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2018 JUN 16 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Fresh data on Oncology - Cancer Biology are presented in a new [...]

OBJECTIVE--Defects in insulin/IGF-1 signaling stimulate muscle protein loss by suppressing protein synthesis and increasing protein degradation. Since an herbal compound, berberine, lowers blood levels of glucose and lipids, we proposed that it would improve insulin/IGF-1 signaling, blocking muscle protein losses. RESEARCH DESIGN AND METHODS---We evaluated whether berberine ameliorates muscle atrophy in db/db mice, a model of type 2 diabetes, by measuring protein synthesis and degradation in muscles of normal and db/db mice treated with or without berberine. We also examined mechanisms for berberine-induced changes in muscle protein metabolism. RESULTS--Berberine administration decreased protein synthesis and increased degradation in muscles of normal and db/db mice. The protein catabolic mechanism depended on berberine-stimulated expression of the E3 ubiquitin ligase, atrogin-1. Atrogin-1 not only increased proteolysis but also reduced protein synthesis by mechanisms that were independent of decreased phosphorylation of Akt or forkhead transcription factors. Impaired protein synthesis was dependent on a reduction in eIF3-f, an essential regulator of protein synthesis. Berberine impaired energy metabolism, activating AMP-activated protein kinase and providing an alternative mechanism for the stimulation of atrogin-1 expression. When we increased mitochondrial biogenesis by expressing peroxisome proliferator-activated receptor γ coactivator-lα berberine-induced changes in muscle protein metabolism were prevented. CONCLUSIONS--Berberine impairs muscle metabolism by two novel mechanisms. It impairs mitochonidrial function stimulating the expression of atrogin-1 without affecting phosphorylation of forkhead transcription factors. The increase in atrogin-1 not only stimulated protein degradation but also suppressed protein synthesis, causing muscle atrophy., There is evidence that an herbal compound, berberine, improves insulin-mediated glucose metabolism and enhances insulin sensitivity in mice (1-3). For example, Lee et al. (1) reported that administering berberine to [...]

OBJECTIVE--Current studies indicate that Hedgehog (Hh) signaling must be excluded during early stages of pancreas formation. However, conflicting evidence suggests that Hh signaling may be active later during pancreas formation and that it is required for insulin production and secretion in cultured β-cell lines. The objective of this study was to address these discrepancies by assessing the in vivo role of epithelial Hh signaling in the pancreas. RESEARCH DESIGN AND METHODS--To identify Hh-active cells in the developing and adult pancreas epithelium, we characterized transgenic reporter Patched1-LacZ mice. To determine the requirement for epithelial Hh signaling in the pancreas, we eliminated an essential Hh signaling component, Smoothened (Smo), in the pancreatic epithelium, and assessed pancreatic development and adult β-cell physiology phenotypes. RESULTS--Characterization of Patched1-LacZ reporter mice revealed low-level LacZ expression in pancreatic epithelial cells throughout development until birth, when LacZ activity increases in intensity specifically in endocrine and ductal cells. In the absence of Hh signaling, Smo-deficient mice have delayed pancreas formation leading to a temporary reduction in pancreatic epithelium and β-cell numbers. Although β-cell numbers recover by birth, adult Smo-deficient mice display glucose intolerance, increased insulin sensitivity, and reduced total insulin production. CONCLUSIONS--These data show that Hh signaling functions early during pancreas morphogenesis to regulate epithelial and [5-cell expansion and to modulate glucose metabolism by regulating insulin production in adult mice., The advancements in stem cell technologies carry the promise toward developing a renewable supply of β-cells and a cure for diabetes. While significant progress has been made in recent years, [...]

