insulin secretion and metabolism

Insulin secretion and metabolism

On this page I discuss three important characteristics of glucose metabolism and how this relates to glucose-stimulated insulin secretion (GSIS). I have separated this section into three parts, cytosolic glucose metabolism, mitochondrial glucose metabolism and factors from the mitochodria that induce insulin secretion.

Cytosolic glucose metabolism

In pancreatic β-cells, glucose metabolism is crucial for GSIS (Figure 1; see β-cell insulin secretion page). There are three main characteristics of cytosolic glucose metabolism in the β-cell. First, glucose can equilibrate rapidly across the b-cell membrane because of the expression of the high capacity, low affinity glucose transporter-2 (GLUT2) (Newgard & McGarry, 1995). Secondly, after glucose has entered the b-cell, it is phosphorylated to glucose-6-phospate by the high K_M glucokinase (GK, hexokinase IV), which constitutes the flux determining step for glycolysis (Newgard & McGarry, 1995;Matschinsky, 1996;De Vos et al., 1995;Iynedjian, 1993). GK has also been proposed to be the “glucose sensor” in the pancreatic b-cell (Matschinsky, 1996). The fact that mutations in the GK gene lead to impaired insulin secretion in maturity onset diabetes of the young type 2 (MODY2) patients further supports a role for glucokinase as a glucose sensor (Froguel et al., 1993). Thirdly, once phosphorylated, glucose is metabolized by glycolysis to produce pyruvate, nicotinamide adenine dinucleotide (NADH) and ATP.

The glycolytic product pyruvate is a substrate for the tricarboxylic acid (TCA) cycle in the mitochondria and has been suggested to be an important downstream modulator of insulin secretion. However, pyruvate (or its membrane permeable forms) fails to consistently stimulate insulin secretion even though it can be oxidized in islets as efficiently as glucose (Sener et al., 1978;Zawalich & Zawalich, 1997;Mertz et al., 1996). Inhibitors of pyruvate transport into the mitochondria or inhibitors of the TCA cycle are not well correlated with GSIS (Dukes et al., 1994;Mertz et al., 1996).

Mitochondrial pyruvate metabolism, although not critical, is still likely important in GSIS since pancreatic b- and a-cells express low levels of lactate dehydrogenase (LDH), the enzyme catalyzing the conversion of pyruvate to lactate (Schuit et al., 1997;Sekine et al., 1994;Ishihara et al., 1999). Low LDH would prevent shunting of pyruvate away from the mitochondrial metabolic pathways (Zhao et al., 2001). Pancreatic b- and a-cells also have been found to have a low ratio LDH to mitochondrial glycerol phosphate dehydrogenase (mGPDH), which is consistent with the important role of the glycerol-phosphate shuttle in GSIS.

Therefore even though pyruvate provides a substrate to the TCA cycle for ATP production it is not the critical glycolytic factor (or at least the only factor) that potentiates insulin secretion. There must be other factor(s) derived from glycolysis, other than pyruvate, that are required for the generation of mitochondrial signals that lead to insulin secretion. One such candidate factor is NADH (Eto & Kadowaki, 1999;Eto et al., 1999;Malaisse et al., 1979b;Hedeskov et al., 1987;Pralong et al., 1990).

A likely possibility of why exogenous pyruvate is not able to stimulate GSIS is that β-cells have extremely low levels of the monocarboxylate transporter (MCT) in the plasma membrane which is involved in lactate and pyruvate transport (Zhao et al., 2001). One likely reason that pyruvate is such a poor stimulus on its own is that exogenous pyruvate levels in the blood vary considerably depending on its production. Therefore, low MCT activity is required for proper GSIS in the b-cell to prevent hypoglycemia in response to increases in circulating pyruvate and lactate such as that seen during exercise and other catabolic states (Eto & Kadowaki, 1999;Sekine et al., 1994;Ishihara et al., 1999).

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