Comprehensive Physiology Wiley Online Library

General Introduction: Reminiscences and Reflections on Fifty Years of the Endocrine Pancreas

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Beginnings
1.1 Endocrine Nature of the Pancreas
2 Action Mechanisms
2.1 Landmarks in Protein Phosphorylation: Mechanism of Action of Glucagon
3 Insulin
3.1 Early Development of Ideas About the Mechanism of Action of Insulin
3.2 Insulin Secretion and Biosynthesis
4 Fuels: Consumption and Selection—The Glucose Fatty Acid Cycle and the Role of the PDH Complex
4.1 Fuel Consumption and Selection
4.2 The Glucose Fatty Acid Cycle
4.3 Role of the Pyruvate Dehydrogenase Complex
4.4 Physiopathological Significance of Pyruvate Dehydrogenase Kinase Regulation in Humans
5 The Thrifty Phenotype Hypothesis in Relation to Insulin Secretion, Insulin Insensitivity, and the Origins of Non‐Insulin‐Dependent Diabetes Mellitus
6 Where Next?
Figure 1. Figure 1.

Shorter‐term and longer‐term mechanisms regulating the activity of the pyruvate dehydrogenase (PDH) complex by reversible phosphorylation in animal tissues. A, Inhibitors of lipolysis (5‐methylpyrazole‐3‐carboxylic acid, acipimox); B, inhibitors of fatty acid oxidation (2‐tetradecylglycidate, etomoxir); C, inhibitors of pyruvate dehydrogenase kinase (dichloroacetate).

Figure 2. Figure 2.

Pathways and mechanisms mediating effects of glucose on insulin secretion and modification by fatty acids. Lower panel: Stimulation of insulin secretion by glucose is mediated by mitochondrial metabolism of pyruvate and of cytosolic NADH, resulting in elevation of [ATP]: [ADP] Ca2+ influx, activation of mitochondrial dehydrogenases (pyruvate, 2‐oxoglutarate, NAD+ isocitrate), and further elevation of [ATP]: [ADP]. Longer‐term fatty acid oxidation may interfere with this response through activation of (PDH) kinase, pyruvate dehydrogenase resulting in inhibition of pyruvate oxidation and (through elevation of islet citrate) inhibition of phosphofructokinase 1 (and possibly phosphofructoldnase 2). Upper panel: Possible mechanism(s) by which glucose‐induced formation of malonyl CoA with concomitant inhibition of carnitine acyl‐transferase and elevation of cytosolic fatty acetyl CoA might augment glucose‐induced insulin release. +, activation; −, inhibition. Glut, glucose transporter; GP, glycerophosphate; TCC, OAA, oxaloacetic acid.



Figure 1.

Shorter‐term and longer‐term mechanisms regulating the activity of the pyruvate dehydrogenase (PDH) complex by reversible phosphorylation in animal tissues. A, Inhibitors of lipolysis (5‐methylpyrazole‐3‐carboxylic acid, acipimox); B, inhibitors of fatty acid oxidation (2‐tetradecylglycidate, etomoxir); C, inhibitors of pyruvate dehydrogenase kinase (dichloroacetate).



Figure 2.

Pathways and mechanisms mediating effects of glucose on insulin secretion and modification by fatty acids. Lower panel: Stimulation of insulin secretion by glucose is mediated by mitochondrial metabolism of pyruvate and of cytosolic NADH, resulting in elevation of [ATP]: [ADP] Ca2+ influx, activation of mitochondrial dehydrogenases (pyruvate, 2‐oxoglutarate, NAD+ isocitrate), and further elevation of [ATP]: [ADP]. Longer‐term fatty acid oxidation may interfere with this response through activation of (PDH) kinase, pyruvate dehydrogenase resulting in inhibition of pyruvate oxidation and (through elevation of islet citrate) inhibition of phosphofructokinase 1 (and possibly phosphofructoldnase 2). Upper panel: Possible mechanism(s) by which glucose‐induced formation of malonyl CoA with concomitant inhibition of carnitine acyl‐transferase and elevation of cytosolic fatty acetyl CoA might augment glucose‐induced insulin release. +, activation; −, inhibition. Glut, glucose transporter; GP, glycerophosphate; TCC, OAA, oxaloacetic acid.

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Philip J. Randle. General Introduction: Reminiscences and Reflections on Fifty Years of the Endocrine Pancreas. Compr Physiol 2011, Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism: 1-22. First published in print 2001. doi: 10.1002/cphy.cp070201