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Peripheral Insulin Resistance (peripheral + insulin_resistance)
Selected AbstractsRole of orexin in the regulation of glucose homeostasisACTA PHYSIOLOGICA, Issue 3 2010H. Tsuneki Abstract Orexin-A (hypocretin-1) and orexin-B (hypocretin-2) are hypothalamic neuropeptides that play key roles in the regulation of wakefulness, feeding, reward, autonomic functions and energy homeostasis. To control these functions indispensable for survival, orexin-expressing neurones integrate peripheral metabolic signals, interact with many types of neurones in the brain and modulate their activities via the activation of orexin-1 receptor or orexin-2 receptor. In addition, a new functional role of orexin is emerging in the regulation of insulin and leptin sensitivities responsible for whole-body glucose metabolism. Recent evidence indicates that orexin efficiently protects against the development of peripheral insulin resistance induced by ageing or high-fat feeding in mice. In particular, the orexin receptor-2 signalling appears to confer resistance to diet-induced obesity and insulin insensitivity by improving leptin sensitivity. In fact, the expression of orexin gene is known to be down-regulated by hyperglycaemia in the rodent model of diabetes, such as ob/ob and db/db mice. Moreover, the levels of orexin receptor-2 mRNA have been shown to decline in the brain of mice along with ageing. These suggest that hyperglycaemia due to insulin insensitivity during ageing or by habitual consumption of a high-fat diet leads to the reduction in orexin expression in the hypothalamus, thereby further exacerbating peripheral insulin resistance. Therefore, orexin receptor controlling hypothalamic insulin/leptin actions may be a new target for possible future treatment of hyperglycaemia in patients with type 2 diabetes. [source] A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents,,HEPATOLOGY, Issue 4 2010Nicola Santoro The genetic factors associated with susceptibility to nonalcoholic fatty liver disease (NAFLD) in pediatric obesity remain largely unknown. Recently, a nonsynonymous single-nucleotide polymorphism (rs738409), in the patatin-like phospholipase 3 gene (PNPLA3) has been associated with hepatic steatosis in adults. In a multiethnic group of 85 obese youths, we genotyped the PNLPA3 single-nucleotide polymorphism, measured hepatic fat content by magnetic resonance imaging and insulin sensitivity by the insulin clamp. Because PNPLA3 might affect adipogenesis/lipogenesis, we explored the putative association with the distribution of adipose cell size and the expression of some adipogenic/lipogenic genes in a subset of subjects who underwent a subcutaneous fat biopsy. Steatosis was present in 41% of Caucasians, 23% of African Americans, and 66% of Hispanics. The frequency of PNPLA3(rs738409) G allele was 0.324 in Caucasians, 0.183 in African Americans, and 0.483 in Hispanics. The prevalence of the G allele was higher in subjects showing hepatic steatosis. Surprisingly, subjects carrying the G allele showed comparable hepatic glucose production rates, peripheral glucose disposal rate, and glycerol turnover as the CC homozygotes. Carriers of the G allele showed smaller adipocytes than those with CC genotype (P = 0.005). Although the expression of PNPLA3, PNPLA2, PPAR,2(peroxisome proliferator-activated receptor gamma 2), SREBP1c(sterol regulatory element binding protein 1c), and ACACA(acetyl coenzyme A carboxylase) was not different between genotypes, carriers of the G allele showed lower leptin (LEP)(P = 0.03) and sirtuin 1 (SIRT1) expression (P = 0.04). Conclusion: A common variant of the PNPLA3 gene confers susceptibility to hepatic steatosis in obese youths without increasing the level of hepatic and peripheral insulin resistance. The rs738409 PNPLA3 G allele is associated with morphological changes in adipocyte cell size. (HEPATOLOGY 2010.) [source] Liver fat and lipid oxidation in humansLIVER INTERNATIONAL, Issue 9 2009Anna Kotronen Abstract Background: Studies in animals show that changes in hepatic fatty acid oxidation alter liver fat content. Human data regarding whole-body and hepatic lipid oxidation are controversial and based on studies of only a few subjects. Aims: We examined whether whole-body and hepatic lipid oxidation are altered in subjects with non-alcoholic fatty liver disease (NAFLD) compared with controls. Methods: In vivo measurements of rates of substrate oxidation and insulin sensitivity (using the euglycaemic hyperinsulinaemic clamp technique in combination with indirect calorimetry and infusion of [3- 3H]glucose) were performed in subjects with NAFLD [mean liver fat 14.0% (interquartile range 7.5,20.5%), n=29] and in control subjects [1.6% (1.0,3.0%), n=29]. Liver fat was measured using proton magnetic resonance spectroscopy. Plasma concentrations of 3-hydroxybutyrate (3-OHB) were measured as markers of hepatic lipid oxidation. Results: In the basal state, substrate oxidation rates and serum 3-OHB concentrations were comparable in subjects with and without NAFLD. Plasma 3-OHB concentrations were