Banting lecture 2011: hyperinsulinemia: cause or consequence?

Abstract

The Banting Medal for Scientific Achievement Award is the American Diabetes Association's highest scientific award and honors an individual who has made significant, long-term contributions to the understanding of diabetes, its treatment, and/or prevention. The award is named after Nobel Prize winner Sir Frederick Banting, who codiscovered insulin treatment for diabetes. Dr. Barbara E. Corkey received the American Diabetes Association's Banting Medal for Scientific Achievement at the Association's 71st Scientific Sessions, 24-28 June 2011, San Diego, California. She presented the Banting Lecture, "Hyperinsulinemia: Cause or Consequence?" on Sunday, 26 June 2011.

FIG. 1.

Model of β-cell secretion of insulin leading to hyperinsulinemia and causing obesity, diabetes, and insulin resistance.

FIG. 2.

Illustration of communication of intracellular redox state to the blood stream: equilibration of cytosolic and mitochondrial redox as reflected in the muscle cytosolic lactate-to-pyruvate ratio (L/P) and liver mitochondrial β/A ratio.

FIG. 3.

Model of redox as master regulator of metabolism affecting insulin secretion, hepatic glucose handling, and adipocyte lipid storage.

FIG. 4.

Insulin secretion. A: Effect of 18-h exposure to 100 μmol/L fatty acid (FA) on insulin secretion from isolated rat islets (73). B: Concentration dependence of MOG-stimulated insulin secretion from dissociated rat islets at basal 3 mmol/L glucose (73). C: Effect of artificial sweeteners on insulin secretion in dissociated rat islets (74). Effect of iron exposure in INS-1 (832/13) cells (Deeney et al., unpublished data). Data shown are means ± SEM for at least three experiments.

FIG. 5.

Time course of glucose-induced metabolic changes after glucose addition (27). PM, plasma membrane. TCA, tricarboxylic acid cycle.

FIG. 6.

Effect of MOG (left panel) and glucose (right panel) on rat islet redox state (73). (A high-quality digital representation of this figure is available in the online issue.)

FIG. 7.

Effect on ROS of agents that stimulate basal insulin secretion in INS-1 (832/13) cells. A: ROS generation by MOG measured in islet cells virally infected with the ROS indicator HyPer_cyto (73). B: Iron increases ROS as documented by the ROS indicator dichlorofluorescein (DCF) (Deeney et al., unpublished data). C: Effect of saccharin (Sacc) on ROS in cells virally infected with the ROS indicator HyPer_cyto (74). D: Effect of ROS scavengers on insulin secretion from INS-1 cells (73). Data shown are means ± SEM for at least three experiments.

FIG. 8.

Effects of 20 mmol/L β-OHB. A: NAD(P)H autofluorescence in islet cells (73). B: ROS generation in INS-1 (832/13) cells virally infected with the ROS indicator HyPer_cyto (73). C: Effect of β-OHB and ROS scavenging by NAC on insulin secretion from islet cells (73). Data shown are means ± SEM for at least three experiments.

FIG. 9.

Inhibition of LC-CoA formation by orlistat (lipase inhibitor) and triacsin C (TC) (acyl-CoA synthetase inhibitor). DG, diacylglycerol; PL, phospholipids; TG, triglyceride.

FIG. 10.

Insulin secretion in response to lipid modulators in clonal β-cells. A: Inhibiting LC-CoA formation with triacsin C inhibits secretion (Deeney et al., unpublished data). B: Inhibiting lipolysis with orlistat inhibits secretion (75). Data shown are means ± SEM for at least three experiments.