leptin and Hypoglycemia

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

A role for the sympathetic nervous system in hypertension has been looked for in relation to the 'metabolic syndrome' with associations between body weight, insulin sensitivity and hypertension. By use of microneurography human sympathetic responses to hypoglycaemia, normoglycaemic hyperinsulinaemia and food intake have been studied. A strong but differentiated influence of insulin-induced hypoglycaemia comprises increase in muscle sympathetic nerve activity (MSNA) and the sudomotor part of skin sympathetic nerve activity (SSNA), whereas vasoconstrictor SSNA is inhibited. Responses to infusion of 2-deoxy-D-glucose are identical, suggesting central nervous system glucopenia and not insulin to be the causative factor. Insulin infusion during normoglycaemia evokes a moderate increase in MSNA; SSNA and blood pressure does not change. After glucose ingestion MSNA displays a sustained increase, which is only partly elicited by insulin. A significant albeit weaker increase occurs after pure protein or fat meals, and after glucose ingestion in C-peptide-negative diabetic patients, with no insulin secretion. In healthy elderly people the MSNA response to food intake is weak, because of a high outflow already at rest; this is suggested to explain postprandial hypotension in the elderly, a paradoxical mechanism behind clinical autonomic failure. A pathophysiological role of MSNA in the metabolic syndrome with hypertension has been speculated. An association between obesity and elevated level of MSNA at rest is established; observed relationships to chronic insulin levels and hypertension are less unanimous. The adipose tissue regulating hormone leptin has become one focus of interest in ongoing attempts to elucidate a possible role of the human sympathetic nervous system in the 'metabolic syndrome' and hypertension.

Topics: Adaptation, Physiological; Adipose Tissue; Eating; Glucose; Hemodynamics; Humans; Hyperinsulinism; Hypoglycemia; Hypotension; Insulin; Leptin; Muscles; Obesity; Peripheral Nerves; Skin Physiological Phenomena; Sympathetic Nervous System; Vasodilation

Lifestyle interventions including meal replacement are suitable for prevention and treatment of obesity and type-2-diabetes. Since leptin is involved in weight regulation, we hypothesised that a meal replacement-based lifestyle intervention would reduce leptin levels more effectively than lifestyle intervention alone. In the international, multicentre, randomised-controlled ACOORH-trial (Almased-Concept-against-Overweight-and-Obesity-and-Related- Health-Risk), overweight or obese participants with metabolic syndrome criteria (n = 463) were randomised into two groups and received telemonitoring devices and nutritional advice. The intervention group additionally used a protein-rich, low-glycaemic meal replacement. Data were collected at baseline, after 1, 3, 6, and 12 months. All datasets providing leptin data (n = 427) were included in this predefined subanalysis. Serum leptin levels significantly correlated with sex, body mass index, weight, and fat mass at baseline (p < 0.0001). Stronger leptin reduction has been observed in the intervention compared to the control group with the lowest levels after 1 month of intervention (estimated treatment difference −3.4 µg/L [1.4; 5.4] for females; −2.2 µg/L [1.2; 3.3] for males; p < 0.001 each) and was predictive for stronger reduction of body weight and fat mass (p < 0.001 each) over 12 months. Strongest weight loss was observed after 6 months (−5.9 ± 5.1 kg in females of the intervention group vs. −2.9 ± 4.9 kg in the control group (p < 0.0001); −6.8 ± 5.3 kg vs. −4.1 ± 4.4 kg (p = 0.003) in males) and in those participants with combined leptin and insulin decrease. A meal replacement-based lifestyle intervention effectively reduces leptin which is predictive for long-term weight loss.

Topics: Body Mass Index; Diet, Reducing; Female; Humans; Hypoglycemia; Leptin; Male; Obesity; Overweight; Weight Loss

Reported rates of hypoglycemia in patients with type 2 diabetes mellitus are lower with glimepiride as compared to glyburide. The aim of this study was to determine whether physiologic differences in counterregulatory neuroendocrine and metabolic mechanisms during hypoglycemia provide a basis for the observed clinical differences between glimepiride and glyburide.. Non-diabetic volunteers (age 38±2years, BMI 26±1kg/m(2)) were studied in a single-blind fashion during separate 2day randomized protocols consisting of 2h hyperinsulinemic (9pmol/kg/min) euglycemic (4.9±0.1mmol) and hypoglycemic (2.9±0.1mmol/L) clamps. Individuals received biologically equivalent doses of glimepiride (4mg) or glyburide (10mg) 1h prior to each glucose clamp (n=11) as well as a control group of placebo studies. Glucose kinetics were calculated using D-Glucose-6-6d2.. Insulin and C-peptide levels were increased (p<0.05) during euglycemia in both sulfonylurea groups as compared to placebo. However, despite equivalent hypoglycemia, insulin and C-peptide levels were higher (p<0.05) only after glyburide. Glucagon responses and endogenous glucose production (EGP) were decreased (p<0.05) during hypoglycemia following glyburide administration as compared to glimepiride. Glyburide reduced (p<0.05) norepinephrine responses during euglycemic clamps. In addition combined epinephrine and norepinephrine responses during hypoglycemia were reduced (p<0.05) following glyburide as compared to placebo. Leptin levels fell by a greater amount (p<0.05) during hypoglycemia with both sulfonylureas as compared to placebo.. In summary, glimepiride and glyburide can both similarly increase insulin and C-peptide levels during hyperinsulinemic euglycemia. However, during moderate hyperinsulinemic hypoglycemia (2.9mmol/L) glyburide resulted in increased C-peptide and insulin, but blunted glucagon, sympathetic nervous system and EGP responses. We conclude that glyburide can acutely reduce key neuroendocrine and metabolic counterregulatory defenses during hypoglycemia in healthy individuals.

Topics: Adult; Blood Glucose; C-Peptide; Female; Glucagon; Glucose Clamp Technique; Glyburide; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Leptin; Male; Pancreatic Polypeptide; Single-Blind Method; Sulfonylurea Compounds

Leptin, produced by adipocytes, has homeostatic effects on body fat mass through inhibition of appetite and stimulation of the sympathetic nervous system. Several studies have reported that high-dose exogenous glucocorticoids increase circulating leptin concentrations in humans. Conversely, leptin has inhibitory effects on the hypothalamic-pituitary-adrenal (HPA) axis, both at the hypothalamic and adrenal levels. We hypothesized that acute hypercortisolism, in the physiological range, may not alter leptin secretion. Four stimuli of the HPA axis were administered to eight healthy male volunteers in a placebo-controlled study. On separate afternoons, in a randomised order, fasting subjects received i.v. injections of saline, naloxone (125 microg/kg); vasopressin (0.0143 IU/kg); naloxone and vasopressin in combination; or insulin (0.15 U/kg; a dose sufficient to induce hypoglycaemia). Plasma concentrations of adrenocorticotrophic hormone (ACTH), cortisol and leptin were measured before and for 120 min after the injection. The cortisol secretory response was greatest after insulin-hypoglycaemia, this response was significantly greater than that following naloxone, naloxone/vasopressin, or vasopressin alone. Despite the cortisol release, leptin concentrations were not increased after any stimulus. Insulin-hypoglycaemia was associated with a decrease in leptin concentration at 60 and 90 min, while naloxone did not alter leptin concentrations. However, basal leptin concentrations were positively correlated with integrated ACTH and cortisol responses to naloxone, but did not correlate with ACTH or cortisol responses to the other stimuli. Thus acute elevations of plasma cortisol, in the physiological range, do not appear to influence plasma leptin concentrations. The fall in plasma leptin concentration after insulin-induced hypoglycaemia may reflect catecholamine secretion after this stimulus.

