leptin and Diabetes-Mellitus--Lipoatrophic

Leptin is an adipocyte-derived hormone that primarily acts in the hypothalamus and plays a key role in the regulation of food intake, body weight, energy expenditure and neuroendocrine function. Leptin has direct peripheral effects on several tissues, and it may be independently involved in insulin secretion and action besides its effects on body weight regulation. Basal plasma leptin and insulin concentrations correlate with each other. Insulin and glucose appear to increase leptin secretion. In turn, leptin increases peripheral insulin sensitivity while decreasing insulin secretion from pancreatic beta cells. Leptin increases skeletal muscle glucose uptake and oxidation, and suppresses hepatic glucose output. Effects of leptin on lipid metabolism might reduce lipotoxicity and therefore contribute to the improvement of hepatic, skeletal and whole body insulin sensitivity. Leptin is the first adipokine used in the treatment of hypoleptinemic clinical disorders. Although leptin therapy has limited success in common obesity, it has impressive effects in congenital leptin deficiency, lipoatrophic diabetes and syndromes of severe insulin resistance. Leptin has been reported to ameliorate hyperinsulinemia and diabetes in the clinical setting of congenital leptin deficiency. It also improves hyperglycemia, insulin resistance, hyperinsulinemia, dyslipidemia and hepatic steatosis in lipoatrophic diabetes. These promising results warrant clinical trials to test the hypothesis that leptin alone or with classical antidiabetic agents may potentially be beneficial in the treatment of hypoleptinemic non-obese individuals with glucose intolerance and diabetes. This review summarizes the clinical applications of leptin, particularly emphasizing the effects of leptin on glucose homeostasis.

Topics: Animals; Diabetes Mellitus; Diabetes Mellitus, Lipoatrophic; Glucose; Homeostasis; Humans; Insulin; Insulin Secretion; Leptin; Liver; Muscle, Smooth

Topics: Adult; Animals; Child; Diabetes Mellitus, Lipoatrophic; Female; GTP-Binding Protein gamma Subunits; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Lamin Type A; Leptin; Male; Mutation; Prognosis

Topics: Adult; Animals; Diabetes Mellitus, Lipoatrophic; Female; Humans; Leptin; Male; Mice

Topics: Biomarkers; Cushing Syndrome; Diabetes Mellitus, Lipoatrophic; Diagnostic Techniques, Endocrine; Enzyme-Linked Immunosorbent Assay; Feeding and Eating Disorders; Gonadal Disorders; Humans; Leptin; Metabolic Syndrome; Obesity; Radioimmunoassay; Reagent Kits, Diagnostic; Receptors, Cell Surface; Receptors, Leptin; Reference Values; Specimen Handling

Topics: Adiponectin; Animals; Diabetes Mellitus, Lipoatrophic; Disease Models, Animal; Genes, Dominant; Genes, Recessive; GTP-Binding Protein gamma Subunits; Heterotrimeric GTP-Binding Proteins; Humans; Intercellular Signaling Peptides and Proteins; Lamin Type A; Leptin; Mice; Mutation; Prognosis; Proteins; Receptors, Retinoic Acid; Retinoid X Receptors; Transcription Factors

The A-ZIP/F-1 mouse is lacking virtually all white adipose tissue. Like humans with extensive deficiencies of adipose tissue, the A-ZIP/F-1 mice develop a severe form of insulin resistant diabetes. We have studied the physiology of the A-ZIP/F-1 mice. Their adaptation to fasting is notable for its rapidity and the use of torpor, a hibernation-like state, to minimize energy needs. Transplantation of adipose tissue reversed the metabolic manifestations in the mice, demonstrating that the lack of adipose tissue is the cause of the insulin resistance. Leptin replacement is not very effective in reversing the diabetes of the A-ZIP/F-1 mice, which contrasts with its efficacy in the aP2-SREBP-lc mouse.

