Duodenal GLP-1 signaling regulates hepatic glucose production through a PKC-δ-dependent neurocircuitry.

Intestinal glucagon-like peptide-1 (GLP-1) is a hormone that stimulates insulin secretion and acts as a neuropeptide to control glucose homeostasis, but little is known whether intestinal GLP-1 has any effect in the control of hepatic glucose production (HGP). Here we found that intraduodenal infusion of GLP-1 activated duodenal PKC-δ, lowered HGP and was accompanied by a decrease in hepatic expression of gluconeogenic enzymes and an increase in hepatic insulin signaling in rats. However, gut co-infusion of either the GLP-1 receptor antagonist Ex-9, or the PKC-δ inhibitor rottlerin with GLP-1, negated the ability of gut GLP-1 to lower HGP and to increase hepatic insulin signaling during clamps.

NAMPT knockdown attenuates atherosclerosis and promotes reverse cholesterol transport in ApoE KO mice with high-fat-induced insulin resistance.

NAMPT has been suggested association with atherosclerosis and insulin resistance. However, the impact of NAMPT on atherosclerosis remained unknown. Therefore, the objective of this study was to use a NAMPT loss-of-function approach to investigate the effect of NAMPT on atherosclerosis in hypercholesterolemic mice.

Excessive caloric intake acutely causes oxidative stress, GLUT4 carbonylation, and insulin resistance in healthy men.

Obesity-linked insulin resistance greatly increases the risk for type 2 diabetes, hypertension, dyslipidemia, and non-alcoholic fatty liver disease, together known as the metabolic or insulin resistance syndrome. How obesity promotes insulin resistance remains incompletely understood. Plasma concentrations of free fatty acids and proinflammatory cytokines, endoplasmic reticulum ( ER) stress, and oxidative stress are all elevated in obesity and have been shown to induce insulin resistance.

Stressful life events are associated with insulin resistance among Chinese immigrant women in the United States.

Background: Chinese immigrants experience increased chronic disease risk following migration to the US. Although the impact of lifestyle changes (e.g.

Tissue factor and Toll-like receptor (TLR)4 in hyperglycaemia-hyperinsulinaemia. Effects in healthy subjects, and type 1 and type 2 diabetes mellitus.

Diabetes mellitus (DM) patients have an increased incidence of cardiovascular events. Blood tissue factor-procoagulant activity (TF-PCA), the initiating mechanism for blood coagulation, is elevated in DM. We have shown that hyperglycaemia (HG), hyperinsulinaemia (HI) and combined HG+HI (induced using 24-hour infusion clamps) increases TF-PCA in healthy and type 2 DM (T2DM) subjects, but not in type 1 DM (T1DM) subjects.

Overexpression of JAZF1 protected ApoE-deficient mice from atherosclerosis by inhibiting hepatic cholesterol synthesis via CREB-dependent mechanisms.

Genome wide association studies have suggested an association of Juxtaposed with another zinc finger gene 1(JAZF1) with type 2 diabetes mellitus (T2DM). As an inhibitor of the TAK1/TR4 signaling pathway, JAZF1 has been shown to be involved in gluconeogenesis, lipid metabolism and insulin sensitivity. However, its role in insulin resistance and atherosclerosis in vivo remains unknown.

Alterations in insulin-signaling and coagulation pathways in platelets during hyperglycemia-hyperinsulinemia in healthy non-diabetic subject.

Introduction: Diabetes mellitus (DM) is a prothrombotic and proinflammatory state. Hyperglycemia (HG) is encountered even in patients without DM. We have shown that combined HG and hyperinsulinemia (HI) in healthy non-diabetic subjects increased circulating tissue factor (TF) and thrombin generation.

Insulin resistance is associated with diminished endoplasmic reticulum stress responses in adipose tissue of healthy and diabetic subjects.

We recently showed that insulin increased ER stress in human adipose tissue. The effect of insulin resistance on ER stress is not known. It could be decreased, unchanged, or increased, depending on whether insulin regulates ER stress via the metabolic/phosphoinositide 3-kinase (PI3K) or alternate signaling pathways.

Silencing of FGF-21 expression promotes hepatic gluconeogenesis and glycogenolysis by regulation of the STAT3-SOCS3 signal.

