Adaptation of β-cell mass to substrate oversupply: enhanced function with normal gene expression

Abstract

Although type 2 diabetes mellitus is associated with insulin resistance, many individuals compensate by increasing insulin secretion. Putative mechanisms underlying this compensation were assessed in the present study by use of 4-day glucose (GLC; 35% Glc, 2 ml/h) and lipid (LIH; 10% Intralipid + 20 U/ml heparin; 2 ml/h) infusions to rats. Within 2 days of beginning the infusion of either lipid or glucose, plasma glucose profiles were normalized (relative to saline-infused control rats; SAL; 0.45% 2 ml/h). During glucose infusion, plasma glucose was maintained in the normal range by an approximately twofold increase in plasma insulin and an approximately 80% increase in beta-cell mass. During LIH infusion, glucose profiles were also maintained in the normal range. Plasma insulin responses during feeding were doubled, and beta-cell mass increased 54%. For both groups, the increase in beta-cell mass was associated with increased beta-cell proliferation (98% increase during GLC and 125% increase during LIH). At the end of the 4-day infusions, no significant changes were observed in islet-specific gene transcription (i.e., the expression of islet hormone genes, glucose metabolism genes, and insulin transcription factors were unaffected). Two days after termination of the infusions, the glucose-stimulated plasma insulin response was increased approximately 67% in glucose-infused animals. No sustained effect on insulin secretory capacity was observed in the LIH animals. The increase in plasma insulin response after glucose infusion was achieved in the absence of any change in insulin clearance. We conclude that, in rats, an increase in insulin demand after an increase in glucose appearance or free fatty acid leads to an increase in beta-cell mass, mediated in part by an increase in beta-cell proliferation, and that these compensatory changes lead to increased insulin secretion, normal plasma glucose levels, and the maintenance of normal islet gene expression.

Cyclical and Alternating Infusions of Glucose and Intralipid in Rats Inhibit Insulin Gene Expression and Pdx-1 Binding in Islets

“…No differences in the expression of islet-specific genes such as insulin, glucokinase, and Pdx-1 were observed in rats infused with glucose or Intralipid versus controls (27) or in cyclin genes involved in ␤-cell proliferation in glucose-infused mice (31). We observed an increase in insulin mRNA expression in glucose-infused rats, which was not observed in animals also receiving Intralipid.…”

“…The lack of effects of glucose and Intralipid on insulin secretion is in marked contrast with the results of previous studies using continuous infusion protocols (15,21-29). While Sako and Grill (22) glucose infusion reduced GSIS, in other studies a marked enhancement was observed (27)(28)(29). Thibault et al (23) observed that sustained hyperglycemia enhances insulin secretion in both normal and hyperglycemic rats.…”

“…In the perfused pancreas model, Sako and Grill (21) (15). In contrast, Steil et al (27) reported no effect of a 96-h Intralipid infusion on insulin secretion. Although not directly tested, we suspect that the different effects of glucose or Intralipid on insulin secretion between our results and previous publications are due, in part, to the discontinuous nature of the infusion.…”

Vhl is required for normal pancreatic β cell function and the maintenance of β cell mass with age in mice

“…When b-cell compensation can adequately meet the insulin demands of the body, normoglycemia is maintained. [5][6][7] However, in susceptible individuals perhaps with genetic defects and/or environmental insults, the b-cells cannot meet the metabolic demands, ultimately resulting in type 2 diabetes. [8][9][10][11] A previous study by Gunton et al 12 reported results of gene expression profiling analyses on islets of humans with type 2 diabetes, and found a significant decrease in aryl-hydrocarbon-receptor nuclear translocator (ARNT)/hypoxiainducible factor-1b (HIF-1b) expression in these islets.…”

Effect of increased plasma non-esterified fatty acids (NEFAs) on arginine-stimulated insulin secretion in obese humans

“…Cross-sectional [34] and longitudinal studies in humans [35] and in experimental studies in animals [36,37] have shown that a reduction in insulin sensitivity is usually associated with a compensatory increase in insulin secretion to maintain glucose homeostasis. This observation has led to the concept of ªdisposition indexº of insulin (DI), which implies that the product of insulin secretion and insulin sensitivity should remain constant for a given population (or individual) if glucose homeostasis is to remain unaltered [38,39].…”