Topics: Adipose Tissue; Animals; Body Composition; Diabetes Mellitus, Lipoatrophic; Disease Models, Animal; Fasting; Humans; Insulin Resistance; Leptin; Mice; Mice, Transgenic; Phenotype; Transcription Factors

Obesity is one of the major risk factors for the development of cardiovascular diseases and is characterized by abnormal accumulation of adipose tissue, including perivascular adipose tissue (PVAT). However, brown adipose tissue (BAT) activation reduces visceral adiposity. To demonstrate that severe brown fat lipoatrophy might accelerate atherosclerotic process, we generated a new mouse model without insulin receptor (IR) in BAT and without apolipoprotein (Apo)E (BAT-specific IR knockout [BATIRKO];ApoE(-/-) mice) and assessed vascular and metabolic alterations associated to obesity. In addition, we analyzed the contribution of the adipose organ to vascular inflammation. Brown fat lipoatrophy induces visceral adiposity, mainly in gonadal depot (gonadal white adipose tissue [gWAT]), severe glucose intolerance, high postprandial glucose levels, and a severe defect in acute insulin secretion. BATIRKO;ApoE(-/-) mice showed greater hypertriglyceridemia than the obtained in ApoE(-/-) and hypercholesterolemia similar to ApoE(-/-) mice. BATIRKO;ApoE(-/-) mice, in addition to primary insulin resistance in BAT, also showed a significant decrease in insulin signaling in liver, gWAT, heart, aorta artery, and thoracic PVAT. More importantly, our results suggest that severe brown fat lipoatrophy aggravates the atherosclerotic process, characterized by a significant increase of lipid depots, atherosclerotic coverage, lesion size and complexity, increased macrophage infiltration, and proinflammatory markers expression. Finally, an increase of TNF-α and leptin as well as a decrease of adiponectin by BAT, gWAT, and thoracic PVAT might also be responsible of vascular damage. Our results suggest that severe brown lipoatrophy aggravates atherosclerotic process. Thus, BAT activation might protect against obesity and its associated metabolic alterations.

Topics: Adiponectin; Adipose Tissue, Brown; Adipose Tissue, White; Adiposity; Animals; Apolipoproteins E; Atherosclerosis; Biomarkers; Diabetes Mellitus, Experimental; Diabetes Mellitus, Lipoatrophic; Glucose; Insulin Resistance; Leptin; Lipid Metabolism; Male; Mice, Inbred C57BL; Mice, Knockout; Receptor, Insulin; Tumor Necrosis Factor-alpha

Familial partial lipodystrophy (FPLD) and obesity are both associated with increased risks of type 2 diabetes and cardiovascular disease. Although adipokines have been implicated, few data exist in subjects with FPLD; therefore we investigated a family with FPLD due to a lamin A/C mutation in order to determine how abnormalities of the plasma adipokine profile relate to insulin resistance and the metabolic syndrome.. Plasma levels of adiponectin, leptin, resistin, IL-1beta, IL-6 and TNF-alpha in 30 subjects (ten patients, 20 controls) were correlated with indices of metabolic syndrome.. Compared with controls, FPLD patients had significantly lower plasma levels of adiponectin (3.7+/-1.0 in FDLP cases vs 7.1+/-0.72 mug/ml in controls, p=0.02), leptin (1.23+/-0.4 vs 9.0+/-1.3 ng/ml, p=0.002) and IL-6 (0.59+/-0.12 vs 1.04+/-0.17 pg/ml, p=0.047) and elevated TNF-alpha (34.8+/-8.1 vs 13.7+/-2.7 pg/ml, p=0.028), whereas IL-1beta and resistin were unchanged. In both groups, adiponectin levels were inversely correlated with body fat mass (controls, r=-0.44, p=0.036; FDLP, r=-0.67, p=0.025), insulin resistance (controls, r=-0.62, p=0.003; FDLP, r=-0.70, p=0.025) and other features of the metabolic syndrome. TNF-alpha concentrations were positively related to fat mass (controls, r=0.68, p=0.001; FDLP, r=0.64, p=0.048) and insulin resistance (controls, r=0.86, p=0.001; FDLP, r=0.75, p=0.013). IL-6, IL-1beta and resistin did not demonstrate any correlations with the metabolic syndrome in either group.. Low adiponectin and leptin and high TNF-alpha were identified as the major plasma adipokine abnormalities in FPLD, consistent with the hypothesis that low adiponectin and high TNF-alpha production may be mechanistically related, and perhaps responsible for the development of insulin resistance and cardiovascular disease in FPLD.

