstrated that treatment with the energy-regulating hormone leptin, alone or in combination with insulin, can more effectively control glycemia in mouse models of type 1 diabetes. Here, we sought to determine whether the fertility defects in a type 1 diabetic mouse model, the Akita mouse, can be rescued with leptin monotherapy in the absence of any exogenous insulin. Akita homozygous mice treated with leptin alone had a larger total body size, testes, and seminal vesicles than their untreated siblings. Leptin treatment prevented testicular degeneration and rescued sperm motility to wild-type levels. Furthermore, sperm obtained from leptin-treated mice could successfully fertilize ooctyes in vitro. Despite completely rescuing spermatogenesis, the critical reproductive hormones LH and testosterone were only modestly higher than in untreated mice, indicating that a minimum threshold of these hormones must be met to maintain spermatogenesis. Cumulatively, these findings implicate the importance of leptin in maintaining fertility and support the use of leptin therapy in the treatment of type 1 diabetes.

Topics: Adiposity; Animals; Atrophy; Diabetes Mellitus, Type 1; Disease Models, Animal; Genetic Carrier Screening; Homozygote; Infertility, Male; Leptin; Luteinizing Hormone; Male; Mice; Spermatogenesis; Testosterone

To investigate the relationship between bone-derived osteocalcin (OC), osteoprotegerin (OPG), Receptor Activator of Nuclear Factor NF-ĸB ligand (RANKL), and fat tissue-derived leptin and adiponectin with a clinical outcome of type 1 diabetes mellitus (T1DM) in children and adolescents.. 78 patients (43 girls and 35 boys), aged 11.5±4.3 years with T1DM and 11 age- and BMI-matched controls were included into the study. Patients were divided into 3 groups according to HbA1c level, I - below 7% [53 mmol/mol], II - 7-9% [53-75 mmol/mol] and III - above 9% [75 mmol/mol]. Blood samples for biochemical measurements were drawn at 8.00 AM, when the patients were in a fasting state. HbA1c was measured by the standardized IFCC method. OC, OPG, RANKL, leptin and adiponectin were measured by ELISA. ANOVA, and multiple regression analysis were used for statistical analysis.. Significant differences in leptin and osteocalcin levels between groups with different HbA1c values were observed (p=0.03, p=0.04). Multiple regression analysis adjusted for age showed that serum OC and leptin negatively correlated with HbA1c levels (r=-0.22, p=0.004 and r=-0.27, p=0.0001, respectively). In contrast, serum OPG correlated positively with HbA1c (r=0.26, p=0.02) as well as with adiponectin (r=0.26, p=0.02) and RANKL (r=0.27, p=0.02) levels. The correlation of OC with HbA1c was the strongest in group I - patients with good metabolic control of DM (r=-0.43, p=0.03). In that group, in multiple regression analysis adjusted for age and BMI leptin correlated positively with daily dose of insulin (r=0.52, r=0.009). In group II and III in multiple regression analysis adjusted for age and BMI OC correlated negatively with leptin (r=-0.37, p=0.01).. Our data suggest significant relationships between bone, fat tissue and glucose metabolism in pediatric patients with T1DM. The results can confirm that poor metabolic control is associated with reduced bone formation. On the other hand fat and bone tissue can influence glucose metabolism, potentiality in insulin-dependent manner. From these data leptin or OC may be potentially used as additional therapeutic agents for T1DM.

Topics: Adiponectin; Adolescent; Biomarkers; Child; Diabetes Mellitus, Type 1; Female; Humans; Insulin; Leptin; Male; Osteocalcin; Osteoprotegerin; RANK Ligand

Leptin treatment reverses hyperglycemia in animal models of poorly controlled type 1 diabetes (T1D), spurring great interest in the possibility of treating patients with this hormone. The antidiabetic effect of leptin has been postulated to occur through suppression of glucagon production, suppression of glucagon responsiveness or both; however, there does not appear to be a direct effect of leptin on the pancreatic alpha cell. Thus, the mechanisms responsible for the antidiabetic effect of leptin remain poorly understood. We quantified liver-specific rates of hepatic gluconeogenesis and substrate oxidation in conjunction with rates of whole-body acetate, glycerol and fatty acid turnover in three rat models of poorly controlled diabetes, including a model of diabetic ketoacidosis. We show that the higher rates of hepatic gluconeogenesis in all these models could be attributed to hypoleptinemia-induced activity of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in higher rates of adipocyte lipolysis, hepatic conversion of glycerol to glucose through a substrate push mechanism and conversion of pyruvate to glucose through greater hepatic acetyl-CoA allosteric activation of pyruvate carboxylase flux. Notably, these effects could be dissociated from changes in plasma insulin and glucagon concentrations and hepatic gluconeogenic protein expression. All the altered systemic and hepatic metabolic fluxes could be mimicked by infusing rats with Intralipid or corticosterone and were corrected by leptin replacement. These data demonstrate a critical role for lipolysis and substrate delivery to the liver, secondary to hypoleptinemia and HPA axis activity, in promoting higher hepatic gluconeogenesis and hyperglycemia in poorly controlled diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Glucagon; Gluconeogenesis; Hypothalamo-Hypophyseal System; Insulin; Leptin; Lipolysis; Pituitary-Adrenal System; Rats

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Hypothalamo-Hypophyseal System; Leptin; Pituitary-Adrenal System

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Hypothalamo-Hypophyseal System; Leptin; Pituitary-Adrenal System

Topics: Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; History, 20th Century; Humans; Leptin; Obesity

Moyamoya disease (MMD) and moyamoya syndrome are vasculopathies characterized by progressive stenosis in the circle of Willis and its branches. The RNF213 gene, which encodes a novel class of proteins, characterized by both E3 ligase and AAA+ATPase activities, has been identified as the susceptibility gene for MMD. However, its physiological functions remain unknown. MMD and moyamoya syndrome are often accompanied by diabetes mellitus. In this study, we generated Rnf213 knockout (KO) C57BL/6 mice (Rnf213(-/-); Ins2(+/+)), which were mated with Akita (C57BL/6 Rnf213(+/+); Ins2(+/C96Y)) mice, a strain that develops diabetes spontaneously by 5 weeks of age, to obtain mice lacking Rnf213 and carrying the Akita mutation (KO/Akita, Rnf213(-/-); Ins2(+/C96Y)). Body weight and blood glucose concentration were measured from 6 to 20 weeks. Glucose tolerance, insulin resistance, plasma insulin and leptin concentrations, food consumption, pancreatic insulin content and histopathology were evaluated at 18 weeks of age. We found that glucose tolerance, as indicated by AUC, was 20% lower (p<0.05) and insulin contents in pancreas were 150% higher (p<0.05), in KO/Akita than in Akita mice. The number of CHOP positive β-cells assayed by histopathological examination was 30% lower and food consumption was 34% lower in KO/Akita than in Akita mice (p<0.05 each). These findings indicated that the disruption of Rnf213 improved glucose tolerance by protecting islet β cells.

Topics: Adenosine Triphosphatases; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 1; Disease Progression; Glucose Tolerance Test; Insulin; Insulin-Secreting Cells; Leptin; Mice; Mice, Knockout; Moyamoya Disease; Transcription Factor CHOP; Ubiquitin-Protein Ligases

Competitive endogenous RNAs (ceRNAs) regulate mRNA transcripts containing common microRNA (miRNA) recognition elements (MREs) through sequestration of shared miRNAs. Interactions of ceRNA have been demonstrated in cancerous cells. However, a paucity of information is available relative to the interactions of ceRNAs interaction in diabetes mellitus and the myocardium. The purpose of this study is to assess the potential role of DKK1 and PTEN in ceRNA regulation utilizing their common miRNAs in diabetic cardiomyocytes. The interactions' regulation between PTEN and DKK1 were determined in two diabetic models in vivo (streptozotocin-induced type-1 DM mice and db/db mice) and in vitro (human cardiomyocytes cells exposed to hyperglycemia). The levels of DKK1 and PTEN (mRNA and protein) were upregulated in parallel in all three diabetic models. DKK1 modulates PTEN protein levels in a miRNA and 3'UTR-dependent manner. RNAi-mediated DKK1 gene silencing resulted in a decreased PTEN expression and vice versa. The effect was blocked when Dicer was inhibited. Silencing either PTEN or DKK1 resulted in an increase of the availabilities of shared miRNAs. The silencing of either PTEN or DKKI resulted in a suppression end of the luciferase-PTEN 3'UTR activity. However, the over expression of DKK1 3'UTR or PTEN 3'UTR resulted in an increase in the activity. The attenuation of DKK1 increased AKT phosphorylation, improved glucose uptake and decreased apoptosis in HCMs exposed to hyperglycemia. The effects were blocked by PI3K inhibition. DKK1 and PTEN transcripts are co-upregulated in DM and hyperglycemia. DKK1 and PTEN serve as ceRNA, affecting the expression of each other via competition for miRNAs binding.

Topics: 3' Untranslated Regions; Animals; Apoptosis; Binding Sites; Binding, Competitive; Blood Glucose; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Gene Expression Regulation; Genes, Reporter; Heart Diseases; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Myocytes, Cardiac; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; RNA Interference; RNA, Messenger; Signal Transduction; Transfection

In rodent models of type 1 diabetes, leptin administration into brain ventricles normalizes blood glucose at doses that have no effect when given peripherally. The ventromedial nucleus of the hypothalamus (VMN) is a potential target for leptin's antidiabetic effects because leptin-sensitive neurons in this brain area are implicated in glucose homeostasis. To test this hypothesis, we injected leptin directly into the bilateral VMN of rats with streptozotocin-induced uncontrolled diabetes mellitus. This intervention completely normalized both hyperglycemia and the elevated rates of hepatic glucose production and plasma glucagon levels but had no effect on tissue glucose uptake in the skeletal muscle or brown adipose tissue as measured using tracer dilution techniques during a basal clamp. To determine whether VMN leptin signaling is required for leptin-mediated normalization of diabetic hyperglycemia, we studied mice in which the leptin receptor gene was deleted in VMN steroidogenic factor 1 neurons using cre-loxP technology. Our findings indicate leptin action within these neurons is not required for the correction of diabetic hyperglycemia by central leptin infusion. We conclude that leptin signaling in the VMN is sufficient to mediate leptin's antidiabetic action but may not be necessary for this effect. Leptin action within a distributed neuronal network may mediate its effects on glucose homeostasis.

Topics: Animals; Diabetes Mellitus, Type 1; Glucagon; Glucagon-Secreting Cells; Gluconeogenesis; Hyperglycemia; Hypoglycemic Agents; Infusions, Intraventricular; Injections, Intraventricular; Leptin; Liver; Male; Mice; Mice, Knockout; Nerve Tissue Proteins; Neurons; Rats; Rats, Wistar; Receptors, Leptin; Recombinant Proteins; Signal Transduction; Ventromedial Hypothalamic Nucleus

Adiponectin, leptin, and resistin are adipokines which play a significant role in the regulation of lipid and carbohydrate metabolism in patients with type 2 diabetes, while little is known about their role in type 1 diabetes mellitus (T1DM). The aim of this study was to measure serum adiponectin, leptin, and resistin levels and to investigate their relationships with some parameters in patients with T1DM and healthy controls.. Fifty children and adolescents with T1DM (21 boys and 29 girls) and 33 healthy control subjects (18 boys and 15 girls) participated in the study. All subjects were patients followed in the Pediatric Endocrinology and Metabolism Unit of Gaziantep University Faculty of Medicine. None of the subjects had hypertension, obesity, hyperlipidemia, anemia, or infection. Adiponectin, leptin, and resistin levels were analyzed with ELISA.. There were no statistically significant differences related with age, sex, pubertal status, or body mass index distribution between the diabetic and control groups. Resistin levels were significantly higher in the diabetic group compared to controls (5.26±3.15 ng/mL vs. 3.50±1.26 ng/mL; p<0.01).. Of the three investigated adipokines, only resistin was associated with T1DM. Resistin may play a role in the process of inflammation and also in the pathophysiology of T1DM.

Topics: Adiponectin; Adolescent; Child; Diabetes Mellitus, Type 1; Female; Humans; Leptin; Male; Resistin

Type 1 diabetes mellitus (T1DM) is still associated with increased risk for severe maternal and fetal complications but their pathomechanism remains unclear. We investigated into possible role of placental leptin (LEP) and its receptor gene (LEPR) in T1DM pregnancies. Fourty nine pregnant women with T1DM and singleton pregnancy were enrolled into the study. Control group consisted of 15 healthy pregnant women in uncomplicated, singleton gestation. We observed higher expression of LEP and LEPR in T1DM placentas in comparison to healthy subjects. We also noticed greater expression of LEP and LEPR in T1DM pregnancies with large for gestational age (LGA) and appropriate for gestational age (AGA) fetuses in comparison to small for gestational age (SGA) diabetic fetuses and controls. We found a significant positive correlation between placental LEP and LEPR expression and neonatal birthweight in overweight T1DM subjects. No such a correlation was found in T1DM subjects with normal weight and controls. We conclude that increased placental LEP and LEPR expression may have a role in stimulating fetal overgrowth in T1DM pregnancy.

Topics: Adolescent; Adult; Birth Weight; Diabetes Mellitus, Type 1; Female; Gene Expression; Humans; Leptin; Overweight; Placenta; Pregnancy; Pregnancy in Diabetics; Receptors, Leptin; Young Adult

We investigated the adipokines adiponectin, leptin and resistin as serum biomarkers of beta-cell function in patients with type 1 diabetes.. One hundred and eighteen patients with type 1 diabetes (20.3 ± 7.5 years) diagnosed <5 years underwent standardized mixed meal test (MMTT) for 2 h. Systemic concentrations of C-peptide, adiponectin, leptin and resistin obtained during MMTT were measured and compared between patient groups by multiple regression analysis.. Patients were divided by their adipokine levels in subgroups above or below the median level ('high versus low'). High adiponectin levels (>10.6 µg/mL) were associated with lower C-peptide compared to the low adiponectin subgroup (p < 0.03). Increased leptin or resistin concentrations associated positively with beta-cell function even after adjustment for metabolic confounders (p < 0.04). The described associations between adipokines and C-peptide concentrations persisted in Spearman correlation tests (p < 0.05). Serum adipokines fell during MMTT (p < 0.05).. Serum adipokine levels differentially correlate with beta-cell function in type 1 diabetes independent of BMI or metabolic control. Serum adipokines should be investigated as biomarkers of beta-cell function in prospective studies and intervention trials in type 1 diabetes.

Topics: Adiponectin; Adolescent; Adult; Biomarkers; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 1; Fasting; Female; Humans; Insulin-Secreting Cells; Leptin; Male; Meals; Resistin

To compare maternal and fetal leptin among women without diabetes, women with type 1 diabetes, and women with type 2 diabetes.. In a prospective study at the National Maternity Hospital, Dublin, 40 women with type 1 diabetes, 10 with type 2 diabetes, and 30 without diabetes were enrolled between July 2006 and July 2008. Maternal (36-week) and cord blood leptin was measured by enzyme-linked immunoassay.. No difference was found in maternal leptin among the groups: without diabetes (mean, range): 325 pg/mL, 36-1492 pg/mL; type 1 diabetes: 343.2 pg/mL, 55.5-1108.2 pg/mL; type 2 diabetes: 202.2 pg/mL, 35.1-1553.3 pg/mL (P>0.05). Leptin levels were higher among fetuses of women with type 1 (223 pg/mL, 25.7-810 pg/mL) and type 2 (447.2 pg/mL, 136.3-679 pg/mL) diabetes than among women without diabetes (80.3 pg/mL, 27.3-623.1 pg/mL; P<0.05). The single significant predictor of fetal leptin for the whole cohort was maternal body mass index (BMI; r=0.39, P=0.01). Only third-trimester glycosylated hemoglobin (HbA1c) was significantly related to fetal leptin after controlling for maternal BMI among women with diabetes (r=0.28, P=0.04).. Fetuses of women with diabetes might have some degree of leptin resistance. This might be important in appetite regulation in extrauterine life.

Topics: Adult; Birth Weight; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Fetal Blood; Humans; Infant, Newborn; Insulin Resistance; Leptin; Pregnancy; Pregnancy in Diabetics; Prospective Studies; Young Adult

Topics: Animals; Diabetes Mellitus, Type 1; Humans; Leptin

Adipokines are markers of insulin resistance and play a role in the atherosclerotic process. The association of adipokines with the macrovascular complications of type 1 diabetes mellitus (DM) needs to be determined. The aim of this study was to measure serum adiponectin, leptin, and resistin levels in type 1 DM patients and investigate their relationship with carotid intima media thickness (CIMT), a clinical marker of atherosclerosis.. Seventy-five type 1 DM patients and 115 sex and age-matched healthy controls were included in the study. Serum adiponectin, leptin, and resistin levels were measured by the enzyme-linked immunosorbent assay (ELISA method). CIMT was assessed by Doppler ultrasonography.. Adiponectin levels in diabetics were higher (25.8±14.8 μg/mL vs. 5.5±7.3 μg/mL; P<0.0001) and leptin levels were lower than controls (9.4±6.2 ng/mL vs. 12.8±8.6 ng/mL; P=0.01). Resistin levels were also higher in the diabetic group compared to controls (2.1±1.4 ng/mL vs. 1.6±0.8 ng/mL; P=0.04). Adiponectin was correlated negatively with CIMT (r=-0.24, P=0.03), age (r=-0.30, P=0.02), BMI (r=-0.33, P=0.02), waist-to-hip ratio (WHR) (r=-0.38, P=0.01) and positively with creatinine (r=0.44, P=0.004). Leptin levels were correlated with total cholesterol (r=0.53, P=0.01) and high-density lipoprotein (HDL) (r=0.67, P=0.001). Resistin was correlated with CIMT (r=0.24, P=0.03) and systolic blood pressure (r=0.48, P=0.009). Multivariate analysis revealed resistin and creatinine to be independent predictors of CIMT among adiponectin, leptin, resistin, WHR, glycosylated hemoglobin (HbA1c), and creatinine.. Increased adiponectin correlates negatively and resistin positively with CIMT in type 1 diabetic patients, but adjusting for other known predictors reveals only resistin to be associated with subclinical atherosclerosis in this group of patients.

Topics: Adipokines; Adiponectin; Adult; Blood Glucose; Blood Pressure; Body Mass Index; Carotid Artery Diseases; Carotid Intima-Media Thickness; Case-Control Studies; Chi-Square Distribution; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Enzyme-Linked Immunosorbent Assay; Female; Glycated Hemoglobin; Humans; Leptin; Lipids; Male; Resistin; Risk Assessment; Risk Factors; Turkey; Ultrasonography, Doppler; Waist Circumference; Young Adult

To determine whether undercarboxylated osteocalcin (UC-OC) or gamma-carboxyglutamic-carboxylated-type osteocalcin (GLA-OC) concentrations deviate from normal in type 1 diabetes (T1D), serum levels were compared between 115 subjects with T1D and 55 age-matched healthy controls. UC-OC and GLA-OC concentrations were similar between groups; however, in T1D, UC-OC correlated positively with markers of insulin exposure, either endogenously produced or exogenously administered.. A study was conducted to determine whether dysregulation of circulating concentrations of UC-OC or GLA-OC occurs in patients with type 1 diabetes, a condition of insulin deficiency without insulin resistance.. We measured serum concentrations of UC-OC and GLA-OC in 115 subjects with T1D, ages 14-40 years, and in 55 age-matched healthy control subjects. Relationships between UC-OC and GLA-OC concentrations and patient characteristics (gender and age), indices of glycemic control (hemoglobin A1c (HbA1c), fasting plasma glucose, C-peptide concentration, 3-day average glucose measured by a continuous glucose sensor, total daily insulin dose) and circulating indices of skeletal homeostasis (total calcium, 25-OH vitamin D, parathyroid hormone, insulin-like growth factor 1 (IGF-1), type 1 collagen degradation fragments (CTX), adiponectin, leptin) were examined. Between group differences in the concentrations of UC-OC and GLA-OC were the main outcome measures.. Although adiponectin levels were higher in the T1D group, between-group comparisons did not reveal statistically significant differences in concentration of UC-OC, GLA-OC, CTX or leptin between the T1D and control populations. Instead, by multivariate regression modeling, UC-OC was correlated with younger age (p < 0.001), higher CTX (p < 0.001), lower HbA1c (p = 0.013), and higher IGF-1 (p = 0.086). Moreover, within the T1D subgroup, UC-OC was positively correlated with C-peptide/glucose ratio (reflecting endogenous insulin secretion), with IGF-1 (reflecting intra-portal insulin sufficiency), and with total daily insulin dose.. In T1D, UC-OC appears to correlate positively with markers of insulin exposure, either endogenously produced or exogenously administered.

Topics: Adiponectin; Adolescent; Adult; Biomarkers; Blood Glucose; C-Peptide; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Female; Humans; Insulin; Leptin; Male; Osteocalcin; Young Adult

At puberty, type 1 diabetes (T1D) among young girls can lead to excess body weight, insulin resistance, deterioration of glycaemic control and dyslipidaemia. Although biological factors contribute largely to such metabolic dysfunction, little is known of the role of behavioural factors such as physical activity and diet.. This study investigated the association between metabolic dysfunction measured after a 12-h overnight fast and behavioural factors, including diet (4-day diary) and physical activity (validated questionnaire), in 19 postmenarchal adolescent girls with T1D compared with 19 healthy girls.. T1D girls displayed higher levels of fat mass, insulin resistance (higher plasma glucose, serum leptin and waist-to-hip ratios) and dyslipidaemia (higher LDL-C and apolipoprotein B levels, lower HDL-C and apolipoprotein A-1 levels). Also, contrary to what is usually observed in T1D adults, serum adiponectin, an important vessel protector, was not raised in T1D adolescent girls compared with healthy controls. Quantity and quality of dietary macronutrient intakes as well as physical activity levels were comparable in both groups, although the T1D girls with the poorest metabolic profiles reported having the healthiest diets (fewer total calories, more protein and less carbohydrates). However, in T1D girls, less physical activity and more time spent watching television were associated with poorer metabolic profiles (higher waist-to-hip ratios, fat mass and leptin levels, and lower adiponectin, HDL-C and apolipoprotein A-1 levels).. Collectively, these data suggest that physical inactivity is linked to metabolic dysfunction to a greater extent than unhealthy dietary habits in postmenarchal T1D adolescent girls.

Topics: Adolescent; Adolescent Behavior; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 1; Diet Records; Energy Intake; Exercise; Fasting; Feeding Behavior; Female; Glycated Hemoglobin; Humans; Insulin Resistance; Leptin; Menarche; Overweight; Quality of Life; Risk Factors; Surveys and Questionnaires; Waist-Hip Ratio; Weight Gain

Youth with diabetes are at increased risk for depression. The objectives of this study were to provide preliminary evidence that this at-risk status for depression is associated with metabolic and inflammatory markers and to inform future, more stringent examinations of the directionality of these associations.. Data from SEARCH for Diabetes in Youth (SEARCH), an observational study of U.S. children diagnosed with diabetes at <20 years of age, were used for these analyses. SEARCH participants were drawn from four geographically defined populations in Ohio, Washington, South Carolina, and Colorado; health plan enrollees in Hawaii and California; and Indian Health Service beneficiaries from four Native American populations. Participants were 2,359 youth with diabetes from the 2001 prevalent and 2002-2004 incident SEARCH cohorts. Depression was measured with the Center for Epidemiologic Studies Depression scale. Eight metabolic and inflammatory markers were measured: adiponectin, leptin, C-reactive protein, serum amyloid A, apolipoprotein B (apoB), lipoprotein A, interleukin-6, and LDL.. Six of eight markers were significantly (P < 0.006) associated with depression in youth with diabetes in bivariate analyses. In general, higher levels of depression were associated with indicators of worse metabolic or inflammatory functioning. In regression models stratified by diabetes type and accounting for demographic and clinical characteristics, only higher levels of apoB remained associated with higher levels of depression in youth with type 1 diabetes.. These data suggest that depression reported by youth with diabetes is partially associated with metabolic abnormalities and systemic inflammation.

