Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin is produced by adipose tissue and acts as a feedback signal to the hypothalamus controlling energy homeostasis, by reducing food consumption and increasing energy expenditure. Because serum leptin levels are highly correlated with body fat mass, they can be used as an index to predict obesity-related diseases. However, the identity of genetic factors that influence the obesity and the obesity-related metabolic disorders remains largely unknown. In this study, we performed a whole-genome scan search, using 382 F2 intercross progeny between the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, an animal model for obese type 2 diabetes in human, and F344 rat, in order to identify loci responsible for the regulation of leptin and other obesity-related plasma substances. We have identified two quantitative trait loci (QTLs) contributing to serum leptin levels. These two loci, designated Olep1 [Chromosome (Chr) 2] and Olep2 (Chr 6), were homologous to those of human genome regions containing several potential candidate genes for obesity. These are fatty acid-binding protein 2 (FABP2), FABP4, and FABP5 for Olep1, and proopiomelanocortin (POMC) and glucose regulatory protein (GCKR) for Olep2.
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PMID:Serum leptin concentration is linked to chromosomes 2 and 6 in the OLETF rat, an animal model of type 2 diabetes with mild obesity. 1472 32

The hormone leptin is secreted from white adipocytes, and serum levels of leptin correlate with adipose tissue mass. Leptin was first described to act on the satiety center in the hypothalamus through specific receptors (leptin receptor [ObR]) to restrict food intake and enhance energy expenditure. Important peripheral actions of leptin involve inhibition of insulin biosynthesis and secretion in pancreatic beta-cells. In turn, insulin stimulates leptin secretion from adipose tissue, establishing a hormonal regulatory feedback loop-the so-called "adipo-insular axis." Multiple signal transduction pathways are involved in leptin signaling in pancreatic beta-cells. We have identified the proinsulin gene and protein phosphatase 1 gene as leptin repressed genes and the gene for the suppressor of cytokine signaling 3 protein as a leptin-induced gene in pancreatic beta-cells. The molecular effects of leptin culminate to restrict insulin secretion and biosynthesis to adapt glucose homeostasis to the amount of body fat. In most overweight individuals, however, physiological regulation of body weight by leptin seems to be disturbed, representing "leptin resistance." This leptin resistance at the level of the pancreatic beta-cell may contribute to dysregulation of the adipo-insular axis and promote the development of hyperinsulinemia and manifest type 2 diabetes in overweight patients.
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PMID:Leptin effects on pancreatic beta-cell gene expression and function. 1474 81

The proband, a 9-year-old Hispanic female, presented with hair loss, strabismus, and weight gain. On magnetic resonance imaging (MRI) she was found to have severe primary hypothyroidism and a large pituitary mass. In addition, acanthosis nigricans, obesity, and hyperinsulinism were observed. Findings were similar in three of four siblings. Thyroid peroxidase antibodies were detected in the father and three of four siblings. Although all family members were obese, and hyperinsulinemia with high proinsulin and C-peptide was found in all except one sibling, only the mother and one child had overt type 2 diabetes mellitus. Because of the unusual association of autoimmune thyroid disease, insulin resistance and obesity rather than insulin deficiency, we searched for possible genetic abnormalities. The HLA haplotypes did not cosegregate with autoimmune thyroid disease or insulin resistance. Mutational analysis of known obesity genes was done. Leptin was not deficient, and sequencing of the proband's DNA showed no mutations in the perixisome proliferator activated receptor (PPAR)-gamma, PPAR-gamma(2), PPAR-alpha or melanocortin 4 receptor genes. Maternally inherited diabetes and deafness was ruled out since no mutations were found in mitochondria DNA. Insulin receptor antibodies were not detected. In conclusion, the remarkably high incidence of childhood autoimmune hypothyroidism, pituitary enlargement, insulin resistance and obesity in this family is not linked to known HLA types or known gene defects.
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PMID:Familial juvenile autoimmune hypothyroidism, pituitary enlargement, obesity, and insulin resistance. 1514 66

Obesity and type 2 diabetes are associated with nonalcoholic steatohepatitis (NASH), but an obese/diabetic animal model that mimics human NASH remains undefined. We examined the induction of steatohepatitis and liver fibrosis in obese and type 2 diabetic db/db mice in a nutritional model of NASH and determined the relationship of the expressions of osteopontin (OPN) and leptin receptors to the pathogenesis of NASH. db/db mice and the corresponding lean and nondiabetic db/m mice were fed a diet deficient in methionine and choline (MCD diet) or control diet for 4 wk. Leptin-deficient obese and diabetic ob/ob mice fed similar diets were used for comparison. MCD diet-fed db/db mice exhibited significantly greater histological inflammation and higher serum alanine aminotransferase levels than db/m and ob/ob mice. Trichrome staining showed marked pericellular fibrosis in MCD diet-fed db/db mice but no significant fibrosis in db/m or ob/ob mice. Collagen I mRNA expression was increased 10-fold in db/db mice, 4-fold in db/m mice, and was unchanged in ob/ob mice. mRNA expressions of OPN, TNF-alpha, TGF-beta, and short-form leptin receptors (Ob-Ra) were significantly increased in db/db mice compared with db/m or ob/ob mice. Parallel increases in OPN and Ob-Ra protein levels were observed in db/db mice. Cultured hepatocytes expressed only Ob-Ra, and leptin stimulated OPN mRNA and protein expression in these cells. In conclusion, our results demonstrate the development of an obese/diabetic experimental model for NASH in db/db mice and suggest an important role for Ob-Ra and OPN in the pathogenesis of NASH.
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PMID:Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis: role of short-form leptin receptors and osteopontin. 1525 62