Topics: Adiponectin; Adult; Case-Control Studies; Diabetes Mellitus, Lipoatrophic; Female; Homeostasis; Humans; Insulin Resistance; Interleukin-1; Interleukin-6; Laminin; Leptin; Male; Metabolic Syndrome; Middle Aged; Multivariate Analysis; Mutation; Obesity; Resistin; Tumor Necrosis Factor-alpha

The Berardinelli-Seip congenital lipodystrophy (BSCL) syndrome is characterized by a near-total congenital absence of fat and predisposition to develop diabetes mellitus. We have previously reported that 22 patients from 16 consanguineous pedigrees living in the northeastern region of Brazil had a homozygous 669insA mutation in the Seipin gene (BSCL2 locus), while all of the 10 investigated subjects from the southeastern region were homozygous for a 1036 bp deletion in the AGPAT2 gene (BSCL1 locus). In this study, we compared the serum insulin and insulin resistance (HOMA), leptin, triglyceride and fasting glucose levels in individuals of these two genetically distinct clusters of BSCL subjects. The onset of diabetes was also estimated. The fasting glucose and triglyceride levels were not significantly different in these groups. Significant differences were detected for leptin, insulin and insulin resistance. BSCL1 patients presented lower serum leptin levels compared to BSCL2 patients. BSCL2 subjects had earlier onset of diabetes and higher insulin levels. In agreement, BSCL2 patients were more insulin resistant, as detected by HOMA. These results indicate phenotypic heterogeneity between BSCL1 and BSCL2 Brazilian subjects.

Topics: Adolescent; Adult; Blood Glucose; Brazil; Child; Consanguinity; Diabetes Mellitus, Lipoatrophic; Female; Glucose; GTP-Binding Protein gamma Subunits; Homozygote; Humans; Insulin; Leptin; Male; Mutation; Phenotype; Polymorphism, Restriction Fragment Length; Syndrome; Time Factors; Triglycerides

To correlate serum leptin and insulin levels, and the glucosic profile of 21 patients shared in diabetics and non diabetics with Congenital Generalized Lipodystrophy (CGL).. In a prospective study, were dosed serum leptin level with radioimmunoassay technique, fasting plasma glucose through of the glucoseoxidase-peroxidase reaction, the hemoglobin glycate using the technique microchromatography for ionic exchange resin and insulin through immunoassay system. The fructosamine concentration serum was determinated for reduction nitroblue tetrazolium method. The Student's test was used to compare results between the groups and the correlation "r" coefficient to analise the relation among the several variants studied, with significant level of 5% (p < 0.05). All the statistical procedures were performed using the Excel by Microsoft and the Statistic program for Windows by StatSoft, Inc. version 5.1 edition 97.. Leptin decreased on the most patients, showing no statistically significant difference between the groups. Also there wasn't difference statistically significant (p = 0.9542) of the insulin's value between diabetics and non diabetics.. The hyperinsulinism and the hypoleptinemia occurred independently of diabetes in the CGL's patients and this can be due to the natural history of disease, in which the raise insulin levels precede the initial diabetes mellitus and the low leptin levels were related to the lipoatrophy.

