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.


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.


U.S. Department of Veterans Affairs (I01BX001060); National Institutes of Health (P30DK017047); Diabetes Research Connection (46)

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.