Topics: Adrenocorticotropic Hormone; Adult; Humans; Hydrocortisone; Hypoglycemia; Hypoglycemic Agents; Hypothalamo-Hypophyseal System; Insulin; Leptin; Male; Middle Aged; Naloxone; Narcotic Antagonists; Pituitary-Adrenal System; Vasoconstrictor Agents; Vasopressins

Hypoglycemia is a major barrier to clinical management of persons with diabetes. Emerging evidence supports a role for leptin in gating hypoglycemic counterregulation. This work demonstrates that male leptin receptor null, Zucker (fa/fa), rats display severe impairments in hypoglycemic counterregulation. Thus, augmenting leptin levels may have clinical utility for preventing hypoglycemia.

Topics: Animals; Glucagon-Like Peptide-1 Receptor; Hypoglycemia; Hypoglycemic Agents; Leptin; Male; Obesity; Rats; Rats, Zucker; Receptors, Leptin

Hypoglycemia-associated autonomic failure (HAAF) is a maladaptive failure in glucose counterregulation in persons with diabetes (PWD) that is caused by recurrent exposure to hypoglycemia. The adipokine leptin is known to regulate glucose homeostasis, and leptin levels fall following exposure to recurrent hypoglycemia. Yet, little is known regarding how reduced leptin levels influence glucose counterregulation, or if low leptin levels are involved in the development of HAAF. The purpose of this study was to determine the effect of hypoleptinemia on the neuroendocrine responses to hypoglycemia. We utilized two separate experimental paradigms known to induce a hypoleptinemic state: 60% caloric restriction (CR) in mice and three days of recurrent hypoglycemia (3dRH) in rats. A sub-set of animals were also treated with leptin (0.5-1.0 μg/g) during the CR or 3dRH periods. Neuroendocrine responses to hypoglycemia were assessed 60 min following an IP insulin injection on the terminal day of the paradigms. CR mice displayed defects in hypoglycemic counterregulation, indicated by significantly lower glucagon levels relative to controls, 13.5 pmol/L (SD 10.7) versus 64.7 pmol/L (SD 45) (p = 0.002). 3dRH rats displayed reduced epinephrine levels relative to controls, 1900 pg/mL (SD 1052) versus 3670 pg/mL (SD 780) (p = 0.030). Remarkably, leptin treatment during either paradigm completely reversed this effect by normalizing glucagon levels in CR mice, 78.0 pmol/L (SD 47.3) (p = 0.764), and epinephrine levels in 3dRH rats, 2910 pg/mL (SD 1680) (p = 0.522). These findings suggest that hypoleptinemia may be a key signaling event driving the development of HAAF and that leptin treatment may prevent the development of HAAF in PWD.

Topics: Animals; Blood Glucose; Caloric Restriction; Epinephrine; Hypoglycemia; Hypoglycemic Agents; Insulin; Leptin; Mice; Rats

The sympathetic nervous system (SNS) is a key regulator of the metabolic and endocrine functions of adipose tissue. Increased SNS outflow promotes fat mobilization, stimulates non-shivering thermogenesis, promotes browning, and inhibits leptin production. Most of these effects are attributed to norepinephrine activation of the Gs-coupled beta adrenergic receptors located on the surface of the adipocytes. Evidence suggests that other adrenergic receptor subtypes, including the Gi-coupled alpha 2 adrenergic receptors might also mediate the SNS effects on adipose tissue. However, the impact of acute stimulation of adipocyte Gs and Gi has never been reported.. We harness the power of chemogenetics to develop unique mouse models allowing the specific and spatiotemporal stimulation of adipose tissue Gi and Gs signaling. We evaluated the impact of chemogenetic stimulation of these pathways on glucose homeostasis, lipolysis, leptin production, and gene expression.. Stimulation of Gs signaling in adipocytes induced rapid and sustained hypoglycemia. These hypoglycemic effects were secondary to increased insulin release, likely consequent to increased lipolysis. Notably, we also observed differences in gene regulation and ex vivo lipolysis in different adipose depots. In contrast, acute stimulation of Gi signaling in adipose tissue did not affect glucose metabolism or lipolysis, but regulated leptin production.. Our data highlight the significance of adipose Gs signaling in regulating systemic glucose homeostasis. We also found previously unappreciated heterogeneity across adipose depots following acute stimulation. Together, these results highlight the complex interactions of GPCR signaling in adipose tissue and demonstrate the usefulness of chemogenetic technology to better understand adipocyte function.

Topics: Adipocytes; Animals; Glucose; GTP-Binding Protein alpha Subunits, Gi-Go; GTP-Binding Protein alpha Subunits, Gs; Homeostasis; Hypoglycemia; Insulin; Leptin; Male; Mice, Inbred C57BL; Receptors, G-Protein-Coupled; Signal Transduction

The objective of the present study was to observe the effect of sitagliptin on obese patients with insulin treatment-induced diabetes mellitus.. A total of 120 obese patients with insulin treatment-induced diabetes mellitus were consecutively selected and divided into the control group (n=35), observation group 1 (n=40), and observation group 2 (n=45). The control group received different types or doses of insulin, observation group 1 received insulin combined with metformin, and observation group 2 received insulin combined with sitagliptin. The therapeutic effects were compared at the 6-month follow-up visit.. Body mass index (BMI) was lower in observation group 1 and observation group 2, and higher in the control group compared with before treatment; the occurrence of hypoglycemia in observation group 2 was lower than in the other two groups, and the differences were statistically significant (p<0.05). After treatment, the fasting insulin (FINS) and homeostatic model assessment insulin-resistance (HOMA-IR) in observation group 2 were significantly lower than in the other two groups (p<0.05). Adiponectin levels were increased and leptin and visfatin levels were decreased in observation group 2 after treatment, and the differences were statistically significant (p<0.05). The levels of fasting blood glucose, hemoglobin A1c, total cholesterol, triglyceride, and low-density lipoprotein in the three groups were not significantly different (p>0.05).. Sitagliptin can reduce BMI and the occurrence of hypoglycemia in obese patients with insulin treatment-induced diabetes mellitus, and the effect may be related to decreased HOMA-IR, decreased leptin and visfatin levels, and increased adiponectin levels.

