Obesity, diabetes, and infection are inflammatory diseases in which glucose disposal is impaired, necessitating compensatory hyperinsulinemia and/or hyperglycemia. The liver has a unique adaptive response, markedly increasing its capacity to take up glucose during increases in glucose availability. Common features of inflammatory diseases are 1) the inability of the liver to adapt to increases in glucose availability and 2) inappropriate glucagon secretion. In each setting glucagon secretion is not suppressed and may be elevated. In individuals with diabetes the insulin response to nutrient delivery is blunted, which may also limit the adaptive response. The failure of the liver to adapt shifts the responsibility of glucose removal to peripheral tissues. Moreover our data suggest that glucagon impairs glucose uptake by peripheral tissues. When accompanied by underlying insulin resistance and pancreatic dysfunction, the risk of developing hyperglycemia increases. The present proposal examines the following questions: Does glucagon play an essential role in facilitating the liver's response to increased glucose availability? What is the mechanism by which glucagon impairs muscle glucose uptake? How does inflammation alter the roles insulin, glucose and glucagon play in modulating glucose disposal? Experiments will be carried out in chronically catheterized conscious dogs. Hepatic glucose metabolism (unidirectional hepatic glucose uptake and production, glucose oxidation) and hindlimb will be assessed using a combination of tracer and arterio-venous difference techniques. Our model provides the unique ability to directly examine the role that individual organs (liver and muscle) play in modulation of nutrient disposition and the factors responsible for the impairment in glucose disposal and the mechanisms by which they occur. Thus, the goal of these studies is to determine the impact insulin and glucagon have in chronically controlling the disposal of glucose by the liver and peripheral tissues and how inflammation disrupts this adaptation. These results would help determine why the liver fails to appropriately adapt when exposed to a continuous plethora of nutrients in individuals with obesity and diabetes or infection. Our goal is that with this knowledge we will be able to develop better treatment strategies to limit hyperglycemia in insulin resistant individuals.
Obesity, diabetes and infection are inflammatory diseases that cause marked alterations in glucose metabolism. Our goal is to understand why inflammation and the excess glucagon secretion that accompanies inflammation alters glucose metabolism. We hope that by determining the mechanisms for the disturbances in glucose metabolism approaches in addition to infusing insulin can be developed to help maintain normal glucose concentrations.
|Barnes, Tammy M; Otero, Yolanda F; Elliott, Amicia D et al. (2014) Interleukin-6 amplifies glucagon secretion: coordinated control via the brain and pancreas. Am J Physiol Endocrinol Metab 307:E896-905|
|Wei, Kevin; Piecewicz, Stephanie M; McGinnis, Lisa M et al. (2013) A liver Hif-2*-Irs2 pathway sensitizes hepatic insulin signaling and is modulated by Vegf inhibition. Nat Med 19:1331-7|
|Tweedell, Andrea; Mulligan, Kimberly X; Martel, Josie E et al. (2011) Metabolic response to endotoxin in vivo in the conscious mouse: role of interleukin-6. Metabolism 60:92-8|
|Chen, Sheng-Song; Zhang, Yiqun; Santomango, Tammy S et al. (2007) Glucagon chronically impairs hepatic and muscle glucose disposal. Am J Physiol Endocrinol Metab 292:E928-35|