Substrate Control of Insulin Release

Abstract

Outlook Potassium ChannelIslet Cells and Hepatocytes p Cells LEVELS OF CIRCULATING NUTRIENTS such as glucose, fatty acids, and amino acids, are precisely controlled in mammals during fasting and feeding alike. Insulin and the pancreatic p cells, which secrete this hormone, play a pivotal role in the control of fuel homeostasis. To serve this critical regulatory function, the p cells are analogous to the thermostat of heating or cooling systems. They measure the nutrient levels of the blood on a moment-tomoment basis and secrete insulin at rates exactly appropriate for maintenance of optimal fuel levels.The concept of the thermostat incorporates the principles of set-point and threshold. Set-point is the desired level of a regulated parameter, that is, the temperature in a heating or cooling system or the fuel levels in the blood.The most prominent role of the p cell is to maintain glucose levels at a set-point of around 5 mM. The threshold of 5 AM stimulate insulin Secretion from islet p cells of essentially all mammals, and this is critical for maintaining glucose levels at or near the set-point. The glucose threshold is the most important niodulator of p-cell function since most other p-cell secretagogues act by potentiating the stimulatory effect of the sugar.The amount of insulin secreted by p cells is also regulated by the insulin responsiveness of the major target tissues of the hormone: muscle, adipocytes, and liver. In insulin-resistant states, such as obesity or in the early stages of non-insulin-dependent diabetes mellitus (NIDDM), a compensatory increase in insulin secretion is required to maintain blood nutrient homeostasis. This compensatory response can involve both an increase in islet p-cell volume and a lowering of the threshold for GSIS. These changes may result in higher rates of insulin secretion at glucose concentrations lower than the normal stimulatory threshold and a consequent increase in the basal level of insulin in the blood. The purpose of this chapter is to expand upon the foregoing simplified description of p-cell function and to present the current understanding of the biochemical and molecular mechanisms involved in nutrient-stimulated insulin secretion. A great deal of research has been carried out in this area since the last edition of this Handbook (99), and it is not the purpose of this chapter to provide a comprehensive review of all of this work. Rather, we highlight major new findings, particularly those that integrate the tools of molecular biology with biochemical and physiological constructs developed earlier or evolving currently. CELLULAR ARCHITECTURE OF PANCREATIC ISLETSis defined as the 1e;el of a regulated parameter that triggers a regulatory function, that is, activation of cooling or heating functions by a specific temperature in the case of a thermostat or activation of insulin secretion by a specific fuel level in the case of the p cell. The threshold for glucose-stimulated insulin secretion (GSIS) coincides with Any discussion of pancreatic P-cell function must...

Research and Development of Glucokinase Activators for Diabetes Therapy: Theoretical and Practical Aspects

“…Still, GK has a control strength in the regulation of glucose metabolism of pancreatic islet tissue (both of glycolysis and oxidation) approaching unity implying that even small changes of the effective enzyme activity (kcat/glucose S 0.5 ), by as little as 10-20%, have a marked effect on glucose metabolism (Matschinsky 1990;Matschinsky 1984, 1986). The coupling between glucose metabolism and stimulation of insulin secretion is absolute and is mediated by coupling factors (Henquin 2000;Matschinsky 1996;Matschinsky et al 2006;Newgard and Matschinsky 2001;Prentki and Matschinsky 1987). It is still hotly debated which metabolites and cofactors qualify as coupling factors in this process.…”

“…In the beta-cells, GK plays the role as glucose sensor and thus controls all their glucose-dependent functions which includes (Matschinsky 1996;Matschinsky and Ellerman 1968;Matschinsky et al 2006;Newgard and Matschinsky 2001) (Fig. 2) (1) glucose-stimulated insulin release and biosynthesis; (2) glucosedependent fuel stimulation of insulin release by fatty acids and amino acids; (3) glucose-dependent receptor-mediated stimulation of insulin release by acetylcholine, GLP1, GIP, and by fatty acids via the GPR40 receptor; (4) beta-cell survival and replication.…”

“…2) (Ahrén 2009;Gromada 2006;Henquin 2000;Matschinsky et al 2006;Newgard and Matschinsky 2001;Wess et al 2007). Activation of the GLP-1 receptor is now considered a promising approach and has resulted in the development of synthetic exendin-4 and DPP-IV Fig.…”

13 C NMR isotopomer analysis reveals a connection between pyruvate cycling and glucose-stimulated insulin secretion (GSIS)

“…, and subsequent exocytosis of insulin (1,2). Glucose oxidation increases in proportion to the external glucose concentration in ␤ cells, and this has been taken as evidence for a direct link between fuel oxidation, ATP production, and insulin secretion (3).…”

Metabolic and ionic coupling factors in amino acid-stimulated insulin release in pancreatic β-HC9 cells

“…amino acids; energy metabolism; oxygen consumption; sodium; mitochondria THE BIOCHEMICAL BASIS OF FUEL SENSING by the insulin-secreting ␤-cells of the pancreatic islets of Langerhans is an issue of fundamental importance. Mechanisms have evolved over time that depend on the metabolism of the fuels rather than direct receptor-mediated recognition of the fuel molecules themselves, which contrast strikingly with the molecular processes mediating smell and taste (5,10,24,39,42,45,46). The study of metabolic events and of the processes that couple metabolism to hormone secretion is therefore central to pancreatic islet cell research.…”