Topics: Adiponectin; Adult; Aged; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Insulin; Insulin Resistance; Leptin; Male; Metformin; Middle Aged; Nicotinamide Phosphoribosyltransferase; Obesity; Sitagliptin Phosphate; Triglycerides

Hypothalamic pro-opiomelanocortin (POMC) neurons regulate energy and glucose metabolism. Intracellular mechanisms that enable these neurons to respond to changes in metabolic environment are ill defined. Here we show reduced expression of activated dynamin-related protein (pDRP1), a mitochondrial fission regulator, in POMC neurons of fed mice. These POMC neurons displayed increased mitochondrial size and aspect ratio compared to POMC neurons of fasted animals. Inducible deletion of DRP1 of mature POMC neurons (Drp1

Topics: Animals; Dynamins; Energy Metabolism; Feeding Behavior; Gene Deletion; Glucose; Hypoglycemia; Leptin; Mice, Inbred C57BL; Mitochondria; Neurons; Potassium Channels, Inwardly Rectifying; PPAR gamma; Pro-Opiomelanocortin; Reactive Oxygen Species; RNA, Messenger

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

The female athlete triad (Triad), links low energy availability (EA), with menstrual dysfunction (MD), and impaired bone health. The aims of this study were to examine associations between EA/MD and energy metabolism and the prevalence of Triad-associated conditions in endurance athletes. Forty women [26.2 ± 5.5 years, body mass index (BMI) 20.6 ± 2.0 kg/m(2), body fat 20.0 ± 3.0%], exercising 11.4 ± 4.5 h/week, were recruited from national teams and competitive clubs. Protocol included gynecological examination; assessment of bone health; indirect respiratory calorimetry; diet and exercise measured 7 days to assess EA; eating disorder (ED) examination; blood analysis. Subjects with low/reduced EA (< 45 kcal/kg FFM/day), had lower resting metabolic rate (RMR) compared with those with optimal EA [28.4 ± 2.0 kcal/kg fat-free mass (FFM)/day vs 30.5 ± 2.2 kcal/kg FFM/day, P < 0.01], as did subjects with MD compared with eumenorrheic subjects (28.6 ± 2.4 kcal/kg FFM/day vs 30.2 ± 1.8 kcal/kg FFM/day, P < 0.05). 63% had low/reduced EA, 25% ED, 60% MD, 45% impaired bone health, and 23% had all three Triad conditions. 53% had low RMR, 25% hypercholesterolemia, and 38% hypoglycemia. Conclusively, athletes with low/reduced EA and/or MD had lowered RMR. Triad-associated conditions were common in this group of athletes, despite a normal BMI range. The high prevalence of ED, MD, and impaired bone health emphasizes the importance of prevention, early detection, and treatment of energy deficiency.

Topics: Adult; Basal Metabolism; Bone Density; Calorimetry, Indirect; Diet Records; Energy Intake; Female; Female Athlete Triad Syndrome; Gynecological Examination; Humans; Hypercholesterolemia; Hypertension; Hypoglycemia; Leptin; Luteinizing Hormone; Menstruation Disturbances; Physical Endurance; Young Adult

Leptin has profound glucose-lowering effects in rodent models of type 1 diabetes, and is currently being tested clinically to treat this disease. In addition to reversing hyperglycaemia, leptin therapy corrects multiple lipid, energy and neuroendocrine imbalances in rodent models of type 1 diabetes, yet the precise mechanism has not been fully defined. Thus, we performed metabolic analyses to delineate the downstream metabolic pathway mediating leptin-induced glucose lowering in diabetic mice.. Mice were injected with streptozotocin (STZ) to induce insulin-deficient diabetes, and were subsequently treated with 20 μg/day recombinant murine leptin or vehicle for 5 to 14 days. Energy-yielding substrates were measured in the liver and plasma, and endogenous glucose production was assessed by tolerance to extended fasting.. STZ-leptin-treated mice developed severe hypoketotic hypoglycaemia during prolonged fasting, indicative of suppressed endogenous ketone and glucose production. STZ-leptin mice displayed normal gluconeogenic and glycogenolytic capacity, but had depleted circulating glycerol and NEFA. The depletion of glycerol and NEFA correlated tightly with the kinetics of glucose lowering in response to chronic leptin administration, and was not mimicked by single leptin injection. Administration of glycerol acutely reversed fasting-induced hypoglycaemia in leptin-treated mice.. The findings of this study suggest that the diminution of circulating glycerol reduces endogenous glucose production, contributing to severe fasting-induced hypoglycaemia in leptin-treated rodent models of type 1 diabetes, and support that depletion of glycerol contributes to the glucose-lowering action of leptin.

Topics: Animals; Blood Glucose; Body Composition; Diabetes Mellitus, Experimental; Glycerol; Hypoglycemia; Insulin; Leptin; Liver; Mice

Leptin has been shown to diminish hyperglycemia via reduced glucagon secretion, although it can also enhance sympathoadrenal responses. However, whether leptin can also inhibit glucagon secretion during insulin-induced hypoglycemia or increase epinephrine during acute or recurrent hypoglycemia has not been examined. To test whether leptin acts in the brain to influence counterregulation, hyperinsulinemic hypoglycemic (∼45 mg/dl) clamps were performed on rats exposed to or not exposed to recurrent hypoglycemia (3 days, ∼40 mg/dl). Intracerebroventricular artificial cerebral spinal fluid or leptin was infused during the clamp. During acute hypoglycemia, leptin decreased glucagon responses by 51% but increased epinephrine and norepinephrine by 24 and 48%, respectively. After recurrent hypoglycemia, basal plasma leptin levels were undetectable. Subsequent brain leptin infusion during hypoglycemia paradoxically increased glucagon by 45% as well as epinephrine by 19%. In conclusion, leptin acts within the brain to diminish glucagon secretion during acute hypoglycemia but increases epinephrine, potentially limiting its detrimental effects during hypoglycemia. Exposure to recurrent hypoglycemia markedly suppresses plasma leptin, whereas exogenous brain leptin delivery enhances both glucagon and epinephrine release to subsequent hypoglycemia. These data suggest that recurrent hypoglycemia may diminish counterregulatory responses in part by reducing brain leptin action.

Topics: Animals; Brain; Feedback, Physiological; Glucagon; Hypoglycemia; Leptin; Male; Rats; Rats, Sprague-Dawley; Recurrence

To show whether intrathecal (i.t.) treatment with pertussis toxin (PTX) produces a hypoglycemic effect in ICR, db/db and streptozotocin-treated mice.. The blood glucose level (BGL) was measured after i.t. treatment with PTX, AB5 toxins and PTX subunits. Insulin or leptin levels were measured after PTX injection. The effect of PTX on the BGL was examined in adrenalectomized (ADX) mice. Glucose transporter (GLUT) levels were determined by Western blotting.. PTX attenuated the elevated BGL in the D-glucose-fed model in a long-term manner. Heat-labile toxin (HLT), HLT subunit B or Shiga toxin, which belong to the AB5 toxins, administered i.t. did not affect the BGL. PTX A protomer (PTX-A) or PTX B oligomers (PTX-B) injected i.t. did not have an effect on the BGL as well. However, combined treatment with PTX-A and PTX-B subunits caused a hypoglycemic effect. The leptin level was gradually reduced by PTX for up to 6 days, without affecting the insulin level. PTX administered i.t. significantly decreased the BGL further in ADX mice. Moreover, GLUT-2 (hypothalamus and pituitary gland), GLUT-4 (muscle) and GLUT-3 (adrenal gland) expression levels were increased, whereas GLUT-1 (brain cortex, liver, muscle and spinal cord), GLUT-2 (liver) and GLUT-3 (brain cortex and pituitary gland) expression levels were decreased.. Our data suggest that PTX administered spinally produces a hypoglycemic effect in a long-term manner, and PTX-induced hypoglycemia appears to be mediated by the reduction in activity of the glucocorticoid system. Furthermore, PTX may modulate the insulin level during hypoglycemia. Among GLUTs, GLUT-4 in muscle, GLUT-2 in the liver, hypothalamus and pituitary gland as well as GLUT-1 in the adrenal gland may be responsible for PTX-induced hypoglycemia.

