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2018 MAR 31 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Staff editors report on the newly launched clinical trial, NCT03459079, which has [...]

OBJECTIVE--The E23K variant in the Kir6.2 subunit of the ATP-sensitive [K.sup.+] channel ([K.sub.ATP] channel) is associated with increased risk of type 2 diabetes. The present study was undertaken to increase our understanding of the mechanisms responsible. To avoid confounding effects of hyperglycemia, insulin secretion and action were studied in subjects with the variant who had normal glucose tolerance. RESEARCH DESIGN AND METHODS--Nine subjects with the E23K genotype K/K and nine matched subjects with the E/E genotype underwent 5-h oral glucose tolerance tests (OGTTs), graded glucose infusion, and hyperinsulinemic-euglycemic clamp with stable-isotope-labeled tracer infusions to assess insulin secretion, action, and clearance. A total of 461 volunteers consecutively genotyped for the E23K variant also underwent OGTTs. Functional studies of the wild-type and E23K variant potassium channels were conducted. RESULTS--Insulin secretory responses to oral and intravenous glucose were reduced by ~40% in glucose-tolerant subjects homozygous for E23K. Normal glucose tolerance with reduced insulin secretion suggests a change in insulin sensitivity. The hyperinsulinemic-euglycemic clamp revealed that hepatic insulin sensitivity is ~40% greater in subjects with the E23K variant, and these subjects demonstrate increased insulin sensitivity after oral glucose. The reconstituted E23K channels confirm reduced sensitivity to inhibitory ATP and increase in open probability, a direct molecular explanation for reduced insulin secretion. CONCLUSIONS--The E23K variant leads to overactivity of the [K.sub.ATP] channel, resulting in reduced insulin secretion. Initially, insulin sensitivity is enhanced, thereby maintaining normal glucose tolerance. Presumably, over time, as insulin secretion falls further or insulin resistance develops, glucose levels rise resulting in type 2 diabetes. Diabetes 58:1869-1878, 2009, The ATP-sensitive [K.sup.+] channel ([K.sub.ATP] channel) plays a central role in glucose-stimulated insulin secretion (GSIS). It is comprised of two subunits, an inward rectifier potassium channel (Kir6.2) and a sulfonylurea [...]

Insulin resistance in muscle and liver and β-cell failure represent the core pathophysiologic defects in type 2 diabetes. It now is recognized that the B-cell failure occurs much earlier and [...]

OBJECTIVE--Obesity is associated with insulin resistance and type 2 diabetes, although the mechanisms linking these pathologies remain undetermined. Recent studies in rodent models revealed endoplasmic reticulum (ER) stress in adipose and liver tissues and demonstrated that ER stress could cause insulin resistance. Therefore, we tested whether these stress pathways were also present in obese human subjects and/or regulated by weight loss. RESEARCH DESIGN AND METHODS--Eleven obese men and women (BMI 51.3 ± 3.0 kg/[m.sup.2]) were studied before and 1 year after gastric bypass (GBP) surgery. We examined systemic insulin sensitivity using hyperinsulinemic-euglycemic clamp studies before and after surgery and collected subcutaneous adipose and liver tissues to examine ER stress markers. RESULTS--Subjects lost 39 ± 9% body wt at 1 year after GBP surgery (P < 0.001), which was associated with a marked improvement in hepatic, skeletal muscle, and adipose tissue insulin sensitivity. Markers of ER stress in adipose tissue significantly decreased with weight loss. Specifically, glucose-regulated protein 78 (Grp78) and spliced X-box binding protein-1 (sXBP-1) mRNA levels were reduced, as were phosphoryiated elongation initiation factor 2α (eIF2α) and stress kinase c-Jun N[H.sub.2]-terminal kinase 1 (JNK1) (all P values CONCLUSIONS--This study presents important evidence that ER stress pathways are present in selected tissues of obese humans and that these signals are regulated by marked weight loss and metabolic improvement. Hence, this suggests the possibility of a relationship between obesity-related ER stress and metabolic dysfunction in obese humans., Increased adiposity is associated with a group of chronic metabolic disorders, including insulin resistance, type 2 diabetes, and nonalcoholic fatty liver disease (1). The prevalence of this cluster of abnormalities [...]

Perspectives on the News commentaries are part of a free monthly CME activity. The Mount Sinai School of Medicine, New York, New York, designates this activity for 2.0 AMA PRA [...]