Leptin signaling may promote atherothrombosis and lead to cardiovascular disease. However, whether leptin is associated with human atherosclerosis, distinct from thrombosis, is unknown. We determined the association of plasma leptin levels with coronary artery calcification (CAC), a measure of coronary atherosclerosis, in a cross-sectional study of type 2 diabetes. Leptin levels were associated with CAC after adjusting for established risk factors [odds ratio (95% confidence interval) for 5 ng/ml leptin increase: 1.31 (1.10-1.55); P = 0.002]. Leptin remained associated with CAC after further controlling for body mass index (BMI) [1.29 (1.07-1.55); P = 0.008], waist circumference [1.30 (1.09-1.57); P = 0.003], C-reactive protein (CRP) levels [1.28 (1.07-1.55); P = 0.008], and subclinical vascular disease [1.30 (1.08-1.57); P = 0.006]. Addition of BMI (P = 0.97), waist (P = 0.55), or CRP (P = 0.39) to a model with leptin failed to improve the model's explanatory power, whereas addition of leptin to a model with BMI (P = 0.029), waist (P = 0.006), or CRP (P = 0.005) improved the model significantly. Plasma leptin levels were associated with CAC in type 2 diabetes after controlling adiposity and CRP. Whether leptin signaling promotes atherosclerosis directly or represents a therapeutic target for the prevention of atherosclerotic cardiovascular disease remains to be explored.
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PMID:Plasma leptin levels are associated with coronary atherosclerosis in type 2 diabetes. 1529 20

Sex steroid hormones are involved in the metabolism, accumulation and distribution of adipose tissues. It is now known that oestrogen receptor, progesterone receptor and androgen receptor exist in adipose tissues, so their actions could be direct. Sex steroid hormones carry out their function in adipose tissues by both genomic and nongenomic mechanisms. In the genomic mechanism, the sex steroid hormone binds to its receptor and the steroid-receptor complex regulates the transcription of given genes. Leptin and lipoprotein lipase are two key proteins in adipose tissues that are regulated by transcriptional control with sex steroid hormones. In the nongenomic mechanism, the sex steroid hormone binds to its receptor in the plasma membrane, and second messengers are formed. This involves both the cAMP cascade and the phosphoinositide cascade. Activation of the cAMP cascade by sex steroid hormones would activate hormone-sensitive lipase leading to lipolysis in adipose tissues. In the phosphoinositide cascade, diacylglycerol and inositol 1,4,5-trisphosphate are formed as second messengers ultimately causing the activation of protein kinase C. Their activation appears to be involved in the control of preadipocyte proliferation and differentiation. In the presence of sex steroid hormones, a normal distribution of body fat exists, but with a decrease in sex steroid hormones, as occurs with ageing or gonadectomy, there is a tendency to increase central obesity, a major risk for cardiovascular disease, type 2 diabetes and certain cancers. Because sex steroid hormones regulate the amount and distribution of adipose tissues, they or adipose tissue-specific selective receptor modulators might be used to ameliorate obesity. In fact, hormone replacement therapy in postmenopausal women and testosterone replacement therapy in older men appear to reduce the degree of central obesity. However, these therapies have numerous side effects limiting their use, and selective receptor modulators of sex steroid hormones are needed that are more specific for adipose tissues with fewer side effects.
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PMID:Direct effects of sex steroid hormones on adipose tissues and obesity. 1545 95

By screening 204 diabetes patients, a male with age 38 was found to have increased C-peptide levels in plasma (over 6 ng/ml) and urine (430 microg/day), both of which were the highest among the screened subjects. He developed type 2 diabetes at age 31, without history of obesity (weight was 52 kg and height 170 cm). He had bilateral testicular atrophy. Fasting plasma glucose level was 160 mg/dl and HbA1c was 8% at age 38. There was hypertriglycemia (290-662 mg/dl). There were no abnormal peaks of IRI or CPR in the serum fractionated by gel filtration (Biogel P 30). Molar ratio of p-CPR/s-IRI was 10.8. Islet cell antibody, anti-insulin binding antibody and anti-insulin receptor antibody were negative. LSH and FSH were both elevated, and free testosterone was decreased. TSH and Leptin levels were elevated. Other laboratory data were within normal range. CT scan revealed fatty liver and horse-shoe kidney. These clinical pictures do not match the criteria to known syndromes associated with diabetes. Although the single case report is insufficient to discuss the C-peptide mechanism of action, this case may give us a hint to understand an aspect of the pathophysiology of C-peptide's bioactivity dysfunction.
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PMID:A case of type 2 diabetes with high levels of plasma and urinary C-peptide. 1556 62