Insulin resistance is a metabolic disorder associated with type 2 diabetes. Recent reports have shown that fibroblast growth factor-21 (FGF-21) plays an important role in the progression of insulin resistance. However, the biochemical and molecular mechanisms by which changes in FGF-21 activation result in changes in the rates of hepatic gluconeogenesis and glycogenolysis remain to be elucidated.

Efficacy and safety of aldose reductase inhibitor for the treatment of diabetic cardiovascular autonomic neuropathy: systematic review and meta-analysis.

Background: Aldose reductase inhibitors (ARIs) can block the metabolism of the polyol pathway, and have been used to slow or reverse the progression of diabetic cardiovascular autonomic neuropathy (DCAN). The purpose of this study was to review the effectiveness and safety of ARIs in the treatment of DCAN as determined by five cardiac autonomic neuropathy function tests.

Methods: CENTRAL, MEDLINE, EMBASE, Scopus databases (inception to May 2012) were searched to identify randomized controlled trials (RCTs) and non-randomized controlled trials (non-RCTs) investigating ARIs for the treatment of DCAN with an English-language restriction.

Hypothalamic nesfatin-1/NUCB2 knockdown augments hepatic gluconeogenesis that is correlated with inhibition of mTOR-STAT3 signaling pathway in rats.

Nesfatin-1, an 82-amino acid neuropeptide, has recently been characterized as a potent metabolic regulator. However, the metabolic mechanisms and signaling steps directly associated with the action of nesfatin-1 have not been well delineated. We established a loss-of-function model of hypothalamic nesfatin-1/NUCB2 signaling in rats through an adenoviral-mediated RNA interference.

Changes in insulin sensitivity and insulin secretion with the sodium glucose cotransporter 2 inhibitor dapagliflozin.

Aim: This randomized, double-blind, placebo-controlled parallel-group study assessed the effects of sodium glucose cotransporter 2 inhibition by dapagliflozin on insulin sensitivity and secretion in subjects with type 2 diabetes mellitus (T2DM), who had inadequate glycemic control with metformin (with or without an insulin secretagogue).

Subjects And Methods: Forty-four subjects were randomized to receive dapagliflozin 5 mg or matching placebo once daily for 12 weeks. Subjects continued stable doses of background antidiabetes medication throughout the study.

Insulin regulates the unfolded protein response in human adipose tissue.

Endoplasmic reticulum (ER) stress is increased in obesity and is postulated to be a major contributor to many obesity-related pathologies. Little is known about what causes ER stress in obese people. Here, we show that insulin upregulated the unfolded protein response (UPR), an adaptive reaction to ER stress, in vitro in 3T3-L1 adipocytes and in vivo, in subcutaneous (sc) adipose tissue of nondiabetic subjects, where it increased the UPR dose dependently over the entire physiologic insulin range (from ∼ 35 to ∼ 1,450 pmol/L).

Comparison of in vivo effects of insulin on SREBP-1c activation and INSIG-1/2 in rat liver and human and rat adipose tissue.

Objective: The stimulatory effects of insulin on de novo lipogenesis (DNL) in the liver, where it is an important contributor to non-alcoholic fatty liver disease (NAFLD), hepatic and systemic insulin resistance, is strong and well established. In contrast, insulin plays only a minor role in DNL in adipose tissue. The reason why insulin stimulates DNL more in liver than in fat is not known but may be due to differential regulation of the transcription and post-translational activation of sterol regulatory element binding proteins (SREBPs).

A Single A1C >= 6.5% Accurately Identifies Type 2 Diabetes/Impaired Glucose Tolerance in African Americans.

Objective: In 2010, the American Diabetes Association revised its criteria for the diagnosis of diabetes to include A1C ≥ 6.5%; however, this has remained controversial, particularly for African Americans. The objective of this pilot study was to examine the usefulness of a single A1C determination in comparison with a same day 2-hour oral glucose tolerance test to diagnose type 2 diabetes in African Americans.

Why does obesity increase the risk for cardiovascular disease?

Insulin resistance and inflammation are recognized as important links between obesity and cardiovascular disease (CVD). Plasma free fatty acids (FFA), either released from the abnormally enlarged adipose tissue or as part of the excessive nutrient intake, produce insulin resistance and inflammation. Both insulin resistance and inflammation are tightly linked to several independent CVD risk factors such as type 2 diabetes (T2DM), hypertension, dyslipidemia and disorders of blood coagulation.