Topics: Animals; Blood Glucose; Blotting, Western; Diabetes Mellitus, Experimental; Glucose Transport Proteins, Facilitative; Hypoglycemia; Hypoglycemic Agents; Injections, Spinal; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Pertussis Toxin; Streptozocin; Time Factors

Hypoglycemia initiates the counter-regulatory response (CRR), in which the sympathetic nervous system, glucagon and glucocorticoids restore glucose to appropriate concentrations. During starvation, low leptin levels restrain energy utilization, enhancing long-term survival. To ensure short-term survival during hypoglycemia in fasted animals, the CRR must overcome this energy-sparing program and nutrient depletion. Here we identify in mice a previously unrecognized role for leptin and a population of leptin-regulated neurons that modulate the CRR to meet these challenges. Hypoglycemia activates neurons of the parabrachial nucleus (PBN) that coexpress leptin receptor (LepRb) and cholecystokinin (CCK) (PBN LepRb(CCK) neurons), which project to the ventromedial hypothalamic nucleus. Leptin inhibits these cells, and Cck(cre)-mediated ablation of LepRb enhances the CRR. Inhibition of PBN LepRb cells blunts the CRR, whereas their activation mimics the CRR in a CCK-dependent manner. PBN LepRb(CCK) neurons are a crucial component of the CRR system and may be a therapeutic target in hypoglycemia.

Topics: Animals; Blood Glucose; Energy Metabolism; Female; Hypoglycemia; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Organ Culture Techniques; Parabrachial Nucleus; Receptors, Leptin

Leptin and glucocorticoids (GCs) are involved in metabolic functions, thymic homeostasis and immune activity through complex interactions. We recently showed that C57BL/6 mice infected with Trypanosoma cruzi revealed a fatal disease associated with a dysregulated immune-endocrine response characterized by weight loss, deleterious synthesis of pro-inflammatory cytokines and GCs-driven thymus atrophy. Extending this study, we now explored the relationship between leptin and GCs, in terms of infection outcome, thymic and metabolic changes. T. cruzi-infected mice showed a food intake reduction, together with hypoglycemia and lipolysis-related changes. Infected animals also displayed a reduction in systemic and adipose tissue levels of leptin, paralleled by a down-regulation of their receptor (ObR) in the hypothalamus. Studies in infected mice subjected to adrenalectomy (Adx) showed a worsened course of infection accompanied by even more diminished systemic and intrathymic leptin levels, for which GCs are necessary not only to decrease inflammation but also to sustain leptin secretion. Adx also protected from thymic atrophy, independently of the reduced leptin contents. Leptin administration to infected mice aggravated inflammation, lowered parasite burden and attenuated GCs release, but did not normalize thymic atrophy or metabolic parameters. Acute T. cruzi infection in C57BL/6 mice coexists with a dysregulation of leptin/hypothalamic ObR circuitry dissociated from body weight and food intake control. Endogenous GCs production attempted to reestablish systemic leptin concentrations, but failed to improve leptin-protective activities at the thymic level, suggesting that the leptin/GCs intrathymic relationship is also altered during this infection.

Topics: Adipose Tissue; Animals; Blood Chemical Analysis; Chagas Disease; Feeding Behavior; Glucocorticoids; Hypoglycemia; Hypothalamus; Immunologic Factors; Leptin; Male; Mice; Mice, Inbred C57BL; Thymus Gland; Trypanosoma cruzi

Mice bearing the genomic mutation Δ337T on the thyroid hormone receptor β (TRβ) gene present the classical signs of resistance to thyroid hormone (TH), with high serum TH and TSH. This mutant TR is unable to bind TH, remains constitutively bound to co-repressors, and has a dominant negative effect on normal TRs. In this study, we show that homozygous (TRβΔ337T) mice for this mutation have reduced body weight, length, and body fat content, despite augmented relative food intake and relative increase in serum leptin. TRβΔ337T mice exhibited normal glycemia and were more tolerant to an i.p. glucose load accompanied by reduced insulin secretion. Higher insulin sensitivity was observed after single insulin injection, when the TRβΔ337T mice developed a profound hypoglycemia. Impaired hepatic glucose production was confirmed by the reduction in glucose generation after pyruvate administration. In addition, hepatic glycogen content was lower in homozygous TRβΔ337T mice than in wild type. Collectively, the data suggest that TRβΔ337T mice have deficient hepatic glucose production, by reduced gluconeogenesis and lower glycogen deposits. Analysis of liver gluconeogenic gene expression showed a reduction in the mRNA of phosphoenolpyruvate carboxykinase, a rate-limiting enzyme, and of peroxisome proliferator-activated receptor-γ coactivator 1α, a key transcriptional factor essential to gluconeogenesis. Reduction in both gene expressions is consistent with resistance to TH action via TRβ, reproducing a hypothyroid phenotype. In conclusion, mice carrying the Δ337T-dominant negative mutation on the TRβ are leaner, exhibit impaired hepatic glucose production, and are more sensitive to hypoglycemic effects of insulin.

Topics: Adiposity; Animals; Eating; Glucose; Glycogen; Growth; Homeostasis; Hypoglycemia; Insulin; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Models, Animal; Mutation; Thyroid Hormone Receptors beta

We previously mapped a type 2 diabetes (T2D) locus on chromosome 16 (Chr 16) in an F2 intercross from the BTBR T (+) tf (BTBR) Lep(ob/ob) and C57BL/6 (B6) Lep(ob/ob) mouse strains. Introgression of BTBR Chr 16 into B6 mice resulted in a consomic mouse with reduced fasting plasma insulin and elevated glucose levels. We derived a panel of sub-congenic mice and narrowed the diabetes susceptibility locus to a 1.6 Mb region. Introgression of this 1.6 Mb fragment of the BTBR Chr 16 into lean B6 mice (B6.16(BT36-38)) replicated the phenotypes of the consomic mice. Pancreatic islets from the B6.16(BT36-38) mice were defective in the second phase of the insulin secretion, suggesting that the 1.6 Mb region encodes a regulator of insulin secretion. Within this region, syntaxin-binding protein 5-like (Stxbp5l) or tomosyn-2 was the only gene with an expression difference and a non-synonymous coding single nucleotide polymorphism (SNP) between the B6 and BTBR alleles. Overexpression of the b-tomosyn-2 isoform in the pancreatic β-cell line, INS1 (832/13), resulted in an inhibition of insulin secretion in response to 3 mM 8-bromo cAMP at 7 mM glucose. In vitro binding experiments showed that tomosyn-2 binds recombinant syntaxin-1A and syntaxin-4, key proteins that are involved in insulin secretion via formation of the SNARE complex. The B6 form of tomosyn-2 is more susceptible to proteasomal degradation than the BTBR form, establishing a functional role for the coding SNP in tomosyn-2. We conclude that tomosyn-2 is the major gene responsible for the T2D Chr 16 quantitative trait locus (QTL) we mapped in our mouse cross. Our findings suggest that tomosyn-2 is a key negative regulator of insulin secretion.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Adaptor Proteins, Vesicular Transport; Animals; Chromosome Mapping; Cloning, Molecular; Diabetes Mellitus, Type 2; Disease Models, Animal; Genetic Predisposition to Disease; Glucose; HEK293 Cells; Humans; Hypoglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Mice; Mice, Inbred C57BL; Polymorphism, Single Nucleotide; Qa-SNARE Proteins; Quantitative Trait Loci; R-SNARE Proteins; Rats; SNARE Proteins; Syntaxin 1

We previously reported that mice subjected to partial hepatectomy exhibit rapid development of hypoglycemia followed by transient accumulation of fat in the early regenerating liver. We also showed that disrupting these metabolic alterations results in impaired liver regeneration. The studies reported here were undertaken to further characterize and investigate the functional importance of changes in systemic adipose metabolism during normal liver regeneration. The results showed that a systemic catabolic response is induced in each of two distinct, commonly used experimental models of liver regeneration (partial hepatectomy and carbon tetrachloride treatment), and that this response occurs in proportion to the degree of induced hepatic insufficiency. Together, these observations suggest that catabolism of systemic adipose stores may be essential for normal liver regeneration. To test this possibility, we investigated the hepatic regenerative response in fatty liver dystrophy (fld) mice, which exhibit partial lipodystrophy and have diminished peripheral adipose stores. The results showed that the development of hypoglycemia and hepatic accumulation of fat was attenuated and liver regeneration was impaired following partial hepatectomy in these animals. The fld mice also exhibited increased hepatic p21 expression and diminished plasma levels of the adipose-derived hormones adiponectin and leptin, which have each been implicated as regulators of liver regeneration.. These data suggest that the hypoglycemia that develops after partial hepatectomy induces systemic lipolysis followed by accumulation of fat derived from peripheral stores in the early regenerating liver, and that these events may be essential for initiation of normal liver regeneration.

