Thirteen-lined ground squirrels (Ictidomys tridecemlineatus) enter hibernation as a survival strategy during extreme environmental conditions. Typical ground squirrel hibernation is characterized by prolonged periods of torpor with significantly reduced heart rate, blood pressure, and blood flow, interrupted every few weeks by brief interbout arousals (IBA) during which blood flow fluctuates dramatically. These physiological conditions should increase the risk of stasisinduced blood clots and myocardial ischemia. However, ground squirrels have adapted to survive repeated bouts of torpor and IBA without forming lethal blood clots or sustaining lethal ischemic myocardial damage. The purpose of this study was to determine if ground squirrels are resistant to thrombosis and myocardial ischemia during hibernation. Blood markers of coagulation, fibrinolysis, thrombosis, and ischemia, as well as histological markers of myocardial ischemia were measured throughout the annual hibernation cycle. Hibernating ground squirrels were also treated with isoprenaline to induce myocardial ischemia. Thrombin-antithrombin complex levels were significantly reduced (p < 0.05) during hibernation, while D-dimer level remained unchanged throughout the annual cycle both consistent with an antithrombotic state. During torpor the ground squirrels were in a hyperfibrinolytic state with an elevated ratio of tissue plasminogen activator complexed with plasminogen activator inhibitor to total plasminogen activator inhibitor (p < 0.05). Histological markers of myocardial ischemia were reversibly elevated during hibernation with no increase in markers of myocardial cell death in the blood. These data suggest that ground squirrels do not form major blood clots during hibernation through suppression of coagulation and a hyperfibrinolytic state. These animals also demonstrate myocardial resistance to ischemia.
Bile acid secretion increases significantly after Roux-in-Y gastric bypass and may play a role in weight loss after bariatric surgery. The acute intrajejunal-delivery or intra-rectal delivery of bile acids improves glucose metabolism. We aimed to study the effect of conjugated bile acids released on the ileo-colonic region (IC-CBAS) on glucose metabolism and body weight. In a placebo-controlled, double-blinded, randomized, 28-days trial, we studied the effect of IC-CBAS 500 mg BID on glucose metabolism, incretin hormones (GLP-1 and FGF-19), gastric emptying (scintigraphy) and weight loss in obese type 2 diabetic subjects (n=24 white patients, age=57±2 years, BMI=38.6±1.3 kg/m2, HbA1c=8.5±0.2%, fasting glucose 9.9±0.4 mmol/L). Participants were taking stable doses of DPP-4 inhibitors and metformin and were instructed to continue their current diet and exercise routine. Subjects underwent a meal challenge at baseline and at the end of the treatment period. The primary analyses compared treatment groups at the end of 28 days’ treatment using analysis of covariance models incorporating the corresponding baseline study value as a covariate. IC-CBAS significantly increases postprandial GLP-1 (mean p=0.04, AAB p=0.04), postprandial insulin (AAB p=0.04) and postprandial c-peptide (AAB p=0.01); and decreases fasting insulin (p=0.04) when compared to placebo. IC-CBAS also induced a numerically (but not statistically significantly) improvement in fasting glucose (delta -16 mg/dl), postprandial glucose (delta mean -14 mg/dl) and weight (delta -0.45±.4 kg) compared to placebo. There were no reported side effects, or dropouts; and no difference in FGF-19, gastric emptying or number of bowel movements. IC-CBAS 28-day treatment results in significant increase in GLP-1 and postprandial insulin, suggesting a beneficial role in incretins, insulin and glucose homeostasis.
Disclosure
G. Calderon Manrique: None. J. Davis: None. A.N. Bonis: None. D. Khemani: None. B. Gedulin: None. A. Vella: Research Support; Self; Novo Nordisk Inc., XOMA Corporation. Advisory Panel; Self; VTV Therapeutics, Bayer AG. M. Camilleri: None. A. Acosta: None.
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