Nutritional regulation of insulin secretion: implications for diabetes

Abstract

Pancreatic β-cells are exquisitely organised to continually monitor and respond to dietary nutrients, under the modulation of additional neurohormonal signals, in order to secrete insulin to best meet the needs of the organism. β-cell nutrient sensing requires complex mechanisms of metabolic activation, resulting in production of stimulus-secretion coupling signals that promote insulin biosynthesis and release. The primary stimulus for insulin secretion is an elevation in blood glucose concentration and β-cells are particularly responsive to this important nutrient secretagogue via the tight regulation of glycolytic and mitochondrial pathways at steps such as glucokinase, pyruvate dehydrogenase, pyruvate carboxylase, glutamate dehydrogenase and mitochondrial redoxshuttles. With respect to development of type-2 diabetes (T2DM), it is important to consider individual effects of different classes of nutrient or other physiological or pharmacological agents on metabolism and insulin secretion and to also acknowledge and examine the interplay between glucose metabolism and that of the two other primary nutrient classes, amino acids (such as arginine and glutamine) and fatty acids. It is the mixed nutrient sensing and outputs of glucose, amino and fatty acid metabolism that generate the metabolic coupling factors (MCFs) essential for signalling for insulin exocytosis. Primary MCFs in the β-cell include ATP, NADPH, glutamate, long chain acyl coenzyme A and diacylglycerol. It is the failure to generate MCFs in a coordinated manner and at sufficient levels that underlies the failure of β-cell secretion during the pathogenesis of T2DM.

Figure.

General view of the mitochondrial metabolism in pancreatic β-cells. Products of carbohydrate, protein and fat metabolism can be converted to CO₂ and water by the mitochondria, using key enzymes of the TCA cycle and the electron transport chain; NADH dehydrogenase (Complex I), succinate dehydrogenase (Complex II), cytochrome bc1 (Complex III), and cytochrome c oxidase (Complex IV). During these reactions, protons (H⁺) are pumped from the matrix to the space between the inner and outer membranes, establishing a proton gradient. Protons diffusing back along this gradient drive the synthesis of ATP by the F₀F₁ATP synthase complex. Mitochondria generate cellular energy through TCA cycle activity and the associated electron transport chain of the inner membrane. The reducing equivalents (NADPH and FADH2) produced from the TCA cycle are reoxidised via a process that involves transfer of electrons through the electron transport chain and associated translocation of protons across the mitochondrial inner membrane, creating the transmembrane electrochemical gradient which is used to provide the electrochemical potential to make ATP through the ATP synthase complex. In the case of β-cells, the increased ATP/ADP ratio leads to the closure of the K⁺_ATP channels leading to membrane depolarisation followed by calcium influx that, together with other co-factors (such as glutamate, NADPH, malonyl-CoA, cAMP, GTP) induces the translocation and exocytosis of the insulin vesicles. ①Pyruvate dehydrogenase, ②Pyruvate carboxylase, ③Citrate synthase, ④Isocitrate dehydrogenase, ⑤α-ketoglutarate dehydrogenase, ⑥Succinate thiokinase, ⑦Succinate dehydrogenase, ⑧Fumarase, ⑨Malate dehydrogenase.