Topics: Adiponectin; Adipose Tissue; Animals; Carbon Tetrachloride Poisoning; Cyclin-Dependent Kinase Inhibitor p21; Fatty Liver; Hepatectomy; Hypoglycemia; Leptin; Lipodystrophy; Liver Regeneration; Mice

Hypoglycaemia is common in preterm and intrauterine growth retarded (IUGR) newborns. Although preterm and IUGR infants have limited adipose tissue stores, the role of adipose tissue and the associated adipocytokines in glucose physiology is not known.. We report the case of a premature intrauterine growth retarded infant who had poor weight gain for the first 6 weeks of life and then developed severe hypoinsulinaemic hypoketotic hypoglycaemia.. There was markedly reduced adiposity with low serum leptin and adiponectin levels. Total energy expenditure and body composition measurements showed that body fat as a percentage of weight averaged 7% at 20 weeks and 28% at 28 weeks. At 20 weeks of age, the patient was equivalent to a deficit of >2 SD scores of body fat, but average fatness by 28 weeks. The hypoglycaemia completely resolved when the patient started gaining weight with an increase in fat mass and a concomitant increase in serum leptin and adiponectin level.. Although the precise mechanism of this patient's severe hypoglycaemia is unclear, further studies are required to understand the role of adipose tissue and adipocytokines in glucose homeostasis in preterm and IUGR infants.

Topics: Adiponectin; Adipose Tissue; Blood Glucose; Body Composition; Body Weight; Fetal Growth Retardation; Humans; Hypoglycemia; Infant, Newborn; Infant, Premature; Infant, Small for Gestational Age; Insulin; Leptin; Male; Weight Gain

Insulin resistance and obesity play an important role in the pathogenesis of polycystic ovary syndrome (PCOS). It is known that experimentally induced insulin resistance diminishes the stimulatory effect of insulin on leptin secretion. It is not yet known whether the long-term insulin resistance as found in PCOS patients alters the leptin response to hypo- and hyperglycaemia.. We induced hyper- and hypoglycaemia by glucose clamp technique in 7 patients with PCOS and 20 healthy controls. After a plasma glucose level of 8.8 mmol/l was reached, the plasma glucose level was reduced stepwise to 6.8, 4.8 and 2.8 mmol/l.. The PCOS patients required lower glucose infusion rates to reach the glycaemic targets (P < 0.05). Serum insulin and C-peptide concentrations increased significantly during the clamp compared with the baseline in both groups (P < 0.001 for insulin, and P < 0.001, P < 0.005 for C-peptide control and PCOS, respectively) and increased significantly more in PCOS patients compared with the control group (both P < 0.05). Basal leptin levels were significantly higher in the PCOS group than in the control group (P = 0.005). In the controls, the leptin concentration increased significantly during the clamp (P < 0.001 for each glycaemic target), whereas in the PCOS group, leptin secretion increased only during hypoglycaemia (P = 0.04).. Compared with the healthy controls, the response of leptin secretion to hyper- and hypoglycaemia was diminished in PCOS patients. Changes in leptin secretion seem not to be caused by hyper- and hypoglycaemia, but rather by hyperinsulinaemia. Reduced insulin sensitivity seems to be responsible for the diminished leptin response, which might contribute to the obesity found in PCOS patients.

Topics: Adult; Blood Glucose; C-Peptide; Female; Humans; Hyperglycemia; Hypoglycemia; Insulin; Insulin Resistance; Leptin; Polycystic Ovary Syndrome

Several established liver diseases of various causes are highly associated with hepatic insulin resistance, which is characterized by the desensitization of target cells to insulin. Peripheral insulin resistance is observed in most patients who have cirrhosis. Conversely, insulin-resistant diabetic patients are at increased risk for developing liver disease. Current therapeutic interventions in insulin resistance are limited and therefore likely to be advanced by new tailor-made drugs. Oltipraz, a prototype dithiolthione, inhibits transforming growth factor beta1 and has the ability to regenerate cirrhotic liver. We investigated the effects of oltipraz and synthetic dithiolthiones on hepatic insulin resistance and the molecular basis of action. Oltipraz and other dithiolethione compounds were tested on tumor necrosis factor alpha (TNF-alpha)-induced insulin resistance and glucose homeostasis in vitro and in vivo via immunoblotting, plasmid transfection, kinase analysis, and functional assays. Oltipraz treatment inhibited the ability of TNF-alpha to activate p70 ribosomal S6 kinase-1 (S6K1) downstream of mammalian target of rapamycin, thus preventing insulin receptor substrate-1 serine phosphorylation and protecting insulin signals. Moreover, oltipraz activated AMP-activated protein kinase (AMPK), whose inhibition by a dominant negative mutant abolished S6K1 inhibition and protected insulin signaling, indicating that AMPK activation leads to S6K1 inhibition. In hepatocyte-derived cell lines, oltipraz inhibited glucose production. Oltipraz prevented hepatic insulin resistance in C57BL/6 mice challenged with endotoxin (or TNF-alpha), leptin-deficient mice, and mice fed a high-fat diet. Synthetic dithiolethiones comparably inhibited insulin resistance.. Our findings led to the identification of dithiolethione compounds that prevent insulin resistance through a mechanism involving AMPK-mediated S6K1 inhibition and thereby sensitize hepatic insulin response.

Topics: AMP-Activated Protein Kinases; Animals; Cell Line; Glucose; Hypoglycemia; Insulin; Insulin Resistance; Leptin; Liver; Mice; Mice, Mutant Strains; Multienzyme Complexes; Phosphorylation; Protein Serine-Threonine Kinases; Pyrazines; Ribosomal Protein S6 Kinases, 70-kDa; Thiones; Thiophenes; Transfection; Transforming Growth Factor alpha

This study aimed to investigate 1) the plasma resistin concentration at birth, 2) the relationship of resistin with leptin and insulin, and 3) the association of resistin with anthropometric indexes in newborn infants. Blood samples for hormonal assay were obtained from preterm and term newborns within the first 2 h of life and before milk feeding or energy intake. Although these infants required blood sampling for clinical reasons, all were proved to be noninfected. Plasma resistin was significantly higher in term than in preterm infants. It was also significantly correlated with serum leptin, and both hormones were significantly associated with gestational age and anthropometric indexes. Infants who were born vaginally were found to have significantly higher plasma resistin levels compared with those who were born by cesarean section. In the multivariate forward stepwise regression models, resistin was found to be significantly associated with the mode of delivery and gestational age or birth weight. The association among resistin, leptin, and anthropometric indexes suggested that both hormones might be gestation related. A high circulating resistin level at term gestation could be advantageous to the infant by promoting hepatic glucose production and preventing hypoglycemia after birth. Infants who were born vaginally had significantly higher plasma resistin levels, suggesting that this hormone might also be associated with stress or inflammation induced by the birth process.

