The basic aim of this grant proposal is to define and validate non-invasive techniques which allow the secretion and hepatic extraction of insulin to be accurately quantitated from peripheral C-peptide and insulin concentrations in human subjects. Insulin secretion rates will be derived from peripheral C-peptide concentrations by using a two compartment mathematical model to analyze the peripheral concentrations of C-peptide. Each subject will receive an intravenous bolus injection of biosynthetic human C-peptide and model parameters will be individually derived from the resulting decay curve. The secretion rate calculations will be based on individual model parameters. Alternative methods of deriving the post hepatic delivery rate of insulin will be compared in conscious mongrel dogs. Specific studies in dogs will compare hepatic extraction calculated as the difference between the secretion and the post hepatic delivery of the hormone with direct measurements based on fluxes of insulin across the liver. Experiments will be performed to determine if the conclusions of the dog studies can be applied to humans. New approaches to studying the effect of oral glucose and mixed meals on the peripheral clearance of insulin will be examined. These studies will involve the infusion of pork insulin as a non- iodinated tracer of human insulin and pork and human insulin will be separated by high pressure liquid chromatography. The accuracy with which urinary C-peptide reflects the secretion rate of insulin will be examined by determining the proportion of secreted C-peptide which is excreted unchanged in the urine. The reproducibility of this measure will be defined and the effects of changes in the plasma concentration of C- peptide and the ingestion of meals on urinary C-peptide clearance will be examined. Finally these techniques will be applied to a series of clinical studies in which the secretion and hepatic extraction of insulin will be studied in normal volunteers, obese subjects and patients with Type II diabetes. It is anticipated that the work performed in the next funding period will lead to improvements in the accuracy with which the secretion and hepatic extraction of insulin can be estimated in clinical studies. The use of well validated and quantitatively accurate approaches to studying these two processes should greatly enhance our understanding of the physiology of insulin secretion and its abnormalities which occur in obesity, diabetes and other disease states.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Metabolism Study Section (MET)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Chicago
Schools of Medicine
United States
Zip Code
Sun, Juan; Mao, Li-Qun; Polonsky, Kenneth S et al. (2016) Pancreatic ?-Cell Death due to Pdx-1 Deficiency Requires Multi-BH Domain Protein Bax but Not Bak. J Biol Chem 291:13529-34
Ren, Decheng; Sun, Juan; Mao, Liqun et al. (2014) BH3-only molecule Bim mediates ?-cell death in IRS2 deficiency. Diabetes 63:3378-87
Ren, Decheng; Sun, Juan; Wang, Changzheng et al. (2014) Role of BH3-only molecules Bim and Puma in ?-cell death in Pdx1 deficiency. Diabetes 63:2744-50
Pedersen, Morten Gram; Mosekilde, Erik; Polonsky, Kenneth S et al. (2013) Complex patterns of metabolic and Ca²? entrainment in pancreatic islets by oscillatory glucose. Biophys J 105:29-39
Klein, Samuel; Fabbrini, Elisa; Patterson, Bruce W et al. (2012) Moderate effect of duodenal-jejunal bypass surgery on glucose homeostasis in patients with type 2 diabetes. Obesity (Silver Spring) 20:1266-72
Reeds, Dominic N; Patterson, Bruce W; Okunade, Adewole et al. (2011) Ginseng and ginsenoside Re do not improve ?-cell function or insulin sensitivity in overweight and obese subjects with impaired glucose tolerance or diabetes. Diabetes Care 34:1071-6
Villareal, Dennis T; Robertson, Heather; Bell, Graeme I et al. (2010) TCF7L2 variant rs7903146 affects the risk of type 2 diabetes by modulating incretin action. Diabetes 59:479-85
Wice, Burton M; Wang, Songyan; Crimmins, Dan L et al. (2010) Xenin-25 potentiates glucose-dependent insulinotropic polypeptide action via a novel cholinergic relay mechanism. J Biol Chem 285:19842-53
Cheverud, James M; Fawcett, Gloria L; Jarvis, Joseph P et al. (2010) Calpain-10 is a component of the obesity-related quantitative trait locus Adip1. J Lipid Res 51:907-13
Fujimoto, Kei; Chen, Yun; Polonsky, Kenneth S et al. (2010) Targeting cyclophilin D and the mitochondrial permeability transition enhances beta-cell survival and prevents diabetes in Pdx1 deficiency. Proc Natl Acad Sci U S A 107:10214-9

Showing the most recent 10 out of 120 publications