Topics: Adiponectin; Adolescent; Apolipoproteins B; C-Reactive Protein; Child; Depression; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Inflammation; Interleukin-6; Leptin; Male

The impact of leptin deficiency and its replacement in T1D remain unclear in the context of dyslipidemia and atherosclerosis. The current study has investigated the physiologic role of leptin in lipid metabolism and atherosclerosis in T1D.. The present study has employed Ins2(+/Akita):apoE(-/-) mouse model that spontaneously develops T1D, hypercholesterolemia, and atherosclerosis. At age 13 weeks, diabetic Ins2(+/Akita):apoE(-/-) mice showed leptin deficiency by ~92% compared with nondiabetic Ins2(+/+):apoE(-/-) mice. From 13 weeks to 25 weeks of age, diabetic Ins2(+/Akita):apoE(-/-) mice were treated with low-dose leptin (at 0.4 μg/g body weight daily). Leptin treatment diminished food intake by 22-27% in diabetic mice without affecting body weight and lean mass throughout the experiment. Importantly, leptin therapy substantially reduced plasma cholesterol concentrations by ~41%, especially in LDL fractions, in diabetic Ins2(+/Akita):apoE(-/-) mice. Moreover, leptin therapy decreased atherosclerotic lesion in diabetic mice by ~62% comparable to that seen in nondiabetic mice. In addition, leptin restored repressed expression of hepatic sortilin-1, a receptor for LDL clearance, and reversed altered expression of several hepatic genes involved in lipogenesis and cholesterol synthesis characteristic of diabetic mice. These findings were accompanied by normalization of reduced hepatic expression of Irs1 and Irs2 mRNA as well as their protein levels, and improved hepatic insulin-receptor signaling.. The present findings suggest that leptin administration may be useful to improve dyslipidemia and reduce atherosclerosis-related cardiovascular disease in human subjects with T1D.

Topics: Adaptor Proteins, Vesicular Transport; Animals; Apolipoproteins E; Atherosclerosis; Cholesterol; Diabetes Mellitus, Type 1; Disease Models, Animal; Disease Progression; Eating; Gene Expression Regulation; Hypercholesterolemia; Injections, Intraperitoneal; Insulin; Insulin Receptor Substrate Proteins; Leptin; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Recombinant Proteins; RNA, Messenger; Time Factors

Obesity and diabetes contribute to cardiovascular disease and alter cytokine profile. The cytokine, tumour necrosis factor alpha (TNFα), activates a protective signalling cascade during ischaemic postconditioning (IPostC). However, most successful clinical studies with IPostC have not included obese and/or diabetic patients. We aimed to investigate the influence of TNFα on the outcome of IPostC in obese or diabetic mice. TNF knockout or wildtype mice were fed for 11 weeks with a high carbohydrate diet (HCD) to induce modest obesity. Diabetes was induced in a separate group by administration of a single intraperitoneal injection of streptozotocin. Hearts were then isolated and subjected to ischaemia (35 min of global ischaemia) followed by 45 min of reperfusion. HCD increased body weight, plasma insulin and leptin levels while the glucose level was unchanged. In streptozotocin-treated mice, blood glucose, plasma leptin and insulin were altered. Control, obese or diabetic mice were protected with IPostC in wiltype animals. In TNF knockout mice, IPostC failed to protect control and diabetic hearts while a slight protection was observed in obese hearts. Our data confirm a bidirectional role for TNFα associated with the severity of concomitant comorbidities and suggest that diabetic and/or modestly obese patients may still benefit from IPostC.

Topics: Animals; Cardiomegaly; Diabetes Mellitus, Type 1; Dietary Carbohydrates; Disease Susceptibility; Heart; Hyperglycemia; Hyperinsulinism; In Vitro Techniques; Ischemic Postconditioning; Leptin; Mice; Mice, Knockout; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Obesity; Organ Size; Severity of Illness Index; Streptozocin; Tumor Necrosis Factor-alpha

The adipokine, leptin, regulates blood glucose and the insulin secretory function of beta cells, while also modulating immune cell function. We hypothesized that the dual effects of leptin may prevent or suppress the autoreactive destruction of beta cells in a virally induced rodent model of type 1 diabetes. Nearly 100% of weanling BBDR rats treated with the combination of an innate immune system activator, polyinosinic:polycytidylic acid (pIC), and Kilham rat virus (KRV) become diabetic within a predictable time frame. We utilized this model to test the efficacy of leptin in preventing diabetes onset, remitting new onset disease, and preventing autoimmune recurrence in diabetic rats transplanted with syngeneic islet grafts. High doses of leptin delivered via an adenovirus vector (AdLeptin) or alzet pump prevented diabetes in>90% of rats treated with pIC+KRV. The serum hyperleptinemia generated by this treatment was associated with decreased body weight, decreased non-fasting serum insulin levels, and lack of islet insulitis in leptin-treated rats. In new onset diabetics, hyperleptinemia prevented rapid weight loss and diabetic ketoacidosis, and temporarily restored euglycemia. Leptin treatment also prolonged the survival of syngeneic islets transplanted into diabetic BBDR rats. In diverse therapeutic settings, we found leptin treatment to have significant beneficial effects in modulating virally induced diabetes. These findings merit further evaluation of leptin as a potential adjunct therapeutic agent for treatment of human type 1 diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Humans; Islets of Langerhans Transplantation; Leptin; Parvoviridae Infections; Parvovirus; Poly I-C; Rats; Rats, Inbred BB; Treatment Outcome

Improved glycaemic control during pregnancy in mothers with type 1 diabetes (T1DM) and gestational diabetes (GDM) has resulted in a marked reduction of perinatal mortality and morbidity, but the prevalence of macrosomia is usually high.. We used non-invasive anthropometric methods to estimate the body composition and the thickness of the interventricular heart septum in 18 infants of mothers with well-controlled T1DM, 10 infants of mothers with GDM and 28 infants of healthy control mothers matched for gestational age and mode of delivery.. Skinfold measurements were obtained with a Harpenden calliper within 48 h after delivery. Echocardiography was also performed to measure the thickness of the interventricular septum. Cord blood was sampled for assays of C-peptide, leptin and IGF-I.. The rates of macrosomia (gestational age-adjusted birth weight >2 standard deviation score, SDS) were 56 and 30% in infants of mothers with T1DM and GDM, respectively, compared to 10% in control infants. The body fat content was 40% (0.2 kg) higher and the interventricular heart septum thickness was increased by 20% in both groups of infants of diabetic mothers. We found no associations between maternal levels of HbA1c during pregnancy and body composition or interventricular heart septum thickness. Cord levels of C-peptide and leptin were significantly higher in infants of T1DM mothers than in control infants. Cord leptin level was associated with birth weight SDS and percent body fat in infants of T1DM mothers. IGF-I was associated with percent body fat in infants of GDM mothers and control mothers. A multiple-regression analysis showed that 50% of the variation in body weight SDS could be determined, with IGF-I, leptin and C-peptide as independent variables.. Both fat mass and cardiac septal thickness are increased in newborn infants of women with T1DM and GDM in spite of efforts to achieve good glycaemic control during pregnancy.

Topics: Adipose Tissue; Adult; Blood Glucose; Body Composition; C-Peptide; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetes, Gestational; Female; Fetal Macrosomia; Glycated Hemoglobin; Heart Septum; Humans; Hypertrophy; Infant, Newborn; Insulin-Like Growth Factor I; Leptin; Pregnancy; Prevalence; Regression Analysis

The aim of the current study was to evaluate the long-term effects of leptin on glucose metabolism, diabetes complications, and life span in an insulin-dependent diabetes model, the Akita mouse.. We cross-mated Akita mice with leptin-expressing transgenic (LepTg) mice to produce Akita mice with physiological hyperleptinemia (LepTg:Akita). Metabolic parameters were monitored for 10 months. Pair-fed studies and glucose and insulin tolerance tests were performed. The pancreata and kidneys were analyzed histologically. The plasma levels and pancreatic contents of insulin and glucagon, the plasma levels of lipids and a marker of oxidative stress, and urinary albumin excretion were measured. Survival rates were calculated.. Akita mice began to exhibit severe hyperglycemia and hyperphagia as early as weaning. LepTg:Akita mice exhibited normoglycemia after an extended fast even at 10 months of age. The 6-h fasting blood glucose levels in LepTg:Akita mice remained about half the level of Akita mice throughout the study. Food intake in LepTg:Akita mice was suppressed to a level comparable to that in WT mice, but pair feeding did not affect blood glucose levels in Akita mice. LepTg:Akita mice maintained insulin hypersensitivity and displayed better glucose tolerance than did Akita mice throughout the follow-up. LepTg:Akita mice had normal levels of plasma glucagon, a marker of oxidative stress, and urinary albumin excretion rates. All of the LepTg:Akita mice survived for >12 months, the median mortality time of Akita mice.. These results indicate that leptin is therapeutically useful in the long-term treatment of insulin-deficient diabetes.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Eating; Glucagon; Hyperglycemia; Insulin; Leptin; Longevity; Mice; Mice, Transgenic; Oxidative Stress; Pancreas

Recent evidence from serum metabolomics indicates that specific metabolic disturbances precede β-cell autoimmunity in humans and can be used to identify those children who subsequently progress to type 1 diabetes. The mechanisms behind these disturbances are unknown. Here we show the specificity of the pre-autoimmune metabolic changes, as indicated by their conservation in a murine model of type 1 diabetes. We performed a study in non-obese prediabetic (NOD) mice which recapitulated the design of the human study and derived the metabolic states from longitudinal lipidomics data. We show that female NOD mice who later progress to autoimmune diabetes exhibit the same lipidomic pattern as prediabetic children. These metabolic changes are accompanied by enhanced glucose-stimulated insulin secretion, normoglycemia, upregulation of insulinotropic amino acids in islets, elevated plasma leptin and adiponectin, and diminished gut microbial diversity of the Clostridium leptum group. Together, the findings indicate that autoimmune diabetes is preceded by a state of increased metabolic demands on the islets resulting in elevated insulin secretion and suggest alternative metabolic related pathways as therapeutic targets to prevent diabetes.

Topics: Adiponectin; Animals; Cluster Analysis; Computational Biology; Diabetes Mellitus, Type 1; Disease Progression; Female; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Leptin; Liver; Lysophosphatidylcholines; Male; Metabolic Networks and Pathways; Metabolome; Mice; Mice, Inbred NOD; Models, Biological; Risk Factors

In nonobese diabetic mice with uncontrolled type 1 diabetes, leptin therapy alone or combined with low-dose insulin reverses the catabolic state through suppression of hyperglucagonemia. Additionally, it mimics the anabolic actions of insulin monotherapy and normalizes hemoglobin A1c with far less glucose variability. We show that leptin therapy, like insulin, normalizes the levels of a wide array of hepatic intermediary metabolites in multiple chemical classes, including acylcarnitines, organic acids (tricarboxylic acid cycle intermediates), amino acids, and acyl CoAs. In contrast to insulin monotherapy, however, leptin lowers both lipogenic and cholesterologenic transcription factors and enzymes and reduces plasma and tissue lipids. The results imply that leptin administration may have multiple short- and long-term advantages over insulin monotherapy for type 1 diabetes.

Topics: Adenylate Kinase; Animals; Blood Glucose; Diabetes Mellitus, Type 1; Drug Implants; Gene Expression Regulation; Glucagon; Insulin; Leptin; Liver; Metabolome; Mice; Mice, Inbred NOD; Phosphorylation; Recombinant Proteins; RNA, Messenger; Triglycerides

Topics: Animals; Diabetes Mellitus, Type 1; Glucose; Humans; Insulin; Leptin; Metabolome; Mice

Increased inflammation may contribute to type 1 diabetes (T1D) complications.. The objective of the study was to investigate the association of inflammation with obesity, hyperglycemia and dyslipidemia in youth with T1D.. This was a cross-sectional study of youth with and without T1D.. The study was conducted in Colorado and South Carolina.. SEARCH Case-Control participants with T1D [n = 553, mean age 15 yr (range 10-22), median duration 2.7 yr] and without diabetes [n = 215, mean age 15 yr (range 10-22)].. This was an observational study.. IL-6, high-sensitivity C-reactive protein (hsCRP), fibrinogen, and leptin were measured.. Inflammatory markers were evaluated by diabetes status, quartiles of glycated hemoglobin, and obesity using multiple linear regression analyses, adjusted for age, sex, study site, race/ethnicity, T1D duration, body mass index, and pubertal status. Compared with controls, youth with T1D had higher IL-6 and fibrinogen levels at all levels of glycemia and obesity, and hsCRP levels were significantly higher in youth with T1D in the top three quartiles of glycated hemoglobin (> or = 7.2%) and among normal-weight subjects. Leptin was lower in youth with poor glycemic control. Higher hsCRP and fibrinogen were correlated with higher total and LDL cholesterol, and apolipoprotein B in youth with T1D, whereas higher fibrinogen was correlated with higher LDL and apolipoprotein B in controls.. T1D is characterized by excess inflammation, independent of adiposity and glycemic control. Even T1D youth in good glycemic control had higher levels of IL-6 and fibrinogen than controls. Elevated inflammatory markers were associated with an atherogenic lipid profile, which may contribute to accelerated atherosclerosis in youth with T1D.

Topics: Adolescent; Anthropometry; Biomarkers; Body Mass Index; C-Reactive Protein; Case-Control Studies; Child; Cross-Sectional Studies; Diabetes Complications; Diabetes Mellitus, Type 1; Dyslipidemias; Ethnicity; Female; Fibrinogen; Glycated Hemoglobin; Humans; Hyperglycemia; Inflammation; Interleukin-6; Leptin; Male; Obesity; Puberty; Young Adult

Topics: Animals; Diabetes Mellitus, Type 1; Disease Models, Animal; Humans; Leptin; Mice

The goals of this study were to examine the influence of maternal type 1 diabetes during pregnancy on offspring adiposity and glucose tolerance at age 7 years and to assess whether metabolic factors at birth (neonatal leptin and insulin) predict adverse outcomes.. We examined 100 offspring of mothers with type 1 diabetes (OT1DM) and 45 offspring of control mothers. Mothers had previously been recruited during pregnancy, and, where possible, birth weight, umbilical cord insulin, and leptin were measured. Children were classed as overweight and obese using age-specific reference ranges.. OT1DM had similar height (control, 1.25 +/- 0. 06 m; OT1DM, 1.24 +/- 0.06 m; P = 0.81) but were heavier (control, 25.5 +/- 3.8 kg; OT1DM, 27.1 +/- 5.7 kg; P = 0.048) and had an increased BMI (control, 16.4 kg/m(2); OT1DM, 17.4 +/- 2.6 kg/m(2), P = 0.005). Waist circumference (control, 56.0 +/- 3.7 cm; OT1DM, 58 +/- 6.8 cm; P = 0.02) and sum of skinfolds were increased (control, 37.5 +/- 17.0 mm [n = 42]; OT1DM, 46.1 +/- 24.2 mm [n = 91]; P = 0.02), and there was a marked increase in the prevalence of overweight and obese children (OT1DM, 22% overweight and 12% obese; control, 0% overweight and 7% obese; chi(2) P = 0.001). Glucose tolerance was not different compared with that in control subjects. BMI at age 7 years correlated with cord leptin (OT1DM, r = 0.25; n = 61, P = 0.047), weakly with adjusted birth weight (r = 0.19; P = 0.06) and hematocrit (r = 0.25; n = 50, P = 0.07), but not cord insulin (OT1DM, r = -0.08; P = 0.54).. OT1DM are at increased risk of overweight and obesity in childhood. This risk appears to relate, in part, to fetal leptin and hematocrit but not insulin.

Topics: Adipose Tissue; Birth Weight; Child; Diabetes Mellitus, Type 1; Female; Fetal Blood; Fetus; Follow-Up Studies; Glucose Intolerance; Hematocrit; Humans; Infant, Newborn; Insulin; Leptin; Mothers; Obesity; Predictive Value of Tests; Pregnancy; Prenatal Exposure Delayed Effects; Prevalence; Risk Factors

Topics: Adipose Tissue; Animals; Child; Diabetes Mellitus, Type 1; Female; Humans; Insulin; Leptin; Liver; Mice; Muscles; Quality of Life

Hyperinsulinemic euglycemic clamp is the gold standard to evaluate the insulin sensitivity, but it is too complicated and expensive to use in clinic. We tried to find an alternative indicator to reflect insulin sensitivity. To evaluate the association between the four adipokines, adiponectin, leptin, resistin and tumor necrosis factor-alpha (TNF-alpha) with insulin sensitivity, we used a hyperinsulinemic euglycemic clamp to test insulin sensitivity in Chinese patients with obesity and type 1 or type 2 diabetes mellitus versus controls.. In this parallel control study, we tested insulin sensitivity using a hyperinsulinemic euglycemic clamp in different groups, then examined levels of adiponectin, leptin, resistin and TNF-alpha in serum, and the relationship between the different adipokines and glucose disposal rate (M value), as well as insulin sensitivity index (M value/insulin, M/I), which are the "gold standard" indices of insulin sensitivity.. There were significant differences in mean leptin values in the four adipokines from the four different groups (P < 0.001; comparison of the variation between different groups was analyzed by variance analysis). Compared to controls (using multiple comparison two-way Dunnett t test), only the leptin level showed significant differences in the four adipokines from the four different groups at the same time (P < 0.001). The association analysis between the different adipokines and M or M/I values also showed that only leptin negatively correlated with M (r = -0.64, P < 0.001) or M/I values (r = -0.56, P < 0.001); there was no relationship between the other three adipokines and M or M/I values.. Only leptin was associated with M or M/I values. Therefore, leptin might be one of the predictive factors of the degree of insulin resistance and risk of the accompanying disease.

Topics: Adipokines; Adiponectin; Asian People; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucose Clamp Technique; Humans; Insulin Resistance; Leptin; Obesity; Resistin; Tumor Necrosis Factor-alpha

Leptin monotherapy reverses the deadly consequences and improves several of the metabolic imbalances caused by insulin-deficient type 1 diabetes (T1D) in rodents. However, the mechanism(s) underlying these effects is totally unknown. Here, we report that intracerebroventricular (icv) infusion of leptin reverses lethality and greatly improves hyperglycemia, hyperglucagonemia, hyperketonemia, and polyuria caused by insulin deficiency in mice. Notably, icv leptin administration leads to increased body weight while suppressing food intake, thus correcting the catabolic consequences of T1D. Also, icv leptin delivery improves expression of the metabolically relevant hypothalamic neuropeptides proopiomelanocortin, neuropeptide Y, and agouti-related peptide in T1D mice. Furthermore, this treatment normalizes phosphoenolpyruvate carboxykinase 1 contents without affecting glycogen levels in the liver. Pancreatic β-cell regeneration does not underlie these beneficial effects of leptin, because circulating insulin levels were undetectable at basal levels and following a glucose overload. Also, pancreatic preproinsulin mRNA was completely absent in these icv leptin-treated T1D mice. Furthermore, the antidiabetic effects of icv leptin administration rapidly vanished (i.e., within 48 h) after leptin treatment was interrupted. Collectively, these results unveil a key role for the brain in mediating the antidiabetic actions of leptin in the context of T1D.

Topics: Animals; Central Nervous System; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Humans; Injections, Intraventricular; Insulin; Insulin-Secreting Cells; Leptin; Male; Mice; Muscle, Skeletal; Pancreas; Placebos; Protein Precursors; Receptors, Leptin

Leptin, as many other hormones and metabolic factors, may play a role in fetal development in pregnancy complicated by type 1 diabetes. Different genetic variants in leptin gene and leptin gene receptor may have influence on leptin synthesis in the course of pregnancy and metabolic state of the mother.. To assess the possible influence of metabolic factors on fetal weight in type 1 diabetic subjects with homozygotic variants in leptin gene (-2548 G/A) and leptin gene receptor (668 G/A).. 30 diabetic and homozygotic subjects (out of 100 diabetic subjects) were qualified to the study Genotyping was performed by PCR-RFLR The following factors were assessed: glycemia, leptin concentration, glycated hemoglobin, lipid profile (total cholesterol, LDL, HDL, triglycerides), maternal body weight. Multiple regression models were developed and ROC curves were used in the analysis.. Mean fetal weight in the analyzed group was 3600 g. The following parameters were found to have influence on fetal weight: I trimester leptin (R2-0.80741288, p < 0.05), I trimester glycemia (R2-0.80741288, p < 0.05), III trimester glycemia (R2-0.80741288, p < 0.05), I trimester HbA1C (R2-0.80741288, p < 0.05), III trimester LDL (R2 = 0.63192254, p < 0.05). Moreover the influence of LDL and maternal BMI (R2-0.81869348, p < 0.05) was found. ROC curve analysis revealed the influence of I trimester leptin--AUC 0.62; sensitivity 0.75; specificity 0.5; cut-off 28.127 ng/ml, III trimester HbA1C AUC 0.66; sensitivity 0.23; specificity 0.91; cut-off 7.9%, III trimester mothers weight AUC 0.63; sensitivity 0.25; specificity 0.93; cut-off 98 kg.. Apart from well-known metabolic factors influencing fetal weight, I trimester leptin concentration was found to have an impact on fetal growth.

Topics: Adult; Body Mass Index; Body Weight; Case-Control Studies; Diabetes Mellitus, Type 1; Female; Fetal Weight; Genotype; Humans; Infant, Newborn; Leptin; Obesity; Polymerase Chain Reaction; Polymorphism, Genetic; Pregnancy; Pregnancy in Diabetics; Receptors, Leptin

Leptin and soluble form of leptin receptor play a great role in both carbohydrate and fat metabolism which is very important in diabetes mellitus type (DMT1) patients.. To asses leptin and soluble leptin receptor levels in children with DMT1 and to analyze correlation with anthropometric parameters, metabolic control and the influence of various kinds of insulin therapy.. 67 patients, aged from 3.71 to 14.81 years, mean ± SD: 10.33 ± 2.21) and 15 age-matched healthy children were included into the study. All children were prepubertal (T <2), suffering for DMT1 for more than two years, without any coexisting diseases. All patients were divided into subgroups according to the kind of therapy. There were no statistically significant differentials between groups as to the metabolic control, age, weight, height and BMI.. Leptin levels in the study group range from 1.27 to 59.90 ng/ml (mean ± SD: 11.34 ± 9.42 ng/ml) and were higher than in control group: from 1.46 to 26, ng/ml (mean ± SD: 8.23 ± 7.62 ng/ml) (p >0.05). The highest leptin levels were observed in multiple insulin injection group, lower in pump group and the lowest conventional insulin therapy group. Soluble leptin receptor levels in study group range from 30.50 to 101.00 ng/ml (mean ± SD: 48.65 ± 13.26 ng/ ml) and were significantly higher than in control group: 27.50 to 61.00 ng/ml (mean ± SD: 39.37 ± 9.23 ng/ml) (p <0.01). The highest soluble leptin receptor levels were observed in the multiple insulin injection group, lower in pump group and the lowest conventional insulin therapy group.. leptin levels are higher in DMT1 children, correlate with anthropometrics parameters, age, age at the beginning of diabetes and depend on the kind of insulin therapy. Soluble leptin receptor levels are significantly higher in children with DMT1, correlate with anthropometrics parameters, metabolic control, age, age at the beginning of diabetes, duration of diabetes and depend on the kind of insulin therapy.

Topics: Adolescent; Child; Child, Preschool; Diabetes Mellitus, Type 1; Female; Humans; Insulin; Leptin; Male; Receptors, Leptin

Leptin is a hormone secreted by adipocytes that is implicated in the regulation of bone density. Serum leptin levels are decreased in rodent models of type 1 (T1-) diabetes and in diabetic patients. Whether leptin mediates diabetic bone changes is unclear. Therefore, we treated control and T1-diabetic mice with chronic (28 days) subcutaneous infusion of leptin or saline to elucidate the therapeutic potential of leptin for diabetic osteoporosis. Leptin prevented the increase of marrow adipocytes and the increased aP2 expression that we observed in vehicle-treated diabetic mice. However, leptin did not prevent T1-diabetic decreases in trabecular bone volume fraction or bone mineral density in tibia or vertebrae. Consistent with this finding, markers of bone formation (osteocalcin RNA and serum levels) in diabetic mice were not restored to normal levels with leptin treatment. Interestingly, markers of bone resorption (TRAP5 RNA and serum levels) were decreased in diabetic mice by leptin treatment. In summary, we have demonstrated a link between low leptin levels in T1-diabetes and marrow adiposity. However, leptin treatment alone was not successful in preventing bone loss.

Topics: Adiposity; Animals; Blood Glucose; Body Weight; Bone Marrow; Bone Resorption; Diabetes Mellitus, Type 1; Feeding Behavior; Hyperphagia; Insulin; Leptin; Mice; Mice, Inbred BALB C

To investigate the possibility of depending on adiponectin and leptin as early predictors of microvascular complications in type 1 diabetic subjects.. We studied 63 type 1 diabetic subjects from the National Institute of Diabetes (30 normoalbuminuric and 33 microalbuminuric). Clinical, demographic characteristics and kidney function tests were monitored. Plasma levels of adiponectin, leptin, interlukein-6 (IL-6), and the high sensitive C-reactive protein (CRP) were measured in these subjects.. Microalbuminuric subjects showed a significant elevation in adiponectin levels and a significant decrease in leptin levels as compared to normoalbuminuric subjects. Adiponectin showed a significant positive correlation with microalbuminuria concentrations while leptin showed a significant negative correlation with both fasting blood glucose and glycated hemoglobin A(1c).. The results of this study introduced the possibility of depending on adiponectin and leptin as early, reliable, and sensitive predictors for the microvascular complications monitored by microalbuminuria concentration and glycemic control indices.