OBJECTIVE--The angiotensin type 1 receptor blocker (ARB) and peroxisome proliferator-activated receptor (PPAR) γ modulator telmisartan has been recently demonstrated to reduce plasma triglycerides in nondiabetic and diabetic hypertensive patients. The present study investigates the molecular mechanisms of telmisartans hypolipidemic actions, in particular its effect on the PPARα pathway. RESEARCH DESIGN AND METHODS--Regulation of PPARα target genes by telmisartan was studied by real-time PCR and Western immunoblotting in vitro and in vivo in liver/skeletal muscle of mice with diet-induced obesity. Activation of the PPARα ligand binding domain (LBD) was investigated using transactivation assays. RESULTS--Telmisartan significantly induced the PPARα target genes carnitine palmitoyl transferase 1A (CPT1A) in human HepG2 cells and acyl-CoA synthetase long-chain family member 1 (ACSL1) in murine AML12 cells in the micromolar range. Telmisartan-induced CPT1A stimulation was markedly reduced after small interfering RNA-mediated knockdown of PPARα. Telmisartan consistently activated the PPARα-LBD as a partial PPARα agonist. Despite high in vitro concentrations required for PPARα activation, telmisartan (3 mg x [kg.sup.-1] x [day.sup.-1]) potently increased ACSL1 and CPT1A expression in liver from diet-induced obese mice associated with a marked decrease of hepatic and serum triglycerides. Muscular CPT1B expression was not affected. Tissue specificity of telmisartan-induced PPARα target gene induction may be the result of previously reported high hepatic concentrations of telmisartan. CONCLUSIONS--The present study identifies the ARB/PPARγ modulator telmisartan as a partial PPARα agonist. As a result of its particular pharmacokinetic profile, PPARα activation by telmisartan seems to be restricted to the liver. Hepatic PPARα activation may provide an explanation for telmisartan's antidyslipidemic actions observed in recent clinical trials., Angiotensin type 1 receptor blockers (ARBs) are commonly used in the treatment of hypertension and related cardiovascular and organ damage (1). Recently, a distinct subgroup of ARBs has been identified [...]

OBJECTIVE--Nonalcoholic fatty liver, affecting 34% of the U.S. population, is characterized by hepatic insulin resistance, which is more marked in the presence of steatohepatitis, and frequently precedes hyperglycemia. The molecular mechanisms underlying the relationship between fatty liver and insulin resistance are still undergoing definition and have not been evaluated in humans. Our aim was to evaluate the relationship between insulin resistance and the expression and regulation of forkhead box-containing protein 0 subfamily-1 (FOXO1), a transcription factor that mediates the effect of insulin on the gluconeogenic genes PEPCK and glucose-6-phosphatase catalytic subunit (G6PC). RESEARCH DESIGN AND METHODS--FOXO1, PEPCK, and G6PC mRNA levels were evaluated in 84 subjects: 26 with steatohepatitis, 28 with steatosis alone, 14 with normal liver histology without metabolic alterations, and 16 with hepatitis C virus chronic hepatitis, of whom 8 were with and 8 were without steatosis. Protein expression and regulation of FOXO1 and upstream insulin signaling were analyzed in a subset. RESULTS--Expression of PEPCK was higher in steatohepatitis compared with steatosis alone and normal liver, and it was correlated with the homeostasis model assessment of insulin resistance (HOMA-IR) index. FOXO1 mRNA levels were higher in steatohepatitis, correlated with PEPCK and G6PC mRNA and with HOMA-IR. FOXO1 upregulation was confirmed at protein levels in steatohepatitis and, in the presence of oxidative stress, was associated with decreased [Ser.sup.256] phosphorylation, decreased Akt1, and increased Jun [NH.sub.2]-terminal kinase-1 activity. Consistently, immunohistochemistry showed increased FOXO1 expression and nuclear localization in steatohepatitis. FOXO1 mRNA levels correlated with nonalcoholic steatohepatitis activity score and were modulated by drugs counteracting hepatic lipogenesis. CONCLUSIONS--FOXO1 expression and activity are increased in patients with steatohepatitis, and mRNA levels are correlated with hepatic insulin resistance., Nonaalchoholic fatty liver disease (NAFLD), affecting ~34% of the U.S. population (1), is considered the hepatic manifestation of the metabolic syndrome. NAFLD is characterized by hepatic insulin resistance, i.e., the [...]

OBJECTIVE--The purpose of this study was to determine whether type 2 diabetic patients have more liver fat than age-, sex-, and BMI-matched nondiabetic subjects and whether liver enzymes (serum alanine [...]

Perspectives on the News commentaries are now part of a new, free monthly CME activity. The Mount Sinai School of Medicine, New York, New York, is designating this activity for [...]

It is estimated that 20 8 million people, i.e., 7.0% of the U.S. population, have diabetes (1). Type 2 diabetes, with its core defects of insulin resistance and relative insulin [...]

BACKGROUND. Understanding the organization of primary care practices is essential for implementing changes related to delivery of preventive or other health care services. A theoretical model derived from complexity theory [...]

* OBJECTIVE Our goals were to determine how often family physicians incorporate smoking cessation efforts into routine office visits and to examine the effect of patient, physician, and office characteristics [...]

Insights from the Process of Conducting Multimethod Transdisciplinary Research in Community Practice * PURPOSE This paper shares insights from the process of conducting the Direct Observation of Primary Care (DOPC) [...]

BACKGROUND * Millions of dollars are spent annually on the production and distribution of patient education materials; however, there are no studies describing their actual use by physicians. Using qualitative [...]

A Balancing Act BACKGROUND. Studies demonstrate significant shortfalls in the quality of care for diabetes. Primary care physicians' views of the management of diabetes have been inadequately explored. The objective [...]