We studied the correlation between the adiponectin-leptin (A/L) ratio and parameters of insulin resistance in 220 Japanese patients with type 2 diabetes (138 men and 82 women). Body mass index (BMI), triglycerides (TGs), HDL cholesterol (HDL), and preheparin serum lipoprotein lipase (LPL mass) were examined as laboratory parameters of the insulin resistance. The correlations between these laboratory parameters and adiponectin, leptin, or A/L ratio were studied. Adiponectin levels correlated significantly with BMI (r = -0.298, P = .0003), TGs (r = -0.221, P = .0092), HDL (r = 0.31, P = .0002), and LPL mass (r = 0.26, P = .0021) in men, and with TGs (r = -0.29, P = .0093), HDL (r = 0.239, P = .0338), and LPL mass (r = 0.499, P < .0001) in women. Leptin levels correlated significantly with only BMI (r = 0.31, P = .0002) in men, and with BMI (r = 0.71, P < .0001) and TGs (r = 0.26, P = .0201) in women. Adiponectin and leptin levels tended to correlate with these parameters in an opposite manner. On the other hand, A/L ratio significantly correlated with BMI (r = -0.4, P < .0001), TG (r = -0.199, P = .0192), HDL (r = 0.235, P = .0054), and LPL mass (r = 0.244, P = .0390) in men, and with BMI (r = -0.482, P < .0001), TG (r = -0.402, P = .0002), HDL (r = 0.358, P = .0011), and LPL mass (r = 0.487, P < .0001) in women. Next, the patients were divided into 3 groups classified by their fasting plasma glucose (FPG) level, and the correlations between the parameters and A/L ratio or homeostasis model assessment (HOMA-R), and the correlation between A/L ratio and HOMA-R were investigated in each group. Significant correlations between the parameters and A/L ratio were tended to be observed as the FPG level rose; however, the significant correlations between the parameters and HOMA-R were no longer seen as FPG level elevated. The results suggested that the A/L ratio was effective in relevance as a parameter of insulin resistance to adiponectin or leptin alone, and a more sensitive and reliable marker of insulin resistance than HOMA-R as the FPG level elevated, in patients with type 2 diabetes.
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PMID:Correlation between the adiponectin-leptin ratio and parameters of insulin resistance in patients with type 2 diabetes. 1573 3

Being overweight or obese has become highly prevalent in Western countries and are rapidly reaching epidemic proportions in the developing world. Obesity-related disorders, such as hypertension and diabetes, are also increasing at an alarming rate. The relationship between obesity, hypertension and insulin resistance is well recognised, but the molecular mechanisms involved remain relatively poorly understood. Adipose tissue plays a key role in the pathogenesis of the metabolic syndrome. It serves as an important source of pro-inflammatory molecules, including leptin, tumour necrosis factor alpha, angiotensin II and interleukin-6, as well as anti-inflammatory molecules, such as adiponectin. Knowledge of how these adipose tissue-derived factors influence metabolic and cardiovascular disease has recently expanded. Leptin is now considered to play a key role in the elevation of sympathetic activity commonly found in obese, hypertensive patients, and decreased secretion of adiponectin appears to be an important predictor of diabetes. The ectopic storage of excess fat in skeletal muscle, liver or pancreas, due to the decreased capacity of adipose tissue to scavenge excess calories, may also play a role in the development of insulin resistance and type 2 diabetes. Overall, continuing research into the relationship between adipose-tissue biology and metabolic abnormalities may lead to a better understanding of the molecular mechanisms underlying the relationship between obesity and cardiovascular disease, and ultimately provide alternative treatments for the control of potentially life-threatening conditions.
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PMID:Obesity, hypertension and insulin resistance. 1586 17

Epidemiological evidence suggests that sex differences exist in type 2 diabetes. Men seem to be more susceptible than women to the consequences of obesity and sedentary lifestyle, possibly because of differences in insulin sensitivity and regional body fat deposition. Thus, lacking androgen receptor (AR) in male individuals may promote insulin resistance. To determine whether lacking AR in male individuals contributes to in vivo insulin resistance, an AR knockout model (AR(-/y)) was used to study the correlation between AR and insulin resistance. Progressive reduced insulin sensitivity and impaired glucose tolerance were seen in AR(-/y) mice with advancing age. Aging AR(-/y) mice displayed accelerated weight gain, hyperinsulinemia, and hyperglycemia, and loss of AR contributes to increased triglyceride content in skeletal muscle and liver. Leptin is higher in serum of AR(-/y) mice. Treatment with exogenous leptin fails to stimulate weight loss in AR(-/y) mice in advanced age, suggesting leptin resistance in the AR(-/y/) mice. Exogenous dihydrotestosterone replacement fails to reverse the metabolic abnormalities and insulin resistance in AR(-/y) mice. Our in vivo studies demonstrate that androgen-AR plays key roles in the development of insulin and leptin resistance, which may contribute to the development of type 2 diabetes and cardiovascular disease.
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PMID:Insulin and leptin resistance with hyperleptinemia in mice lacking androgen receptor. 1591 93


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