Topics: Adiponectin; Adolescent; Albuminuria; Biomarkers; Blood Glucose; C-Reactive Protein; Child; Child, Preschool; Diabetes Mellitus, Type 1; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Fasting; Female; Glycated Hemoglobin; Humans; Interleukin-6; Kidney Function Tests; Leptin; Male; Predictive Value of Tests; Regression Analysis; Vascular Diseases

We tested the association of adiponectin/leptin ratio with diabetes type after adjusting for multiple factors in 1156 youths with newly diagnosed diabetes in the SEARCH study. Although adiponectin/leptin ratio is associated with diabetes type in youth, it is due to differences in adiponectin, but not leptin levels.

Topics: Adiponectin; Adolescent; Body Mass Index; Child; Child, Preschool; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Leptin; Male; Population Surveillance; United States; Waist Circumference; Young Adult

Alteration of placental structure may influence fetal overgrowth and complications of maternal diabetes. We examined the placenta in a cohort of offspring of mothers with type 1 diabetes (OT1DM) to assess structural changes and determine whether these were related to maternal A1C, fetal hematocrit, fetal hormonal, or metabolic axes.. Placental samples were analyzed using stereological techniques to quantify volumes and surface areas of key placental components in 88 OT1DM and 39 control subjects, and results related to maternal A1C and umbilical cord analytes (insulin, leptin, adiponectin, IGF-I, hematocrit, lipids, C-reactive protein, and interleukin-6).. Intervillous space volume was increased in OT1DM (OT1DM 250 + or - 81 cm(3) vs. control 217 + or - 65 cm(3); P = 0.02) with anisomorphic growth of villi (P = 0.025). The placentas showed a trend to increased weight (OT1DM 690 + or - 19 g; control 641 + or - 22 g; P = 0.08), but villous, nonparenchymal, trophoblast, and capillary volumes did not differ. Villous surface area, capillary surface area, membrane thickness, and calculated morphometric diffusing capacity were also similar in type 1 diabetic and control subjects. A1C at 26-34 weeks associated with birth weight (r = 0.27, P = 0.03), placental weight (r = 0.41, P = 0.0009), and intervillous space volume (r = 0.38, P = 0.0024). In multivariate analysis of cord parameters in OT1DM, fetal IGF-I emerged as a significant correlate of most components (intervillous space, villous, trophoblast, and capillary volumes, all P < 0.01). By contrast, fetal insulin was only independently associated with capillary surface area (positive, r(2) = 6.7%; P = 0.02).. There are minimal placental structural differences between OT1DM and control subjects. Fetal IGF-I but not fetal insulin emerges as a key correlate of placental substructural volumes, thereby facilitating feedback to the placenta regarding fetal metabolic demand.

Topics: Adiponectin; Diabetes Mellitus, Type 1; Female; Fetal Blood; Fetus; Glucocorticoids; Glycated Hemoglobin; Hematocrit; Humans; Infant, Newborn; Insulin; Insulin-Like Growth Factor I; Leptin; Maternal-Fetal Exchange; Placenta; Pregnancy; Pregnancy Complications; Proinsulin

Maternal diabetes is associated with polycythaemia and thrombocytopaenia in the offspring; however, the relationship with fetal hormones is unknown. We assessed the association of maternal glycaemic control, birthweight and fetal hormones with haematological indices in pregnancies complicated by maternal diabetes.. Prospective study using cord blood samples from 89 offspring of mothers with Type 1 diabetes (OT1DM) and 34 control offspring. Full blood count, insulin, leptin, adiponectin, cortisol, insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3, intercellular adhesion molecule 1 and C-reactive protein were measured in the umbilical vein at birth.. Haematocrit was higher in OT1DM (OT1DM 0.55 +/- 0.17%, control offspring 0.51 +/- 0.06%; P = 0.02). The difference in platelets count was not statistically significant [OT1DM 214 x 10(9)/l (173-259); control offspring 253 x 10(9)/l (180-310), P = 0.06]. Maternal glycated haemoglobin (HbA(1c)) showed a moderate positive correlation with fetal haematocrit (r = 0.30, P = 0.02). Cord platelet counts were negatively associated with birthweight in OT1DM (r = -0.27, P = 0.01). In multivariate models, cord insulin was not associated with haematocrit, but cord leptin was negatively associated with platelets in control offspring (P < 0.001) and OT1DM (P = 0.046), with additional contributions from male sex (P = 0.08) in OT1DM, and IGF-1 (P = 0.04) and insulin (P = 0.04) in control offspring.. Fetal haematocrit is increased in response to diabetes in pregnancy and is related to maternal glycaemic control. Fetal hyperinsulinism, hyperleptinaemia or macrosomia, although readily demonstrable in this cohort, do not emerge as determinants of raised fetal haematocrit in OT1DM. Both increased birthweight and fetal leptin are negatively associated with platelet count.

Topics: Biomarkers; Diabetes Mellitus, Type 1; Female; Fetal Blood; Fetal Macrosomia; Humans; Infant, Newborn; Insulin-Like Growth Factor I; Leptin; Male; Polycythemia; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy in Diabetics; Prospective Studies

Both type 1 and 2 diabetes are associated with differential regulation of leptin, adiponectin and ASP. Our aim was to examine whether or not acute hyperinsulinaemia and/or hyperglycaemia per se have differential regulation of these hormones in healthy subjects.. We examined changes in leptin, adiponectin and ASP concentrations and subcutaneous white adipose tissue mRNA expression with 3-hour hyperinsulinaemic (HI, n=10), hyperglycaemic (HG, n=7) and hyperinsulinaemic-hyperglycaemic (HGHI, n=8) clamps in healthy lean young men. As somatostatin was used for the HG and HGHI clamps, a control somatostatin clamp was carried out (n=4). Changes in the expression of HKII and p85alpha Pi3K were examined as positive controls for the induction of gene expression by the insulin pathway.. HI, HG and HGHI clamps increased expression of HKII and p85alpha Pi3K while somatostatin did not. The HI clamp decreased serum adiponectin (-15%, P<0.001) and increased serum leptin (+11%, P=0.031), while the HG clamp reduced serum leptin (-20%, P=0.003). The HGHI clamp increased serum ASP (+21%, P=0.047) and expression of C3 (+26%, P=0.018) and leptin (+50%, P=0.024). Interestingly, the control somatostatin clamp suppressed both serum leptin (-17%, P=0.043) and adiponectin (-7%, P=0.020).. HG and/or HI per se regulated the concentrations and expression of leptin, adiponectin and ASP in healthy lean young men, suggesting a contribution to dysregulation of these hormones in diabetes.

Topics: Adiponectin; Adipose Tissue, White; Adult; Blood Glucose; Complement C3; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucose Clamp Technique; Humans; Hyperglycemia; Hyperinsulinism; Insulin; Leptin; Male; Somatostatin

Studies investigating the effect of leptin on bone mass were inconsistent and some related it to the effect of insulin. We intend in this cross-sectional study to investigate the effect of leptin on bone mass in type 1 diabetic patients. We recruited 42 patients with type 1 diabetes for which we determined weight, height, HbA1c, microalbuminuria, serum leptin, bone mineral content (BMC) and density (BMD), and body composition. The patients had an average age of 20.1 +/- 0.6 years, an average body mass index (BMI) of 23.6 +/- 0.5 kg/cm(2) and an average duration of diabetes of 9.1 +/- 1.0 years. The Z-score was not correlated with HbA1c or duration of the disease, and the average Z-score was not different in patients with microalbuminuria as compared to patients with no reported microalbuminuria. On the other hand, Z-score and BMC correlated negatively with leptin (r = -0.31; p = 0.04 and -0.60, p < 0.01, respectively). These correlations persisted after adjustment for fat mass. We conclude that not metabolic control of diabetes, but serum leptin has a negative effect on bone density in young patients with type 1 diabetes. This negative effect of leptin on bone density maybe, in part, due to deficiency of endogenous insulin secretion in these patients.

Topics: Adipose Tissue; Age of Onset; Body Mass Index; Bone Density; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Insulin; Insulin Secretion; Leptin; Male; Young Adult

Leptin, as well as many other hormones, may play an important role in the pathogenesis of obesity. Several genetic variants of both leptin and its receptor genes may influence human body weight. To investigate the role of leptin gene polymorphism promotion region (-2548G/A) and leptin gene receptor polymorphism (668 A/G) in regulation of body weight in the group of women with type 1 diabetes (PGDM-1).. 78 PGDM-1 first trimester pregnant women were qualified for the study group (SG). They were divided into normal and overweight subgroups, based on pre-pregnancy BMI. Control group (CG) consisted of first trimester healthy pregnant women with normal pre-pregnancy body weight Genetic variants of leptin gene and its receptor were analyzed with the help of PCR-RFLP assays. In the SG, the following metabolic parameters were estimated: MBG, HbA1c, insulin dose, LDL, HDL, T-CHOL, triglycerids, creatinine, creatinine clearance and blood pressure.. A tendency for the majority of homozygous A and G variants in LEP -2548 G/A and LEPR 668 A/G was found in overweight and obese patients, in comparison to normal-weight subjects. No specific differences in selected first trimester metabolic parameters were found in relation to patients' genotypes in the diabetic group.

Topics: Adult; Body Mass Index; Body Weight; Case-Control Studies; Diabetes Mellitus, Type 1; DNA Mutational Analysis; Female; Humans; Leptin; Obesity; Polymerase Chain Reaction; Polymorphism, Genetic; Pregnancy; Pregnancy in Diabetics; Receptors, Leptin

There have been several genetic causes of obesity discussed by past authors, among others leptin, that have provided information regarding signaling pathways in energy expenditure in humans. Genetic variants of the leptin gene and its receptor may influence body weight.. To investigate the role of the leptin gene's polymorphism promotion region (2548 G/A) and the leptin gene receptor polymorphism (668 A/G) and its associations with body weight in pregnant women with type 1 diabetes (PGDM-1).. 78 PGDM-1 were qualified to the study group (SG) which was divided into normal and over-weight individuals according to BMI criteria. The control group (CG) consisted of first trimester healthy pregnant women with normal body weight. Genetic variants of the leptin gene and its receptor were analyzed using PCR-RFLP assays. Within the SG, the following metabolic parameters were estimated: MBG, HbA1C, insulin dose, LDL, HDL, T-CHOL, creatinine, creatinine clearance and blood pressure.. There was a trend found among the majority of homozygous A and G variants in LEP -2548 G/A and LEPR 668 A/G in over-weight and obese individuals in comparison to normal-weight subjects (CG). There were no specific differences found in selected first trimester metabolic parameters in relation to patients' genotypes.

Topics: Body Mass Index; Body Weight; Diabetes Mellitus, Type 1; Female; Genotype; Humans; Leptin; Obesity; Polymerase Chain Reaction; Polymorphism, Genetic; Pregnancy; Pregnancy in Diabetics; Promoter Regions, Genetic; Receptors, Leptin

Topics: Adiponectin; Adult; Biomarkers; Case-Control Studies; Cytokines; Diabetes Mellitus, Type 1; Female; GPI-Linked Proteins; Humans; Lectins; Leptin

Maternal leptin affects placental growth hormone (GH), whereas ghrelin, a natural ligand of the growth-hormone-secretagogue receptor, modulates GH action. Both hormones may affect fetal growth, and dysregulation in diabetes may lead to fetal growth disturbances. The aim was to investigate changes in maternal ghrelin during pregnancy with diabetes and to establish reference leptin levels.. Twelve healthy non-diabetic (ND) and 12 pregnant women with Type 1 diabetes (T1DM) were recruited. Age and body mass index (BMI) [ND: age 29.9 +/- 4.7 years (mean +/- sd), BMI 25.2 +/- 3.7 kg/m2; T1DM: age 31 +/- 5.5 years, BMI 27 +/- 3.1 kg/m2] were similar in the groups. HbA1c in T1DM was 6.2 +/- 1.1% at 20 weeks, 6.3 +/- 1.1% at 30 weeks' gestation and 7.8 +/- 2.1% postpartum. Fasting plasma ghrelin, total leptin, free leptin (FL) and soluble leptin receptor (sOB-R) levels were measured at 20 and 30 weeks' gestation and postpartum and determined by radioimmunoassay.. All pregnancies resulted in full-term singleton births with no differences in birth weight between groups [T1DM: 3.4 +/- 0.56 kg (mean +/- SE); ND: 3.6 +/- 0.3 kg, P = NS]. Ghrelin levels were lower in T1DM when corrected for age and mothers' weight (T1DM: 458 +/- 36 pg/ml and 432.9 +/- 26.6 pg/ml; ND: 562 +/- 52 pg/ml and 515.8 +/- 63 pg/ml at 20 and 30 weeks, respectively, P < 0.05). T1DM mothers had higher levels of sOB-R and FL levels declined at 30 weeks' gestation in T1DM (P = 0.04) but not in ND.. In a population of pregnant women with expected changes in leptin levels as previously reported, ghrelin levels were lower in T1DM pregnancies at 20 and 30 weeks. This may have implications for fetal development and requires further study in diabetes, particularly in pregnancies that result in macrosomia.

Topics: Adult; Birth Weight; Diabetes Mellitus, Type 1; Female; Fetal Development; Ghrelin; Growth Hormone; Humans; Leptin; Pregnancy; Pregnancy in Diabetics; Pregnancy Outcome; Reference Values; Young Adult

Acquired generalized lipodystrophy (AGL) is marked by severe insulin resistance and hypertriglyceridemia. Rarely, AGL and type 1 diabetes (T1D) coexist.. Our objective was to describe the response to leptin therapy in patients with coexisting AGL and T1D and to document the autoimmune diseases associated with AGL.. We conducted an open-label prospective study at the Clinical Research Center of the National Institutes of Health.. Participants included 50 patients with generalized or partial lipodystrophy (acquired or congenital); two patients had both AGL and T1D.. Patients were treated with 12 months of recombinant human leptin administration to achieve high-normal serum concentrations.. Two patients had both AGL and T1D. The first was diagnosed with T1D at age 8 yr. Beginning at age 11 yr, he developed generalized lipodystrophy, elevated transaminases, and poor glycemic control [hemoglobin A 1c (HbA 1c) 10.7%] despite markedly increased insulin requirements (3.3-5 U/kg.d). Further evaluation revealed hypoleptinemia and hypertriglyceridemia. At age 15 yr, leptin therapy was initiated, and after 1 yr, his insulin requirements fell to 1 U/kg.d, his glycemic control improved (HbA 1c 8.4%), and both his triglycerides and transaminases normalized. The second patient developed concurrent AGL and T1D at age 6 yr. Despite insulin doses of up to 32 U/kg.d, she developed poor glycemic control (HbA 1c 10.6%), hypertriglyceridemia (2984 mg/dl), elevated transaminases, and nonalcoholic steatohepatitis. At age 13 yr, leptin therapy was started, and after 1 yr, her glycemic control improved (HbA 1c 7.3%) and her insulin requirements decreased (17 U/kg.d). Her triglycerides remained elevated but were improved (441 mg/dl).. Long-term recombinant leptin therapy is effective in treating the insulin resistance of patients with the unusual combination of T1D and AGL.

Topics: Adolescent; Alanine Transaminase; Aspartate Aminotransferases; Blood Glucose; Diabetes Mellitus, Type 1; Fatal Outcome; Female; Glycated Hemoglobin; Humans; Hypertriglyceridemia; Insulin Resistance; Leptin; Lipodystrophy; Male; Prospective Studies; Recombinant Proteins; Triglycerides

To assess the association of fetal hormones with placental growth and fetal weight-to-placental weight ratio index (FPI) in pregnancies complicated by maternal diabetes.. We conducted a prospective study using umbilical venous blood samples taken at birth from 122 offspring of mothers with type 1 diabetes (OT1D) and 46 control subjects.. Placental weight (P = 0.009) and gestation-adjusted birth weight (P < 0.001) were increased in OT1D, but FPI was unaltered (P = 0.33). Placental weight correlated with birth weight (P < 0.001) and cord leptin (P < 0.001) in control subjects and OT1D, with further relationships with cord insulin, IGF-1, IGF-binding protein-3 (IGFBP-3), and triceps and subscapular thickness in OT1D. FPI was associated with adiponectin in both groups, even after adjustment for confounders.. Placental and fetal growth show a parallel increase in mothers with type 1 diabetes. The possible role of adiponectin in matching of fetal and placental growth merits further study.

Topics: Adiponectin; Birth Weight; Diabetes Mellitus, Type 1; Female; Fetal Blood; Fetal Development; Fetal Weight; Humans; Infant, Newborn; Insulin; Insulin-Like Growth Factor I; Leptin; Organ Size; Placenta; Pregnancy; Pregnancy Complications

One of the most common symptoms of diabetes is extreme hunger, but the brain mechanism underlying this hyperphagia is unknown. The endocannabinoid system has emerged as one of the main food intake regulators in the brain. However, the effects of type 1 diabetes on the endocannabinoid system are not completely known. Thus, the aim of the present work is to establish the possible alterations induced by type 1 diabetes on the brain endocannabinoid system in rats. Western blot and immunocytochemistry were used to measure CB1 and phosphorylated CB1 receptor expression in several prosencephalic regions in streptozotocin-induced type 1 diabetic rats. Serum leptin levels were measured by ELISA. CB1 receptor expression was increased in striatum and hypothalamus of diabetic animals, with no changes in other brain areas studied. CB1 receptor phosphorylation was also increased in the same brain areas. Type 1 diabetes induced significant weight loss, and serum leptin levels were severely decreased. These results reinforce the possible role of the CB1 receptor as a pharmacological target for the clinical management of appetite in diabetic patients.

Topics: Animals; Appetite; Blood Glucose; Body Weight; Brain; Diabetes Mellitus, Type 1; Eating; Leptin; Male; Phosphorylation; Protein Kinases; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1

Topics: Adult; Blood Glucose; Blood Pressure; Body Mass Index; Cholesterol; Diabetes Mellitus, Type 1; Fatty Acids, Nonesterified; Female; Glycated Hemoglobin; Humans; Insulin Resistance; Leptin; Male; Prospective Studies

Offspring of mothers with type 1 diabetes (OT1DM) demonstrate increased fat deposition, hyperinsulinemia, and hyperleptinemia in utero. We examined the influence of maternal diabetes on cord lipids at birth and relationship to body composition, cord insulin, leptin, and other hormonal measures.. We performed an observational study measuring fetal, HDL, and LDL cholesterol; triglycerides; and nonesterified fatty acids (NEFAs) in a total of 139 OT1DM and 48 control subjects at birth and assessed cross-sectional relationships with birth weight, fetal insulin, leptin, adiponectin, and IGF-1.. Concentrations of total cholesterol (male OT1DM [mean +/- SD] 1.49 +/- 0.45 mmol/l and male control subjects 1.74 +/- 0.33 mmol/l; P < 0.001), HDL cholesterol (0.53 +/- 0.21 and 0.74 +/- 0.19 mmol/l, respectively; P < 0.001), and NEFA (median 0.17 [interquartile range 2.30-2.95] and 0.21 [0.18-0.36], respectively; P < 0.001) were significantly lower in male OT1DM, with no significant differences in female subjects. Differences in male subjects were independent of mode of delivery. Cord lipids were unrelated to birth weight in OT1DM and did not show consistent relationships with fetal insulin. Unexpectedly, IGF-1 was a strong correlate of HDL cholesterol in control subjects (r = 0.40, P = 0.002) and OT1DM (r = 0.32, P < 0.001) but a negative correlate of triglycerides in control subjects (r = -0.48, P < 0.001) and OT1DM (r = -0.21, P = 0.004), with these relationships present in both sexes. In OT1DM, leptin was also independently correlated (negatively, P < 0.001) with HDL cholesterol in male and female subjects.. Maternal diabetes is associated with significant alterations in lipid levels in male fetuses. IGF-1, leptin, and male sex rather than insulin may be the major determinants of HDL cholesterol and triglycerides in utero.

Topics: Adult; Birth Weight; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 1; Female; Fetal Blood; Gestational Age; Humans; Infant, Newborn; Insulin; Insulin-Like Growth Factor I; Leptin; Lipoproteins; Male; Parity; Pregnancy; Pregnancy Complications; Reference Values

was to estimate the relationship between serum leptin levels and insulin sensitivity and components of metabolic syndrome in type 1 diabetic children and adolescents.. 158 patients with type 1 diabetes mellitus (70 girls and 88 boys) aged from 8.2 to 18.4 years (mean: 14.1+/-3.1 years) were included into the study. The diabetes duration ranged from 1.6 to 14.7 years (mean: 3.8+/-2.5 years). The height, weight, waist circumference (WC), skin folds and blood pressure were measured. Body mass index (BMI-SDS), body fat (BF) according to Slaughter formula, and daily dose of insulin were calculated. HbA1c (HPLC method) and serum lipids (enzymatic method) concentrations were examined. Serum leptin concentration was measured by ELISA method. Euglycemic-hyperinsulinemic clamp was performed to estimate insulin resistance. Glucose disposal rate (M index) determined during the last 30 min of the test was calculated as a surrogate of insulin resistance.. Serum leptin levels ranged from 1.47 to 57.39 ng/ml (median [quartiles]: 4.60 [3.18-10.2]). M index was 2.10-15.19 mg/kg/min. (median [quartiles]: 7.04 [5.57-8.69]. Leptin was positively correlated with BMI-SDS, WC, skin folds and BF. During puberty leptin levels increased in girls, but in boys the highest levels were observed at Tanner stage 3. Leptin concentrations, normalized for BMI-SDS or BF, were significantly higher in females than in males at Tanner stages 4 (pc=0.047) and 5 (pc<0.001). Leptin was negatively correlated with M index (r=-0.26; p=0.001 adjusted for sex and puberty), but after adjusting for BF or BMI-SDS there were no significant correlations. Leptin was not significantly associated with HDL-cholesterol, SBP and DBP. Using the multivariate linear regression models, we found that plasma leptin remained significantly associated with TG.. It is likely that the observed relationship between leptin concentration and insulin resistance in young patients with type 1 diabetes is due to body fat composition rather than represents an independent association in this group.

Topics: Adolescent; Body Mass Index; Child; Diabetes Mellitus, Type 1; Enzyme-Linked Immunosorbent Assay; Female; Humans; Insulin Resistance; Leptin; Male; Sex Factors

Type 1 diabetes (T1DM) is increasing in incidence worldwide, particularly in young children. Studies have suggested that weight gain in early childhood may play a role in determining disease risk, with increased risk in children who have gained more weight. We hypothesized that leptin may be involved by promoting a Th1-type immune response in individuals at risk for the development of T1DM. Insulin, GAD65, and IA-2 autoantibodies and leptin levels were measured in relatives of T1DM patients and in control subjects. After adjusting for HLA risk and age, autoantibody-positive relatives were compared with sex- and BMI-matched autoantibody-negative control subjects. BMI-matched individuals had similar leptin levels, and the leptin levels increased with increasing BMI Z-score, as expected. However, we did not demonstrate higher leptin levels in autoantibody-positive relatives, compared with autoantibody-negative control subjects. Thus, elevations in leptin levels do not appear to be a major determinant of whether an individual develops autoimmunity. If elevated BMI and associated elevations in leptin levels are risk factors for the initiation and/or progression of autoimmunity, they may act more as permissive factors in this process, in the setting of a certain degree of genetic predisposition.

Topics: Adolescent; Adult; Autoantibodies; Body Mass Index; Child; Diabetes Mellitus, Type 1; Female; Glutamate Decarboxylase; Histocompatibility Antigens Class II; Humans; Insulin; Leptin; Male; Risk

The purpose of this study was to determine the relationship between serum leptin levels and body composition and to evaluate the variables related to disease in children and adolescents with type 1 diabetes. We studied 49 diabetic patients aged 6-16 years (age: 11.2+/-2.9 years, M/F: 26/23), and 37 healthy controls. Body composition was determined by dual-energy X-ray absorptiometry. Serum leptin, glycated hemoglobin (HbA1c), free thyroxin, thyrotropin, testosterone and estradiol levels were measured in patients and controls. We did not observe significant difference in serum leptin levels between patients and controls. Girls had significantly higher serum leptin levels than boys in both patient and control groups. Serum leptin levels did not correlate significantly with HbA1c, disease duration or daily insulin dose but, correlated positively with body mass index (BMI) and fat mass (FM) in patients as in controls. Body composition in diabetic girls and boys was similar with respective controls. When analyzed by pubertal stage, BMI, lean body mass (LBM), FM, and total bone mineral density (BMD) were significantly higher in pubertal girls with type 1 diabetes compared to prepubertal ones. In pubertal boys with type 1 diabetes, LBM and FM were significantly higher than prepubertal ones. The results of the present study showed that neither serum leptin levels nor body composition was significantly altered in children and adolescents with type 1 diabetes managed with intensive insulin therapy.

