Long- But Not Short-Term Adult-Onset, Isolated GH Deficiency in Male Mice Leads to Deterioration of β-Cell Function, Which Cannot Be Accounted for by Changes in β-Cell Mass

Abstract

Developmental models of GH deficiency (GHD) and excess indicate that GH is positively associated with β-cell mass. Therefore, the reduction in GH levels observed with age and weight gain may contribute to the age-related decline in β-cell function. To test this hypothesis, β-cell mass and function were assessed in a mouse model of adult-onset, isolated GHD (AOiGHD). β-Cell mass did not differ between low-fat (LF)-fed AOiGHD and controls. However, high fat-fed AOiGHD mice displayed impaired expansion of β-cell mass and a reduction of bromodeoxyuridine-labeled islet cells, whereas in vitro β-cell function (basal and glucose-stimulated insulin secretion [GSIS]) did not differ from controls. In contrast, duration of AOiGHD differentially altered in vitro β-cell function in LF-fed mice. Specifically, islets from young LF-fed AOiGHD mice showed significant reductions in insulin content and basal insulin secretion, but GSIS was similar to that of controls. A similar islet phenotype was observed in a developmental model of isolated GHD (GH-releasing hormone knockout). Given that LF- and high fat-fed AOiGHD mice, as well as GH-releasing hormone knockout mice, display improved insulin sensitivity, islet changes may be due to reduced insulin demand, rather than primary β-cell dysfunction. However, islets from older LF-fed AOiGHD mice exhibited impaired GSIS, associated with reduced expression of genes important to maintain glucose sensing, suggesting that factors secondary to AOiGHD can alter β-cell function with age. AOiGHD mice exhibited postprandial hypertriglyceridemia and increased pancreatic expression of lipid/inflammatory stress response genes (activating transcription factor 3 and peroxisome proliferator activator receptor β/δ). Therefore, we speculate that these changes may initially protect the AOiGHD β-cell, but with age, lipotoxicity may impair β-cell function.