similarly suppressed by insulin in both the groups. During the insulin infusion, whole-body lipid oxidation was inversely correlated with insulin-stimulated glucose disposal (r=,0.48, P<0.0001), which was lower in subjects with NAFLD [3.7±0.2 mg/(kg fat-free mass min)] than in the control subjects [5.0±0.3 mg/(kg fat-free mass min), P=0.0008]. Conclusions: Hepatic lipid oxidation is unchanged in NAFLD. Whole-body lipid oxidation is increased because of peripheral insulin resistance. These data imply that alterations in hepatic fatty acid oxidation do not contribute to liver fat content in humans. [source] The role of oestrogens in the adaptation of islets to insulin resistanceTHE JOURNAL OF PHYSIOLOGY, Issue 21 2009Angel Nadal Pregnancy is characterized by peripheral insulin resistance, which is developed in parallel with a plasma increase of maternal hormones; these include prolactin, placental lactogens, progesterone and oestradiol among others. Maternal insulin resistance is counteracted by the adaptation of the islets of Langerhans to the higher insulin demand. If this adjustment is not produced, gestational diabetes may be developed. The adaptation process of islets is characterized by an increase of insulin biosynthesis, an enhanced glucose-stimulated insulin secretion (GSIS) and an increase of ,,cell mass. It is not completely understood why, in some individuals, ,,cell mass and function fail to adapt to the metabolic demands of pregnancy, yet a disruption of the ,,cell response to maternal hormones may play a key part. The role of the maternal hormone 17,-oestradiol (E2) in this adaptation process has been largely unknown. However, in recent years, it has been demonstrated that E2 acts directly on ,,cells to increase insulin biosynthesis and to enhance GSIS through different molecular mechanisms. E2 does not increase ,,cell proliferation but it is involved in ,,cell survival. Classical oestrogen receptors ER, and ER,, as well as the G protein-coupled oestrogen receptor (GPER) seem to be involved in these adaptation changes. In addition, as the main production of E2 in post-menopausal women comes from the adipose tissue, E2 may act as a messenger between adipocytes and islets in obesity. [source] Effect of Withania somnifera on Insulin Sensitivity in Non-Insulin-Dependent Diabetes Mellitus RatsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 6 2008Tarique Anwer NIDDM was induced by single intraperitoneal injection of streptozotocin (100 mg/kg) to 2 days old rat pups. WS (200 and 400 mg/kg) was administered orally once a day for 5 weeks after the animals were confirmed diabetic (i.e. 75 days after streptozotocin injection). A group of citrate control rats (group I) were also maintained that has received citrate buffer on the second day of their birth. A significant increase in blood glucose, glycosylated haemoglobin (HbA1c) and serum insulin levels were observed in NIDDM control rats. Treatment with WS reduced the elevated levels of blood glucose, HbA1c and insulin in the NIDDM rats. An oral glucose tolerance test was also performed in the same groups, in which we found a significant improvement in glucose tolerance in the rats treated with WS. The insulin sensitivity was assessed for both peripheral insulin resistance and hepatic insulin resistance. WS treatment significantly improved insulin sensitivity index (KITT) that was significantly decreased in NIDDM control rats. There was significant rise in homeostasis model assessment of insulin resistance (HOMA-R) in NIDDM control rats whereas WS treatment significantly prevented the rise in HOMA-R in NIDDM-treated rats. Our data suggest that aqueous extract of WS normalizes hyperglycemia in NIDDM rats by improving insulin sensitivity. [source] Will the potential of peroxisome proliferator-activated receptor agonists be realized in the clinical setting?CLINICAL CARDIOLOGY, Issue S4 2004Florian Blaschke M.D. Abstract Drugs targeting both peroxisome proliferator-activated receptor-gamma (PPAR-,) agonists (the thiazolidinediones) and PPAR-, (the fibrates) have already been developed for clinical use. However, the thiazolidinediones, currently prescribed to treat hyperglycemia and improve peripheral insulin resistance, may also have cardiovascular benefits that have yet to be fully realized. Animal models of atherosclerosis have shown that the thiazolidinediones reduce the extent of atherosclerotic lesions and inhibit macrophage accumulation. Clinical studies have also shown that these drugs improve the lipid profile of patients at risk of developing atherosclerosis and reduce circulating levels of inflammatory markers. This combination of lower lipid concentrations and reduced inflammation may explain the cardiovascular benefits of this class of drugs. Early trials in patients with coronary stents have reported promising findings, with restenosis rates being greatly reduced with thiazolidinedione therapy. It is hoped that the results of future clinical trials will continue to be encouraging, so that the thiazolidinediones' cardiovascular benefits can be fully realized in the clinic. [source] | |||||||||||||