Targeting type 2 diabetes.

The evolving concept of how nutrient excess and inflammation modulate metabolism provides new opportunities for strategies to correct the detrimental health consequences of obesity. In this review, we focus on the complex interplay among lipid overload, immune response, proinflammatory pathways and organelle dysfunction through which excess adiposity might lead to type 2 diabetes. We then consider evidence linking dysregulated CNS circuits to insulin resistance and results on nutrient-sensing pathways emerging from studies with calorie restriction. Subsequently, recent recommendations for the management of type 2 diabetes are discussed with emphasis on prevailing current therapeutic classes of biguanides, thiazolidinediones and incretin-based approaches.

Synthesis and in vitro evaluation of (S)-2-([11C]methoxy)-4-[3-methyl-1-(2-piperidine-1-yl-phenyl)-butyl-carbamoyl]-benzoic acid ([11C]methoxy-repaglinide): a potential beta-cell imaging agent.

The 11C-labeled sulfonylurea receptor 1 (SUR1) ligand (S)-2-([11C]methoxy)-4-[3-methyl-1-(2-piperidine-1-yl-phenyl)-butyl-carbamoyl]-benzoic acid ([11C]methoxy-repaglinide) was synthesized in an overall radiochemical yield of 35% after 55 min with a radiochemical purity higher than 99%. This compound is considered for the noninvasive investigation of the SUR1 receptor status of pancreatic beta-cells by positron emission tomography (PET) in the context of type 1 and type 2 diabetes. The specific activity was 40-70 GBq/micromol. In vitro testing of the nonradioactive methoxy-repaglinide was performed to characterize the affinity for binding to the human SUR1 isoform. Methoxy-repaglinide induced a complete monophasic inhibition curve with a Hill coefficient close to 1 (1.03) yielding a dissociation constant (KD) of 83 nM and an IC50 of 163 nM. Insulin secretion experiments on isolated rat islets were performed to prove biological activity, which was determined to be in the same range as that of original repaglinide.

Nucleotide sensitivity of pancreatic ATP-sensitive potassium channels and type 2 diabetes.

Type 2 diabetes is generally perceived as a polygenic disorder, with disease development being influenced by both hereditary and environmental factors. However, despite intensive investigations, little progress has been made in identifying the genes that impart susceptibility to the common late-onset forms of the disease. E23K, a common single nucleotide polymorphism in K(IR)6.2, the pore-forming subunit of pancreatic beta-cell ATP-sensitive K(+) (K(ATP)) channels, significantly enhances the spontaneous open probability of these channels, and thus modulates sensitivities toward inhibitory and activatory adenine nucleotides. Based on previous association studies, we present evidence that with an estimated attributable proportion of 15% in Caucasians, E23K in K(IR)6.2 appears to be the most important genetic risk factor for type 2 diabetes yet identified.

The common single nucleotide polymorphism E23K in K(IR)6.2 sensitizes pancreatic beta-cell ATP-sensitive potassium channels toward activation through nucleoside diphosphates.

E23K, a common polymorphism in the pore-forming subunit K(IR)6.2 of pancreatic beta-cell ATP-sensitive K(+) (K(ATP)) channels, is functionally relevant and thus might play a major role in the pathophysiology of common type 2 diabetes. In this study, we show that in the simultaneous presence of activatory and inhibitory nucleotides, the polymorphism exerts opposite effects on the potencies of these modulators: channel opening through nucleoside diphosphates is facilitated, whereas sensitivity toward inhibition through ATP is slightly decreased. The results support the conclusion that E23K predisposes to type 2 diabetes by changing the channel's response to physiological variation of cytosolic nucleotides, resulting in K(ATP) overactivity and discrete inhibition of insulin release.

K(IR)6.2 polymorphism predisposes to type 2 diabetes by inducing overactivity of pancreatic beta-cell ATP-sensitive K(+) channels.

E23K, a common single nucleotide polymorphism in K(IR)6.2, the pore-forming subunit of pancreatic beta-cell ATP-sensitive K(+) channels, significantly enhanced open probability of these channels, thus reducing their sensitivity toward inhibitory ATP(4-) and increasing the threshold concentration for insulin release. Previous association studies and high allelic frequency suggest this effect to critically inhibit secretion and play a major role in pathogenesis of common type 2 diabetes. Based on evidence for functional relevance of E23K in both the heterozygous (E/K; with E in position 23 of K(IR)6.2 in one allele and K in the other) and homozygous (K/K; with K in position 23 of K(IR)6.2 in both alleles) genotype, we propose a model in which enhanced susceptibility to type 2 diabetes is associated with evolutionary advantage of the E/K state.