Topics: Absorptiometry, Photon; Adolescent; Body Composition; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 1; Estradiol; Female; Glycated Hemoglobin; Humans; Leptin; Male; Testosterone

To determine the influence of Type 1 diabetes mellitus on circulating adipocytokines in children.. The circulating concentrations of leptin, adiponectin, resistin and tumour necrosis factor (TNF)-alpha were measured in 91 children, aged 11.1 +/- 2.7 years, with Type 1 diabetes mellitus (T1DM). Ninety-one healthy children were selected as control subjects.. Body mass index-adjusted leptin concentrations were higher in the pubertal diabetic children compared with the control children. There was a significant positive correlation between leptin and daily insulin dose in the diabetic group. Circulating adiponectin concentrations were higher in the prepubertal diabetic children and were positively associated with HbA(1c). Resistin concentrations were lower in the prepubertal non-diabetic subjects compared with the pubertal non-diabetic children, whose values were higher than those of the diabetic children. TNF-alpha concentrations were similar in non-diabetic and diabetic children.. Circulating concentrations of adipocytokines are abnormal in Type 1 diabetic children, although the direction of change differs by cytokine. Pubertal development, in addition to insulin treatment and glycaemic control, also influences the concentrations.

Topics: Adiponectin; Adolescent; Analysis of Variance; Blood Glucose; Body Mass Index; Case-Control Studies; Child; Cytokines; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Insulin; Leptin; Male; Puberty; Resistin; Tumor Necrosis Factor-alpha

Our own studies confirm the hypothesis, that insulin resistance of various degree is often observed in children and adolescents with type 1 diabetes mellitus (T1DM). The knowledge of this parameter characterizing individual patients may be of great value not only for better understanding of the disease course but also as a potential source of specific treatment. Reliable estimation of insulin resistance with hyperinsulinemic euglycemic clamp is a complex, laborious and costly procedure. These facts were enough to motivate us to make an attempt to elaborate an indirect, simplified method of insulin resistance assessment in T1DM children, that would be based on patients characteristics and on clinical parameters of the disease course.. 142 children and adolescents with T1DM (79 boys, 63 girls) aged 7.7-20.3 years (mean age - 13.7+/-3.3 years) were included into the study. Duration of diabetes was 0.5-12.5 years (mean 2.7+/-2.3 years). The stage of puberty was assessed by the Tanner scale. Euglycemic-hyperinsulinemic clamp by de Fronzo was performed to estimate insulin resistance. Glucose disposal rate (M index) determined during the last 30 min of the test estimated insulin resistance. Looking for clinical and metabolic factors characterizing insulin resistance: a) the plasma cholesterol, HDL-Ch, triglycerides and HbA1c were examined, b) the height, weight, waist circumference and blood pressure were measured, c) body mass index and daily dose of insulin were calculated. For statistical analysis the multiple regression was used (forward stepwise method).. In the study group M index ranged from 2.1 to 17.4 mg/kg/min (mean 7.27+/-2.62 mg/kg/min). The boys presented better insulin sensitivity than girls (7.79 vs. 6.62, p=0.008). The insulin resistance depended on the patients' age (r=-0.46, p<0.001) and stage of puberty (p<0.001). A correlation between M index and insulin dose (r=-0.34, p<0.05) and HbA1c (r=-0.17; p=0.04) were found. There was a significant relationship between M index and parameters of adiposity, lipids and blood pressure. All significant clinical parameters of insulin resistance were subjected to the analysis. Multiple linear regression analysis was performed. The model with the strongest correlation with index M was used to work out the formula: M index = 17.065 + 1.547 x (gender: boys=1, girls=0) - 0,183 x (age) - 0,117 x (Waist circumference) - 2,019 x (Daily insulin dose) - 0,016 x (LDL-CH) + 0,041 x (DBP).. In T1DM children and adolescents it is possible to estimate for daily use extent of insulin resistance on the basis of clinical features.

Topics: Adolescent; Adult; Aging; Blood Glucose; Child; Cholesterol, HDL; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Male; Multivariate Analysis; Puberty; Sex Factors; Triglycerides

Adiponectin has antidiabetic properties. Our aim was to determine plasma adiponectin levels during pregnancy and postpartum (PP), in women with type 1 diabetic mellitus (T1DM) and nondiabetic (ND) women.. Fasting plasma adiponectin and leptin levels were measured in 20 ND and 19 T1DM women, at 20 and 30 weeks' gestation, and 9 months' PP. Insulin measurements were made in ND women.. In both groups, after accounting for body mass index (BMI), leptin levels increased during pregnancy (P < 0.01) and were significantly higher than PP (P < 0.001). However, no significant differences in leptin levels were noted between both groups at any stage (P = 0.46). Conversely, adiponectin levels were higher in T1DM at all stages of the study (P < 0.001). A significant fall in adiponectin levels was seen between 20 and 30 weeks' gestation in both groups (ND: P < 0.001; T1DM: P < 0.05); however, this decrease was attenuated in the T1DM group. Adiponectin levels PP were significantly higher than at 30 weeks (ND: P < 0.001; T1DM: P < 0.001). Furthermore, in T1DM, adiponectin appeared to correlate negatively with leptin, but only reached significance PP (r = -0.46, P < 0.001). In the ND group, adiponectin correlated negatively with both leptin (PP: r = -0.56, P < 0.0001) and insulin (P < 0.005).. Higher adiponectin levels were noted in T1DM throughout gestation compared to ND pregnancies, with no difference in leptin levels. The significance of these findings needs to be determined.

Topics: Adiponectin; Adult; Case-Control Studies; Diabetes Mellitus, Type 1; Female; Humans; Insulin; Leptin; Multivariate Analysis; Postpartum Period; Pregnancy; Pregnancy in Diabetics; Pregnancy Trimester, Second; Pregnancy Trimester, Third

Orexins (hypocretins) are involved in the regulation of energy homeostasis and sleeping behavior. Orexins were also implicated in the regulation of neuroendocrine and autonomic functions. Recent data show the expression of orexin receptors within the hypothalamic-pituitary-adrenal (HPA) axis and suggest specific actions of orexins at the pituitary and adrenal glands. To further evaluate the role of orexin in the HPA axis, we investigated the mRNA expression of prepro-orexin (PPO) and orexin receptors within the HPA axis of streptozotocin-injected (STZ) rats showing type-1 like diabetes. PPO, as well as OX(1) and OX(2) receptor levels were analyzed by quantitative real-time PCR (qPCR). STZ rats were characterized by decreased body weight, plasma insulin, and leptin levels and by increased plasma glucose. Hypothalamic PPO mRNA levels were significantly reduced in STZ compared to non-diabetic control rats. No differences were found in the mRNA levels of hypothalamic or pituitary OX(1) and OX(2) receptors between control and STZ rats. In adrenals, OX(1) receptor mRNA levels were significantly elevated in STZ rats while OX(2) receptors were significantly reduced. Our results imply distinct functions of adrenal orexin receptor subtypes during type-1 like diabetes.

Topics: Adrenal Glands; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 1; Hypothalamus; Insulin; Intracellular Signaling Peptides and Proteins; Leptin; Male; Neuropeptides; Orexin Receptors; Orexins; Pituitary Gland; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; RNA, Messenger; Streptozocin

Hypomagnesaemia and hyperleptinemia are common in patients with diabetes. Moreover, it has been demonstrated that leptin stimulates diuresis and natriuresis. The aim of this study was to evaluate the relationship between serum leptin, serum magnesium (Mg) and urinary Mg/urinary creatinine levels in patients with type 1 diabetes.. Serum leptin and Mg and urinary Mg/urinary creatinine levels were measured in 67 patients with diabetes (33 girls and 34 boys). The age, diabetes duration, anthropometric and metabolic parameters of the subjects were matched between girls and boys. The relation of serum leptin levels to serum and urinary Mg/urinary creatinine levels was assessed.. Serum leptin levels of girls with diabetes were higher than those of the boys (14 +/- 5.3 microg/L vs 5.8 +/- 1.5 microg/L, P < 0.001, respectively). The differences for serum Mg and for urinary Mg/urinary creatinine levels were not significant between girls and boys with diabetes. Leptin levels were correlated with urinary Mg/urinary creatinine levels in both girls and boys (r = 0.39, P = 0.02 and r = 0.37, P = 0.03, respectively). In a multivariate regression model, leptin emerged as independent correlates for mean urinary Mg/urinary creatinine in both girls and boys with the total variance explained being 14%, and 15%, respectively.. The data suggest that serum leptin might be related to increased urinary Mg loss in patients with type I diabetes.

Topics: Adolescent; Case-Control Studies; Child; Creatinine; Diabetes Mellitus, Type 1; Female; Humans; Kidney; Leptin; Magnesium; Male; Multivariate Analysis; Regression Analysis

Type 1 diabetes mellitus (T1DM) leads to increased serum levels of the soluble leptin receptor (sOB-R) by an as yet unknown cellular mechanism. The aim of our study was to investigate potential metabolic factors that may be associated with the induction of the sOB-R release from its membrane receptor.. Twenty-five children (aged between 1.5 and 17.0 years) were studied at the onset of T1DM. Blood samples were collected before (n = 25), during the first 18 h (mean +/- S.D. 11.1 +/- 4.3 h, n = 16) and 92 h (47.5 +/- 22.5 h; n = 14) after beginning insulin therapy. Serum sOB-R and leptin levels were determined by in-house immunoassays.. The sOBR-level and the molar sOB-R/leptin ratio were significantly higher before than after starting insulin treatment (P < 0.05). In contrast, leptin levels were significantly lower (P < 0.05) before insulin therapy. The correlation between sOB-R and blood glucose (r = 0.49; P < 0.05), as well as sOB-R with parameters of ketoacidosis, such as pH (r = -0.72), base excess (r = -0.70), and bicarbonate (r = -0.69) (P < 0.0001) at diagnosis of T1DM remained significant during the first 18 h of insulin treatment. Multiple regression analysis revealed that base excess predicted 41.0% (P < 0.001), age 16.4% (P < 0.05), and height SDS 13.9% (P < 0.01) of the sOB-R variance.. Metabolic decompensation in children with new onset T1DM is associated with dramatic changes of the leptin axis; serum levels of sOB-R are elevated and of leptin are reduced. The molar excess of sOB-R over leptin (median 11.3) in this condition may contribute to leptin insensitivity. Upregulation of the soluble leptin receptor appears to be a basic mechanism to compensate for intracellular substrate deficiency and energy-deprivation state.

Topics: Adolescent; Child; Child, Preschool; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Fatty Acids, Nonesterified; Humans; Hyperglycemia; Infant; Leptin; Receptors, Cell Surface; Receptors, Leptin

Pancreatic beta-cell growth and survival and insulin production are stimulated by growth hormone and prolactin through activation of the transcription factor signal transducer and activator of transcription (STAT)5. To assess the role of STAT5 activity in beta-cells in vivo, we generated transgenic mice that expressed a dominant-negative mutant of STAT5a (DNSTAT5) or constitutive active mutant of STAT5b (CASTAT5) under control of the rat insulin 1 promoter (RIP). When subjected to a high-fat diet, RIP-DNSTAT5 mice showed higher body weight, increased plasma glucose levels, and impairment of glucose tolerance, whereas RIP-CASTAT5 mice were more glucose tolerant and less hyperleptinemic than wild-type mice. Although the pancreatic insulin content and relative beta-cell area were increased in high-fat diet-fed RIP-DNSTAT5 mice compared with wild-type or RIP-CASTAT5 mice, RIP-DNSTAT5 mice showed reduced beta-cell proliferation at 6 months of age. The inhibitory effect of high-fat diet or leptin on insulin secretion was diminished in isolated islets from RIP-DNSTAT5 mice compared with wild-type islets. Upon multiple low-dose streptozotocin treatment, RIP-DNSTAT5 mice exhibited higher plasma glucose levels, lower plasma insulin levels, and lower pancreatic insulin content than wild-type mice, whereas RIP-CASTAT5 mice maintained higher levels of plasma insulin. In conclusion, our results indicate that STAT5 activity in beta-cells influences the susceptibility to experimentally induced type 1 and type 2 diabetes.

Topics: Animals; Blood Glucose; Cell Proliferation; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dietary Fats; Glucose Tolerance Test; Insulin; Insulin Secretion; Insulin-Secreting Cells; Leptin; Mice; Mice, Transgenic; STAT5 Transcription Factor

To determine the effect of the initial metabolic imbalance and its restoration after insulin therapy on adiponectin and acylated ghrelin levels in children with type 1 diabetes mellitus (T1DM).. Twenty prepubertal children with newly diagnosed T1DM were prospectively studied at diagnosis and after 1 and 4 months of therapy. Body mass index (BMI) and serum levels of adiponectin, resistin, total and acylated ghrelin, leptin, tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6) were determined. The control group comprised 40 healthy prepubertal children.. BMI was decreased at diagnosis, normalized at 1 month, and remained so thereafter. Adiponectin levels at diagnosis were similar to controls, increasing significantly after 1 month and normalizing at 4 months. Acylated ghrelin levels were lower at diagnosis, with a significant increase at 1 month and normalizing at 4 months. Resistin levels were normal at all time points. Leptin levels were decreased, while TNF-alpha and IL-6 were increased at diagnosis and normalized at 1 month.. These findings suggest that BMI is not the main predictor of acylated ghrelin or adiponectin levels in newly diagnosed T1DM subjects and that these peptides may play an important role in the metabolic adaptation in this disease.

Topics: Acylation; Adiponectin; Body Mass Index; Child; Diabetes Mellitus, Type 1; Female; Ghrelin; Humans; Insulin; Interleukin-6; Leptin; Male; Peptide Hormones; Prospective Studies; Resistin; Tumor Necrosis Factor-alpha

To assess the prevalence and severity of bone disease in type 1 diabetic patients and to determine serum markers of bone remodeling as well as their relationship with bone mineral density (BMD).. BMD [by dual energy x-ray absorptiometry (DXA)] and serum markers of bone remodeling [osteocalcin, c-terminal telopeptide of type I collagen (CTX)], leptin and osteoprotegerin (OPG) were measured in 42 adult males with type 1 diabetes. Twenty-four non-diabetic subjects served as controls.. In 40% of the patients, osteopenia at the lumbar spine (L1-L4) and/or at the left hip was found, and 7% met criteria for osteoporosis. L1-L4 BMD z-score was correlated with age (r=0.365, P=0.018) and a similar trend was observed at left hip. L1-L4 BMD z-score was negatively correlated with CTX and osteocalcin (r=-0.343, P=0.028; r=-0.376, P=0.024, respectively). A significant correlation was evidenced between BMD z-score at both lumbar spine and left hip and leptin values (r=0.343, P=0.03; r=0.395, P=0.012, respectively) but after adjustment for weight this correlation was no longer significant. Osteocalcin, CTX and leptin concentrations were comparable between patients and controls, while OPG concentrations tend to be higher in diabetic subjects (P=0.08). CTX was negatively correlated with age (r=-0.390, P=0.012) and positively correlated with osteocalcin (r=0.696, P<0.001). OPG was positively correlated with age (r=0.507, P=0.001).. Our results suggest that in diabetic subjects osteopenia is a relatively frequent complication but bone loss is attenuated with age progression. Whether this is also mediated by OPG and/or leptin remains to be confirmed.

Topics: Adult; Aged; Biomarkers; Bone Density; Bone Remodeling; Collagen; Diabetes Mellitus, Type 1; Humans; Leptin; Male; Middle Aged; Osteocalcin; Osteoprotegerin; Reference Values

To study the circulating levels of two gut-derived peptides in children with type 1 (insulin-dependent) diabetes mellitus (IDDM).. Plasma levels of ghrelin, both total ghrelin (TG) and the acylated form (AG), and galanin and their relationships with insulin dosage, metabolic control, IGFBP-1, body mass and pubertal development were evaluated in 91 children, aged 11.1 +/- 2.7 years, affected by IDDM and treated with insulin. Ninety-one healthy children were selected as controls.. Body mass index (BMI)-adjusted levels of both forms of ghrelin were reduced in IDDM compared with healthy subjects, with greater values in prepubertal than pubertal IDDM subjects. A negative association was found between AG and fasting insulin serum levels and insulin resistance [measured by using the homeostasis model assessment of insulin resistance (HOMA IR)] among the healthy children. IDDM children showed a negative association of their plasma ghrelin (both acylated and total) with daily insulin dosage, and the three adiposity indices (BMI, skinfold thickness and percentage fat mass). IGFBP-1 levels were higher among the IDDM children without any association with ghrelin serum values. BMI-adjusted plasma levels of galanin were higher among IDDM compared to healthy subjects, irrespective of sex or pubertal development. Greater values for galanin were found among pubertal than prepubertal subjects in both groups without any significant differences between the genders. A positive association was found between galanin and BMI in both groups and between galanin and haemoglobin A1c (HbA1c) among the IDDM children. No relationship existed between either galanin and fasting serum insulin among the healthy subjects or galanin and both insulin dosage or duration of treatment among the IDDM subjects.. The associations found between both ghrelin and galanin with adiposity indices could be considered as an indirect signal of involvement of the two peptides in the development of the nutritional status of the IDDM adolescents. The reduction in both forms of ghrelin could be involved in the development of the body mass increase of IDDM subjects with opposite effects, either influencing insulin sensitivity or exerting a compensatory restraint of feeding.

Topics: Acylation; Adolescent; Blood Glucose; Body Mass Index; Child; Child, Preschool; Diabetes Mellitus, Type 1; Drug Administration Schedule; Female; Galanin; Ghrelin; Humans; Insulin; Insulin Resistance; Leptin; Male; Peptide Hormones; Puberty; Sex Factors

Prevalence of uterine progesterone receptors over estrogen ones, high uterine cAMP level, and low uterine prostaglandin level are necessary conditions of normal pregnancy. In cases of spontaneous and antiprogestin RU486-induced abortions, estrogen receptors prevail over progesterone ones, cAMP level decreases, and prostaglandin concentration in decidual tissue increases. Porcine and bovine beta-lipotropines were the first proteins, whose correct amino acid sequence was first determined in Russia. Several research centers carried out collaborative studies of the nucleotide sequences of human and animal proopiomelanocortin (lipotropin precursor) and prolactin cDNA. Researchers constructed genetic engineering producers of human pre-proinsulin and somatostatin, identified structural genes expressed in pancreatic beta-cells, studied antigenic properties of glutamic acid decarboxylase (GAD), which determine insulin-dependent diabetes, and identified the cholesterase determinant. They revealed mutations in the genes of proopiomelanocortin and melanocortin receptors (MC4-P), which inhibit leptin regulation of appetite and are associated with human obesity.

Topics: Abortifacient Agents, Steroidal; Abortion, Induced; Abortion, Spontaneous; Animals; Appetite; beta-Lipotropin; Cattle; Diabetes Mellitus, Type 1; Female; Genetic Engineering; Glutamate Decarboxylase; Humans; Leptin; Lipid Metabolism; Male; Mifepristone; Mutation; Obesity; Pregnancy; Receptors, Estrogen; Receptors, Melanocortin; Receptors, Progesterone; Reproduction; Research; RNA, Messenger; Sterol Esterase; Swine; Uterus

The prevalence of cardiovascular disease (CVD) and inflammation is high in patients with end-stage renal disease (ESRD). Adiponectin is an adipocytokine that may have significant anti-inflammatory and anti-atherosclerotic effects. Low adiponectin levels have previously been found in patients with high risk for CVD.. In a cohort of 204 (62% males) ESRD patients aged 52 +/- 1 years the following parameters were studied: presence of CVD, body composition, plasma adiponectin (N= 107), cholesterol, triglycerides, HDL-cholesterol, serum leptin, high-sensitivity C-reactive protein (hs-CRP), urinary albumin excretion (UAE), and single-nucleotide polymorphisms (SNPs) in the apM1 gene at positions -11391, -11377, 45, and 276. Thirty-six age- (52 +/- 2 years) and gender-matched (64% males) healthy subjects served as control subjects.. Markedly (P < 0.0001) elevated median plasma adiponectin levels were observed in ESRD patients (22.2 microg/mL), especially type 1 diabetic patients (36.8 microg/mL), compared to control subjects (12.2 microg/mL). Log plasma adiponectin correlated to visceral fat mass (R=-0.29; P < 0.01) and Log hs-CRP (R=-0.26; P < 0.01). In a stepwise (forward followed by backward) multiple regression model only type-1 diabetes (P < 0.001) and visceral fat mass (P < 0.05) were independently associated with plasma adiponectin levels. The adiponectin gene -11377 C/C genotype was associated with a lower prevalence of CVD (25 vs. 42%) compared to the G/C genotype.. The present cross-sectional study demonstrates that, whereas genetic variations seem to have a minor impact on circulating adiponectin levels, lower visceral fat mass and type 1 diabetes mellitus are associated with elevated plasma adiponectin levels in ESRD patients. Furthermore, low levels of adiponectin are associated with inflammation in ESRD.

Topics: Adiponectin; Albuminuria; Biomarkers; Body Composition; C-Reactive Protein; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Female; Fibrinogen; Genetic Variation; Glomerular Filtration Rate; Humans; Intercellular Signaling Peptides and Proteins; Kidney Failure, Chronic; Leptin; Lipids; Male; Middle Aged; Phenotype; Proteins

Protein tyrosine phosphatase-1b (Ptp1b) inhibits insulin and leptin signaling by dephosphorylating specific tyrosine residues in their activated receptor complexes. Insulin signals are mediated by tyrosine phosphorylation of the insulin receptor and its downstream targets, such as Irs1 and Irs2. Irs2 plays an especially important role in glucose homeostasis because it mediates some peripheral actions of insulin and promotes pancreatic beta-cell function. To determine whether the deletion of Ptp1b compensates for the absence of Irs2, we analyzed mice deficient in both Ptp1b and Irs2. Pancreatic beta-cell area decreased in Ptp1b(-/-) mice, consistent with decreased insulin requirements owing to increased peripheral insulin sensitivity. By contrast, peripheral insulin sensitivity and beta-cell area increased in Irs2(-/-)::Ptp1b(-/-) mice, which improved glucose tolerance in Irs2(-/-)::Ptp1b(-/-) mice and delayed diabetes until 3 months of age. However, beta-cell function eventually failed to compensate for absence of Irs2. Our studies demonstrate a novel role for Ptp1b in regulating beta-cell homeostasis and indicate that Ptp1b deficiency can partially compensate for lack of Irs2.

Topics: Animals; Blood Glucose; Crosses, Genetic; Diabetes Mellitus, Type 1; Glucose Tolerance Test; Insulin; Insulin Receptor Substrate Proteins; Intracellular Signaling Peptides and Proteins; Islets of Langerhans; Kinetics; Leptin; Male; Mice; Mice, Knockout; Models, Animal; Phosphoproteins; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases; Signal Transduction

Ghrelin is secreted primarily by the stomach, although other tissues such as the pancreas synthesize a minor proportion. The discovery of a new cell type that produces ghrelin in the human pancreas and that this organ expresses GHS-R opens new perspectives in the understanding of the control of glucose metabolism. We have studied 22 children with newly diagnosed type 1 diabetes mellitus at four different points: at diagnosis before insulin therapy, after 48-60 h of insulin therapy, and after 1 and 4 mo of insulin treatment. At each point circulating levels of ghrelin, leptin, IGF-I, IGF binding protein (IGFBP)-1, IGFBP-2, IGFBP-3, and glucose were determined. Ghrelin levels were significantly decreased at diagnosis (573 +/- 68 pg/mL, p < 0.01) compared with controls (867 +/- 38 pg/mL) and remained decreased after insulin therapy (d 2: 595 +/- 68 pg/mL; 1 mo: 590 +/- 61 pg/mL; 4 mo: 538 +/- 67 pg/mL) with no differences before or after insulin treatment. There was a negative correlation between ghrelin levels and body mass index at all of the study points, whereas a negative correlation between ghrelin and glucose concentrations was only observed after insulin therapy. No correlation between ghrelin and HbA1c was found at any point. A positive correlation between ghrelin and IGFBP-1 was found after insulin therapy, but no correlation with other members of the IGF system or leptin was found. In conclusion, these data could indicate a possible link between glucose concentrations and ghrelin; hence, the persisting low ghrelin levels in diabetic children may suggest a defensive mechanism against hyperglycemia.