Topics: Adipose Tissue; Adolescent; Adult; Blood Glucose; Body Mass Index; Child; Child, Preschool; Consanguinity; Diabetes Mellitus, Lipoatrophic; Female; Fructosamine; Glycated Hemoglobin; Humans; Hyperinsulinism; Insulin Resistance; Leptin; Lipodystrophy, Congenital Generalized; Male; Prospective Studies

Generalized lipodystrophy is a rare disorder of adipose tissue, whose etiology remains unknown. Pathophysiology of this disorder is characterized by generalized loss of body fat associated with an infrequent form of diabetes mellitus (lipoatrophic diabetes). Main features of this form of diabetes mellitus are the severe insulin resistance and the absence of ketoacidosis. Lipodystrophy can be congenital or acquired. In the acquired form, metabolic disturbances usually begin in the first years of life and the response to conventional treatment is very poor. Some alterations in serum adipocytokines have been described in this disease. We report the case of a 74-year-old woman with acquired generalized lipodystrophy who presented with low-normal serum concentrations of leptin, low adiponectin and resistin levels, and high serum levels of TNF alpha. Patient was initially treated with fenofibrate, metformin and high doses of subcutaneous insulin achieving an adequate metabolic control. During this period, serum adipocytokines were periodically measured. We comment on the different etiopathogenic mechanisms and the therapeutic modalities of this rare syndrome.

Topics: Adiponectin; Aged; Blood Glucose; Cytokines; Diabetes Mellitus, Lipoatrophic; Diabetes Mellitus, Type 2; Female; Fenofibrate; Hormones, Ectopic; Humans; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Metformin; Resistin; Tumor Necrosis Factor-alpha; Weight Loss

Topics: Adult; Child; Diabetes Mellitus, Lipoatrophic; Female; Glycated Hemoglobin; Humans; Hypertriglyceridemia; Leptin; Liver; Male; Triglycerides

Diseases due to mutations in the lamin A/C gene (LMNA) are highly heterogeneous, including neuromuscular and cardiac dystrophies, lipodystrophies, and premature ageing syndromes. In this study we characterized the neuromuscular and cardiac phenotypes of patients bearing the heterozygous LMNA R482W mutation, which is the most frequent genotype associated with the familial partial lipodystrophy of the Dunnigan type (FPLD). Fourteen patients from two unrelated families, including 10 affected subjects, were studied. The two probands had been referred for lipoatrophy and/or diabetes. Lipodystrophy, exclusively observed in LMNA-mutated patients, was of variable severity and limited to postpubertal subjects. Lipodystrophy and metabolic disturbances were more severe in women, even if an enlarged neck was a constant finding. The severity of hypertriglyceridemia and hirsutism in females was related to that of insulin resistance. Clinical muscular alterations were only present in LMNA-mutated patients. Clinical and histological examination showed an invalidating, progressive limb-girdle muscular dystrophy in a 42-yr-old woman that had been present since childhood, associated with a typical postpubertal FPLD phenotype. Six of eight adults presented the association of calf hypertrophy, perihumeral muscular atrophy, and a rolling gait due to proximal lower limb weakness. Muscular histology was compatible with muscular dystrophy in one of them and/or showed a nonspecific excess of lipid droplets (in three cases). Immunostaining of lamin A/C was normal in the six muscular biopsies. Surprisingly, calpain 3 expression was undetectable in the patient with the severe limb-girdle muscular dystrophy, although the gene did not reveal any molecular alterations. At the cardiac level, cardiac septal hypertrophy and atherosclerosis were frequent in FPLD patients. In addition, a 24-yr-old FPLD patient had a symptomatic second degree atrioventricular block. In conclusion, we showed that most lipodystrophic patients affected by the FPLD-linked LMNA R482W mutation show muscular and cardiac abnormalities. The occurrence and severity of the myopathic and lipoatrophic phenotypes varied and were not related. The muscular phenotype was evocative of limb girdle muscular dystrophy. Cardiac hypertrophy and advanced atherosclerosis were frequent. FPLD patients should receive careful neuromuscular and cardiac examination whatever the underlying LMNA mutation.