Topics: Anthropometry; Blood Glucose; Enzyme-Linked Immunosorbent Assay; Female; Gestational Age; Hormones; Humans; Hypoglycemia; Infant, Newborn; Infant, Premature; Inflammation; Insulin; Leptin; Male; Multivariate Analysis; Premature Birth; Regression Analysis; Resistin; Sex Factors; Time Factors

Mice bearing IL-1beta-secreting tumor were used to study the chronic effect of IL-1beta on glucose metabolism. Mice were injected with syngeneic tumor cells transduced with the human IL-1beta gene. Serum IL-1beta levels increased exponentially with time. Secretion of IL-1beta from the developed tumors was associated with decreased food consumption, reduced body weight, and reduced blood glucose levels. Body composition analysis revealed that IL-1beta caused a significant loss in fat tissue without affecting lean body mass and water content. Hepatic phosphoenolpyruvate carboxykinase and glucose-6-phosphatase activities and mRNA levels of these enzymes were reduced, and 2-deoxy-glucose uptake by peripheral tissues was enhanced. mRNA levels of glucose transporters (Gluts) in the liver were determined by real-time PCR analysis. Glut-3 mRNA levels were up-regulated by IL-1beta. Glut-1 and Glut-4 mRNA levels in IL-1beta mice were similar to mRNA levels in pair-fed mice bearing nonsecreting tumor. mRNA level of Glut-2, the major Glut of the liver, was down-regulated by IL-1beta. We concluded that both decreased glucose production by the liver and enhanced glucose disposal lead to the development of hypoglycemia in mice bearing IL-1beta-secreting tumor. The observed changes in expression of hepatic Gluts that are not dependent on insulin may contribute to the increased glucose uptake.

Topics: Animals; Anorexia; Blood Glucose; Body Composition; Body Weight; C-Peptide; Cell Line, Tumor; Eating; Female; Fibrosarcoma; Gluconeogenesis; Glucose; Glucose-6-Phosphatase; Glycogen; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Interleukin-1; Leptin; Liver; Mice; Mice, Inbred C57BL; Monosaccharide Transport Proteins; Neoplasm Transplantation; Protein Serine-Threonine Kinases; RNA, Messenger

We previously showed, through direct neural recording in conscious rats, that hypoglycemia increases adrenal sympathetic nerve activity (SNA) both acutely and 24 hours following the second of 2 daily antecedent hypoglycemic episodes. Nonetheless, antecedent hypoglycemia impaired catecholamine responsiveness to subsequent acute hypoglycemia. Here we hypothesized that antecedent, nonhypoglycemic adrenal sympathetic stimulation by leptin would impair acute adrenal catecholamine responsiveness to subsequent hypoglycemia. We also hypothesized that acute leptin administration (after 2 days of antecedent hypoglycemia) would enhance adrenal SNA and thereby enhance catecholamine responsiveness to concurrent hypoglycemia. Leptin or saline was administered to normal rats in repeated subcutaneous injections for 2 days prior to acute insulin-induced hypoglycemia. In contrast to our hypothesis, antecedent leptin did not change catecholamine responsiveness or glycemic change in response to subsequent acute insulin administration. In additional studies, intravenous leptin or saline was acutely administered beginning 1 hour before insulin-induced hypoglycemia. All rats had been exposed to antecedent hypoglycemia. In these experiments, acute leptin did not alter catecholamine responses to insulin or glycemic change during or after termination of insulin. We conclude that antecedent nonhypoglycemic sympathetic stimulation by leptin does not alter subsequent catecholamine or glycemic responses to insulin. Moreover, concurrent leptin does not enhance catecholamine responses to insulin in rats exposed to antecedent hypoglycemia.

Topics: Adrenal Glands; Animals; Blood Glucose; Blood Pressure; Catecholamines; Heart Rate; Hypoglycemia; Hypoglycemic Agents; Injections, Intravenous; Insulin; Leptin; Mice; Rats; Rats, Sprague-Dawley; Sympathetic Nervous System

Ghrelin is an acylated peptide, whose lipid modification is essential for its biological activities. Previous studies demonstrated that it strongly stimulates GH release and has a potent orexigenic action. Meanwhile, there is enough evidence showing that feeding states influence plasma ghrelin levels. Fasting stimulates ghrelin secretion, and feeding reduces plasma ghrelin levels. In this study we examined the regulation of plasma ghrelin by fasting in genetically obese animals considering its molecular forms. Plasma levels of active form of ghrelin as well as those of total ghrelin were reduced in ob/ob and db/db mice compared with those in their control mice. Zucker fatty (fa/fa) rats also showed lower plasma ghrelin levels by fasting than the control rats. Insulin-induced hypoglycemia, however, stimulated ghrelin secretion in the fasted fatty rats. Moreover, glucose injection was revealed to reduce plasma ghrelin levels in rats. The effect of the severity of obesity on secretory regulation of ghrelin was also studied. Older fatty rats showed low plasma ghrelin levels even after 48-h fasting. These data suggest that the short-term secretory regulation of total ghrelin and the active form of ghrelin is delayed in obese animals and that blood glucose levels may be involved in the delayed regulation.

Topics: Aging; Animals; Fasting; Food Deprivation; Ghrelin; Glucose; Humans; Hypoglycemia; Insulin; Leptin; Male; Mice; Mice, Obese; Obesity; Peptide Hormones; Peptides; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Rats, Zucker; Stomach

Leptin, an adipocyte-derived factor, has multiple biological roles including mitogenesis. We investigated the effect of normal development, acute and chronic hyperglycemia and hypoglycemia, and selective acute hyperglycemia, or hyperinsulinemia, on fetal ovine white adipose tissue (WAT) leptin mRNA concentrations. Leptin mRNA amounts expressed as a ratio to the internal control ribosomal S2 mRNA decreased threefold with advancing gestational age (P < 0.05). This gestational decrease was opposite to the 10-fold increase in fetal body weight during the same developmental period. Chronic hyperglycemia with hyperinsulinemia led to no change in WAT leptin mRNA concentrations over a 1- to 10-day duration, but it caused a 40% increase over a 14- to 20-day duration (P < 0.05) along with an increase in fetal body weight (P < 0.05). In contrast, hypoglycemia with hypoinsulinemia, while not affecting WAT leptin mRNA from 1 to 34 days, resulted in a 50% decline over a 36- to 76-day duration along with a decline in fetal body weight (P < 0.05). Acute 24-h studies of selective hyperglycemia with euinsulinemia showed no significant change in WAT leptin mRNA, but in response to selective hyperinsulinemia with euglycemia at 24 h, a twofold increase was observed (P < 0.05). We conclude that fetal WAT leptin mRNA amounts are regulated by fetal development and circulating insulin concentrations. We speculate that chronic in utero metabolic perturbations that alter circulating insulin concentrations affect fetal leptin production that may mediate insulin's influence on fetal growth.

