Islet insulin content and release are increased in male mice with elevated endogenous GH and IGF-I, without evidence of systemic insulin resistance or alterations in β-cell mass

• Modest elevations in endogenous GH and IGF-I raise insulin, but lower glucose and lipids.
• Modest elevations in endogenous GH and IGF-I does not promote expansion of β-cell mass.
• Modest elevations in endogenous GH and IGF-I does not increase GSIS.

It is clear that elevations in circulating GH can lead to an increase in insulin levels. This increase in insulin may be due to GH-mediated insulin resistance and enhanced lipolysis. However, there is also in vitro and in vivo evidence that GH acts directly to increase β-cell proliferation and insulin production. Our laboratory recently developed an animal model with elevated endogenous GH levels associated with a small (25%), but significant, increase in IGF-I (HiGH mice). As expected, insulin levels were elevated in HiGH mice; however, whole body insulin sensitivity was not altered and glucose tolerance was improved. This metabolic phenotype suggests that modest elevations in circulating GH and IGF-I may enhance β-cell mass and/or function, in the absence of systemic insulin resistance, thus improving glucose homeostasis.ObjectiveTo determine if β-cell mass and/or function is altered in HiGH mice.DesignMale HiGH mice and their littermate controls were fed a low-fat or high-fat diet. Body composition and circulating metabolic endpoints were monitored overtime. The pancreas was recovered and processed for assessment of β-cell mass or in vitro basal and glucose-stimulated insulin secretion.ResultsHiGH mice showed elevated circulating insulin and normal glucose levels, while non-esterified FFA levels and triglycerides were reduced or normal, depending on diet and age. β-cell mass did not differ between HiGH and control mice, within diet. However, islets from HiGH mice contained and released more insulin under basal conditions, as compared to control islets, while the relative glucose-stimulated insulin release did not differ.ConclusionsTaken together, these results suggest moderate elevations in circulating GH and IGF-I can directly increase basal insulin secretion without impacting β-cell mass, independent of changes in whole body insulin sensitivity and hyperlipidemia.