Poster Session 2 - E10
1Alexandre Martchenko, 1Matthew Clemenzi, Gurges,1Patrick, 1,2Patricia L. Brubaker
1 Department of Physiology, University of Toronto; 2 Department of Medicine, University of Toronto
Glucagon-like peptide-1 (GLP-1) is an intestinal incretin hormone released by the L cell in response to nutrient intake, whose main action is to enhance glucose-stimulated insulin secretion. Over evolutionary time, organisms have developed circadian rhythms in order to coordinate digestion, absorption, and utilization of nutrients in association with pre-defined environmental changes such as the light-dark cycle. We have recently identified a circadian pattern of GLP-1 secretion that closely parallels the pattern in food intake and insulin secretion, suggesting that GLP-1 may be a key link in the metabolic clock. Obesogenic diets are known disruptors of circadian clocks and our previous studies in rats as well as in vitro using murine cells, have shown that the high-fat/high-sucrose western diet (WD), and its major component the saturated fatty acid palmitate, impair L cell clock function and the GLP-1 secretory rhythm at peak and trough time-points. However, a comprehensive understanding of the role of circadian GLP-1 secretion in maintaining metabolic homeostasis under conditions of WD-induced metabolic clock dysfunction remains elusive. Therefore, I hypothesize that diurnal GLP-1 secretion is essential to maintaining glucose homeostasis throughout the 24-hour day under diet-induced circadian disruption. C57Bl/6J mice were fed either regular chow (RC) or WD for 16 weeks to induce obesity, as characterized by increased body weight (p<0.001), subcutaneous fat (p<0.01), and visceral fat (p<0.001). Furthermore, when 24-hour energy intake patterns were measured, RC animals displayed a rhythm peaking in the middle of the dark/active period at zeitgeber time 16 (ZT; hours after lights on) while WD-fed animals exhibited a shifted pattern, peaking 3 hours earlier at ZT13. Fasting blood glucose in both RC and WD-fed animals peaked at ZT6; however, WD-fed animals had significantly higher glycemia overall (p<0.01-0.001). This was accompanied by fasting hyperinsulinemia (p<0.05-0.01) but no difference in fasting levels of GLP-1. Insulin tolerance followed a 24-hour rhythm in both RC and WD-fed animals; however, there was a shift in peak sensitivity which occurred at the onset of the dark/active period (ZT12) in the normal mice but was during the light/rest phase (ZT9) in the WD-fed animals. Furthermore, WD-fed animals exhibited insulin resistance between ZT10-22 (p<0.05-0.01) corresponding to their fasting hyperglycemia and insufficient insulinemia throughout these times of the day. Oral glucose tolerance tests were performed on groups of 4-hour fasted mice every 4 hours during the 24-hour day, with no impairment in glycemic responses being observed in the WD-fed animals. Both insulin and GLP-1 secretion followed a 24-hour period in response to oral glucose in RC mice; in contrast, WD-animals had significantly elevated responses in insulin (p<0.05-0.01) and GLP-1 (p<0.05-0.01) but lost their rhythmic secretory patterns. Interestingly, when glucose was administered by the intraperitoneal route, which bypasses the effects of gut incretin hormones, there was an impairment in glycemic tolerance (p<0.05-0.001) throughout the 24-hour day and dampened insulin secretion (p<0.05) at several time points in the day in WD-fed animals. In combination, these data implicate the gut incretin hormone GLP-1 as an essential regulator of 24-hour glucose homeostasis. Furthermore, under conditions of diet-induced obesity the compensatory increase in GLP-1 secretion allows for elevated levels of insulin which are able to overcome whole-body insulin resistance and maintain normoglycemia and prevent the onset of type 2 diabetes. Therefore, understanding the normal rhythm of GLP-1 secretion, and how it is affected by time and diet, is crucial to the development of novel therapeutic strategies for the treatment and/or prevention of type 2 diabetes.