Abstract
Role of GLP-1 and GIP in beta cell compensatory responses to beta cell attack and insulin resistance were examined in C57BL/6 mice lacking functional receptors for GLP-1 and GIP. Mice were treated with multiple low dose streptozotocin or hydrocortisone. Islet parameters were assessed by immunohistochemistry and hormone measurements were determined by specific enzyme linked immunoassays. Wild-type streptozotocin controls exhibited severe diabetes, irregularly shaped islets with lymphocytic infiltration, decreased Ki67/TUNEL ratio with decreased beta cell and increased alpha cell areas. GLP-1 and GIP were co-expressed with glucagon and numbers of alpha cells mainly expressing GLP-1 were increased. In contrast, hydrocortisone treatment and induction of insulin resistance increased islet numbers and area, with enhanced beta cell replication, elevated mass of beta and alpha cells, together with co-expression of GLP-1 and GIP with glucagon in islets. The metabolic responses to streptozotocin in GLP-1RKO and GIPRKO mice were broadly similar to C57BL/6 controls, although decreases in islet numbers and size were more severe. In contrast, both groups of mice lacking functional incretin receptors displayed substantially impaired islet adaptations to insulin resistance induced by hydrocortisone, including marked curtailment of expansion of islet area, beta cell mass and islet number. Our observations cannot be explained by simple changes in circulating incretin concentrations, suggesting that intra-islet GLP-1 and GIP make a significant contribution to islet adaptation, particularly expansion of beta cell mass and compensatory islet compensation to hydrocortisone and insulin resistance.
Highlights
Glucagon-like peptide-1 (GLP-1) together with the sister incretin hormone gastric inhibitory polypeptide (GIP) are secreted from intestinal L-cell and K-cells in response to feeding and exert pleiotropic metabolic effects [1,2,3,4,5]
The number of islets in hydrocortisone treated GIPRKO mice was less than C57BL/6 mice (p,0.01, Figure 2A)
Classically considered as enteroinsular hormones [36], this study has examined the possibility that intra-islet production of GLP-1 or GIP, together with circulating incretins from the gut, contributes to mechanisms controlling beta-cell function, the regulation of beta-cell mass and adaptive responses to beta cell toxins and insulin resistance
Summary
Glucagon-like peptide-1 (GLP-1) together with the sister incretin hormone gastric inhibitory polypeptide (GIP) are secreted from intestinal L-cell and K-cells in response to feeding and exert pleiotropic metabolic effects [1,2,3,4,5]. Apart from positive actions on cognition via effects at the hippocampus, the effects of the two peptides differ, with GIP inhibiting gastric acid secretion and exerting anabolic effects on both adipose tissue and bone whereas GLP-1 inhibits gastric emptying and satiety, while affording cardioprotection [5,6,7,8]. DPPIV inhibitors which normally block the rapid enzymatic breakdown of both incretin hormones and augment the actions of GIP have been introduced [11]
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