A constantly changing environment leads to challenges such as feast/famine cycles, puberty, pregnancy, and infection, which cause wide swings in the sensitivity of tissues to insulin. The healthy mammalian organism is able to compensate exquisitely, defending fasting and postprandial glucose. A major mechanism for this defense is hyperinsulinemic compensation. The latter concept reflects the appropriate increases in the fasting and postprandial blood insulin concentrations which accompany and compensate for insulin resistance. Failure of hyperinsulinemic compensation is an early sign of pre-Type 2 diabetes. Normal compensatory hyperinsulinemia can be due to either 1) increased pancreatic beta-cell function and/or 2) reduced metabolic clearance of insulin. We have obtained compelling evidence in normal animals that hyperinsulinemic compensation will occur without significant changes in arterial glucose at any hour of the day or night. The question arises, what mechanisms other than elevated glucose can contribute to the propensity of insulin to increase in the face of insulin resistance? Identification of these mechanisms will result in a deeper understanding of the pathogenesis of Type 2 diabetes. We propose to study three mechanisms for mediating hyperinsulinemic compensation.
Specific Aim 1 : We have demonstrated a powerful increase in plasma FFA levels during the night which is observed in fat-fed obese dogs. We will test the hypothesis that the "nocturnal surge" in FFA plays a causal role in hyperinsulinemic compensation during fat-feeding induced insulin resistance. Also, we will test whether the nocturnal surge in lipolysis is related to sympathetic innervation of the visceral fat depot in the dog.
Specific Aim 2 : We will examine the hypothesis that appearance of nutrients, including glucose, in the portal circulation during postprandial absorption is a necessary component of hyperinsulinemic compensation. We will test whether the effect of nutrient absorption is mediated by specific receptors for nutrients (or hormones) in the portal circulation.
Specific Aim 3 : We will consider the "positive feedback" hypothesis: An endogenous beta-cell secretory "trigger" excites an early insulin response;the resulting modest hyperinsulinemia then acts on the 2-cells directly to sensitize beta-cells to further stimulation by nutrients. The latter results in more plasma insulin, which in turn further sensitizes the beta-cells, and so on - resulting in the full-blown hyperinsulinemic response to insulin resistance. Understanding the physiological underpinnings of normal compensation for insulin resistance will provide a firm basis for studying failure of compensation-part and parcel of development of Type 2 diabetes.

Public Health Relevance

Significance. Type 2 diabetes mellitus is a growing problem in the U.S. and throughout the world. It is caused by the pancreas'failure to release enough of the hormone insulin when the effects of insulin are reduced to due obesity or other factors. These experiments will teach us the underlying causes of why the pancreas knows to make more insulin in the obese person, and why it may lose that ability in some people, increasing the possibility of their getting diabetes. The studies will unearth new approaches to predict, prevent, treat and possibly cure Type 2 diabetes mellitus.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
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Laughlin, Maren R
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Cedars-Sinai Medical Center
Los Angeles
United States
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Castro, Ana V B; Woolcott, Orison O; Iyer, Malini S et al. (2015) Increase in visceral fat per se does not induce insulin resistance in the canine model. Obesity (Silver Spring) 23:105-11
Ionut, Viorica; Castro, Ana Valeria B; Woolcott, Orison O et al. (2014) Hepatic portal vein denervation impairs oral glucose tolerance but not exenatide's effect on glycemia. Am J Physiol Endocrinol Metab 307:E644-52
Ionut, Viorica; Castro, Ana Valeria B; Woolcott, Orison O et al. (2014) Essentiality of portal vein receptors in hypoglycemic counterregulation: direct proof via denervation in male canines. Endocrinology 155:1247-54
Woolcott, Orison O; Castillo, Oscar A; Gutierrez, Cesar et al. (2014) Inverse association between diabetes and altitude: a cross-sectional study in the adult population of the United States. Obesity (Silver Spring) 22:2080-90
Lee, C C; Lorenzo, C; Haffner, S M et al. (2013) The association of inflammatory and fibrinolytic proteins with 5 year change in insulin clearance: the Insulin Resistance Atherosclerosis Study (IRAS). Diabetologia 56:112-20
Kolka, Cathryn M; Bergman, Richard N (2013) The endothelium in diabetes: its role in insulin access and diabetic complications. Rev Endocr Metab Disord 14:13-9
Ionut, Viorica; Burch, Miguel; Youdim, Adrienne et al. (2013) Gastrointestinal hormones and bariatric surgery-induced weight loss. Obesity (Silver Spring) 21:1093-103
Ader, Marilyn; Stefanovski, Darko; Kim, Stella P et al. (2013) Variable hepatic insulin clearance with attendant insulinemia is the primary determinant of insulin sensitivity in the normal dog. Obesity (Silver Spring) :
Lee, C C; Lorenzo, C; Haffner, S M et al. (2013) Components of metabolic syndrome and 5-year change in insulin clearance - the Insulin Resistance Atherosclerosis Study. Diabetes Obes Metab 15:441-7
Stefanovski, Darko; Youn, Jang H; Rees, Matthew et al. (2012) Estimating hepatic glucokinase activity using a simple model of lactate kinetics. Diabetes Care 35:1015-20

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