GLP-1 analogue prevents NAFLD in ApoE KO mice with diet and Acrp30 knockdown by inhibiting c-JNK.

Background & Aims: Liraglutide, a Glucagon-like peptide-1(GLP-1) analogue with 97% sequence identity to human GLP-1, increases insulin secretion and insulin sensitivity. Its effect on non-alcoholic fatty liver disease (NAFLD) remains poorly understood. In this study, we examined whether liraglutide can protect against inflammatory stress by inhibiting activation of c-Jun N-terminal protein kinase (JNK).

Systematic review of the effectiveness of hyperbaric oxygenation therapy in the management of chronic diabetic foot ulcers.

Objective: To assess the efficacy and safety of hyperbaric oxygenation (HBO) therapy as adjunctive treatment for diabetic foot ulcers with a systematic review and meta-analysis of the literature.

Methods: MEDLINE, EMBASE, and the Cochrane Library were searched to find relevant articles published up to April 20, 2012, without restriction as to language or publication status. All controlled trials that evaluated adjunctive treatment with HBO therapy compared with treatment without HBO for chronic diabetic foot ulcers were selected.

Zinc-α2-glycoprotein is associated with insulin resistance in humans and is regulated by hyperglycemia, hyperinsulinemia, or liraglutide administration: cross-sectional and interventional studies in normal subjects, insulin-resistant subjects, and subjects with newly diagnosed diabetes.

Objective: Zinc-α2-glycoprotein (ZAG) has been proposed to play a role in the pathogenesis of insulin resistance. Previous studies in humans and in rodents have produced conflicting results regarding the link between ZAG and insulin resistance. The objective of this study was to examine the relationships between ZAG and insulin resistance in cross-sectional and interventional studies.

Liraglutide increases FGF-21 activity and insulin sensitivity in high fat diet and adiponectin knockdown induced insulin resistance.

Background: Liraglutide is a glucagon-like peptide-1 analogue that stimulates insulin secretion and improves β-cell function. However, it is not clear whether liraglutide achieves its glucose lowering effect only by its known effects or whether other as yet unknown mechanisms are involved. The aim of this study was to examine the effects of liraglutide on Fibroblast growth factor-21 (FGF-21) activity in High-fat diet (HFD) fed ApoE(-/-) mice with adiponectin (Acrp30) knockdown.

Nesfatin-1 action in the brain increases insulin sensitivity through Akt/AMPK/TORC2 pathway in diet-induced insulin resistance.

Nesfatin-1, derived from nucleobindin 2, was recently identified as an anorexigenic signal peptide. However, its neural role in glucose homeostasis and insulin sensitivity is unknown. To evaluate the metabolic impact and underlying mechanisms of central nesfatin-1 signaling, we infused nesfatin-1 in the third cerebral ventricle of high-fat diet (HFD)-fed rats.

Long-term high-fat diet links the regulation of the insulin-sensitizing fibroblast growth factor-21 and visfatin.

High-fat diet (HFD) is associated with insulin resistance, hyperinsulinemia, elevated plasma free fatty acid (FFA), and increased risk for atherosclerotic vascular disease. However, the mechanisms underlying the HFD-induced insulin resistance have not been fully clarified. The aim of present study is to evaluate the effects of long-term HFD on the regulation of the insulin-sensitizing fibroblast growth factor-21 (FGF-21) and visfatin in ApoE(-/-) mice.

Whole-blood tissue factor procoagulant activity is elevated in type 1 diabetes: effects of hyperglycemia and hyperinsulinemia.

Objective: To determine tissue factor procoagulant activity (TF-PCA) in patients with type 1 diabetes and to examine effects of hyperglycemia and hyperglycemia plus hyperinsulinemia on TF-PCA.

Research Design And Methods: We have determined circulating TF-PCA and other coagulation factors under basal (hyperglycemic) conditions, after acute correction of hyperglycemia, in response to 24 h of selective hyperglycemia, and in response to 24 h of hyperglycemia plus hyperinsulinemia in nine type 1 diabetic patients and in seven nondiabetic control subjects.

Results: As shown previously in patients with type 2 diabetes, basal TF-PCA and plasma coagulation factor VIIa (FVIIa) were higher in patients with type 1 diabetes than in nondiabetic control subjects.