The islet b-cell: fuel responsive and vulnerable

Anaplerosis: Replenishment or ‘filling up’ of the carbon pool in the tricarboxylic acid (TCA) cycle. The major anaplerotic reaction in the b-cell is catalyzed by pyruvate carboxylase that produces the 4 carbon TCA cycle intermediate oxaloacetate from pyruvate. Pyruvate metabolism catalyzed by pyruvate dehydrogenase that produces the 2 carbon TCA cycle intermediate acetyl-CoA is not anaplerotic because two carbons are lost in one turn of the cycle. Cataplerosis: Exiting of carbons from the TCA carbon pool. For example, citrate exits from the mitochondrion for pyruvate cycling and malonyl-CoA synthesis. Fuel surfeit: Chronic oversupply of energy from food. Glucose-stimulated insulin secretion (GSIS): Increase in insulin secretion over basal in response to an increase in glucose levels. GSIS can be modified by the presence of other nutrients, e.g. amino acids and free fatty acids, and by neurohormonal signals. Glycerolipids (GL): Complex lipid molecules with a glycerol backbone including the neutral mono-, diand triacylglycerols and polar glycerophospholipids. Glycerolipid/fatty acid (GL/FA) cycling: Cyclic process of FFA esterification onto a glycerol backbone to synthesize GL followed by hydrolysis with the release of FFA that can be re-esterified. GL/FA cycling allows for production of a wide array of both neutral and polar GL, in addition to participating in acylchain exchange between various GL molecules. G protein-coupled receptor (GPCR): Large protein family of transmembrane receptors that sense molecules outside the cell and activate intracellular signal transduction pathways and ultimately, cellular responses. GPR40 is a GPCR that is highly expressed in islet b-cells and activated by medium to long chain fatty-acids. KATP channel dependent triggering pathway: b-Cell nutrient-secretion coupling pathway in which metabolic activation results in an increase in the ATP/ ADP ratio, closure of ATP-sensitive K (KATP) channels, depolarisation of the plasma membrane, opening of voltage dependent Ca channels and Ca triggering of insulin granule exocytosis. Metabolic coupling factors (MCFs): Molecules such as ATP, NAPDH, malonylCoA and diacylglycerol produced by nutrient metabolism that have signaling roles for the promotion of insulin biosynthesis and secretion. Pyruvate cycling processes: Anaplerotic/cataplerotic metabolic processes that begin and end with pyruvate. These processes include the malate-pyruvate, citrate-pyruvate and isocitrate/a-ketoglutarate-pyruvate shuttles that all generate NADPH. The pancreatic b-cell senses blood nutrient levels and is modulated by neurohormonal signals so that it secretes insulin according to the need of the organism. Nutrient sensing involves marked metabolic activation, resulting in the production of coupling signals that promote insulin biosynthesis and secretion. The b-cell’s high capacity for nutrient sensing, however, necessitates reduced protection to nutrient toxicity. This potentially explains why in susceptible individuals, chronic fuel surfeit results in b-cell failure and type 2 diabetes. Here we discuss recent insights into first, the biochemical basis of b-cell signaling in response to glucose, amino acids and fatty acids, and second, b-cell nutrient detoxification. We emphasize the emerging role of glycerolipid/fatty acid cycling in these processes.