3-LB: Effects of Sustained Somatostatin Receptor 2 Antagonism (SSTR2a) on Glycemia in Type 2 Diabetic (T2D) Male Rats—A Pilot Study

Abstract

Introduction: Somatostatin may be elevated in diabetes, which can reduce glucagon secretion at mealtimes and during hypoglycemia. In this pilot study, we investigated the effect of a sustained low-dose delivery of a novel SSTR2a (ZT-01), using a mini-osmotic pump, on oral glucose tolerance (OGT) and response to an insulin-induced hypoglycemia challenge in a T2D rat model. Methods: Male Sprague Dawley rats (n=4/5 per group) were placed on a high-fat diet (3 weeks) then injected with low-dose streptozotocin (35 mg/kg), inducing T2D. Basal bolus insulin was administered for 7 days (2-3 units/day) to maintain fed-state glycemia targeting 12-25 mmol/L, after which the rats were treated with ZT-01 (0.18 mg/day) or vehicle using implanted mini-osmotic pumps (Alzet). An OGT test on day 3 was followed by a hypoglycemic challenge (12U regular insulin) on day 5. Results: Drug and vehicle groups displayed similar glycemic levels in the fasted state and post oral glucose ingestion. Glycemia was also similar prior to insulin challenge and there was no difference in basal glucagon between groups, but SSTR2a treatment attenuated the drop in blood glucose after bolus insulin. Conclusion: Sustained exposure to low-dose SSTR2a does not appear to affect basal glucose or glucagon levels, nor affect the response to OGT but may improve the glucose response to insulin-induced hypoglycemia in this T2D model. Disclosure N. Aleali: None. N. C. D'souza: None. D. Shakeri: None. E. Simonson: None. R. Liggins: Employee; Zucara Therapeutics, Stock/Shareholder; Zucara Therapeutics. O. Chan: None. M. C. Riddell: Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Indigo Diabetes, Consultant; Lilly Diabetes, Eli Lilly and Company, Jaeb Center for Health Research, Speaker's Bureau; Dexcom, Inc., Novo Nordisk, Sanofi, Stock/Shareholder; Supersapiens, Zucara Therapeutics. Funding GlycoNet (CD-85); Zucara Therapeutics Inc.