Normal glucose tolerance is maintained by a balance between insulin secretion and insulin action to enhance glucose disposal and regulate glucose output. In normal individuals basal and postprandial insulinemia increases so that glycemia does not exceed the normal range at basal and with meals. This compensation is due to upregulation of beta cell sensitivity to secretagogues, as well as downregulation of first-pass liver insulin clearance. Impaired glucose tolerance results when there is inadequate compensation for insulin resistance, and as this dysfunction progresses, diabetes develops. The precise mechanisms by which resistance results in beta-cell upregulation are not known. We are examining several mechanisms which may play a role in hyperinsulinemic compensation for insulin resistance. We exploit the isocaloric or hypercaloric fat-fed dog model, which develops visceral adiposity, insulin resistance and a well-defined pattern of compensation. We will determine whether postprandial or nocturnal glucose or free fatty acids explain upregulation of beta-cell function. We will counter increases in postprandial nutrients with pharmacological agents (acarbose and/or metformin). We examine the relationship between cortisol and growth hormone and metabolic compensation, and disrupt the secretion/action of these hormones with antagonists infused systemically or into the third ventricle of the brain. We consider whether gastrointestinal peptide GLP-1 is an important mediator of the compensatory response to insulin resistance. We hypothesize that GLP-1 is stimulated in the fat-fed model and acts via specific receptors in the portal vein. The putative GLP-1 reflex will be blocked by denervation of the portal vein, or with portal infusion of GLP- 1 antagonists. We will examine whether portal GLP-1 plays a vital role in the putative action of the peptide to upregulate islets in the insulin resistant state. Failure of """"""""compensatrins"""""""" to upregulate may be the earliest change in the pathogenesis of Type 2 diabetes. Identification of the origin and metabolic actions of such molecules should lead to more accurate identification of those at risk for diabetes, and allow for prevention of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK029867-21A1
Application #
6573309
Study Section
Metabolism Study Section (MET)
Program Officer
Laughlin, Maren R
Project Start
1981-08-01
Project End
2007-11-30
Budget Start
2003-02-01
Budget End
2003-11-30
Support Year
21
Fiscal Year
2003
Total Cost
$469,755
Indirect Cost
Name
University of Southern California
Department
Physiology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Broussard, Josiane L; Bergman, Richard N; Bediako, Isaac Asare et al. (2018) Insulin Access to Skeletal Muscle is Preserved in Obesity Induced by Polyunsaturated Diet. Obesity (Silver Spring) 26:119-125
Woolcott, Orison O; Bergman, Richard N (2018) Relative fat mass (RFM) as a new estimator of whole-body fat percentage ? A cross-sectional study in American adult individuals. Sci Rep 8:10980
Santaren, Ingrid D; Watkins, Steven M; Liese, Angela D et al. (2017) Individual serum saturated fatty acids and markers of chronic subclinical inflammation: the Insulin Resistance Atherosclerosis Study. J Lipid Res 58:2171-2179
Morton, Gregory J; Muta, Kenjiro; Kaiyala, Karl J et al. (2017) Evidence That the Sympathetic Nervous System Elicits Rapid, Coordinated, and Reciprocal Adjustments of Insulin Secretion and Insulin Sensitivity During Cold Exposure. Diabetes 66:823-834
Piccinini, Francesca; Polidori, David C; Gower, Barbara A et al. (2017) Hepatic but Not Extrahepatic Insulin Clearance Is Lower in African American Than in European American Women. Diabetes 66:2564-2570
Polidori, David C; Bergman, Richard N; Chung, Stephanie T et al. (2016) Hepatic and Extrahepatic Insulin Clearance Are Differentially Regulated: Results From a Novel Model-Based Analysis of Intravenous Glucose Tolerance Data. Diabetes 65:1556-64
Scarlett, Jarrad M; Rojas, Jennifer M; Matsen, Miles E et al. (2016) Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents. Nat Med 22:800-6
Iyer, Malini S; Bergman, Richard N; Korman, Jeremy E et al. (2016) Renal Denervation Reverses Hepatic Insulin Resistance Induced by High-Fat Diet. Diabetes 65:3453-3463
Broussard, Josiane L; Castro, Ana V B; Iyer, Malini et al. (2016) Insulin access to skeletal muscle is impaired during the early stages of diet-induced obesity. Obesity (Silver Spring) 24:1922-8
Lee, C Christine; Watkins, Steve M; Lorenzo, Carlos et al. (2016) Branched-Chain Amino Acids and Insulin Metabolism: The Insulin Resistance Atherosclerosis Study (IRAS). Diabetes Care 39:582-8

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