Increased Islet Expression of Somatostatin and Glucagon in Male Rats with Insulin-Dependent Type 2 Diabetes

Background: Pancreatic islet remodelling in type 1 diabetes increases somatostatin (SST) expression, which inhibits glucagon counterregulation to hypoglycemia. Here, we characterized islet morphology and hormone composition in a rodent model of insulin-deficient type 2 diabetes (T2D) . Methods: Hypoinsulinemic T2D was induced in 8-9-week-old, male, Sprague-Dawley rats (n=4) via 3 weeks of high-fat feeding and a low-dose injection of streptozotocin (STZ; 35 mg/kg) . After 2 weeks of basal insulin treatment, pancreas tissue was extracted from T2D and healthy control (n=5) rats for immunohistochemical staining of representative islets. Results: Fasted plasma C-peptide levels of hyperglycemic (24.8±3.3 mmol/l) T2D rats were reduced by ∼44% (624±64 vs. 1107±121 pmol/l; p<0.001) , while glucagon was unchanged (75±31 vs. 98±39 pg/ml) . Fractional islet area of glucagon and SST were elevated by 40% (21±15 vs. 15±10%; p<0.001) and 83% (11±8 vs. 6±5%; p<0.001) , respectively, as compared to control rats (Figure) , which was most pronounced in small and medium-sized islets. Conclusions: Fractional area expression of glucagon and SST increased per islet in insulin-treated rats with advanced T2D. These findings may help account for the increase in SST signaling that underscores defective glucagon counterregulation to hypoglycemia in insulin-deficient diabetic states. Disclosure E. G. Hoffman: None. S. C. Atherley: None. N. Akbarian: None. N. Dsouza: None. R. Liggins: Employee; Zucara Therapeutics, Stock/Shareholder; Zucara Therapeutics. M. Riddell: Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Consultant; Eli Lilly and Company, Jaeb Center for Health Research, Speaker’s Bureau; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk. Funding GlycoNet