OBJECTIVE--Glucose homeostasis is achieved by triggering regulation of glycogen synthesis genes in response to insulin when mammals feed, but the underlying molecular mechanism remains largely unknown. The aim of our study was to examine the role of the signal transducers and activators of transcription 3 (STAT3) in insulin signaling. RESEARCH DESIGN AND METHODS--We generated a strain of mice carrying a targeted disruption of Stat3 gene in the liver ([L-Stat3.sup.-/-] mice). Hepatocytes of the [L-Stat3.sup.-/-] mice were isolated to establish ceil lines for mechanistic studies. Nuclear translocation and DNA-protein interaction of STAT3 was analyzed with immunofluorescent and chromatin immunoprecipitation methods, respectively. Levels of glucose, insulin, leptin, and glucagon were profiled, and putative downstream molecules of STAT3 were examined in the presence of various stimuli in [L-Stat3.sup.-/-] and control mice. RESULTS--STAT3 was found to sensitize the insulin signaling through suppression of GSK-3β, a negative regulator of insulin signaling pathway. During feeding, both mRNA and protein levels of GSK-3β decreased in [Stat3.sup.f/+] mice, which reflected the need of hepatocytes for insulin to induce glycogen synthesis. In contrast, the [L-Stat3.sup.-/-] mice lost this control and showed a monophasic increase in the GSK-3β level in response to insulin. Administration of GSK-3β inhibitors lithium chloride and L803-mts restored glucose homeostasis and rescued the glucose intolerance and impaired insulin response in [L-Stat3.sup.-/-] mice. CONCLUSIONS--These data indicate that STAT3 sensitizes insulin signaling by negatively regulating GSK-3β. Inactivation of STAT3 in the liver contributes significantly to the pathogenesis of insulin resistance., The hallmark of type 2 diabetes, the most common metabolic disorder, is a defect in the insulin-signaled glucose metabolism of peripheral tissues, a phenomenon defined as insulin resistance. Physiologically, insulin [...]

OBJECTIVE--Emerging evidence suggests that dietary phytoestrogens can have beneficial effects on obesity and diabetes, although their mode of action is not known. Here, we investigate the mechanisms mediating the action of dietary phytoestrogens on lipid and glucose metabolism in rodents. RESEARCH DESIGN AND METHODS--Male CD-1 mice were fed from conception to adulthood with either a high soy-containing diet or a soy-free diet. Serum levels of circulating isoflavones, ghrelin, leptin, free fatty acids, triglycerides, and cholesterol were quantified. Tissue samples were analyzed by quantitative RT-PCR and Western blotting to investigate changes of gene expression and phosphorylation state of key metabolic proteins. Glucose and insulin tolerance tests and euglycemic-hypefinsulinemic clamp were used to assess changes in insulin sensitivity and glucose uptake. In addition, insulin secretion was determined by in situ pancreas perfusion. RESULTS--In peripheral tissues of soy-fed mice, especially in white adipose tissue, phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase was increased, and expression of genes implicated in peroxisomal fatty acid oxidation and mitochondrial biogenesis was upregulated. Soy-fed mice also showed reduced serum insulin levels and pancreatic insulin content and improved insulin sensitivity due to increased glucose uptake into skeletal muscle. Thus, mice fed with a soy-rich diet have improved adipose and glucose metabolism. CONCLUSIONS--Dietary soy could prove useful to prevent obesity and associated disorders. Activation of the AMPK pathway by dietary soy is likely involved and may mediate the beneficial effects of dietary soy in peripheral tissues., A better understanding of the factors regulating lipid and glucose metabolism are of eminent interest due to the pandemic development of obesity and its related metabolic disorders. Preventive strategies to [...]

OBJECTIVE--To determine the prevalence of disturbances in glucose metabolism in patients with acute stroke. RESEARCH DESIGN AND METHODS--Consecutively admitted acute stroke patients (n = 286) were screened for glucose tolerance [...]