Topics: Adipose Tissue; Animals; Female; Gene Expression Regulation, Developmental; Gestational Age; Glucose; Hyperglycemia; Hyperinsulinism; Hypoglycemia; Hypoglycemic Agents; Insulin; Leptin; Obesity; Pregnancy; RNA, Messenger; Sheep

Insulin is thought to be an important regulator of leptin secretion. However, increasing evidence suggests that insulin-mediated glucose uptake rather than insulin per se regulates circulating leptin concentration. Here, we hypothesised that a reduction of insulin sensitivity, ie insulin resistance, will diminish the stimulatory effect of insulin on leptin secretion as a consequence of decreased insulin-mediated glucose uptake.. Changes in serum leptin concentration during 30 hyperinsulinaemic-hypoglycaemic clamps were studied after induction of different levels of insulin resistance in normal-weight men. In 15 subjects insulin sensitivity was reduced by exposing them to a 2.5 h antecedent hypoglycaemia (3.1 mmol/l) induced by a high rate of insulin infusion (15.0 mU/min/kg) on the day before the proper experiment ('ante-hypo' condition). In the other 15 subjects no antecedent hypoglycaemia was induced ('control' condition). The proper experiment on both conditions was a 6 h stepwise hypoglycaemic clamp induced by a constant rate of insulin infusion (1.5 mU/min/kg).. Experiments were carried out in 30 lean healthy subjects (age, mean +/- s.e.m., 26 +/- 1 y; body mass index, 23.1 +/- 0.6 kg/m2).. As expected, glucose demand during the clamp was lower in the ante-hypo condition than in the control condition (gram of glucose infused per kilogram body weight, 1.52 +/- 0.16 vs 2.01 +/- 0.17 g/kg; P < 0.05). During the clamp, leptin levels increased by 25.4 +/- 4.3% in the control condition (P < 0.05), but not in the ante-hypo condition (+4.8 +/- 4.5%; P > 0.25). Thus, serum leptin response to the clamp significantly differed between the two conditions (P < 0.01). Across both conditions, the increase of leptin levels during the clamp was correlated with the amount of glucose infused (r = 0.37; P < 0.05).. Considering that insulin concentrations were identical during both clamp conditions, the data indicate that experimentally-induced insulin resistance diminishes the stimulatory effect of insulin on leptin secretion.

Topics: Adult; Blood Glucose; Body Mass Index; Glucose Clamp Technique; Humans; Hydrocortisone; Hyperinsulinism; Hypoglycemia; Insulin Resistance; Kinetics; Leptin; Male

Ghrelin is a novel gut-brain peptide that binds to the growth hormone secretagogue receptor (GHS-R), thereby functioning in the regulation of growth hormone (GH) release and food intake. Ghrelin-producing cells are most abundant in the oxyntic glands of the stomach. The regulatory mechanism that governs the biosynthesis and secretion of ghrelin has not been clarified. We report that ghrelin mRNA expression in the gastric fundus was increased, but that ghrelin peptide content decreased after a 48-h fast. Both values returned to control levels after refeeding. The ghrelin plasma concentration in the gastric vein and systemic venous blood increased after 24- and 48-h fasts. Furthermore, des-octanoylated ghrelin and n-octanoylated ghrelin were found in rat stomach, with the ratio of des-octanoylated ghrelin to n-octanoylated ghrelin markedly increased after fasting. The ghrelin mRNA level in the stomach also increased after administration of insulin and leptin. Conversely, db/db mice, which are deficient in the leptin receptor, had lower ghrelin mRNA levels than control mice. These findings suggest that this novel gastrointestinal hormone plays a role in the regulation of energy balance.

Topics: Animals; Carrier Proteins; Chromatography, High Pressure Liquid; Fasting; Gastric Mucosa; Ghrelin; Hypoglycemia; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Peptide Hormones; Peptides; Rats; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger; Stomach; Up-Regulation

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

Malnutrition induces profound deleterious effects on several metabolic and neuroendocrine functions. In the present study, we examined the impact of maternal food restriction, during gestation and lactation, on the metabolic-neuroendocrine function of their male offspring at 21 and 60 d of age. Well-nourished (WN) and undernourished (UN) pregnant rats were used, during gestation and lactation, until pups were weaned. Twenty-one-day-old WN and UN male pups were studied in basal and postinsulin conditions. Additional groups of weaned (WN and UN) male rats were fed either ad libitum (WN-WN and UN-WN) or in a restricted fashion (WN-UN and UN-UN) until experimentation at age 60 d. Body weights of mothers and their male offspring were monitored. Basal and postinsulin plasma concentrations of several metabolic fuels were evaluated. Our results indicate that 21-d-old UN male rats exhibited (vs their WN counterparts), decreased body weights, similar basal and postinsulin glycemia, similar basal plasma adrenocorticotropic hormone (ACTH) and corticosterone levels but diminished ACTH response to insulin treatment, and basal hypoleptinemia and significant insulin-induced leptin release. Finally, at 60 d of age, long-term UN (WN-UN and UN-UN) rats showed lower plasma (basal and postinsulin) glucose, and basal triglyceride levels than their counterparts (WN-WN and UN-WN). Sixty-day-old rats submitted to either food restriction protocol also showed a reduced hypothalamo-pituitary-adrenal axis response to insulin-induced hypoglycemia and basal hypoleptinemia, in spite of restoration of normal body weights. These results further indicate a clear metabolic-neuroendocrine dysfunction in male pups of UN mothers, with the abnormality partially present at weaning and deteriorated by adulthood, even after the recovery of normal body weight. Our study strongly supports the importance of the irreversibility of a deleterious allostatic state resulting from fetal and early postnatal undernutrition.

Topics: Adipocytes; Adrenocorticotropic Hormone; Animals; Blood Glucose; Blood Proteins; Body Weight; Eating; Female; Glucocorticoids; Hypoglycemia; Hypothalamo-Hypophyseal System; Lactation; Leptin; Male; Nutrition Disorders; Pituitary-Adrenal System; Pregnancy; Rats; Rats, Inbred F344; Triglycerides

A 6.5-year-old male with normal linear growth, despite septo-optic dysplasia, panhypopituitarism and a deficient GH/IGF axis, is presented. In addition to measuring IGF-I, IGF-II and IGFBP-3, serum IGFBP-1, -2, -4 and -5 were measured. A human osteosarcoma cell line was used to assess growth-promoting activity in the patient's serum. The role of leptin in linear growth in this case was investigated. There was no evidence for hyperinsulinism or hyperandrogenism. GH was undetectable upon multiple stimulation. GHBP was elevated. Serum IGF-I (25 microg/l), IGF-II (194 microg/l), IGFBP-3 (0.4 mg/l), and IGFBP-5 (87 microg/l) levels were low compared to age-matched prepubertal children. Serum IGFBP-4 level was normal. Molecular size of IGF-II in the patient's serum was normal, suggesting normal IGF-II bioavailability. Human osteosarcoma cell proliferation in response to the patient's serum was similar to sera from age-matched normal controls. Leptin levels were markedly elevated. Osteoblast cell proliferation was not stimulated by leptin. The data demonstrate that normal growth and osteoblast cell proliferation in this patient is not mediated by GH, total IGFs, insulin, or leptin, and suggest the presence of a yet unidentified growth factor or mechanism. The case offers a detailed picture of binding proteins in a case of growth without GH. It introduces osteoblast cell proliferation as a method of assessing serum growth-promoting activity in such cases. It adds IGF-II and leptin to the list of excluded growth-promoting candidates in GH-independent growth, and further demonstrates our incomplete understanding of the phenomenon of growth.

