leptin and Pancreatic-Diseases

Type 2 diabetes mellitus (T2DM) is characterized by impaired insulin secretion. Chronically increased levels of plasma nonesterified fatty acids (NEFA) and triglyceride-rich lipoproteins impair beta-cell function, a process referred to as lipotoxicity. Furthermore, when NEFA supply exceeds metabolic capacity, lipids accumulate in nonadipose tissues, such as pancreatic islets, inducing organ dysfunction. The purpose of this review is to describe the mechanisms underlying lipotoxicity in vitro, to discuss the evidence for lipotoxicity in vivo and to address whether pancreatic lipid accumulation interferes with insulin secretion in humans.. Although numerous in-vitro studies have shown that chronically elevated NEFA levels induce beta-cell dysfunction and apoptosis, studies in humans are less conclusive. It has been acknowledged that concurrent hyperglycaemia amplifies the adverse effects of elevated plasma NEFA levels on beta-cell function; therefore glucolipotoxicity should be the preferred term. Lipid accumulation in pancreatic islets impaired beta-cell secretory capacity in leptin-deficient rodents. In humans, recent studies employing noninvasive magnetic resonance-technology and computed tomography-technology, lipid accumulation in the pancreas was increased in individuals with impaired glucose metabolism and T2DM. However, there was no clear association with beta-cell dysfunction.. To date, it is difficult to provide evidence that intraislet lipid accumulation truly exists in humans and that it is indeed causal to beta-cell dysfunction. Additional research is warranted to further detail the nature and role of pancreatic lipid content in humans, its consequence for the postulated processes pertinent to glucolipotoxicity and its contribution to the progressive nature of beta-cell dysfunction in prediabetes.

Topics: Animals; Apoptosis; Blood Glucose; Diabetes Complications; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Humans; Hyperglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Lipid Metabolism Disorders; Pancreas; Pancreatic Diseases

Decreases in both mass and secretory function of insulin-producing beta-cells contribute to the pathophysiology of type 2 diabetes. The histology of islets from patients with type 2 diabetes displays an inflammatory process characterized by the presence of cytokines, apoptotic cells, immune cell infiltration, amyloid deposits, and eventually fibrosis. This inflammatory process is probably the combined consequence of dyslipidemia, hyperglycemia, and increased circulating adipokines. Therefore, modulation of intra-islet inflammatory mediators, in particular interleukin-1 beta, appears as a promising therapeutic approach.

Topics: Cytokines; Diabetes Mellitus, Type 2; Dyslipidemias; Glucose; Humans; Hypoglycemic Agents; Inflammation; Insulin-Secreting Cells; Interleukin-1beta; Islets of Langerhans; Leptin; Obesity; Pancreatic Diseases

In insulin resistance (IR), it is thought that pancreatic fat accumulation may decrease pancreatic volume, cause an impaired endocrine function, and simultaneously lead to an exocrine dysfunction before diabetes develops.. The association between pancreatic exocrine function and insulin resistance (IR) was assessed in a population with insulin resistance.. This was a descriptive cross-sectional study that included 43 IR cases with no other comorbid diseases or pregnancy and 41 healthy controls. Fasting blood adiponectin, leptin, pancreatic amylase, lipase, and stool fecal elastase-1 (FE-1) were studied and compared in both groups.. The IR group consisted of 38 females (88.3%) and five males (11.6%), while the control group consisted of 31 females (75.6%) and ten males (24.3%). FE-1 levels were significantly lower in the IR group (P-value <0.01). Blood glucose, insulin, and HbA1c levels were significantly higher in the IR group than in the control (P-value of <0.01, <0.01, <0.01, respectively). Leptin levels were significantly higher in the IR group compared to the controls (P-value = 0.013). After dividing the whole group (n: 84) into two groups as FE-1 <200 μg/g (n: 61) and FE-1 ≥200 μg/g (n: 23), logistic regression analysis was performed; the significant predictor of low FE-1 was HOMA-IR (ODD ratio: 4.27, P-value <0.01, 95% confidence interval for ODD ratio: 1.95-9.30).. This study showed that IR is associated with pancreatic exocrine dysfunction.