Lifestyle modification reduces the risk of developing type 2 diabetes and may have its effect through improving insulin sensitivity, β-cell function, or both. To determine whether diet and exercise improve insulin sensitivity and/or β-cell function and to evaluate these effects over time, we quantified insulin sensitivity and the acute insulin response to glucose (AIRg) in 62 Japanese Americans (age 56.5 ± 1.3 years; mean ± SE) with impaired glucose tolerance (IGT) who were randomized to the American Heart Association (AHA) Step 2 diet plus endurance exercise (n = 30) versus the AHA Step 1 diet plus stretching (n = 32) for 24 months. β-Cell function (disposition index [DI] was calculated as [S.sub.i] X AIRg, where [S.sub.i] is the insulin sensitivity index. The incremental area under the curve for glucose (incAUCg) was calculated from a 75-g oral glucose tolerance test. Intra-abdominal fat (IAF) and subcutaneous fat (SCF) areas were measured by computed tomography. At 24 months, the Step 2/endurance group had lower weight (63.1 ± 2.4 vs. 71.3 ± 2.9 kg; P = 0.004) and IAF (75.0 ± 7.9 vs. 112.7 ± 10.4 [cm.sup.2]; P = 0.03) and SCF (196.5 ± 18.0 vs. 227.7 ± 19.9 [cm.sup.2]; P < 0.001) areas, greater [S.sub.i] (4.7 ± 0.5 vs. 3.3 + 0.3 x [10.sup.-5] min x [pmol.sup.-1] x [1.sup.-1]; P = 0.01), and a trend toward lower AIRg (294.9 ± 50.0 vs. 305.4 ± 30.0 pmol/l; P = 0.06) and incAUCg (8,217.3 ± 350.7 vs. 8,902.0 ± 367.2 mg x [dl.sup.-1] x 2 [h.sup.-1]; P = 0.08) compared with the Step 1/stretching group after adjusting for baseline values. There was no difference in the DI (P = 0.7) between the groups. [S.sub.i] was associated with changes in weight (r = -0.426, P = 0.001) and IAF (r = -0.395, P = 0.003) and SCF (r = -0.341, P = 0.01) areas. Thus, the lifestyle modifications decreased weight and central adiposity and improved insulin sensitivity in Japanese Americans with IGT. However, such changes did not improve β-cell function, suggesting that this degree of lifestyle modifications may be limited in preventing type 2 diabetes over the long term., The prevalence of obesity and type 2 diabetes is increasing in the U.S. (1). In 2000, data from the Behavioral Risk Factor Surveillance System found a 19.8% prevalence of obesity [...]

Effects of diverse stimuli, including insulin, muscle contraction, and phorbol 12-myristate-13-acetate (PMA), were determined on phosphorylation of mitogen-activated protein kinase (MAPK) signaling modules (c-Jun N[H.sub.2]-terminal kinase [JNK], p38 MAPK, and extracellular signal-related kinase [ERK1/2]) in skeletal muscle from lean and ob/ob mice. Insulin increased phosphorylation of JNK, p38 MAPK, and ERK1/2 in isolated extensor digitorum longus (EDL) and soleus muscle from lean mice in a time- and dose-dependent manner. Muscle contraction and PMA also elicited robust effects on these parallel MAPK modules. Insulin action on JNK, p38 MAPK, and ERK1/2 phosphorylation was significantly impaired in EDL and soleus muscle from ob/ob mice. In contrast, muscle contraction-mediated JNK, p38 MAPK, and ERK1/2 phosphorylation was preserved. PMA effects on phosphorylation of JNK and ERK1/2 were normal in ob/ob mice, whereas effects on p38 MAPK were abolished. In conclusion, insulin, contraction, and PMA activate MAPK signaling in skeletal muscle. Insulin-mediated responses on MAPK signaling are impaired in skeletal muscle from ob/ob mice, whereas the effect of contraction is generally well preserved. In addition, PMA-induced phosphorylation of JNK and ERK1/2 are preserved, whereas p38 MAPK pathways are impaired in skeletal muscle from ob/ob mice. Thus, appropriate MAPK responses can be elicited in insulin-resistant skeletal muscle via an insulin-independent mechanism., Multiple mechanisms contribute to the regulation of glucose metabolism and gene expression in skeletal muscle. Insulin signaling along the insulin receptor substrate (IRS)/ phosphatidylinositol (PI) 3-kinase pathway is considered to [...]