Topics: Body Height; Body Mass Index; Body Weight; Child; Child, Preschool; Diabetes Mellitus, Type 1; Female; Ghrelin; Glucose; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Linear Models; Male; Pancreas; Peptide Hormones; Radioimmunoassay; Time Factors

Previous studies have demonstrated that leptin is an angiogenic factor, and an increase in intravitreous leptin concentrations in diabetic patients with proliferative diabetic retinopathy (PDR) has also been described. The aim of the present study was to investigate the source of intravitreal leptin and to determine whether it is related to PDR activity.. Serum and vitreous fluid samples were obtained simultaneously at the time of vitreoretinal surgery from 25 patients with PDR and 32 nondiabetic patients with nonproliferative ocular diseases (controls). Both groups were matched by age, sex, and body mass index. Leptin levels were determined by ELISA.. We did not observe any significant differences in vitreal levels of leptin between diabetic patients with PDR and controls (4.22 [2.6-9.7] versus 3.49 [1.9-9.7] ng/mL; P = not significant). Leptin concentrations were lower in vitreous fluid than in serum samples from diabetic patients with PDR (P < 0.001) and controls (P < 0.001). A direct correlation between serum and vitreous leptin concentrations was detected in diabetic patients with PDR (r = 0.60; P = 0.01) and controls (r = 0.51; P = 0.01). Finally, we did not observe any relationship between intravitreous leptin levels and PDR activity.. The intraocular production of leptin is not critically involved in the etiopathogenesis of PDR. In addition, our results suggest that serum diffusion is a relevant source of leptin in vitreous fluid.

Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Enzyme-Linked Immunosorbent Assay; Female; Humans; Leptin; Male; Middle Aged; Vitreous Body

mRNA levels of kinin B1 and B2 receptors were determined in HPA axis of type 1 (STZ-induced) and type 2 diabetic rats (ZDF and obese Zucker rats). B2 mRNA levels were elevated in hypothalamus of STZ-induced diabetic (STZ-D) and ZDF rats. Pituitary B2 mRNA levels were elevated in ZDF and obese rats. Adrenal B2 mRNA level was attenuated in STZ-D rats. Kinin B1 receptor may not play a role in HPA axis in diabetes since its expression was unchanged. Enhanced mRNA expression of B2 receptors in hypothalamus of STZ-D and ZDF rats parallels a rise in plasma glucose and reflect a functional relationship. Enhanced pituitary B2 mRNA in type 2 and reduced adrenal in type 1 diabetes account for a differential pattern in release of transmitters.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Hypothalamo-Hypophyseal System; Insulin; Leptin; Male; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; Rats, Zucker; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Subclinical inflammation has been implicated in the initiation and/or progression of atherosclerosis. Diabetes mellitus and obesity are risk factors for atherosclerosis, and asymptomatic low grade inflammation occurs prior to overt vascular lesions in these patients. In contrast to adults, little information exists concerning low grade inflammation in young type 1 diabetes and juvenile obesity.. To investigate low grade inflammation and immune activation in juvenile diabetes mellitus and obesity.. hs-CRP, soluble interleukin-2 receptor (sIL-2R), C-peptide, insulin, cortisol, vitamin B12, folic acid, leptin, and homocysteine were determined in 148 patients with juvenile type 1 diabetes, 86 obese children and 142 normal weighted age-matched healthy controls. Intima-media thickness (IMT) and lumen diameter of both common carotid arteries (CCA) was measured by ultrasonography in 52 healthy pediatric controls, 10 diabetics, and 34 obese juveniles.. Serum hs-CRP was significantly elevated in patients with type 1 diabetes (p < 0.0001), and obese children (p < 0.0001) as compared to the control group. The obese juveniles (p < 0.0001) and the diabetics (p < 0.0001) showed significantly increased values for IMT of CAAs. Levels of homocysteine, sIL-2R, insulin, cortisol, vitamin B12, and folic acid did not differ from the controls. The elevation of hs-CRP was more pronounced in obesity as compared to type 1 diabetes (p < 0.0001), and the hs-CRP values correlated significantly with body mass index standard deviation score (BMI-SDS) values. Furthermore, the IMT and the luminal diameter of CCAs showed significant correlations with BMI-SDS values.. A low grade inflammation as determined by serum hs-CRP is significantly increased in children with type 1 diabetes, and even more pronounced in apparently healthy juveniles with obesity. The increased IMT of CCAs strongly argues for an association between this low grade inflammation and early atherosclerotic vessel injury.

Topics: Adolescent; Arteriosclerosis; Body Mass Index; C-Peptide; C-Reactive Protein; Carotid Artery, Common; Child; Diabetes Mellitus, Type 1; Female; Folic Acid; Homocysteine; Humans; Inflammation; Leptin; Male; Obesity; Receptors, Interleukin-2; Tunica Intima; Vitamin B 12

The incidence of pediatric type 2 diabetes has recently seen an alarming increase. To improve our understanding of pediatric type 2 diabetes and identify markers that discriminate these subjects from those with type 1 diabetes, we performed a multivariant analysis associating serum adiponectin and leptin levels with anthropometrical parameters and disease state.. Samples from children and adolescents with type 1 diabetes (n = 41) and type 2 diabetes (n = 17) and from nondiabetic individuals of similar age from the general population (n = 43) were investigated. An analysis included the parameters of matching for BMI and Tanner stage. Receiver-operator characteristic (ROC) curves were established to assess these analytes' association with disease.. Contrary to studies of adult type 1 diabetes, adiponectin levels in our pediatric type 1 diabetic subjects (10.2 microg/ml [95% CI 8.6-11.7]) did not differ from those of healthy control subjects (10.6 microg/ml [9.2-12.0]; P = NS). Children with type 2 diabetes (5.5 microg/ml [4.8-6.2]) had significantly lower adiponectin levels than both of those groups. Conversely, type 2 diabetic subjects showed marked elevations in serum leptin concentrations (24.3 ng/ml [17.1-31.5]) compared with healthy control subjects (2.7 ng/ml [1.3-4.1]; P < 0.001) and type 1 diabetic subjects (5.1 ng/ml [3.5-6.7]; P < 0.001). Importantly, each of the properties ascribed to pediatric type 2 diabetes was present when the comparison was restricted to healthy children or type 1 diabetic patients whose BMI was >85th percentile or who had Tanner stage 4 and 5. The evaluation of adiponectin-to-leptin ratios revealed a striking difference between children with type 1 diabetes (6.3 [3.8-8.8]) and type 2 diabetes (0.3 [0.2-0.5]; P < 0.001).. In pediatric diabetes, where diagnosis of disease is often difficult, these studies suggest that the adiponectin-to-leptin ratio may provide additional help in the discrimination between type 1 and type 2 diabetes.

Topics: Adiponectin; Adolescent; Adult; Autoantibodies; Biomarkers; Child; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Female; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Male; Reference Values; Regression Analysis

The aim of this study was to investigate the relationship between cytokines, leptin and vascular tone-related chemokine and nitric oxide (NO) in type 1 diabetic children.. Serum samples were collected from 58 children with type 1 diabetes and 33 of their healthy siblings.. Serum interleukin (IL)-8 was significantly higher and serum nitric oxide was significantly lower in the children with diabetes than in their healthy siblings. Stepwise regression analysis showed that there were significantly positive correlations between IL-1beta and IL-6, IL-1beta and nitric oxide, IL-4 and tumor-necrosis factor (TNF)-alpha, IL-4 and leptin, IL-8 and IL-2, and interferon (IFN)-gamma and IL-6, as well as significantly inversed correlations between IL-6 and IL-2, IL-8 and interferon-gamma, and leptin and TNF-alpha in siblings, not in the children with diabetes. However, there were significantly positive correlations between IL-2 and IL-4, IL-2 and leptin, IL-4 and IL-6, and TNF-alpha and IL-6 in children with diabetes.. Our results suggest that the alterations of circulating IL-8 and nitric oxide levels and cytokine network in children with diabetes may be associated with the cardiovascular disease in their adulthood.

Topics: Adolescent; Adult; Body Mass Index; Body Weight; Chemokines; Child; Child, Preschool; Cytokines; Diabetes Mellitus, Type 1; Enzyme-Linked Immunosorbent Assay; Female; Humans; Infant; Interferon-gamma; Interleukin-1; Interleukin-2; Interleukin-6; Interleukin-8; Leptin; Male; Nitric Oxide; Regression Analysis

Maternal diabetes is associated with excess foetal growth. We have assessed the influence of maternal diabetes on hormones associated with foetal growth and the relationship of these hormones to birthweight.. Case-control study.. Singleton offspring of mothers with type 1 diabetes (ODM, n = 140) and control mothers (Control, n = 49).. Birthweight, cord blood insulin, proinsulin, 32-33 split proinsulin, leptin, IGF-1, IGFBP-3, cortisol.. Maternal diabetes was associated with higher birthweight (ODM 3.80 +/- 0.69 kg; Control; 3.56 +/- 0.52 kg, P = 0.02) and marked increases in insulin (median [interquartile range]: ODM 110 [60-217] pmol/l; Control 22 [15-37] pmol/l; P < 0.0001) and leptin (ODM 32 [15-60] ng/ml; Control 9 [4-17] ng/ml; P < 0.0001) but no absolute difference in IGF-1 (ODM 7.9 [6.2-9.8] nmol/l, Control 7.5 [6.2-9.8] nmol/l, P = 0.24) or its principle binding protein IGFBP-3 (ODM 1.63 +/- 0.38 micro g/ml, Control 1.63 +/- 0.28 micro g/ml; P = 0.12). Individually, insulin, insulin propeptides, leptin, IGF-1 and IGFBP-3 were significantly (P < 0.05) correlated with birthweight (in ODM and Control). IGF-1 and leptin were positively related to birthweight independently of each other and insulin in both ODM and Control. By contrast, insulin showed independent relationships to birthweight in ODM (P < 0.0001) but not in Control (P = 0.4).. Maternal diabetes is associated with marked elevation of insulin and leptin in cord blood of their offspring. Hormonal correlates of birthweight differ between ODM and Control with an independent relationship of insulin to birthweight observed only in ODM.

Topics: Adult; Birth Weight; Case-Control Studies; Diabetes Mellitus, Type 1; Female; Fetal Blood; Glycated Hemoglobin; Humans; Hydrocortisone; Infant, Newborn; Insulin; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Pregnancy; Pregnancy in Diabetics

Leptin and insulin-like growth factor-1 (IGF-1) have been suggested to be involved in the pathogenesis of atherosclerosis. The aim of this study was to evaluate the relationship between serum leptin, IGF-1 and intima-media thickness (IMT) and functions of common carotid artery (CCA) in children and adolescent patients with type 1 diabetes.. Serum leptin and IGF-1 levels were measured in 45 diabetic patients (23 girls and 22 boys). Age, diabetes duration as well as major cardiovascular risk factors, including anthropometric and metabolic parameters, were matched between girls and boys. The relation of serum leptin and IGF-1 levels to CCA structure and functions were measured by ultrasonography as IMT, cross-sectional compliance (CSC), cross-sectional distensibility (CSD), diastolic wall stress (DWS) and incremental elastic modulus (IEM).. Serum leptin levels of diabetic girls were higher than those in the boys (21.8 +/- 14.5 microg/l vs 8.9 +/- 10.6 micro/l, p = 0.002). However, the difference for serum IGF-I levels was not significant between diabetic girls and boys (240.7 +/- 96.8 ng/ml vs 234.7 +/- 93.2 ng/ml; p > 0.05). In all subjects, leptin levels were correlated with CSC (p = 0.04), CSD (p = 0.04) and IEM (p = 0.01), and IGF-1 levels were only correlated with CSC (p = 0.01). Leptin did not show any correlation with ultrasonographic measurements in both girls and boys separately. IGF-1 was correlated with CSC (p = 0.001), CSD (p = 0.002) and IEM (p < 0.001) in boys but not in girls. In a multivariate regression model, IGF-1 emerged as independent correlates for mean CSD and IEM in boys but not in girls.. Serum leptin and IGF-1 levels in children and adolescent patients with type 1 diabetes are associated with functions of common carotid artery, and the association of IGF-1 levels is influenced by sex.

Topics: Adolescent; Adult; Arteriosclerosis; Carotid Artery, Common; Child; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Female; Humans; Insulin-Like Growth Factor I; Leptin; Linear Models; Male; Multivariate Analysis; Tunica Intima; Ultrasonography, Doppler

This study aimed to investigate 1) the effect of maternal diabetes mellitus on ghrelin, resistin, leptin, and insulin in term newborns; 2) the interrelationship of these metabolic hormones in the early postnatal period; and 3) the association of the hormones with anthropometric parameters at birth. A total of 120 term newborns were prospectively enrolled and categorized into three groups: 40 were infants of nondiabetic mothers (group N), 42 were infants born to mothers with gestational diabetes on low energy dietary treatment (group D), and 38 were infants born to mothers with preexisting or severe gestational diabetes who required exogenous insulin for stabilization of blood sugar during pregnancy (group I). Plasma ghrelin and resistin were significantly lower in group I than in either group N or group D infants (P < 0.048). Plasma ghrelin and subscapular skinfold thickness were significantly higher in female than in male infants [plasma ghrelin: median (interquartile range), 3.8 (3.0-4.8) vs. 3.0 (2.4-4.0) ng/ml in females and males, respectively; P = 0.003; subscapular skinfold thickness: 4.9 (4.2-5.6) vs. 4.6 (3.9-5.2) mm; P = 0.03]. In group N, plasma ghrelin was significantly, but negatively, associated with birth weight (r = -0.31; P = 0.05) and body length (r = -0.33; P = 0.04), whereas in group I, plasma ghrelin was negatively correlated with plasma resistin (r = -0.37; P = 0.02). Plasma ghrelin and resistin are suppressed in infants of insulin-dependent diabetic mothers, suggesting that the metabolic hormonal system is probably operational in fetal and early postnatal life. A low circulating ghrelin concentration may be advantageous to these infants, because a reduction in appetite may prevent excessive weight gain postnatally and counterbalances the in utero anabolic effect of hyperinsulinism in poorly controlled diabetic mothers. The suppressive effect of insulin on resistin may partially explain the excess accumulation of adipose tissue in infants of diabetic mothers by reducing the inhibitory effect of resistin on adipogenesis. Female infants have significantly higher plasma ghrelin levels than male infants, suggesting that sexual dimorphism exists in utero. This study has also shown an association between some of the metabolic hormones in specific groups of infants and thus suggests that these hormones could have interacted in utero to regulate growth and fat storage during this critical period.

Topics: Diabetes Mellitus, Type 1; Female; Ghrelin; Hormones, Ectopic; Humans; Infant, Newborn; Insulin; Leptin; Male; Multivariate Analysis; Peptide Hormones; Pregnancy; Pregnancy in Diabetics; Resistin; Sex Factors

Leptin is a 16 kD polypeptide hormone produced predominantly by white adipose tissue and exerts profound effects on food intake and energy balance. More recent studies have shown extra sites of leptin production in human and rodent tissues and have ascribed additional roles for the hormone, e.g., in immune and reproductive functions. A role for the hormone has also been implicated in insulin-dependent diabetes mellitus in the non-obese diabetic (NOD) mouse. However, whether leptin originates from islet cells of the mouse is not known. Here dual-label immunohistochemistry was employed to examine leptin expression in islet cells, and its distribution and cellular sources in pancreatic sections of female NOD/Ak and CD-1 mice of various ages. For comparison, leptin immunolabelling was examined in adult pancreatic sections from male NOD/Ak CD-1, Balb/c and FVB/N mice and female severe combined immunodeficient CB. 17 mice. Pancreatic tissues from adult female guinea pig, sheep and cattle and neonatal pigs were also studied. Our results show that in the day 1 NOD and CD-1 mice, leptin immunolabelling was observed in selective glucagon cells within the developing islets while at days 15 and 22, it became more intense and co-incident. This pattern of staining was maintained at days 40, 90, 150 and 250. In the female NOD mouse, leptin was absent in intra-islet immune cells. Its expression was variable in islets from male NOD and CD-1 mice. In spontaneously diabetic female NOD mice and following acceleration of diabetes with cyclophosphamide, despite the persistence of strong immunolabelling for glucagon in the re-distributed alpha cells, leptin expression was either absent, diminished or present in only a proportion of alpha cells. The reduction in leptin labelling was often associated with diabetic islets which had insulitis in association with only a small number of residual beta cells. Leptin expression was absent in guinea pig, ovine, bovine and neonatal porcine islet cells, despite the expression of intensely labelled glucagon cells. The present results demonstrate leptin co-localization in glucagon cells of the mouse islet. Its expression diminishes in the presence of inadequate insulin. Leptin produced within the mouse islet may have bi-directional influences on leptin and insulin regulation and may play local functions in islet development and metabolism.

Topics: Animals; Cattle; Diabetes Mellitus, Type 1; Female; Gene Expression Regulation; Glucagon; Guinea Pigs; Insulin; Islets of Langerhans; Leptin; Male; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Sheep; Species Specificity; Swine

The mechanism of the pubertal delay seen in some adolescents with type 1 diabetes mellitus is not entirely clear. Since leptin has been implicated as a neuroendocrine modulator of puberty, we measured serum leptin levels longitudinally in 24 post-'honeymoon' patients with diabetes mellitus (M/F = 15/9) with a mean (+/- SD) age of 10.5 +/- 0.9 years and 26 controls (M/F = 15/11) with a mean age of 10.0 +/- 1.1 years. Physical examinations; serum leptin, IGF-I, IGFBP-3 and IGFBP-1 levels; and bone age X-rays were performed annually for up to 48 months. Glycosylated hemoglobin (HbA1c) was measured 2-4 times a year in patients with diabetes mellitus. Serum leptin levels strongly correlated with the body mass index z-scores (BMI-Z) in both controls (r = 0.666, p <0.00001) and diabetic patients (r = 0.577, p <0.00001). Girls had increased serum leptin levels for a given BMI compared to boys (p <0.005). There were no significant differences in serum leptin levels of patients with diabetes mellitus compared to controls, nor were differences seen when the groups were stratified by age, Tanner stage, or gender. There were also no significant correlations between serum leptin levels and degree of metabolic control (i.e. HbA1c) or insulin dose standardized for body weight. Although there was no significant diabetes-related or metabolic control-related delay in bone age z-score or pubertal development, there was a significant negative correlation between HbA1c and growth velocity z-score, indicating that children with poor diabetes control had modest but significant slowing of growth. It is concluded that neither pubertal development nor serum leptin levels are significantly altered in adolescents with diabetes mellitus managed with standard therapy. The potential role of leptin in initiation of pubertal development is not easily demonstrable in observational studies.

Topics: Adolescent; Child; Cohort Studies; Diabetes Mellitus, Type 1; Female; Humans; Leptin; Longitudinal Studies; Male

Leptin is secreted by adipose tissue and acts upon receptors located in the hypothalamus to modify energy balance. Investigations of the relationship between leptin and physical activity energy expenditure (PAEE) at population level are scarce. The majority of studies addressing this topic are limited by their measurement of PAEE (i.e. questionnaires or ecological comparisons between rural and urban ethnic groups). To our knowledge, no studies have directly examined the relationship of objectively assessed PAEE and leptin in a large free-living population-based cohort. Therefore, we measured fasting plasma leptin and insulin concentrations, cardiorespiratory fitness (O(2max.pred)), PAEE, and body composition in 758 Caucasian people (aged 40-65 yr). In sex-combined multiple regression analyses, leptin was significantly associated with PAEE (beta = -0.19, P = 0.0027), but not with O(2max.pred) (beta = -0.0002, p = NS). The association between PAEE and leptin was significant in men when adjusted for percentage of body fat (beta = -0.28, P = 0.004) but not women (beta = -0.12, P = 0.18) but was significant in both men and women when adjusted for body mass index (men: beta = -0.28, P = 0.005; women: beta = -0.23, P = 0.01; combined: beta = -0.26, P = 0.00008). These data suggest the existence in this population of an independent inverse association between PAEE and fasting plasma leptin level.

Topics: Adult; Aged; Body Composition; Cohort Studies; Diabetes Mellitus, Type 1; Energy Metabolism; Fasting; Female; Humans; Insulin; Leptin; Male; Middle Aged; Motor Activity; United Kingdom

It has been assumed that the uptake of long chain fatty acids (LCFAs) into skeletal muscle and the heart muscle, as well as other tissues, occurred via passive diffusion. In recent years our work has shown that the LCFA uptake into skeletal muscle is a highly regulated process. The use of giant sarcolemmal vesicles obtained from skeletal muscle and heart has been used to demonstrate that LCFA uptake into these tissues occurs via a protein-mediated mechanism involving the 40 kDa plasma membrane associated fatty acid binding protein (FABPpm) and the 88 kDa fatty acid translocase, the homologue of human CD36 (FAT/CD36). Both are ubiquitously expressed proteins and correlate with LCFA uptake into heart and muscle, consistent with the known differences in LCFA metabolism in these tissues. It has recently been found that FAT/CD36 is present in an intracellular (endosomal) compartment from which it can be translocated to the plasma membrane within minutes by muscle contraction and by insulin, to stimulate LCFA uptake. In rodent models of obesity and type 1 diabetes LCFA uptake into heart and muscle is also increased, either by permanently relocating FAT/CD36 to the plasma membrane without altering its expression (obesity) or by increasing the expression of both FAT/CD36 and FABPpm (type 1 diabetes). Chronic leptin treatment decreases LCFA transporters and transport in muscle. Clearly, recent evidence has established that LCFA uptake into heart and muscle is regulated acutely and chronically.

Topics: Animals; Biological Transport, Active; Cell Membrane; Diabetes Mellitus, Type 1; Fatty Acids; Humans; Insulin; Leptin; Muscle Contraction; Muscle, Skeletal; Muscles; Myocardium; Obesity; Proteins; Rats

In adults, adiponectin is reduced in association with excess adiposity, type 2 diabetes, and hyperinsulinemia. We assessed whether adiponectin was 1) present in the fetal circulation, 2) altered in the fetal circulation in the presence of maternal diabetes, and 3) had relations to fetal cord blood insulin or adiposity.. We assessed adiponectin in cord blood in a large cohort of singleton offspring of diabetic mothers (ODM; n = 134) and control mothers (n = 45).. Adiponectin was present in cord blood and, in ODM, was higher in those delivered at later gestational ages (Spearman r = 0.18, P = 0.03). Adiponectin was slightly lower in ODM than control subjects (ODM 19.7 +/- 6.1 vs. control 21.8 +/- 5.3 micro g/ml; P = 0.04), although this difference could potentially reflect different gestational ages in the two groups (ODM 37.6 +/- 1.5 and control 40.1 +/- 1.1 weeks). In contrast to adults, adiponectin levels in the fetus were unrelated to the degree of adiposity, blood insulin, or leptin in either control subjects or ODM.. Adiponectin is present in cord blood but does not show expected physiological relations with adiposity as observed in adults.

Topics: Adiponectin; Adipose Tissue; Adult; Birth Weight; Diabetes Mellitus, Type 1; Female; Fetal Blood; Gestational Age; Humans; Infant, Newborn; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Pregnancy; Pregnancy in Diabetics; Proteins

A diabetic mouse model of accelerated neointimal formation would be a useful tool to understand the increased incidence of restenosis in patients with diabetes.. Femoral artery endoluminal wire injury was performed in diabetic insulin 2 Akita (ins2Akita) and leptin receptor db/db (leprdb/db) mutant mice. Neointima size in ins2Akita mouse arteries was unchanged compared with nondiabetic wild-type littermates. Although Ki67 labeling demonstrated similar rates of replication in the neointima of leprdb/db mouse arteries, neointimal formation in leprdb/db mice was surprisingly reduced by approximately 90% compared with nondiabetic lepr+/+ mice. Four hours after arterial injury, medial smooth muscle cell death was diminished in leprdb/db arteries, suggesting that the initial response to arterial injury was altered in leprdb/db mice.. These studies highlight a differential response to arterial injury in leprdb/db mice and suggest a potential role for leptin in the regulation of neointimal formation in response to arterial injury.