Topics: Adolescent; Adult; Arteriosclerosis; Calpain; Cardiomegaly; Child; Diabetes Mellitus, Lipoatrophic; Female; Humans; Lamin Type A; Leptin; Male; Middle Aged; Muscles; Muscular Dystrophies, Limb-Girdle; Mutation; Triglycerides

Familial partial lipodystrophy (FPLD) is a monogenic form of diabetes characterised by a dominantly inherited disorder of adipose tissue associated with the loss of subcutaneous fat from the limbs and trunk, with excess fat deposited around the face and neck. The lipodystrophy causes severe insulin resistance, resulting in acanthosis nigricans, diabetes, dyslipidaemia, and increased risk of cardiovascular disease. Preliminary results from animals and man suggest that increasing subcutaneous fat by treatment with thiazolidinediones should improve insulin resistance and the associated features of this syndrome.. We report a 24-year-old patient with FPLD caused by a mutation in the LMNA gene (R482W) treated with 12 months of rosiglitazone. Subcutaneous fat increased following rosiglitazone treatment as demonstrated by a 29% generalised increase in skin-fold thickness. Leptin levels increased from 5.8 to 11.2 ng/ml. Compared with treatment on Metformin, there was an increase in insulin sensitivity (HOMA S% 17.2-31.6) but no change in glycaemic control. The lipid profile worsened during the follow-up period.. This initial case suggests that, for modification of cardiovascular risk factors, there are no clear advantages in treating patients with FPLD with rosiglitazone despite increases in subcutaneous adipose tissue. Larger series will be needed to identify moderate beneficial effects and treatment may be more effective in patients with generalised forms of lipodystrophy.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Lipoatrophic; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Resistance; Lamin Type A; Leptin; Mutation; Receptors, Cytoplasmic and Nuclear; Rosiglitazone; Skinfold Thickness; Thiazolidinediones; Transcription Factors

Severe adipose tissue deficiency (lipoatrophy) causes insulin-resistant diabetes, elevated serum triglyceride and fatty acid levels, and massive triglyceride deposition in the liver. In lipoatrophic A-ZIP/F-1 mice, transplantation of normal adipose tissue greatly improved these parameters, whereas 1 week of leptin infusion had more modest effects. In contrast, leptin infusion was strikingly more effective in the aP2-n sterol response element binding protein 1 lipoatrophic mouse. Here we show that a longer duration of leptin infusion further improves the metabolic status of the A-ZIP/F-1 mice and that genetic background does not make a major contribution to the effect of leptin on glucose and insulin levels. Adipose transplantation using leptin-deficient ob/ob fat had no effect on the phenotype of the A-ZIP/F-1 mice. Moreover, the presence of ob/ob adipose tissue did not enhance the effects of leptin infusion. Serum adiponectin levels were 2% of control levels in the A-ZIP/F-1 mouse and increased only twofold with adipose transplantation and not at all after leptin infusion, suggesting that adiponectin deficiency is not a major contributor to the diabetic phenotype. Taken together, these results suggest that sequestration of triglycerides into fat may not be enough to restore a nondiabetic phenotype and that leptin deficiency plays a major role in causing the metabolic complications of lipoatrophy.

Topics: Adiponectin; Adipose Tissue; Animals; Diabetes Mellitus, Lipoatrophic; Intercellular Signaling Peptides and Proteins; Leptin; Mice; Mice, Inbred Strains; Phenotype; Proteins; Treatment Failure

Based on the phenotypes of knockout mice and cell lines, as well as pathway-specific analysis, the insulin receptor substrates IRS-1, IRS-2, IRS-3, and IRS-4 have been shown to play unique roles in insulin signal transduction. To investigate possible functional complementarity within the IRS family, we generated mice with double knockout of the genes for IRS-1/IRS-3 and IRS-1/IRS-4. Mice with a combined deficiency of IRS-1 and IRS-4 showed no differences from Irs1(-/-) mice with respect to growth and glucose homeostasis. In contrast, mice with a combined deficiency of IRS-1 and IRS-3 developed early-onset severe lipoatrophy associated with marked hyperglycemia, hyperinsulinemia, and insulin resistance. However, in contrast to other models of lipoatrophic diabetes, there was no accumulation of fat in liver or muscle. Furthermore, plasma leptin levels were markedly decreased, and adenovirus-mediated expression of leptin in liver reversed the hyperglycemia and hyperinsulinemia. The results indicate that IRS-1 and IRS-3 play important complementary roles in adipogenesis and establish the Irs1(-/-)/Irs3(-/-) double knockout mouse as a novel model of lipoatrophic diabetes.