Topics: Cross-Sectional Studies; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Pancreatic Diseases; Turkey

Obesity is a worldwide epidemic and a significant risk factor for pancreatic diseases including pancreatitis and pancreatic cancer; the mechanisms underlying this association are unknown. Metabolomics is a powerful new analytical approach for describing the metabolome (compliment of small molecules) of cells, tissue or biofluids at any given time. Our aim was to analyze pancreatic fat content in lean and congenitally obese mice using both metabolomic analysis and conventional chromatography.. The pancreatic fat content of 12 lean (C57BL/6J), 12 obese leptin-deficient (Lep(ob)) and 12 obese hyperleptinemic (Lep(db)) mice was evaluated by metabolomic analysis, thin-layer and gas chromatography.. Pancreata of congenitally obese mice had significantly more total pancreatic fat, triglycerides and free fatty acids, but significantly less phospholipids and cholesterol than those of lean mice. Metabolomic analysis showed excellent correlation with thin-layer and gas chromatography in measuring total fat, triglycerides and phospholipids.. Differences in pancreatic fat content and character may have important implications when considering the local pancreatic proinflammatory milieu in obesity. Metabolomic analysis is a valid, powerful tool with which to further define the mechanisms by which fat impacts pancreatic disease.

Topics: Adipose Tissue; Animals; Cholesterol; Female; Leptin; Lipids; Magnetic Resonance Spectroscopy; Metabolomics; Mice; Mice, Obese; Obesity; Pancreas; Pancreatic Diseases; Phospholipids; Triglycerides

Prion diseases are fatal neurodegenerative diseases that can induce endocrinopathies. The basis of altered endocrine function in prion diseases is not well understood, and the purpose of this study was to investigate the spatiotemporal relationship between energy homeostasis and prion infection in hamsters inoculated with either the 139H strain of scrapie agent, which induces preclinical weight gain, or the HY strain of transmissible mink encephalopathy (TME), which induces clinical weight loss. Temporal changes in body weight, feed, and water intake were measured as well as both non-fasted and fasted concentrations of serum glucose, insulin, glucagon, beta-ketones, and leptin. In 139H scrapie-infected hamsters, polydipsia, hyperphagia, non-fasted hyperinsulinemia with hyperglycemia, and fasted hyperleptinemia were found at preclinical stages and are consistent with an anabolic syndrome that has similarities to type II diabetes mellitus and/or metabolic syndrome X. In HY TME-infected hamsters, hypodipsia, hypersecretion of glucagon (in both non-fasted and fasted states), increased fasted beta-ketones, fasted hypoglycemia, and suppressed non-fasted leptin concentrations were found while feed intake was normal. These findings suggest a severe catabolic syndrome in HY TME infection mediated by chronic increases in glucagon secretion. In both models, alterations of pancreatic endocrine function were not associated with PrP(Sc) deposition in the pancreas. The results indicate that prominent endocrinopathy underlies alterations in body weight, pancreatic endocrine function, and intake of food. The prion-induced alterations of energy homeostasis in 139H scrapie- or HY TME-infected hamsters could occur within areas of the hypothalamus that control food satiety and/or within autonomic centers that provide neural outflow to the pancreas.

Topics: Animals; Blood Glucose; Body Weight; Cricetinae; Drinking; Eating; Energy Metabolism; Glucagon; Glucose Tolerance Test; Homeostasis; Hypothalamus; Insulin; Leptin; Male; Mesocricetus; Pancreatic Diseases; Prion Diseases; PrPSc Proteins

Expression of peroxisome proliferator-activated receptor alpha (PPARalpha) and enzymes of fatty acid (FA) oxidation is markedly reduced in the fat-laden, dysfunctional islets of obese, prediabetic Zucker diabetic fatty (fa/fa) rats with mutated leptin receptors (OB-R). Leptin, PPARalpha/retinoid x receptor ligands, and FA all up-regulate PPARalpha and enzymes of FA oxidation and stimulate [3H]-palmitate oxidation in normal islets but not in islets from fa/fa rats. Overexpression of normal OB-R in islets of fa/fa rats corrects all of the foregoing abnormalities and reverses the diabetic phenotype. PPARalpha is a OB-R-dependent factor required for normal fat homeostasis in islet cells.

Topics: Animals; Base Sequence; Clofibrate; DNA Primers; Gene Expression Regulation; Islets of Langerhans; Leptin; Male; Pancreatic Diseases; Proteins; Rats; Rats, Mutant Strains; Receptors, Cytoplasmic and Nuclear; Transcription Factors; Tretinoin