FP13-3 β-Cell Expression of Cholecystokinin Ameliorates the Diabetic Phenotype in Akita Mice

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP13-GI Peptides, Beta Cells & Glycemia
Translational
Saturday, June 15, 2013: 11:00 AM-11:30 AM
Presentation Start Time: 11:10 AM
Room 304 (Moscone Center)

Poster Board SAT-836
Mieke Baan*, Muhammad K Ahmed, Carly R Kibbe, Jeremy A Lavine and Dawn Belt Davis
University of Wisconsin, Madison, WI
Diabetes mellitus (DM) is caused by a reduced number of functional β-cells in the pancreas. Identifying factors that can protect β-cells from apoptotic stressors is important in developing effective diabetes therapies. The hormone cholecystokinin (CCK) is expressed in pancreatic islets of obese mice and is necessary for maintenance of β-cell mass in obesity (1). CCK treatment ex vivo prevents islet apoptosis secondary to thapsigargin-induced ER-stress (1). To test whether overexpression of CCK could protect β-cells from apoptosis in vivo, we generated transgenic mice with Cck expression driven by the mouse insulin promoter (MIP-CCK). As a model of in vivo β-cell apoptosis we used Akita mice, as they carry a missense mutation in the insulin gene causing misfolding of the protein, resulting in ER overload and β-cell apoptosis (2). Heterozygotes develop a diabetic phenotype around one month of age. MIP-CCK/Akita+/- males were compared with Akita+/- males. At 4 weeks of age, random fed glucose concentrations were elevated in both groups, but not significantly different (246 +/- 124 mg/dL vs 224 +/- 83 mg/dL, respectively, p=0.70, n=7). However, at 14 weeks MIP-CCK/Akita+/- males have less hyperglycemia than controls (429 +/- 53 mg/dL vs 289 +/- 102 mg/dL, n=7-9, p=0.0057). We examined pancreatic morphology with insulin and TUNEL staining in 14-16 week old animals.  By this stage, there is massive β-cell loss and ongoing apoptosis is no longer detectable.  However, the CCK overexpressors had more residual fractional β-cell area than controls (0.44% vs. 0.07%, n=2, p=0.015). In addition, mean islet size was larger in MIP-CCK/Akita+/- (4550 unit area vs. 1041 unit area, p=0.047). In summary, localized β-cell expression of CCK protects from ER-stress mediated β-cell loss in vivo, and CCK directed therapies may provide benefit in maintaining β-cell mass in diabetes.

1. Lavine JA, et al. (2010) Endocrinology 151(8):3577-3588. 2. Wang J, et al. (1999) J Clin Invest 103(1):27-37.

Nothing to Disclose: MB, MKA, CRK, JAL, DBD

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH Ruth L. Kirschstein National Research Service Award Institutional Training Grant T32 RR023916 and T32 OD010423 from the National Center for Research Resources to MB. Medical Scientist Training Program at the University of Wisconsin (T32GM08692) to JAL. NIH/NIDDK K08DK083442 to DBD.