Topics: Animals; Coronary Restenosis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Femoral Artery; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Muscle, Smooth, Vascular; Neovascularization, Pathologic; Sex Factors; Tunica Intima; Tunica Media

To evaluate the interaction between serum free insulin, insulin-like binding protein (IGFBP)-1 and leptin concentrations during puberty in insulin-dependent diabetes mellitus (IDDM).. Adolescent patients with IDDM (n=101, age >9 years, duration >2 years) from the Outpatient Clinic of the Department of Pediatrics at Oulu University Hospital, and non-diabetic controls, were recruited to the study. Free insulin, IGFBP-1, leptin and insulin antibody concentrations were measured from a fasting serum sample.. Free insulin concentrations were lower in the patients than in the controls (4.3+/-2.3 mU/l compared with 6.5+/-3.1 mU/l, P<0.001), and there was an inverse correlation between free insulin and fasting blood glucose in the boys with diabetes (r=-0.53, P<0.001), whereas a positive correlation was observed between free insulin and leptin concentrations in the girls with diabetes (r=0.30, P=0.020). The IGFBP-1 concentrations were greater in the patients than in the controls (16.5+/-10.6 microg/l compared with 4.0+/-3.3, P<0.001), and they correlated significantly with blood glucose (r=0.63, P<0.001) and free insulin (r=-0.35, P<0.001). No significant difference was observed in the leptin concentrations between the patients and controls overall, despite greater total body fat in the girls with diabetes compared with the control girls.. Adolescents with IDDM are characterised by morning hypoinsulinaemia and high circulating IGFBP-1 concentrations, which may contribute to insulin resistance and impaired metabolic control during puberty. The mechanism behind the increased total body fat in the postpubertal female patients remains to be determined.

Topics: Adolescent; Autoantibodies; Blood Glucose; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Insulin; Insulin-Like Growth Factor Binding Protein 1; Leptin; Male; Puberty

In a family with agenesis of the dorsal pancreas only the mother presents with insulin-dependent diabetes mellitus, whereas her sons are glucose tolerant. We examined whether metabolic defects can be detected early in this disease. Plasma glucose profiles were obtained from patients with dorsal pancreas agenesis and from matched healthy subjects. Hepatic glycogen synthesis and breakdown were determined from the time course of glycogen concentrations using noninvasive (13)C nuclear magnetic resonance spectroscopy. Gluconeogenesis was calculated from the difference between glucose production (measured with D-[6,6-(2)H(2)]glucose) and glycogen breakdown. Frequently sampled iv glucose tolerance tests were performed to assess insulin secretion and sensitivity. The mean plasma glucose level was higher (12.9 +/- 0.4 vs. 5.9 +/- 0.1 mmol/liter), whereas the peak plasma insulin level was lower (236 vs. 397 +/- 23 pmol/liter) in the diabetic mother than in her nondiabetic sons and healthy subjects. In all patients, however, glycogen synthesis and breakdown were reduced by approximately 55% (P < 0.05) and 40% (P < 0.02), respectively. Gluconeogenesis (6.8 +/- 0.8 vs. 4.2 +/- 0.3 micro mol/kg.min; P < 0.05) and hepatic insulin clearance (6.8 +/- 1.3 vs. 2.8 +/- 1.0 ml/kg.min) were increased in all patients. In conclusion, patients with complete agenesis of the dorsal pancreas exhibit marked defects in hepatic glycogen metabolism, which are present even in the nondiabetic offspring.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Fatty Acids, Nonesterified; Female; Glucagon; Gluconeogenesis; Glucose Tolerance Test; Glycogen; Human Growth Hormone; Humans; Hydrocortisone; Insulin; Insulin Resistance; Insulin Secretion; Kinetics; Leptin; Liver; Magnetic Resonance Spectroscopy; Male; Middle Aged; Norepinephrine; Pancreas

The subject was a 26-year-old Japanese woman of 148 cm height, 96.2 kg of body weight (BW) (body mass index (BMI) of 43.8 kg/m(2)). She was referred to our hospital on May 1, 2000 for the evaluation of marked hyperglycemia with clinical symptom of general malaise, polydipsia, and ketonuria (3+). She did not smoke, or drink alcohol. But, she tended to eat lots of sweet food every day before the onset of this symptom. Her father was diagnosed type 2 diabetes mellitus. Her fasting plasma glucose and HbA(1c), and serum C-peptide were 398 mg/dl, 7.8% and less than 0.05 ng/ml [normal range: 0.94-2.8], respectively. She tested negative for anti-glutamic acid decarboxylase (GAD) antibodies and islet-cell antibodies. C-peptide level in her urine was as low as 3.4 microg/day. We immediately started insulin treatment under the diagnosis of abrupt onset of diabetes mellitus with diabetic ketoacidosis on the day of her admission, and the insulin treatment was continued after her being discharged. She showed continuous BW reduction until her BW reached approximately 60 kg, followed by her BW being plateau. During the period, intra-abdominal visceral fat (VF) and subcutaneous fat (SF) volume assessed by helical computerized tomography (CT) showed a substantial reduction [3.9-0.5 l for VF, 19-3.2 l for SF volume]. Pre-heparin plasma lipoprotein lipase (LPL) mass showed a considerably lower value when she had continuous BW reduction than did it when her BW reduction discontinued. These findings suggest that in this subject, continuous BW reduction after the abrupt onset of diabetes is closely associated with intra-abdominal fat mass reduction, which may be related to decreased production of LPL.

Topics: Adipose Tissue; Adult; Body Mass Index; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Female; Glycated Hemoglobin; Humans; Insulin; Japan; Leptin; Lipids; Obesity; Regression Analysis; Tomography, X-Ray Computed

We examined short-term effects of arginine infusion on plasma leptin in diabetic and healthy subjects.. Arginine stimulation tests were performed in C-peptide negative type 1 [DM1; hemoglobin A(1c); 7.3 +/- 0.3%], hyperinsulinemic type 2 diabetic (DM2; 7.6 +/- 0.7%), and nondiabetic subjects (CON; 5.4 +/- 0.1%).. Fasting plasma leptin correlated linearly with body mass index among all groups (r = 0.61, p = 0.001). During arginine infusion, peak plasma insulin was lower in DM1 than in DM2 (p < 0.05) and CON (p < 0.01). Plasma leptin decreased within 30 minutes by approximately 11% in DM1 (p < 0.001), DM2 (p < 0.01), and CON (p < 0.005), slowly returning to baseline thereafter. Plasma free fatty acids (FFAs) were higher in DM1 (0.6 +/- 0.1 mM) and DM2 (0.6 +/- 0.1 mM) than in CON (0.4 +/- 0.1 mM, p < 0.05) and transiently declined by approximately 50% (p < 0.05) at 45 minutes in all groups before rebounding toward baseline. To examine the direct effects of FFAs on plasma leptin, we infused healthy subjects with lipid/heparin and glycerol during fasting, and somatostatin-insulin ( approximately 35 pM) -glucagon ( approximately 90 ng/mL) clamps were performed. In both protocols, plasma leptin continuously declined by approximately 25% (p < 0.05) during 540 minutes without any difference between the high and low FFA conditions.. Arginine infusion transiently decreased plasma leptin concentrations both in insulin-deficient and hyperinsulinemic diabetic patients, indicating a direct inhibitory effect of the amino acid but not of insulin or FFAs.

Topics: Adult; Arginine; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Glucagon; Glycerol; Heparin; Humans; Insulin; Kinetics; Leptin; Male; Middle Aged; Somatostatin

Although obesity is a frequent feature of type 2 diabetes mellitus (DM), many patients with type 1 DM are prone to high body mass index (BMI). We measured serum leptin concentrations in a cohort of children (n = 55) with type 1 diabetes mellitus (DM), as well as their anthropometric parameters including BMI, skin fold thickness at multiple sites, and midarm circumference. Glycemic control was assessed by blood glucose (BG) monitoring before meals, and measurement of glycated hemoglobin (HbA1c) and insulin dose/kg/d was recorded. Dietary evaluation and assessment of caloric intake (kg/d) was performed by an expert dietitian. In the newly diagnosed children (n = 10) before initiation of insulin therapy, circulating leptin concentration was significantly lower (1.1 +/- 0.8 ng/dL) versus 5 days after insulin therapy (1.45 +/- 0.7 ng/dL). The decreased leptin level appears to be related to insulinopenia in these patients. In 45 children with type 1 DM on conventional therapy (2 doses of insulin mixture (NPH and regular) subcutaneous (SC) before breakfast and dinner for more than 2 years), serum leptin concentration was significantly higher (2.15 +/- 1 ng/dL) compared with age-matched normal children (1.3 +/- 1 ng/dL). Diabetic children were further divided into 2 groups according to their HbA1c level: group 1 with HbA1C less than 7.5% (less than 2 SD above the mean for normal population) (n = 29) and group 2 with HbA1c greater than 7.5%. (greater than 2 SD above the mean for normal population) (n = 16). Patients with a higher HbA1c level (group 2) had a higher leptin concentration (2.3 +/- 0.8 ng/dL), higher BMI (17.8 +/- 1.7), and were receiving higher insulin dose/kg (0.92 +/- 0.2 U/kg/d) compared with group 1 (lower HbA1c) (1.78 +/- 0.8 ng/dL, 16.7 +/- 1.5, and 0.59 +/- 0.2 U/kg/d, respectively). Group 2 patients had a higher incidence of late morning hypoglycemia (9/29) versus group 1 patients (2/16). Analysis of dietary intake showed that patients with a higher HbA1c (group 2) consumed more calories (73.5 +/- 10.5 kcal/kg/d) versus patients with lower HbA1c (64.2 +/- 8.7 kcal/kg/d). These findings pointed to the unphysiologic nature of injecting a mixture of insulin twice daily. To cover the relatively big lunch meal (40% to 50% of the total caloric intake in the Arab countries) and prevent afternoon hyperglycemia, there is a great tendency to increase NPH dose before breakfast. This, in turn, induces late-morning hypoglycemia and increases appetite and f

Topics: Blood Glucose; Body Mass Index; Child; Child, Preschool; Cohort Studies; Diabetes Mellitus, Type 1; Energy Intake; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Leptin; Male; Osmolar Concentration; Skinfold Thickness

We have recently shown that leptin, the product of the obese gene, can directly influence T-cell function. In the work presented here, we explored the role of leptin in the development of spontaneous autoimmunity in the nonobese diabetic (NOD) mouse, an animal model for the study of human insulin-dependent diabetes mellitus (type 1 diabetes). We found that expression of serum leptin increased soon before the onset of hyperglycemia and diabetes in susceptible females. A pathogenetic role of leptin was assessed by administering recombinant leptin to young female and male NOD mice. Intraperitoneal injections of leptin accelerated autoimmune destruction of insulin-producing beta-cells and significantly increased interferon-gamma production in peripheral T-cells. These findings indicate that leptin can favor proinflammatory cell responses and directly influence development of autoimmune disease mediated by Th1 responses.

Topics: Animals; Autoimmunity; Diabetes Mellitus, Type 1; Disease Models, Animal; Female; Gene Expression; Interferon-gamma; Leptin; Male; Mice; Mice, Inbred NOD; Pancreas; RNA, Messenger; Species Specificity; Th1 Cells

Leptin is the protein product of the obese (ob) gene, a lipostatic hormone that contributes to body weight regulation through suppressing appetite and/or stimulating energy expenditure in humans and/or rodents. In humans, serum leptin concentrations are increased in relation to increased body fat content. Studies have shown a higher leptin level in women compared with men. However, the gender influence on serum leptin concentrations has never been evaluated in patients with type 1 diabetes. In this study, serum leptin levels and percentage body fat mass were measured in men and women with type 1 diabetes. Fasting serum leptin levels were higher in women (16.7 + 11.6 ng/mL) than in men (3.0 +/- 1.5 ng/mL; P < 0.05) and were independent of exogenous insulin intake and of glucose control. Percentage body fat and fat mass were significant determinants of leptin concentration, whereas age and duration of diabetes were not related to leptin concentration. Subgroups of men (n = 12) and women (n = 11) with total body fat between 20 and 30% were compared. Leptin levels were also higher in women compared with men (13.5 +/- 8.3 ng/mL versus 3.2 +/- 1.7 ng/mL; P < 0.05, respectively). In conclusion, our findings indicate that gender is an important determinant of serum leptin concentration in type 1 diabetics, this gender difference is partly explained by body fat distribution and that type 1 diabetic women may be more resistant than type 1 diabetic men to leptin's alleged lipostatic actions.

Topics: Adipose Tissue; Adolescent; Adult; Diabetes Mellitus, Type 1; Female; Humans; Leptin; Male; Sex Factors

Adolescents, in particular girls, with type 1 diabetes may gain excessive weight during puberty. We present the results of a longitudinal study aimed to determine the roles of leptin and insulin in changes in body composition in subjects with type 1 diabetes and controls. Forty-six children (23 boys) with type 1 diabetes and 40 controls (20 boys) were followed from 8-17 yr of age. Height, weight, and sc skinfolds were assessed every 6 months, and a blood sample taken for leptin determination. Throughout the age range, body mass index (mean +/- SEM) was greater by 1.45 +/- 0.69 kg/m(2) in girls and 1.46 +/- 0.55 kg/m(2) in boys with type 1 diabetes compared with control values. In girls with type 1 diabetes, this reflected greater percent body fat (3.2 +/- 1.0%; P = 0.002), whereas in boys it related to differences in fat-free mass. Both boys and girls with type 1 diabetes had higher leptin levels adjusted for percent body fat than controls; in the girls this was related to insulin dose (regression coefficient B = 0.006 +/- 0.003; P = 0.04) and greater gains in fat mass. Hyperinsulinemia and raised leptin levels are associated with gains in fat mass throughout puberty in girls, but not boys, with type 1 diabetes.

Topics: Adipose Tissue; Adolescent; Aging; Body Composition; Body Height; Body Weight; Child; Diabetes Mellitus, Type 1; Female; Humans; Insulin; Leptin; Longitudinal Studies; Male; Puberty; Sex Characteristics; Skinfold Thickness

Topics: Adult; Blood Pressure; Diabetes Mellitus, Type 1; Female; Humans; Leptin; Male; Radioimmunoassay; Reagent Kits, Diagnostic; Reference Values; Smoking

The aim was to investigate the relationship between body mass index (BMI), plasma leptin, glucose, insulin and C-peptide levels in the offspring of diabetic mothers (DM) and non-diabetic healthy mothers (HM).. Seventy-two offspring (37 girls and 35 boys, age 4-20 years) of DM were investigated in a prospective study. Those 14-16 years old (Tanner stage II-IV) were compared with age-matched offspring of HM (33 girls and 33 boys).. BMI strongly correlated with plasma leptin concentration in the offspring of both DM and HM children. There were higher BMI and plasma leptin and glucose levels in DM than in HM children. There was no difference in plasma insulin or C-peptide levels between HM and age-matched DM children. There was a highly significant positive correlation between plasma leptin and C-peptide in boys of DM.. The higher plasma leptin found in the offspring of DM reflects their higher BMI. A moderately high but still normal glycemia might be a preclinical sign of insulin resistance or other disturbance of glucoregulation.

Topics: Adolescent; Adult; Blood Glucose; Body Mass Index; C-Reactive Protein; Child; Child, Preschool; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Humans; Insulin; Leptin; Longitudinal Studies; Male; Pregnancy; Pregnancy in Diabetics; Prospective Studies

To investigate the frequency of macrosomia in an homogeneous cohort of type 1 diabetic mothers and to analyze the influence of maternal factors and glycemic control on the incidence of fetal macrosomia.. Fifty-five consecutive type 1 diabetic first-pregnancies were prospectively studied. Macrosomia was defined by a ponderal index above the 90(th) percentile. Venous cord blood levels of insulin, C peptide and leptin were measured at delivery. The influence of HbA1c levels and other maternal variables on the occurrence of macrosomia and on the ponderal index was assessed using a stepwise regression logistic model.. The mean (+/- SD) birth weight was 3482 (+/- 497) g at 37.4 +/- 1.0 weeks gestation. Macrosomia occurred in 29 cases (53.7%). Fetal insulin, C peptide and leptin levels were significantly higher in macrosomic than in non macrosomic infants. Maternal age, duration of diabetes, pregravid body mass index, parity, weight gain during pregnancy, presence of a microangiopathy, nephropathy, smoking habits, gestational hypertension or preeclampsia, and HbA1c levels throughout pregnancy did not differed between mothers of macrosomic and non macrosomic infants. In the stepwise analysis none of these covariates was explanatory of the ponderal index.. The frequency of macrosomia remains very high in infants of type 1 diabetic mothers despite a reasonable degree of glycemic control. The variability of the fetal growth response to mild hyperglycemia prompts for the identification of other factors involved in the modulation of fetal growth.

Topics: Adult; Birth Weight; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Embryonic and Fetal Development; Female; Fetal Macrosomia; Gestational Age; Glycated Hemoglobin; Humans; Hypoglycemia; Infant, Newborn; Insulin; Leptin; Maternal Age; Placenta; Pregnancy; Pregnancy in Diabetics; Prospective Studies; Reference Values

Leptin is an important weight regulator and during pregnancy leptin is not only synthesized in adipose tissue but also in the placenta.. To examine changes in serum leptin levels in women with type 1 diabetes mellitus during pregnancy and post delivery in relation to concomitant changes in maternal body weight, birth weight, glycemic control, and blood pressure.. Non-fasting serum leptin from 45 women with type 1 diabetes mellitus were studied consecutively throughout pregnancy and 3 months post partum.. Serum leptin was positively associated with HbA1c in week 18, 22 and 30 (r=0.38, 0.41, and 0.54, respectively, p<0.05, adjusted for body weight). Moreover, serum leptin correlated positively with maternal body weight and BMI (0.4525 kg/m2), the changes during pregnancy and the level of serum leptin were significantly greater compared to lean women (p<0.05). The women with low ambulatory blood pressure (lower tertile, mean arterial blood pressure <83.4 mmHg) showed the lowest level of serum leptin throughout pregnancy and it changed significantly differently from the women with higher blood pressure (p<0.05).. Changes in serum leptin levels of pregnant women with type 1 diabetes mellitus were associated with parallel changes in maternal body weight and glycemic control. Women with low blood pressure had the lowest serum leptin levels throughout pregnancy.

Topics: Adult; Birth Weight; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Insulin; Leptin; Pregnancy; Pregnancy in Diabetics

Infants of diabetic mothers have been characterized by macrosomia due to hyperinsulinism. A relation has been observed between circulating levels of leptin and the intrauterine growth pattern.. We studied the leptin and insulin concentrations in the cord blood of 29 newborn infants of mothers with type 1 diabetes (iT1DM), 70 newborn infants of mothers with gestational diabetes and 105 newborn infants of nondiabetic mothers.. There were significant differences (p < 0.001) between the 3 groups with the highest leptin levels 24.9 microg/l (range 1.7-94.1) in infants of mothers with iT1DM and the second-highest levels 14.0 microg/l (range 2.6-74.9) in infants of mothers with gestational diabetes (iGDM), whereas the control infants had the lowest leptin levels 10.0 microg/l (range 0.10-45.9). Girls had higher leptin concentrations than boys among the iT1DM and control infants. The insulin concentrations were 18.1 mU/l (range 1.9-123.3), 6.1 mU/l (range 1.1-51.4) and 3.6 mU/l (range 0.5-21.5) in the 3 groups (p < 0.001), respectively. A significant correlation was observed between leptin and insulin concentrations in iGDM and control infants (r = 0.51; p < 0.001 and r = 0.25; p < 0.05). Both absolute and relative birth weights correlated with leptin levels in all 3 groups (r = 0.60, p = 0.01 and r = 0.51, p = 0.05 in iT1DM; r = 0.51 and 0.56, p < 0.001 in iGDM and r = 0.42 and 0.59, p < 0.001 in control infants).. Our results confirm the relation between leptin concentrations and birth weight. They also suggest that leptin may be involved in the increased accumulation of adipose tissue characteristic of infants of diabetic mothers.

Topics: Diabetes Mellitus, Type 1; Diabetes, Gestational; Female; Fetal Blood; Gestational Age; Humans; Infant, Newborn; Insulin; Leptin; Male; Pregnancy

To evaluate the changes of serum leptin levels after weight reduction in diabetic subjects with and without microalbuminuria, we studied 10 obese healthy subjects, 12 obese diabetics with persistent microalbuminuria and 10 obese diabetic subjects without microalbuminuria. Obese diabetic patients with microalbuminuria showed serum leptin levels significantly higher than normoalbuminuric diabetics, while no difference was found between obese diabetics without microalbuminuria and healthy controls. All obese subjects followed a 12-month intensive weight reduction program during which the mean change in body mass index was similar between obese diabetic and obese healthy subjects (obese diabetics without microalbuminuria: 35.2+/-4.3 vs 29.9+/-4.1, p<0.05; obese diabetics with microalbuminuria: 35.7+/-3.9 vs 30.3+/-4.0, p<0.05; obese healthy subjects: 35.5+/-4.0 vs 30.1+/-3.9, p<0.05). The mean changes in serum leptin levels tended to be similar in two groups of subjects studied (obese diabetics without microalbuminuria: 37.6+/-4.1 vs 19.7+/-4.9, p<0.001; obese healthy subjects: 37.1+/-4.3 vs 20.1+/-5.1, p<0.001); obese microalbuminuric subjects showed higher leptin levels (42.4+/-4.0 vs 30.3+/-4.2, p<0.001) than normoalbuminuric diabetic and obese healthy subjects. In conclusion, during weight loss, independently from the quality of metabolic control, serum leptin concentrations declined in both groups of obese diabetics. The changes of leptin in diabetics seem to be similar to those observed in healthy obese subjects.

Topics: Adolescent; Albuminuria; Body Mass Index; Body Weight; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Follow-Up Studies; Humans; Leptin; Obesity; Weight Loss

To study the contribution of a normal intake of nutrients to the variability of serum leptin concentrations in persons with type 1 diabetes mellitus.. We studied the relation between serum leptin and nutrient intake in a cross-sectional study.. Serum leptin measured by radioimmunoassay, nutritional data determined by a self-administered 7-day nutritional questionnaire, and the fatty acid composition of the serum phospholipids (measured by thin layer chromatography and gas chromatography) were determined in 60 patients with type 1 diabetes mellitus. Correlation and regression analyses were performed between serum leptin and dietary fatty acids and serum phospholipid fatty acids.. In the prediction models for the concentrations of serum leptin in men with type 1 diabetes mellitus, the dietary fatty acids displaced the anthropometric variables, and were independent of the serum testosterone concentrations. This fact remained when the prediction was made on the basis of indirect markers of the intake, such as the serum phospholipid fatty acids. In the women, the fatty acids from the diet or from the serum phospholipids also partly explained the variation in serum leptin, although not displacing the anthropometric variables.. Our data suggest that, in non-experimental conditions, the concentrations of serum leptin in men with type 1 diabetes mellitus and, to a lesser extent, those in women with diabetes, may be influenced by the composition of the habitual diet, especially the type of dietary fat.

Topics: Adolescent; Adult; Chromatography, High Pressure Liquid; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Dietary Fats; Dietary Proteins; Energy Intake; Fatty Acids; Feeding Behavior; Female; Humans; Leptin; Male; Phospholipids; Predictive Value of Tests; Radioimmunoassay; Regression Analysis; Surveys and Questionnaires

Leptin circulates in serum bound to high molecular weight proteins. Hypothesizing that leptin binding proteins may regulate the functional efficiency of leptin, we characterized auxologic and hormonal factors that influence leptin binding in three disparate groups: normal adolescents, obese children, and teenagers with type I diabetes mellitus (IDDM). Specific leptin binding activity (sLBA) was assessed by column chromatography after incubation of serum with 125I-leptin in the presence and absence of excess unlabeled leptin. Mean sLBA was 17.0 +/- 7% (SD) in the healthy adolescents (n=41), 6.6 +/-4.3% in the obese children (n=26), and 14.9 +/-7.3% in the diabetic teenagers (n=17). At any value of sLBA, obese children had higher serum leptin levels than non-obese adolescents or diabetic teenagers, consistent with "leptin resistance" in the obese group. sLBA was higher in males than in females only in those with diabetes (18.6 +/- 7.3 vs 10.9 +/- 5.1%, p<0.05). sLBA correlated inversely with serum insulin-like growth factor-I values in the normal group (r= -0.45, p<0.01) and with insulin in the obese children (r= -0.53, p<0.01). There was no correlation between sLBA or serum leptin values and HbA1c, in the diabetic group. The serum leptin concentration was the principal determinant explaining the total variability of sLBA in all three cohorts. However, body mass index (BMI = weight/ height2) accounted for more of the total variability of percent specific binding in the healthy adolescents than in the other groups. We conclude that sLBA reflects circulating leptin levels, body composition, and hormonal milieu. Thus, in addition to leptin, qualitative and quantitative characteristics of leptin binding may play a physiological role in the regulation of appetite and in the "leptin resistance" of obesity.