Glucokinase (GK) has a major role in the control of blood glucose homeostasis and is a strong potential target for the pharmacological treatment of type 2 diabetes. We report here the mechanism of action of two novel and potent direct activators of GK: 6-[(3-isobutoxy-5-isopropoxybenzoyl)amino]nicotinic acid (GKA1) and 5-({3-isopropoxy-5-[2-(3-thienyl)ethoxy] benzoyl}amino)-1,3,4-thiadiazole-2-carboxylic acid (GKA2), which increase the affinity of GK for glucose by 4- and 11-fold, respectively. GKA1 increased the affinity of GK for the competitive inhibitor mannoheptulose but did not affect the affinity for the inhibitors palmitoyl-CoA and the endogenous 68-kDa regulator (GK regulatory protein [GKRP]), which bind to allosteric sites or to N-acetylglucosamine, which binds to the catalytic site. In hepatocytes, GKA1 and GKA2 stimulated glucose phosphorylation, glycolysis, and glycogen synthesis to a similar extent as sorbitol, a precursor of fructose 1-phosphate, which indirectly activates GK through promoting its dissociation from GKRP. Consistent with their effects on isolated GK, these compounds also increased the affinity of hepatocyte metabolism for glucose. GKA1 and GKA2 caused translocation of GK from the nucleus to the cytoplasm. This effect was additive with the effect of sorbitol and is best explained by a 'glucose-like' effect of the GK activators in translocating GK to the cytoplasm. In conclusion, GK activators are potential antihyperglycemic agents for the treatment of type 2 diabetes through the stimulation of hepatic glucose metabolism by a mechanism independent of GKRP., Type 2 diabetes is a complex disease caused by defects in both the action and secretion of insulin, leading to fasting hyperglycemia and vascular complications. Current therapies do not achieve [...]

OBJECTIVE--Type 2 diabetes and impaired glucose metabolism (IGM) are associated with an increased cardiovascular disease (CVD) risk. Increased left ventricular mass (LVM) is thought to increase CVD risk through several [...]

Recently, a role for uncoupling protein-3 (UCP3) in carbohydrate metabolism and in type 2 diabetes has been suggested. Mice overexpressing UCP3 in skeletal muscle showed reduced fasting plasma glucose levels, improved glucose tolerance after an oral glucose load, and reduced fasting plasma insulin levels. However, data regarding the expression of UCP3 in patients with type 2 diabetes is inconsistent, and so far, there have been no reports of UCP3 protein content. Here we compared, for the first time, the protein levels of UCP3 in vastus lateralis muscle in 14 male type 2 diabetic patients (age 49.8 ± 2.1 years; BMI 27.2 ± 1.2 kg/[m.sup.2]; mean ± SE) with 16 male control subjects (age 48.0 ± 1.9 years; BMI 23.4 ± 0.6 kg/[m.sup.2]). We found that UCP3 protein levels were twice as low in patients with type 2 diabetes compared with control subjects (117 ± 16 vs. 58 ± 12 AU; P = 0.007). There was no correlation between UCP3 content and BMI. In conclusion, UCP3 content is lower in type 2 diabetic patients compared with healthy control subjects. These results are consistent with a role for UCP3 in glucose homeostasis and suggest a role for UCP3 in type 2 diabetes., The human uncoupling protein UCP3 uncouples oxidative phosphorylation from ATP production and is therefore thought to play a role in human energy metabolism and obesity (1). Recently, a role for [...]

Taniyama et al. (1) have recently reported that angiotensin II (Ang II) in vitro decreases insulin receptor substrate-1 protein levels via Src, phosphoinositide-dependent kinase-1, and reactive oxygen species-mediated phosphorylation of [...]