Increased endogenous glucose production (EGP) is a hallmark of type 2 diabetes mellitus. While there is evidence for central regulation of EGP by activation of hypothalamic ATP-sensitive potassium (K ATP ) channels in rodents, whether these central pathways contribute to regulation of EGP in humans remains to be determined. Here we present evidence for central nervous system regulation of EGP in humans that is consistent with complementary rodent studies. Oral administration of the K ATP channel activator diazoxide under fixed hormonal conditions substantially decreased EGP in nondiabetic humans and Sprague Dawley rats. In rats, comparable doses of oral diazoxide attained appreciable concentrations in the cerebrospinal fluid, and the effects of oral diazoxide were abolished by i.c.v. administration of the K ATP channel blocker glibenclamide. These results suggest that activation of hypothalamic K ATP channels may be an important regulator of EGP in humans and that this pathway could be a target for treatment of hyperglycemia in type 2 diabetes mellitus.

Background . Over 70% of the world’s patients with diabetes reside in low-and middle-income countries (LMICs), where adequate infrastructure and resources for diabetes care are often lacking. Therefore, academic institutions, health care organizations, and governments from Western nations and LMICs have worked together to develop a variety of effective diabetes care models for resource-poor settings. Methods . A focused search of PubMed was conducted with the goal of identifying reports that addressed the implementation of diabetes care models or initiatives to improve clinical and/or biochemical outcomes in patients with diabetes mellitus. Results . A total of 15 published manuscripts comprising nine diabetes care models in 16 locations in sub-Saharan Africa, Latin America, and Asia identified by the above approach were systematically reviewed. The reviewed models shared a number of principles including collaboration, education, standardization, resource optimization, and technological innovation. The most comprehensive models used a number of these principles, which contributed to their success. Conclusions . Reviewing the principles shared by these successful programs may help guide the development of effective future models for diabetes care in low-income settings.

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Objective-The American Diabetes Association has called for further research on how patient demographics should determine drug choices for individuals with type 2 diabetes mellitus (T2DM). Here, using in-depth physiology studies, we investigate whether obese patients with T2DM are likely to benefit from thiazolidinediones, medications with a known side effect of weight gain.Materials and Methods-11 obese and 7 non-obese individuals with T2DM participated in this randomized, placebo-controlled, double-blind, crossover study. Each subject underwent a pair of "stepped" pancreatic clamp studies with subcutaneous adipose tissue biopsies following 21 days of pioglitazone (45 mg) or placebo.Results-Obese subjects demonstrated significant decreases in insulin resistance and many adipose inflammatory parameters with pioglitazone relative to placebo. Specifically, significant improvements in glucose infusion rates, suppression of hepatic glucose production, and whole fat expression of certain inflammatory markers (IL-6, IL-1b, and iNOS) were observed in obese subjects but not in non-obese subjects. Additionally, adipose tissue from obese subjects demonstrated reduced infiltration of macrophages, dendritic cells, and neutrophils as well as increased expression of factors associated with fat "browning" (PGC-1α and UCP-1).Conclusions-These findings support the efficacy of pioglitazone to improve insulin resistance and reduce adipose tissue inflammation in obese patients with T2DM.

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Cholangiocyte proliferation is one of the hallmarks of the response to cholestatic injury. We previously reported that the winged helix transcription factor Foxl1 is dramatically induced in cholangiocytes following bile duct ligation. In this study, we investigated the function of Foxl1 in the bile duct ligation model of cholestatic liver injury in Foxl1 À/À and control mice. We found that Foxl1 À/À livers exhibit an increase in parenchymal necrosis, significantly impaired cholangiocyte and hepatocyte proliferation, and failure to expand bile ductular mass. Wnt3a and Wnt7b expression was decreased in the livers of Foxl1 À/À mice along with reduced expression of the b-catenin target gene Cyclin D1 in Foxl1 À/À cholangiocytes. These results show that Foxl1 promotes liver repair after bile-duct-ligation-induced liver injury through activation of the canonical wnt/b-catenin pathway.

The challenges of achieving optimal glycemic control in type 2 diabetes highlight the need for new therapies. Inappropriately elevated endogenous glucose production (EGP) is the main source of hyperglycemia in type 2 diabetes. Because activation of central ATP-sensitive potassium (KATP) channels suppresses EGP in nondiabetic rodents and humans, this study examined whether type 2 diabetic humans and rodents retain central regulation of EGP. The KATP channel activator diazoxide was administered in a randomized, placebo-controlled crossover design to eight type 2 diabetic subjects and seven age- and BMI-matched healthy control subjects. Comprehensive measures of glucose turnover and insulin sensitivity were performed during euglycemic pancreatic clamp studies following diazoxide and placebo administration. Complementary rodent clamp studies were performed in Zucker Diabetic Fatty rats. In type 2 diabetic subjects, extrapancreatic KATP channel activation with diazoxide under fixed hormonal conditions failed to suppress EGP, whereas matched control subjects demonstrated a 27% reduction in EGP (P = 0.002) with diazoxide. Diazoxide also failed to suppress EGP in diabetic rats. These results suggest that suppression of EGP by central KATP channel activation may be lost in type 2 diabetes. Restoration of central regulation of glucose metabolism could be a promising therapeutic target to reduce hyperglycemia in type 2 diabetes.

The anti-Fpn and anti-Jak2 rows in Figure 2A Figure 3B of that manuscript.The authors regret the error.