Discovery of orally active hepatoselective glucokinase activators for treatment of Type II Diabetes Mellitus.

Systemically acting glucokinase activators (GKA) have been demonstrated in clinical trials to effectively lower blood glucose in patients with type II diabetes. However, mechanism-based hypoglycemia is a major adverse effect that limits the therapeutic potential of these agents. We hypothesized that the predominant mechanism leading to hypoglycemia is GKA-induced excessive insulin secretion from pancreatic ß-cells at (sub-)euglycemic levels. We further hypothesized that restricting GK activation to hepatocytes would maintain glucose-lowering efficacy while significantly reducing hypoglycemic risk. Here we report the discovery of a novel series of carboxylic acid substituted GKAs based on pyridine-2-carboxamide. These GKAs exhibit preferential distribution to the liver versus the pancreas in mice. SAR studies led to the identification of a potent and orally active hepatoselective GKA, compound 6. GKA 6 demonstrated robust glucose lowering efficacy in high fat diet-fed mice at doses ⩾10mpk, with ⩾70-fold liver:pancreas distribution, minimal effects on plasma insulin levels, and significantly reduced risk of hypoglycemia.

Proinsulin-Transferrin Fusion Protein Exhibits a Prolonged and Selective Effect on the Control of Hepatic Glucose Production in an Experimental Model of Type 1 Diabetes.

An ideal basal insulin (INS) replacement therapy requires the distribution or action of exogenous INS to more closely mimic physiological INS in terms of its preferential hepatic action. In this paper, we introduce a novel strategy to exert liver-specific INS action by hepatic activation of INS's precursor, proinsulin (ProINS). We demonstrated the conversion of human ProINS-transferrin (Tf) fusion protein, ProINS-Tf, into an active and immuno-reactive form of INS-Tf in the liver via the slow Tf receptor mediated recycling pathway. ProINS-Tf displayed prolonged basal blood glucose lowering effects for up to 40 h in streptozotocin-induced type 1 diabetic mice following a single subcutaneous injection. The effect of ProINS-Tf on blood glucose levels was observed predominantly under fasting conditions, with little effect under free-feeding conditions. In addition, both the pyruvate tolerance assay in normal mice and the Akt-phosphorylation assay in H-4-II-E hepatoma cells indicated that the hepatic-activated ProINS-Tf possessed a much longer effect on the control of hepatic glucose production than INS. These results indicated that ProINS-Tf may serve as an effective and safe hepatoselective INS analog to reduce the frequency of INS injections as well as avert severe hypoglycemia episodes and other side effects frequently encountered with long-acting INS therapeutics due to their peripheral action.

Insulin detemir may be less efficacious in patients with nonalcoholic fatty liver disease and hypertriglyceridemia.

Insulin detemir is commonly used in obese patients with diabetes mellitus as it is considered hepatoselective and causes less weight gain. We describe a relative lack of effectiveness of detemir in patients with significant NAFLD and hypertriglyceridemia, compared to isophane insulin. This may affect how such patients are managed with insulin.

Molecular targeting of the GK-GKRP pathway in diabetes.

INTRODUCTION: Type 2 diabetes mellitus is a major healthcare concern. Significant efforts are being devoted toward developing new, safe, and more effective treatments. One approach involves activating glucokinase (GK). Earlier GK activator (GKA) approaches have focused on direct activation of GK through allosteric activators. AREAS COVERED: This review summarizes the roles of GK and its key partner glucokinase regulatory protein in glucose metabolism and describes approaches that may alleviate hypoglycemic risk observed with GKAs. EXPERT OPINION: The current GKA therapeutic approaches are associated with disappointing success rates. In rodent animal models, efficacy was observed with GKA. However, in all human studies, GKAs effectively lowered blood glucose, but at the expense of an increased risk of hypoglycemia. Other liabilities like loss of efficacy with time and increase in blood pressure or triglyceride levels have been reported with different molecules. To avoid hypoglycemic risk, alternative approaches to regulate GK activity have been initiated. Data from clinical trials using these agents are either not yet available to the public or the compounds are too early in development for humans. GK is a promising target for antidiabetic therapy. Despite encouraging biology, more research is required to fully understand GK as a drug target.

Discovery of an intravenous hepatoselective glucokinase activator for the treatment of inpatient hyperglycemia.

Glucokinase (hexokinase IV) continues to be a compelling target for the treatment of type 2 diabetes given the wealth of supporting human genetics data and numerous reports of robust clinical glucose lowering in patients treated with small molecule allosteric activators. Recent work has demonstrated the ability of hepatoselective activators to deliver glucose lowering efficacy with minimal risk of hypoglycemia. While orally administered agents require a considerable degree of passive permeability to promote suitable exposures, there is no such restriction on intravenously delivered drugs. Therefore, minimization of membrane diffusion in the context of an intravenously agent should ensure optimal hepatic targeting and therapeutic index. This work details the identification a hepatoselective GKA exhibiting the aforementioned properties.