292-LB: Cholesterol Accumulation in Islets Exacerbates Insulin Secretory Defects in a Model of Mild ß-Cell Dysfunction

Abstract

Hypercholesterolemia is common in diabetes. We sought to determine whether cholesterol (Chol) can exacerbate impaired insulin secretion in islets from a mouse model of mild β-cell dysfunction. To induce β-cell dysfunction, C57BL/6J male mice were treated with low-dose (30 mg/kg, i.p.) streptozotocin (STZ) or vehicle (VEH) once daily on 3 consecutive days. Mice were then fed a 9% fat diet for 4 weeks, after which islets were isolated and cultured for 24 h ± Chol prior to endpoint measures. After 4 weeks, body weight (STZ 28.9±1.0 vs VEH 29.1±1.1 g) and fed glucose (STZ 191.2±11.0 vs VEH 177.8±8.2 mg/dl) did not differ. When cultured with 0 mM Chol, isolated islets from STZ-treated mice showed reduced glucose (20 mM)-stimulated insulin secretion (GSIS: 973.9±191.7 vs 1714.8±384.6 pM, n=5, p<0.05) and a trend for lower insulin content (180.6±18.2 vs 230.4±22.9 nM, n=5, p=0.06), compared to islets from VEH-treated mice. Having established STZ-induced β-cell dysfunction, islets from STZ-treated mice were cultured ± 0.5 mM Chol, then Chol content and GSIS measured. Culture in 0.5 mM (vs 0 mM) Chol resulted in increased islet Chol content (58.9 ± 4.3 vs 17.6 ± 3.0 µg/mg protein; n=3, p<0.01). A trend for increased basal insulin secretion (2.8 mM glucose: 185.8±64.7 vs 32.8±3.5 pM, n=5, p=0.09) and reduced GSIS (305.3±60.3 vs 973.9±191.7 pM, n=5, p<0.05) were observed in islets cultured with 0.5 mM Chol. Insulin content was also reduced (125.8±10.8 vs 180.6±18.2 nM, n=5, p<0.01) with 0.5 mM Chol culture. In sum, we have developed a STZ-based, euglycemic mouse model of subclinical β-cell dysfunction. Chol treatment of islets from these mice exacerbates β-cell dysfunction, in keeping with a deleterious effect of Chol. This model now provides the ability to determine whether hypercholesterolemia in vivo results in further impairment of β-cell dysfunction and the development of hyperglycemia, an observation that would be relevant to the progression of prediabetes to diabetes and diabetes per se. Disclosure R. Akter: None. B. Barrow: None. R. L. Hull-meichle: Employee; Veterans Administration, Research Support; Casma Therapeutics, Cystic Fibrosis Foundation, NIH - National Institutes of Health, Veterans Administration. S. Zraika: None. S. E. Kahn: Advisory Panel; Anji Pharmaceuticals, Bayer Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Merck & Co., Inc., Other Relationship; Novo Nordisk. Funding U.S. Department of Veterans Affairs (I01BX001060); National Institutes of Health (P30DK017047); Diabetes Research Connection (46)