Topics: Body Height; Child; Human Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Hypothyroidism; Immune Sera; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Karyotyping; Leptin; Male; Thyroxine; Vision Disorders

Orexins (hypocretins), novel peptides expressed in specific neurons of the lateral hypothalamic area (LHA), stimulate feeding when injected intracerebroventricularly. We investigated their role in feeding in the rat by measuring hypothalamic prepro-orexin mRNA levels under contrasting conditions of increased hunger. Prepro-orexin mRNA levels increased significantly after 48 h of fasting (by 90-170%; P < 0.05) and after acute (6 h) hypoglycemia when food was withheld (by 90%; P < 0.02). By contrast, levels were unchanged during chronic food restriction, streptozotocin-induced diabetes, hypoglycemia when food was available, voluntary overconsumption of palatable food, or glucoprivation induced by systemic 2-deoxy-D-glucose. Orexin expression was not obviously related to changes in body weight, insulin, or leptin, but was stimulated under conditions of low plasma glucose in the absence of food. Orexins may participate in the short-term regulation of energy homeostasis by initiating feeding in response to falls in glucose and terminating it after food ingestion. The LHA is known to contain neurons that are stimulated by falls in circulating glucose but inhibited by feeding-related signals from the viscera; orexin neurons may correspond to this neuronal population.

Topics: Animals; Blood Glucose; Deoxyglucose; Diabetes Mellitus, Experimental; Eating; Fasting; Food Deprivation; Gene Expression Regulation; Hyperphagia; Hypoglycemia; Hypothalamic Area, Lateral; Insulin; Intracellular Signaling Peptides and Proteins; Leptin; Male; Neurons; Neuropeptides; Orexins; Protein Precursors; Rats; Rats, Sprague-Dawley; Rats, Wistar; Transcription, Genetic

The effects of leptin on the secretion of insulin and glucagon were examined. In an experiment involving insulin response to an i.v. glucose load in vagotomized rats, the plasma concentrations of insulin were significantly lower in the leptin (20 nmol/kg BW)-treated group than in a control group. However, in intact rats and rats that had undergone both vagotomy and chemical sympathectomy, this suppressive effect of leptin on insulin secretion was not detected. In an experiment involving a hypoglycemia-induced glucagon secretion test in intact rats, an i.v. injection of leptin (20 nmol/kg BW) augmented the plasma glucagon response to hypoglycemia. In the case of sympathectomized rats, however, this stimulative effect of leptin on glucagon secretion was not detected. In an experiment with perfused rat pancreas, the addition of leptin (20 nM) to the perfusate slightly suppressed insulin secretion, but had no effect on basal or glucopenia-induced glucagon secretion. In intact rats infused with leptin (0.31 micromol/day), the expression of uncoupling protein-1 messenger RNA in interscapular brown adipose tissue was increased, whereas no such effect of leptin on the uncoupling protein-1 messenger RNA expression was observed in brown adipose tissue in chemically sympathectomized rats. These findings suggest that leptin might indirectly affect pancreatic endocrine functions, probably through its stimulative effects on the sympathetic nervous system.

Topics: Adipose Tissue, Brown; Animals; Carrier Proteins; Glucagon; Glucose; Hypoglycemia; Injections, Intravenous; Insulin; Insulin Secretion; Ion Channels; Islets of Langerhans; Leptin; Male; Membrane Proteins; Mitochondrial Proteins; Oxidopamine; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sympathectomy; Sympathetic Nervous System; Uncoupling Protein 1; Vagotomy

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

Acute immunoneutralization of circulating leptin, with an anti-leptin antibody, significantly reduced rectal temperature at 30 min and 75 min post-injection in overnight fasted and at 30 min in overnight fed mice, while no effects in metabolic and ponderal indicators were observed after antibody administration for 22 days. Furthermore, hyperinsulinemia and hypoglycemia were induced by passive immunization against leptin, being both influenced by the post-prandrial status. These experiments confirm through an indirect approach that leptin is involved in energy, but also in glucose homeostasis.

Topics: Animals; Antibodies, Monoclonal; Blood Glucose; Eating; Fasting; Hyperinsulinism; Hypoglycemia; Hypothermia; Immunization, Passive; Insulin; Leptin; Mice; Mice, Inbred BALB C; Proteins; Triglycerides; Weight Gain

Hypoglycemia causes hyperphagia and weight gain, through unknown peripheral and central signals. We investigated the effect of hypoglycemia on NPY and leptin expression and the ability of leptin to inhibit hypoglycemia-induced hyperphagia. Acute hypoglycemia (60 U/kg SC insulin; n = 8) increased food intake (p < 0.01) compared with controls (n = 8). Insulin- and leptin-treated rats (300 microg/kg IP leptin; n = 8) had reduced hyperphagia (p < 0.05 vs. controls; p < 0.05 vs. insulin alone) and a 15% fall in NPY mRNA levels compared with controls (p < 0.01). Chronic hypoglycemia, (20-60 U/kg/day insulin; n = 8) increased food intake compared with vehicle-treated controls (p < 0.01). Leptin and insulin administration (300 microg/kg/day IP leptin; n = 8) reduced hyperphagia (p < 0.01 vs. controls, p < 0.05 vs. insulin alone), and NPY mRNA fell by 18% vs. controls (p < 0.01). We conclude that hypoglycemia-induced hyperphagia is not mediated by either a fall in leptin or an increase in hypothalamic NPY mRNA. Leptin can inhibit feeding in hyperphagic hypoglycemic rats, and this may partly be attributable to its inhibition of the NPY neurons.

Topics: Acute Disease; Analysis of Variance; Animals; Arcuate Nucleus of Hypothalamus; Blood Glucose; Body Weight; Chronic Disease; Eating; Hyperphagia; Hypoglycemia; Insulin; Leptin; Male; Models, Biological; Neuropeptide Y; Protein Biosynthesis; Proteins; Rats; Rats, Wistar; RNA, Messenger

Current knowledge of the regulatory mechanisms of leptin synthesis and release is limited. To elucidate the role of short-term hyperinsulinaemia and hypoglycaemia on circulating levels of leptin, 7 healthy lean men underwent a 360-min hyperinsulinaemic (insulin infusion rate: 1.5 mU/kg/min) clamp in two conditions: (i) during 360 min of euglycaemia and (ii) during 120 min of euglycaemia followed by 240 min of graded hypoglycaemia (nadir 2.9 +/- 0.1 mmol/l). During hyperinsulinaemic euglycaemia, serum leptin levels were initially stable and then rose gradually after 180 min to a peak value of 147 +/- 7% of baseline (ANOVA, p < 0.01). During the hypoglycaemic clamp, the leptin profile differed from that of euglycaemic conditions (p < 0.01) since the increase was postponed and reduced. In both clamp studies, leptin dynamics contrasted with the changes in a control study performed in 7 other men whose serum leptin fell significantly (p < 0.05) to 77 +/- 4% of baseline values during a 360-min fast (following overnight fasting). It is concluded that hyperinsulinaemia for more than 3 h increases circulating levels of leptin in lean males, whereas hyperinsulinaemia with concomitant hypoglycaemia leads to transient suppression. The exact nature of the underlying mechanisms, e.g. changes in levels of insulin, glucose, various substrates, glucose turnover and/or counterregulatory hormones, remains to be determined.

Topics: Adult; Analysis of Variance; Blood Glucose; Case-Control Studies; Fatty Acids, Nonesterified; Glucose Clamp Technique; Hormones; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Leptin; Male; Obesity; Proteins; Reference Values