Topics: Adenoviridae; Adipose Tissue; Animals; Diabetes Mellitus, Lipoatrophic; Disease Models, Animal; Fatty Acids, Nonesterified; Glucose; Hyperglycemia; Hyperinsulinism; Immunoenzyme Techniques; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Leptin; Mice; Mice, Knockout; Phosphoproteins; Transfection; Triglycerides

Lipoatrophic diabetes is caused by a deficiency of adipose tissue and is characterized by severe insulin resistance, hypoleptinemia, and hyperphagia. The A-ZIP/F-1 mouse (A-ZIPTg/+) is a model of severe lipoatrophic diabetes and is insulin resistant, hypoleptinemic, hyperphagic, and shows severe hepatic steatosis. We have also produced transgenic "skinny" mice that have hepatic overexpression of leptin (LepTg/+) and no adipocyte triglyceride stores, and are hypophagic and show increased insulin sensitivity. To explore the pathophysiological and therapeutic roles of leptin in lipoatrophic diabetes, we crossed LepTg/+ and A-ZIPTg/+ mice, producing doubly transgenic mice (LepTg/+:A-ZIPTg/+) virtually lacking adipose tissue but having greatly elevated leptin levels. The LepTg/+:A-ZIPTg/+ mice were hypophagic and showed improved hepatic steatosis. Glucose and insulin tolerance tests revealed increased insulin sensitivity, comparable to LepTg/+ mice. These effects were stable over at least 6 months of age. Pair-feeding the A-ZIPTg/+ mice to the amount of food consumed by LepTg/+:A-ZIPTg/+ mice did not improve their insulin resistance, diabetes, or hepatic steatosis, demonstrating that the beneficial effects of leptin were not due to the decreased food intake. Continuous leptin administration that elevates plasma leptin concentrations to those of LepTg/+:A-ZIPTg/+ mice also effectively improved hepatic steatosis and the disorder of glucose and lipid metabolism in A-ZIP/F-1 mice. These data demonstrate that leptin can improve the insulin resistance and diabetes of a mouse model of severe lipoatrophic diabetes, suggesting that leptin may be therapeutically useful in the long-term treatment of lipoatrophic diabetes.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Lipoatrophic; Eating; Gene Expression; Infusion Pumps; Injections; Insulin Resistance; Leptin; Lipids; Mice; Mice, Inbred Strains; Mice, Transgenic; Organ Size; Transgenes

To further examine the relationships between leptin and female reproductive axis, we conducted hormonal studies in two patients with lipoatropic diabetes that occurred before puberty. Despite complete atrophy of sc and visceral adipose tissue, menarche occurred in these two patients between 11-12 yr of age, followed by regular menstrual cycles. One patient had been pregnant three times, giving birth to children who did not develop the disease. In our two patients, repeated analysis revealed leptin levels below 1 ng/mL (normal range for 20 insulin-treated diabetic women, 2-23 ng/mL for body mass index of 14-39 kg/m2; personal data). We measured peripheral levels of estradiol, progesterone, FSH, LH, free testosterone, and androstenedione within the first 5 days of the menstrual cycle, and we tested the reactivity of pituitary after iv injection of 100 microg GnRH. The variation in body temperature in the morning before arising was also analyzed. We showed that 1) all measured levels of hormones were in the normal range for both patients; and 2) low levels of leptin did not impair the development of reproductive function in one patient and was associated with normal gonadal function in both patients. We conclude that puberty and fertility can occur despite chronic low serum levels of leptin. This suggests that leptin is not fundamental to the maintenance of normal reproductive function in humans.

Topics: Adult; Diabetes Mellitus, Lipoatrophic; Female; Fertility; Humans; Leptin; Puberty; Reference Values; Reproduction; Tomography, X-Ray Computed

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