Topics: Adolescent; Body Mass Index; Case-Control Studies; Child; Diabetes Mellitus, Type 1; Female; Humans; Leptin; Male; Obesity; Protein Binding

Leptin, the product of the ob gene, is an adipocyte-derived hormone that positively correlates with body fat percantage and body mass index (BMI). There are many data which demonstrate a significant relationship between leptin and insulin, but the mechanism underlying the changes of leptin induced by insulin and vice versa remains to be studied in more detail. In this review, we analysed the data on the behaviour of serum leptin levels in non-obese and obese children with type 1 diabetes mellitus. It has been shown that the diminished serum leptin concentrations in patients with newly discovered insulin-dependent diabetes mellitus (IDDM) could be caused by insulin deficiency and/or increased lipolysis. Moreover, while in some studies in diabetic children with good metabolic control the serum leptin levels are similar to those of healthy children, in other studies children with IDDM have leptin levels higher than non diabetic children; it is possible that in some diabetic children intensified insulin therapy could cause chronic hyperinsulinemia with high leptin levels. The mean serum leptin concentrations in the obese diabetic subjects were significantly higher when compared with non-obese diabetics. Obese diabetic patients showed no significant differences in leptin concentrations in comparison to the non diabetic obese group matched by age, sex and BMI. In obese diabetics, during weight loss, independent of the quality of metabolic control, serum leptin concentration declines. The changes of leptin in diabetes seem to be similar to those observed in healthy obese subjects.

Topics: Adult; Age Factors; Child; Child, Preschool; Diabetes Mellitus; Diabetes Mellitus, Type 1; Female; Humans; Insulin; Leptin; Male; Obesity; Sex Factors; Weight Gain; Weight Loss

The ratio of two families of inositol phosphoglycans (IPG-A:IPG-P), insulin second messengers, is raised in non-insulin-dependent diabetes mellitus (NIDDM) and obesity. It is shown here that IPG A type inhibits leptin release from adipocytes, contrasting with the action of insulin (stimulation) and IPG P type (no effect). The significance of inhibitory effects of IPG A type on leptin release is important in relation to obesity and NIDDM in view of the action of leptin in promoting Lep expression and fat oxidation in muscle, in addition to its effects on satiety. Energy conservation and oxidation via interorgan regulation by leptin could be compromised by a rise in the IPG-A:IPG-P ratio.

Topics: Adipocytes; Animals; Body Mass Index; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Humans; Inositol Phosphates; Insulin; Leptin; Male; Obesity; Polysaccharides; Rats; Rats, Wistar

The purpose of this study was to examine whether fetal leptin concentration correlates with severity of chronic or subchronic fetal hypoxia as indicated by increased fetal concentrations of erythropoietin in fetuses of mothers with Type I (insulin dependent) diabetes mellitus.. We measured leptin and erythropoietin concentrations in cord plasma and amniotic fluid with radioimmunoassay in 25 pregnancies (gestational age 37.2 +/- 1.0 weeks). Fetuses with amniotic fluid erythropoietin over 22.5 mU/ml were classified as hypoxic (n = 9) and those with amniotic fluid erythropoietin below 22.5 mU/ml (n = 16) as non-hypoxic.. The hypoxic fetuses had significantly higher cord leptin concentrations than non-hypoxic fetuses (median 36.8; range, 12.5-135.1 vs median 16.2; range, 3.7-52.2 micrograms/l), (p = 0.0066). Cord plasma leptin (n = 25) correlated directly with amniotic fluid erythropoietin (r = 0.727, p = 0.0001), with cord plasma erythropoietin (r = 0.644, p = 0.0005) and with the maternal last trimester HbA1C (r = 0.612, p = 0.0019) and negatively with cord artery pO2 (r = -0.440, p = 0.032), and pH (r = -0.414, p = 0.040).. Fetal leptin concentrations increased concomitantly with erythropoietin during chronic or subchronic hypoxia. This phenomenon could indicate a role for leptin in fetal adaptation to hypoxia.

Topics: Amniotic Fluid; Birth Weight; Body Constitution; Diabetes Mellitus, Type 1; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Gestational Age; Glycated Hemoglobin; Humans; Infant, Newborn; Leptin; Male; Pregnancy; Pregnancy in Diabetics; Reference Values; Regression Analysis

Leptin expression in third trimester placenta (p) and leptin concentrations in umbilical cord blood (cb) were investigated in normal pregnancies [n = 10 (p), 31 (cb)] and abnormal pregnancies complicated with (i) maternal insulin-dependent diabetes [IDDM: n = 3 (p), 13 (cb)], (ii) gestational diabetes [GD: n = 2 (p), 10 (cb)] and (iii) fetal growth retardation [FGR: n = 5 (p), 5 (cb)]. By in-situ hybridization and immunohistochemistry, placental leptin mRNA and protein were co-localized to the syncytiotrophoblast and villous vascular endothelial cells. Leptin receptor was immunolocalized to the syncytiotrophoblast. Relative to controls, the FGR group was characterized by low concentrations of placental and cord blood leptin. In a twin pregnancy, the normal-sized infant exhibited more placental and cord blood leptin than its growth-retarded twin. In contrast, both diabetic groups exhibited high concentrations of placental leptin mRNA and protein. The IDDM group exhibited the highest concentrations of leptin in cord blood. No change was observed in the expression of the leptin receptor in either the growth-retarded or diabetic pregnancies. In conclusion, the localization of placental leptin suggests that it may be released into both maternal and fetal blood. Furthermore, in fetal growth-retarded and diabetic pregnancies, the changes in leptin expression in the placenta and in leptin concentrations in umbilical cord blood appear to be related.

Topics: Carrier Proteins; Diabetes Mellitus, Type 1; Female; Fetal Blood; Fetal Growth Retardation; Humans; Insulin; Leptin; Placenta; Pregnancy; Pregnancy in Diabetics; Pregnancy Trimester, First; Pregnancy Trimester, Third; Receptors, Cell Surface; Receptors, Leptin; Reference Values

To determine the relation between plasma leptin concentrations and metabolic control in human diabetes mellitus.. Cross sectional study consisting of 156 patients with diabetes mellitus type 1 (n=42), type 2 (n=114), and non-diabetic subjects (n=74).. Plasma leptin concentrations were lower (P<0.05) in type 1 (8.3+/-1.7 ng/ml) and type 2 diabetic (14.9+/-1.8 ng/ml) than in non-diabetic humans (18.3+/-1.9 ng/ml). Only female type 1 and type 2 diabetic subjects also had decreased leptin/BMI ratios (P<0.05 vs non-diabetic females). The log rank test identified age-adjusted correlation of plasma leptin concentration with sex (P<0.0004) and body mass index (P<0.0218), but not with glycosylated haemoglobin A1c (P>0.5) in all groups. Plasma leptin was correlated with age (P<0.0058) and serum triglycerides (P<0.0199) in type 1 diabetic patients, and with serum cholesterol (P<0.0059) and LDL (P<0.0013) in type 2 diabetic patients.. Defective leptin production and/or secretion might be present independently of metabolic control in female patients with type 1 or type 2 diabetes mellitus.

Topics: Adult; Body Mass Index; Case-Control Studies; Cholesterol; Cholesterol, LDL; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Leptin; Male; Middle Aged; Obesity; Sex Factors; Triglycerides

To compare serum leptin levels in type 1 diabetic and obese children.. We studied serum leptin levels in 35 type 1 diabetic, 32 obese, and 35 healthy children. Seven of 35 were new-onset diabetics with ketoacidosis. C-peptide (CPE) levels were used for estimating insulin secretion.. Serum leptin levels were lower in diabetics than in controls (p<0.001). Obese children had higher leptin and CPE levels than diabetics and controls. In new-onset diabetics, 1 month insulin treatment did not cause any change in leptin levels (p>0.05). Leptin was correlated positively with body mass index and CPE (p<0.001) and inversely with glucose (p = 0.001) and HbA1c (p<0.05) in the combined group. HbA1c and gender were the independent predictors of leptin in diabetic children (p<0.01).. Low serum leptin levels in type 1 diabetic children may be due to chronic insulin deficiency related with their metabolic control. Leptin and insulin may have complementary roles in maintaining a stable body weight.

Topics: Adolescent; Body Mass Index; Body Weight; C-Peptide; Child; Diabetes Mellitus, Type 1; Female; Humans; Insulin; Leptin; Male; Matched-Pair Analysis; Obesity; Statistics as Topic

It is proposed that an important function of leptin is to confine the storage of triglycerides (TG) to the adipocytes, while limiting TG storage in nonadipocytes, thus protecting them from lipotoxicity. The fact that TG content in nonadipocytes normally remains within a narrow range, while that of adipocytes varies enormously with food intake, is consistent with a system of TG homeostasis in normal nonadipocytes. The facts that when leptin receptors are dysfunctional, TG content in nonadipocytes such as islets can increase 100-fold, and that constitutively expressed ectopic hyperleptinemia depletes TG, suggest that leptin controls the homeostatic system for intracellular TG. The fact that the function and viability of nonadipocytes is compromised when their TG content rises above or falls below the normal range suggests that normal homeostasis of their intracellular TG is critical for optimal function and to prevent lipoapoptosis. Thus far, lipotoxic diabetes of fa/fa Zucker diabetic fatty rats is the only proven lipodegenerative disease, but the possibility of lipotoxic disease of skeletal and/or cardiac muscle may require investigation, as does the possible influence of the intracellular TG content on autoimmune and neoplastic processes.

Topics: Adipocytes; Aged; Animals; Cell Transformation, Neoplastic; Colorectal Neoplasms; Diabetes Mellitus; Diabetes Mellitus, Type 1; Energy Intake; Fatty Acids; Fatty Acids, Nonesterified; Homeostasis; Humans; Islets of Langerhans; Leptin; Liver Diseases; Models, Biological; Obesity; Proteins; Rats; Rats, Zucker; Risk Factors; Triglycerides

To determine the effect of acute insulin withdrawal and its subsequent replacement on components of the insulin-like growth factor (IGF)-1 binding protein system and on circulating leptin levels in patients with type 1 diabetes. Seventeen patients (age 31 yr +/-10) with type 1 diabetes treated with continuous subcutaneous insulin infusion (HbA1c 7.6% +/-1.0) were studied. The protocol consisted of two phases: acute insulin withdrawal of up to 8 h followed by a further 2-h period of insulin replacement. For the first phase the basal insulin infusion was stopped (at 0300 h), and for the second a single dose of either regular human or insulin lispro was given subcutaneously (0.2 U/kg). Plasma insulin, glucose, growth hormone, glucagon, IGF-1, free IGF-1, IGFBP-1, -2, -3 and leptin were measured.. After interruption of the basal insulin infusion, plasma free insulin levels fell from 60+/-12.0 pmol/L to 10.8+/-4.2 pmol/L, and plasma glucose rose from 5.6+/-0.4 mmol/L to 14.8+/-1.2 mmol/L (P< 0.01). During insulin withdrawal, IGFBP-1 increased by more than 6-fold (from 32+/-8 to 205+/-17 ng/mL, P<0.001), IGFBP-3 increased significantly (from 2631+/-118 to 3053+/-101 ng/mL, P<0.001), and total IGF-1 levels declined modestly (from 226+/-33 to 182+/-26 ng/mL, P<0.001). In contrast, free IGF-1 concentrations (0.72+/-0.22 ng/mL at baseline) were markedly suppressed during insulin withdrawal to values below the detection limit of the assay (0.08 ng/mL) in 15 of the 17 patients (P<0.001). Circulating plasma leptin declined markedly in females from 20+/-3 ng/mL to 11+/-2 ng/mL (P<0.0001) and in males from 10+/-2 ng/mL to 7+/-2 ng/mL (P<0.02). Within 2 h of insulin replacement, the changes in circulating concentrations of IGFBP-1 and IGFBP-3 were partially reversed, and free IGF-1 levels rebounded to 0.54+/-0.22 ng/mL (P<0.1 vs. insulin withdrawal). Growth hormone, glucagon, and IGFBP-2 levels did not change significantly throughout the study. Despite the rapid restoration of plasma insulin and substrate levels, circulating leptin levels continued to fall in the 2-h period after insulin replacement in both females and males. The marked reduction in circulating free IGF-1 after insulin withdrawal and its increase after insulin administration suggest that acute changes in IGFBP concentrations induced by insulin are important regulators of IGF-1 bioavailability in patients with type 1 diabetes. In both males and females, the rapid induction of severe insulin deficiency is associated with a consistent fall in plasma leptin levels.

Topics: Adolescent; Adult; Blood Glucose; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Humans; Infant, Newborn; Insulin; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Middle Aged; Proteins; Sex Characteristics

The growth hormone (GH)/insulin-like growth factor-I (IGF-I) system and leptin both play an important role in the regulation of body composition. Although the regulation of these two hormonal systems by insulin has been under intense investigation, the physiologic interactions between leptin and the GH/IGF-I system remain unknown. In this study, we examined the relationships among circulating leptin and key elements of the IGF-I system in 60 subjects (27 nondiabetic lean, 21 nondiabetic obese, and 12 type 1 diabetic subjects) with a wide range of insulin secretory capacity. Leptin, glucose, insulin, free IGF-I, total IGF-I, IGF-binding protein-1 (IGFBP-1), and IGFBP-3 levels were measured in the basal state after an overnight fast, and the acute insulin response to glucose (AIRG) was determined after intravenous glucose injection. AIRG was significantly higher (P < .01) in the obese (3,365+/-562 pmol/L x min) versus lean subjects (1,624+/-155 pmol/L x min). In simple regression analysis, the serum leptin concentration was positively correlated with the body mass index ([BMI] men, r = .51, P = .005; women, r = .71, P < .001), IGFBP-3 (men, r = .20, P = nonsignificant; women, r = .41, P < .025), and AIRG (men, r = .73, P < .001; women, r = .62, P < .01). There was a nonlinear correlation between leptin and IGFBP-1, but there was no correlation between leptin and free or total IGF-I. In multiple regression analysis with leptin as the dependent variable, gender, BMI, and IGFBP-3 entered the equations at a statistically significant level. The correlation of leptin with IGFBP-3 was independent of obesity and persisted after correction for AIRG, suggesting a link between leptin and GH action.

Topics: Adult; Body Mass Index; Diabetes Mellitus, Type 1; Female; Glucose; Humans; Injections, Intravenous; Insulin; Insulin Secretion; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Obesity; Proteins; Reference Values

The aims of this study were to analyse the changes of serum leptin in newly diagnosed children and adolescents with Type I (insulin-dependent) diabetes mellitus after insulin treatment and to examine the possible impact of ketoacidosis on these changes.. Baseline serum leptin concentrations were measured in 28 newly diagnosed Type I diabetic patients [age 8.75 +/- 4.05 years (means +/- SD); BMI 15.79 +/- 2.47 kg/m(2); HbA(1 c) 11.3 +/- 1.9 %] with (n = 18) and without (n = 10) ketoacidosis before commencement of insulin treatment, at the time of diagnosis. Thereafter, during a 4-day course of continuous intravenous insulin injection to gain and maintain euglycaemia, serum leptin concentrations were assessed.. Baseline serum leptin concentrations, adjusted to age, BMI, sex and pubertal stage, differed among these patients. There was, however, an increase of leptin in all subjects from 1.37 +/- 0.56 ng/ml (mean +/- SD) up to 2.97 +/- 1.52 ng/ml by 117 % (p < 0.0001) after insulin therapy. On average, peak serum leptin concentration was obtained after 42 h of insulin treatment. Further, there was no difference in the mean increase of serum leptin concentrations in the two groups, namely with and without ketoadicosis, of insulin-dependent diabetic children and adolescents. In addition, there was no correlation between serum leptin concentrations and correction of ketoacidosis during insulin treatment.. Insulin increases serum leptin, within 1 day, in children and adolescents with newly diagnosed Type I diabetes. Ketoacidosis does not influence this interaction between insulin and leptin.

Topics: Adolescent; Blood Glucose; Child; Child, Preschool; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Female; Humans; Hypoglycemic Agents; Infant; Insulin; Kinetics; Leptin; Male; Proteins

Leptin has been implicated in the regulation of body weight and energy balance; Leptin is produced by adipocytes and placental tissue. Chronic fetal hyperinsulinemia and accelerated fetal growth with increased amounts of body fat are frequent findings in the offspring of diabetic mothers. In this study, we examined whether leptin levels in cord blood of infants of type 1 diabetic mothers (n = 29), gestational diabetic mothers (n = 6 and controls (n = 96) correlated with level of maternal glucose control, maternal leptin level at delivery, gender, fetal and placental size, and C-peptide in cord blood at birth. Leptin was significantly elevated in infants of type 1 diabetic (24.7 ng/ml) and gestational diabetic mothers (29.3 ng/ml) as compared to controls (7.9 ng/ml). C-peptide was also significantly higher in infants of type 1 diabetic (0.91 nmol/l) and gestational diabetic mothers (0.99 nmol/l) vs controls (0.34 nmol/l). Infants of type 1 diabetic mothers with a leptin level in cord blood above the upper normal range, i.e. > 30 ng/ml (n = 13), had an average maternal HbA1c level of 5.4% (normal < 5.5%) that was not different from 5.2% in infants with a leptin level < 30 ng/ml (n = 15). In both neonatal groups of diabetic mothers, leptin in cord blood did not correlate with maternal leptin concentrations, placental weight, birthweight, gender and cord blood C-peptide. In controls, leptin in cord blood was higher in girls than in boys (p = 0.044) and correlated significantly with birthweight (p = 0.41, p < 0.001) and cord blood C-peptide (p = 0.44, p < 0.001) but not with maternal leptin level or placental weight. The 3-4 times higher leptin levels in the offspring of diabetic mothers than normal could reflect increased adipose tissue mass and/or increased contribution from other sources such as placental tissue.

Topics: Birth Weight; C-Peptide; Diabetes Mellitus, Type 1; Diabetes, Gestational; Female; Fetal Blood; Gestational Age; Humans; Infant, Newborn; Leptin; Male; Organ Size; Placenta; Pregnancy; Pregnancy in Diabetics; Proteins; Sex Characteristics

Secretion of leptin, the obese gene product, is stimulated by insulin and glucocorticoids and reduced by fasting. In subjects with diabetic ketoacidosis (DKA), severe insulinopenia and prolonged fasting might cause a decrease in serum leptin levels, and subsequent insulin therapy would reverse the decrease. Otherwise, some other confounding factors, neither insulin nor fasting, might affect serum leptin levels in patients with DKA. The present study was undertaken to address these issues. Eleven patients with type 1 diabetes mellitus (seven males and four females, aged 44+/-6 years, mean +/- SEM), admitted to Jichi Medical School Hospital presenting DKA, were studied during the therapeutic period. Thirty-five sex-, age- and body mass index-matched healthy subjects served as controls. Serum leptin levels at the hospitalization were significantly greater than those of the matched control subjects (5.5+/-1.0 vs. 3.2+/-0.3 microg/l, P < 0.01). After the start of therapy with a small dose of short-acting insulin and a large volume of fluid infusion, serum leptin concentrations further increased to 10.6+/-3.6 microg/l at 24 h, and thereafter the concentrations gradually decreased and normalized at the discharge (3.3+/-0.7 microg/l, day 24+/-4). The peak levels at 24 h were significantly higher than the levels at the discharge (P < 0.05), and also +77+/-34% higher than those at the hospitalization (P < 0.005). Serum cortisol levels (1830+/-200 nmol/l) were markedly elevated at hospitalization. These results indicate that serum leptin levels are increased even under insulinopenia and fasting in the patients with DKA. Such a finding may be associated with marked hyperglycemia or enhanced secretion of glucocorticoid hormone, although the exact mechanisms remain to be elucidated. We speculate that leptin may serve as a stress peptide in DKA, but further analysis is necessary to explore a physiological role of leptin in DKA.

Topics: Adolescent; Adult; Aged; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Ketone Bodies; Leptin; Male; Middle Aged; Reference Values; Time Factors

Children with diabetes mellitus are prone to develop obesity and to experience a delay in onset of the pubertal process. In order to understand the role of leptin in these abnormalities, serum leptin levels were analysed in children with type 1 diabetes mellitus.. Twenty diabetic girls, 23 diabetic boys and 66 healthy children (selected from a reference population of 706 normal children), age-, sex- and BMI-matched with diabetic patients, were studied.. Standing height, weight and BMI were determined in each child. Serum testosterone, oestradiol and leptin were measured by specific radioimmunoassays, and HBA1c by high performance liquid chromatography.. Both diabetic girls and boys showed higher leptin levels than the normative healthy population and a group of age-, sex- and BMI-matched normal children. In an age-related analysis, leptin levels in diabetic girls rose from 7.4 +/- 1.2 and 8.1 +/- 2.1 microg/l for the 5-7.99 and 8-10.99 year groups, to 12.6 +/- 2.4 microg/l for the 11-13.99 year group, and to 15.6 +/- 4.0 microg/l in the 14-15.99 year group in parallel with body weight. Leptin concentrations were parallel but higher (P < 0.05) than those of healthy girls. Diabetic boys had lower leptin levels than girls and, in contrast with normal boys, did not show a drop after the 10-year period. Leptin levels were 4.9 +/- 2.2, 3.9 +/- 0.2, 5.5 +/- 0.6 and 5.1 +/- 0.9 microg/l for the 5-7.99, 8-10. 99, 11-13.99 and 14-15.99 year groups, respectively. When divided by pubertal stage, leptin levels in the prepuberty stage of diabetic girls (8.6 +/- 1.0 microg/l) were higher (P < 0.05) than those in the controls (4.1 +/- 0.4 microg/l). In overt puberty girls, leptin was higher (P < 0.05) for diabetic (15.9 +/- 2.9 microg/l) than for healthy girls (9.2 +/- 1.1 microg/l). In prepubertal boys, differences were observed in leptin levels (4.9 +/- 0.5 microg/l for diabetic boys and 3.4 +/- 0.6 microg/l for healthy boys). In the overt puberty stage, diabetic boys showed higher (P < 0.05) levels of leptin (5.2 +/- 0.7 microg/l) than the healthy matched controls (2.1 +/- 0.2 microg/l). A multiple step regression analysis in the diabetic children revealed no associations between leptin and other relevant variables such as glycosylated haemoglobin, daily insulin dose, or years of suffering from the disease.. Serum leptin levels were higher in diabetic than in healthy children. These differences were not attributable to age, adiposity or stage of pubertal development, and were probably conditioned by the metabolic perturbation intrinsic to the diabetic state, or the chronic hyperinsulinemia.

Topics: Adolescent; Age Factors; Body Mass Index; Case-Control Studies; Child; Child, Preschool; Cross-Sectional Studies; Diabetes Mellitus; Diabetes Mellitus, Type 1; Estradiol; Female; Humans; Leptin; Male; Obesity; Puberty; Regression Analysis; Sex Factors; Testosterone

To test the hypothesis that insulin regulates leptin, we measured the plasma leptin concentration before and during treatment of diabetic ketoacidosis (DKA), a condition characterized by extreme insulin deficiency. The study included 17 patients with type 1 diabetes (7 males and 10 females), aged 10+/-1 yr (mean +/- SE), with a body mass index of 17.6+/-1.9 kg/m2. Patients were treated with continuous insulin infusion and fluid and electrolyte replacement. Plasma leptin was measured every 6 h in the first 24 h, during which patients received a total insulin dose of 0.6-2.0 U/kg. Plasma leptin concentrations were also measured in a control group of 29 stable type 1 diabetic children (12 males and 17 females) and 25 healthy children (11 males and 14 females), aged 11+/-1 yr, with a body mass index of 18.5+/-1.1 kg/m2. Before treatment, plasma leptin concentrations were significantly lower in patients with DKA than those in diabetic and healthy controls (4.9+/-1.2 vs. 9.0+/-1.8 and 11.2+/-2.1 ng/mL, respectively; P < 0.05). In the DKA patients, plasma leptin increased to 6.4+/-1.5, 7.5+/-1.9, 9.1+/-2.7, and 8.9+/-2.5 at 6, 12, 18, and 24 h, respectively, after starting treatment (P = 0.001). Thus, leptin levels increased by 38+/-10% and 92+/-38% within 6 and 24 h of starting treatment. There was no difference in the change in plasma leptin by 24 h between subjects who could eat (n = 7) and those who could not (n = 10). The plasma leptin increase was paralleled by a rise in insulin level and a decline in glucose and cortisol levels at 6 and 24 h. In conclusion, DKA was associated with decreased plasma leptin concentrations. Treatment resulted in a significant increase in plasma leptin, which may be due to the effect of insulin on leptin production. Our data lend support to the hypothesis that insulin is the link between caloric intake and plasma leptin.

