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.

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.

Gastrointestinal (GI) bleeding is a serious complication associated with use of antiplatelet therapy, and proton pump inhibitors (PPIs) are known to be beneficial in decreasing such risk. Several studies in the recent past have suggested concerns regarding interaction between clopidogrel and PPIs, presumably due to inhibition of clopidogrel activity and thus attenuation of its antiplatelet activity. A web-based literature and guidelines search was done using the keywords ''clopidogrel,'' ''omeprazole,'' ''proton pump inhibitors'' and ''interaction.'' Of the available results, relevant studies (n = 11) were then systematically reviewed and summarized. The studies were categorized based on their retrospective or prospective nature. Most of the retrospective, observational studies suggested a link between the 2; however, recent prospective studies have shown no interaction, as well as a positive influence of PPIs in preventing the GI side effects of antiplatelet therapy. There is currently insufficient clinical evidence to suggest interaction between clopidogrel and PPIs and decision to add PPI therapy to clopidogrel should be guided by its clinical indications rather than as a routine prophylactic measure.