Topics: Blood Glucose; Body Mass Index; Child; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Electrolytes; Female; Fluid Therapy; Humans; Hydrocortisone; Insulin; Kinetics; Leptin; Male

Leptin is a recently discovered hormone that appears as a regulator of energy balance. It is important to know whether leptin concentrations are changed under conditions of altered energy homeostasis. Consequently, we examined the effects of exercise with fasting and exercise with feeding on circulating leptin concentrations in healthy men and in type 1 diabetic patients with normal body weight and well controlled diabetes.. Leptin concentrations were determined with radioimmunoassay.. During a 3-h cycle ergometer exercise with fasting, leptin decreased by 42% (P < 0.01) in nine healthy men and by 23% (P = 0.05) in eight male type 1 diabetic patients. Leptin fell equally by 12% (P < 0.03) both in nine healthy men and in eight male type 1 diabetic patients who were studied as a resting control group. The absolute fall in leptin in healthy men was similar in the exercise and resting control groups (0.8 +/- 0.1 microgram.L-1 vs 0.8 +/- 0.2 microgram.L-1). However, due to lower leptin concentration before the exercise, the relative decrease (42%) was greater than during the resting control study (12%, P < 0.005). This difference was not seen in the diabetic patients. Fasting leptin concentration correlated positively with BMI (r = 0.75, P < 0.001) and fasting insulin (r = 0.71, P < 0.01) in healthy men as well as with insulin level (r = 0.54, p < 0.05) in type 1 diabetic patients. When exercise was performed with feeding, and this was associated with a significant rise in serum cortisol level (marathon run, 14 healthy men and 7 type 1 diabetic patients), leptin concentration did not change significantly.. 1) During morning hours, leptin decreases both in healthy men and in type 1 diabetic patients, reflecting a diurnal variation of leptin concentration and the effect of fasting on leptin concentration. 2) The fall in leptin during morning hours is augmented by physical exercise in healthy men. 3) If exercise is performed with feeding and associated with a rise in serum cortisol level, leptin concentration remains unchanged. These data suggest that although exercise may reduce circulating leptin levels, the effect is small and can be counterbalanced by feeding or a rise in serum cortisol concentration.

Topics: Adult; Circadian Rhythm; Diabetes Mellitus, Type 1; Exercise; Fasting; Humans; Leptin; Male; Proteins; Time Factors

The ob protein, termed leptin, is produced by adipocytes and is thought to act as an afferent satiety signal regulating weight through suppressing appetite and stimulating energy expenditure in humans and/or rodents. Insulin has been found to be a potent stimulator of leptin expression in rodents. It is unclear at present whether this insulin action is a direct or an indirect effect. To investigate whether leptin concentrations in children and adolescents with type 1 diabetes (IDDM) were related to metabolic status, body weight, body mass index and insulin treatment, we have measured leptin concentrations in serum from 13 newly diagnosed IDDM patients before the beginning of insulin treatment (8 girls, 5 boys, aged 4.7-17.5 years) and in 134 patients with IDDM during treatment (64 girls, 70 boys, aged 2.6-20.1 years) using a specific radioimmunoassay. The data from patients with diabetes were compared with normative data that were derived from a large cohort of healthy children and adolescents. Serum from children with newly diagnosed diabetes had significantly lower levels of leptin (mean 1.28+/-1.60 ng/ml, range 0.14-6.13 ng/ml) compared with healthy children (n=710) (mean 2.2 ng/ml, range 0.26-14.4ng/ml) and compared with insulin-treated children and adolescents (mean 5.18+/-5.48 ng/ml, range 0.26-29.77 ng/ml) (P<0.0001) even after adjustment for gender and body mass index (BMI). Serum leptin levels in patients with IDDM were significantly correlated with BMI (r=0.42, P<0.0001). Multiple regression analysis showed that age and BMI were significantly correlated with leptin levels, while duration of diabetes, mean HbA1c levels, insulin dose and plasma glucose, triglyceride and cholesterol levels were not. Females had higher serum leptin concentrations than males even when adjusted for BMI (P<0.0001). Surprisingly and most importantly, leptin levels in insulin-treated young adult (Tanner stage 5) patients were significantly higher than values found in the healthy nondiabetic reference population when adjusted for sex, Tanner stage and BMI. These findings suggest that leptin levels in IDDM patients show a similar dependency on adipose tissue and age as in healthy, normal children. The data provide evidence that insulin may be of importance as a regulator of serum leptin levels in vivo not only in rodents but also in humans. It is hypothesized that the elevated BMI-adjusted leptin levels in adolescents with IDDM could indicate either that these patients may

Topics: Adolescent; Body Mass Index; Child; Child, Preschool; Diabetes Mellitus; Diabetes Mellitus, Type 1; Female; Humans; Leptin; Male; Obesity; Proteins; Reference Values; Regression Analysis

The impact of pregnancy and food intake on plasma leptin levels was investigated in insulin-dependent diabetes mellitus (IDDM) patients and healthy normal-weight women. Fourteen women with IDDM and 11 women with no diabetes or family history of diabetes were served a 707-kcal lunch in gestational weeks 34 to 38. Six breast-feeding women from each group were examined a second time within 1 month after delivery. Leptin levels were not different in the two groups either during pregnancy or postpartum. In addition to a positive correlation to body mass index (BMI), leptin levels tended to correlate with gestational weight gain. The leptin concentration during pregnancy was higher than the postpartum level, which was within the range of previously reported levels in non-obese nonpregnant women. Ingestion of the test meal did not affect leptin levels and there were no relationships between leptin and insulin or glucose, for either basal or postprandial (60-minute) levels. Only the insulin dose taken by the diabetic women correlated to leptin level. During pregnancy, there is an augmented energy expenditure and maternal metabolism is altered to increase fat stores. The present observation that leptin levels were elevated in pregnant women suggests an additional role for leptin in the accumulation of body fat.

Topics: Adipose Tissue; Adult; Blood Glucose; Diabetes Mellitus, Type 1; Female; Humans; Insulin; Leptin; Obesity; Pregnancy; Pregnancy Trimester, Third; Proteins

To evaluate serum leptin levels in children and young adults with type 1 (insulin-dependent) diabetes mellitus and to investigate whether they are different in prepuberty, puberty and young adulthood.. Three groups of diabetics (prepubertal, pubertal and young adults) subdivided into obese and non-obese were studied. Three groups of healthy subjects matched for sex, age and body mass index served as controls.. Diabetic patients had serum leptin concentrations similar to those of controls in all three groups. A small non-significant increase in leptin from the prepubertal to the young adult age group for both diabetics and controls was found. A significant association of serum leptin level with body mass index (P < 0.001), female sex (P < 0.001) and age (P < 0.01) in both the diabetic and control group was present. Insulin-dependent diabetes was not associated with higher leptin concentration.. Serum leptin concentrations are similar in diabetic patients and healthy controls. The association between obesity and leptin concentration was similar in the diabetic and non-diabetic subjects. Type 1 diabetes mellitus does not modify serum leptin concentration.

Topics: Adolescent; Adult; Aging; Body Mass Index; Child; Diabetes Mellitus; Diabetes Mellitus, Type 1; Female; Humans; Leptin; Male; Obesity; Proteins; Regression Analysis; Sex Characteristics

Leptin can be considered as a peripheral signal which informs the centers about the mass of energy stores. Studies done on the human adult population have demonstrated that degree of adiposity and insulin levels play a major role as determinants of leptin circulating levels. The aim of this study was to evaluate which factors may influence leptin levels at birth. We examined the role played by baby size and by the metabolic environment the fetus was exposed to during pregnancy. We considered 85 newborns from normal (n = 60), gestational (GDM, n = 17) and pregestational (IDDM = 8) diabetes mellitus mothers. At delivery, blood was taken from the umbilical cord vein. Babies from normal and GDM mothers were subdivided into AGA (appropriate for gestational age) and LGA (large for gestational age). There was no difference in leptin levels between babies from normal or GDM mothers belonging to the same weight category, but leptin levels were always higher in LGA than in AGA newborns, and highly correlated with birth weight (r = 0.34, P = 0.001). Moreover, IDDM mothers gave birth to newborns with significantly higher levels of leptin and insulin when compared with normal and GDM mothers. Diabetes of both GDM and IDDM mothers was clinically well controlled (HbA1c was 4.0 and 7.2, respectively). The correlation between leptin and insulin was significant only when newborns from IDDM mothers were included in the regression analysis (r = 0.39, P = 0.0002). Our results suggest that degree of adiposity is one of the main regulators of leptin concentration in the human newborn and that babies exposed to an altered, though clinically controlled, metabolic environment, as in IDDM mothers, have increased levels of leptin.

Topics: Adipose Tissue; Adult; Birth Weight; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes, Gestational; Female; Glycated Hemoglobin; Humans; Infant, Newborn; Insulin; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor I; Leptin; Multivariate Analysis; Pregnancy; Proteins; Regression Analysis; Testosterone

Insulin is one of the hormonal regulators of leptin synthesis and participates in adipose tissue maintenance. The present study was undertaken to clarify the association of endogenous insulin secretion and mode of therapy with body fat and serum leptin levels in diabetic subjects. We measured the fasting serum C-peptide level, as an estimate of endogenous insulin secretion, and the serum leptin level in 176 Japanese diabetic subjects (79 men and 97 women; age, 55.9+/-14.3 years; body mass index [BMI], 23.8+/-4.1 kg/m2 [mean+/-SD]). Thirty-one subjects were treated with diet therapy alone, 66 with sulfonylurea (SU), and 79 with insulin (including 29 with type I diabetes mellitus). Body fat was analyzed by the impedance method. Serum leptin levels significantly correlated with the BMI and body fat and were higher in women, mainly because of their greater body fat. Serum C-peptide concentrations positively correlated with body fat and serum leptin in subjects treated with diet and SU. In insulin-treated type II diabetic subjects, both serum C-peptide and the daily insulin dose were weakly associated with body fat and serum leptin. In those subjects, despite a lower percent body fat and body fat mass, serum leptin concentrations (10.3+/-8.4 ng/mL) were comparable to the levels in subjects treated with diet (8.8+/-8.5 ng/mL). When compared within the same BMI and body fat groups (BMI 20 to 25 and > 25 kg/m2) including the control subjects matched for age and sex, serum leptin levels were higher in insulin-treated type II diabetic subjects versus the control subjects and diabetic patients treated with diet or SU. Stepwise regression analysis for all of the diabetic subjects showed that both the serum C-peptide level and exogenous insulin administration, as well as the BMI, gender, and age, were determinants of the serum leptin level. In conclusion, endogenous insulin secretion is closely associated with body fat and serum leptin in diabetic subjects treated with diet therapy and SU. In Japanese insulin-treated type II diabetic subjects, both endogenous and exogenous insulin are associated with body fat and serum leptin, which is maintained at levels comparable to or somewhat higher than the levels in control subjects and diabetic patients treated without insulin.

Topics: Adipose Tissue; Adult; Aged; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 1; Female; Humans; Insulin; Insulin Secretion; Ketones; Leptin; Lipids; Male; Middle Aged; Proteins

The regulation of leptin secretion is complex and not entirely understood in humans. Insulin has been shown to stimulate leptin secretion in humans, whereas in vitro data suggest that catecholamines inhibit leptin secretion. The present studies were therefore undertaken to examine the leptin response to hyperinsulinemia in the presence and absence of elevated plasma levels of endogenous catecholamines in humans. Leptin concentrations were determined during both a euglycemic and hypoglycemic hyperinsulinemic clamp study in 10 normal and 10 type I diabetic subjects. Serum leptin increased during the hyperinsulinemic euglycemic clamp in normal (from 6.1 +/- 0.9 to 7.2 +/- 1.1 ng/dl, p = 0.003) and diabetic subjects (from 6.2 +/- 1.4 to 7.8 +/- 1.8 ng/dl, p = 0.001). During hyperinsulinemic hypoglycemia leptin concentrations increased significantly in type 1 diabetic patients (from 5.6 +/- 1.1 to 7.6 +/- 1.7 ng/dl, p = 0.003) but remained unaltered in normals (from 5.5 +/- 0.7 to 5.7 +/- 0.9 ng/dl, p = 0.7). During hypoglycemia in all subjects the increase in leptin was negatively correlated with the increase in epinephrine (r = 0.60, p = 0.005) and positively with the decrease in free fatty acids (r = 0.71, p = 0.003). In conclusion our results indicate that catecholamines play a suppressive role in the regulation of leptin secretion.

Topics: Adult; Blood Glucose; Catecholamines; Diabetes Mellitus, Type 1; Epinephrine; Fatty Acids, Nonesterified; Female; Glucose Clamp Technique; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Leptin; Male; Proteins

To evaluate the relationship between serum levels of leptin and insulin in prepubertal lean, obese and insulin-dependent diabetes mellitus (IDDM) children.. Prepubertal children, 16 lean, 17 obese and 16 IDDM were included in the study. Fastang serum leptin and insulin concentrations were measured by radioimmunoassays.. The serum level of leptin was significantly higher in obese children than in lean and IDDM children (P < 0.0001 and P < 0.0001, respectively), and showed a positive correlation with body mass index (BMI) for the combined group (lean, obese and IDDM; r = 0.77, P < 0.0001). In addition, the serum leptin level was higher in IDDM children than in lean controls (P < 0.01), whereas no difference was found in BMI between the two groups. The mean fasting serum levels of insulin were significantly elevated in IDDM children as compared with lean controls (P < 0.01). A significant positive correlation was found between serum insulin and leptin levels for the combined group (r = 0.37, P < 0.01). When a multiple regression analysis for all subjects was performed, the total contribution of all parameters, including gender, BMI and log insulin, accounted for 75% of the leptin variation. BMI (57.8%), log insulin (14.0%) and gender (3.2%) contributed significantly to this variation.. The elevated concentration of leptin in insulin-dependent diabetic children, independent of body mass index, was probably caused by chronically increased serum insulin levels. We demonstrated that not only body mass index but also insulin was a significant independent predictor of serum leptin concentrations. It is therefore suggested that insulin might play an important role in regulating serum leptin concentrations independent of adiposity.

Topics: Analysis of Variance; Body Mass Index; Child; Diabetes Mellitus, Type 1; Female; Humans; Insulin; Leptin; Male; Obesity; Proteins; Regression Analysis; Sex Factors

To investigate the relationship between leptin levels and IDDM with and without microalbuminuria, fasting serum levels of leptin, insulin, insulin-like growth factor-1 (IGF-1), sex hormone-binding globulin (SHBG), testosterone (SHBG) ratio, blood pressure and body mass index (BMI) were measured in 18 normo- and 11 microalbuminuric females with >5 years of IDDM, and 24 healthy controls in late puberty. Leptin levels were higher in micro- than normoalbuminuric IDDM patients, and lower in healthy controls than in both IDDM groups (p < 0.05, respectively). In multiple regression analysis, presence of IDDM and BMI independently contributed to increased leptin values (R2 = 0.34, p < 0.001). Including IDDM females only, solely low IGF-1 and high testosterone/SHBG were associated with leptin (R2 = 0.39, p = 0.009). Albumin excretion rate (AER) was correlated to leptin (r = 0.48, p = 0.01). With AER as the dependent variable only serum leptin and diastolic blood pressure added to the regression (R2 = 0.59, p < 0.001). In conclusion, serum leptin, independently of BMI, is: (1) increased in IDDM females of late puberty; (2) associated with low IGF-1 and hyperandrogenemia, and (3) related to increased albumin excretion rate in IDDM females.

Topics: 3-Hydroxybutyric Acid; Adolescent; Adult; Albuminuria; Blood Pressure; Body Mass Index; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Fluoroimmunoassay; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Hyperandrogenism; Insulin; Insulin-Like Growth Factor I; Leptin; Proteins; Puberty; Radioimmunoassay; Regression Analysis; Sex Hormone-Binding Globulin; Testosterone

Insulin stimulates ob gene expression and increases serum leptin concentrations in mice and in noninsulin-dependent diabetes mellitus patients. Obese women have higher ob gene messenger ribonucleic acid levels than obese men, suggesting that sex hormones are involved in the regulation of leptin synthesis. We studied the relationship among leptin, insulin, and testosterone in 15 men with insulin-dependent diabetes mellitus (IDDM; age, 29 +/- 2 yr; body mass index, 22.7 +/- 0.5 kg/m2; body fat, 9.5 +/- 1.0%; insulin dose, 44 +/- 4 U/day; hemoglobin A1c, 8.1 +/- 0.3%; diabetes duration, 12.7 +/- 2.0 yr) and 15 healthy control subjects (age, 27 +/- 1 yr; body mass index, 22.6 +/- 0.4 kg/m2; body fat, 9.6 +/- 0.5%) in the fasting state. In addition, the effect of a 4-h euglycemic hyperinsulinemia (approximately 600 pmol/L) on the plasma leptin concentration was determined. The fasting leptin concentration was negatively correlated to plasma testosterone (r = -0.55; P < 0.05) in IDDM patients. The fasting plasma leptin level rose 25% in healthy subjects (from 1.0 +/- 0.2 to 1.3 +/- 0.3 ng/mL; P < 0.05). The leptin levels were higher in IDDM subjects (P < 0.01) and remained unchanged (2.7 +/- 0.2 vs. 2.7 +/- 0.2 ng/mL) during hyperinsulinemia. We reached the following conclusions. 1) In nonobese IDDM patients, leptin synthesis is resistant to the acute effect of insulin. 2) Serum testosterone may contribute to the regulation of leptin synthesis in IDDM patients.

Topics: Adult; Diabetes Mellitus, Type 1; Drug Resistance; Humans; Insulin; Leptin; Male; Osmolar Concentration; Protein Biosynthesis; Proteins; Reference Values; Testosterone

We have studied mechanisms by which leptin overexpression, which reduces body weight via anorexic and thermogenic actions, induces triglyceride depletion in adipocytes and nonadipocytes. Here we show that leptin alters in pancreatic islets the mRNA of the genes encoding enzymes of free fatty acid metabolism and uncoupling protein-2 (UCP-2). In animals infused with a recombinant adenovirus containing the leptin cDNA, the levels of mRNAs encoding enzymes of mitochondrial and peroxisomal oxidation rose 2- to 3-fold, whereas mRNA encoding an enzyme of esterification declined in islets from hyperleptinemic rats. Islet UCP-2 mRNA rose 6-fold. All in vivo changes occurred in vitro in normal islets cultured with recombinant leptin, indicating direct extraneural effects. Leptin overexpression increased UCP-2 mRNA by more than 10-fold in epididymal, retroperitoneal, and subcutaneous fat tissue of normal, but not of leptin-receptor-defective obese rats. By directly regulating the expression of enzymes of free fatty acid metabolism and of UCP-2, leptin controls intracellular triglyceride content of certain nonadipocytes, as well as adipocytes.

Topics: Adipocytes; Animals; Cells, Cultured; Diabetes Mellitus, Type 1; DNA Primers; Enzyme Induction; Epididymis; Fatty Acids, Nonesterified; Homozygote; Ion Channels; Islets of Langerhans; Leptin; Male; Membrane Transport Proteins; Mitochondria; Mitochondrial Proteins; Obesity; Palmitic Acid; Peritoneal Cavity; Polymerase Chain Reaction; Protein Biosynthesis; Proteins; Rats; Rats, Zucker; Recombinant Proteins; RNA, Messenger; Skin; Transcription, Genetic; Transfection; Uncoupling Protein 2

Interleukin 1beta (IL-1beta)-induced beta cell cytotoxicity has been implicated in the autoimmune cytotoxicity of insulin-dependent diabetes mellitus. These cytotoxic effects may be mediated by nitric oxide (NO). Since long-chain fatty acids (FFA), like IL-1beta, upregulate inducible nitric oxide synthase and enhance NO generation in islets, it seemed possible that islets might be protected from IL-1beta-induced damage by lowering their lipid content. We found that IL-1beta-induced NO production varied directly and islet cell viability inversely with islet triglyceride (TG) content. Fat-laden islets of obese rats were most vulnerable to IL-1beta, while moderately fat-depleted islets of food-restricted normal rats were less vulnerable than those of free-feeding normal rats. Severely lipopenic islets of rats made chronically hyperleptinemic by adenoviral leptin gene transfer resisted IL-1beta cytotoxicity even at 300 pg/ml, the maximal concentration. Troglitazone lowered islet TG in cultured islets from both normal rats and obese, leptin-resistant rats and reduced NO production and enhanced cell survival. We conclude that measures that lower islet TG content protect against IL-1beta-induced NO production and cytotoxicity. Leptin or troglitazone could provide in vivo protection against insulin-dependent diabetes mellitus.

Topics: Animals; Cell Survival; Cells, Cultured; Chromans; Diabetes Mellitus, Type 1; Fatty Acids, Nonesterified; Gene Transfer Techniques; Interleukin-1; Islets of Langerhans; Leptin; Lipids; Nitric Oxide; Obesity; Proteins; Rats; Rats, Zucker; Thiazoles; Thiazolidinediones; Triglycerides; Troglitazone

The influence of exogenous insulin and estrogen substitution on serum leptin-like immunoreactivity was studied longitudinally in patients with type-I diabetes and Turner syndrome using a specific radioimmunoassay. Prepubertal, pubertal and postpubertal samples of 17 patients (9 girls, 8 boys) with type-I diabetes mellitus developing obesity were compared to those of 17 normal-weight controls matched for gender, age and diabetes duration. Six obese and six normal-weight girls with Turner syndrome were studied without hormone substitution, with ethinylestradiol alone, and with cyclic estradiol/gestagen substitution. The mean leptin levels of the girls with diabetes were two times higher than boys at all times, while insulin doses and glycemic control had no influence. In Turner syndrome estrogen substitution led to increased leptin levels only in the obese group. This study revealed that both body weight above normal and female sex steroids seem to be necessary to elevate leptin concentrations, while exogenous insulin has no effect.

Topics: Adolescent; Child; Diabetes Mellitus, Type 1; Estrogens; Female; Humans; Insulin; Leptin; Longitudinal Studies; Male; Obesity; Sex Factors; Turner Syndrome

OB-R is a high affinity receptor for leptin, an important circulating signal for the regulation of body weight. We identified an alternatively spliced transcript that encodes a form of mouse OB-R with a long intracellular domain. db/db mice also produce this alternatively spliced transcript, but with a 106 nt insertion that prematurely terminates the intracellular domain. We further identified G --> T point mutation in the genomic OB-R sequence in db/db mice. This mutation generates a donor splice site that converts the 106 nt region to a novel exon retained in the OB-R transcript. We predict that the long intracellular domain form of OB-R is crucial for initiating intracellular signal transduction, and as a corollary, the inability to produce this form of OB-R leads to the severe obese phenotype found in db/db mice.

Topics: Alternative Splicing; Amino Acid Sequence; Animals; Base Sequence; Carrier Proteins; Diabetes Mellitus, Type 1; DNA Primers; DNA, Complementary; Humans; Leptin; Mice; Mice, Inbred Strains; Mice, Obese; Molecular Sequence Data; Obesity; Phenotype; Point Mutation; Polymerase Chain Reaction; Proteins; Receptors, Cell Surface; Receptors, Cytokine; Receptors, Leptin; Sequence Homology, Amino Acid; Signal Transduction

Hyperinsulinemia. is associated with an overexpression of mRNA for the ob protein leptin in rodent models of genetic obesity, and insulin has been reported to directly stimulate leptin mRNA in rat adipocytes. Human obesity is also associated with increased leptin mRNA as well as plasma levels, but there have been no reports of the effect of insulin on leptin secretion. We, therefore, tested the hypothesis that insulin stimulates leptin secretion in humans. Using a newly developed leptin assay, immunoreactive leptin was measured in fasting and postprandial plasma samples from 27 healthy adults and in samples before and during euglycemic-hyperinsulinemic then stepped hypoglycemic (hourly steps at 85, 75, 65, 55, and 45 mg/dl) clamps from 10 healthy subjects and 11 patients with IDDM. Plasma leptin was correlated (r = 0.84, P = 0.0005) with BMI in obese but not nonobese subjects and with fasting (r = 0.75, P = 0.008) but not postprandial plasma insulin levels. (Leptin levels did not change postprandially.) Euglycemic hyperinsulinemia did not alter leptin levels, nor did hyperinsulinemic hypoglycemia. Thus, because circulating leptin levels are not increased during postprandial hyperinsulinemia or during euglycemic (or hypoglycemic) hyperinsulinemia, we conclude that, at least in the short term, insulin does not increase leptin secretion in humans and that hyperleptinemia in obese individuals is not likely the result of hyperinsulinemia.

Topics: Adipocytes; Adult; Animals; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 1; Fasting; Female; Glucose Clamp Technique; Humans; Infusions, Intravenous; Insulin; Leptin; Male; Obesity; Proteins; Rats; Reference Values

Topics: Adipocytes; Animals; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glycation End Products, Advanced; Glycosylation; Humans; Hypoglycemic Agents; Kidney Failure, Chronic; Leptin; Metformin; Mice; Mice, Mutant Strains; Mice, Obese; Obesity; Protein Biosynthesis; Proteins