Type 2 diabetes is characterized by insulin resistance and disordered beta-cell function, especially a defect in glucose-stimulated insulin-secretion. Insulin receptors and signaling proteins are found within the beta-cells themselves. Recent evidence in rodents suggests the insulin signaling pathway is functional in islets and is important for glucose sensing. The physiologic role of insulin signaling within beta-cells in humans remains unknown. Our preliminary studies demonstrate that in healthy humans beta-cells are insulin sensitive tissues and raising circulating insulin levels by exogenous insulin administration can enhance glucose induced insulin secretion. We hypothesize that dysfunctional insulin signaling, i.e. insulin resistance, at the level of the beta-cell may be one mechanism underlying blunted insulin secretion in persons with type 2 diabetes and insulin resistant syndromes, which would be manifest as reduced insulin potentiation of glucose induced insulin secretion. We propose to further our understanding of insulin's effects on the beta-cell in healthy persons and to determine whether insulin potentiation of glucose induced insulin secretion is blunted in persons with type 2 diabetes. We demonstrate insulin potentiates glucose induced insulin secretion in the setting of suppression of circulating FFA. Several studies suggest an essential role for FFA in both basal and glucose stimulated insulin secretion, while other studies suggest that excess FFA are lipotoxic to the a-cell. To test whether replacement of FFA will enhance insulin potentiation of glucose induced insulin secretion, or whether the response is secondary to the suppression of circulating FFA, we will evaluate the role of free fatty acids in insulin potentiation of glucose induced insulin production. We demonstrate a marked increase in glucose disposal rates with dextrose administration following insulin pre-exposure. We will evaluate whether this occurs within hepatic or muscle tissues using positron emission tomography imaging. To better understand the molecular pathways underlying these processes, mechanistic studies will be conducted in control and insulin receptor deficient islets, in vitro. These studies may provide a unifying explanation linking the combined defects in insulin secretion and action that underlie type 2 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK070648-02S1
Application #
7266103
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Abraham, Kristin M
Project Start
2005-09-30
Project End
2009-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
2
Fiscal Year
2006
Total Cost
$74,733
Indirect Cost
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
Halperin, Florencia; Lopez, Ximena; Manning, Raquel et al. (2012) Insulin augmentation of glucose-stimulated insulin secretion is impaired in insulin-resistant humans. Diabetes 61:301-9
Goldfine, A B; Kulkarni, R N (2012) Modulation of ýý-cell function: a translational journey from the bench to the bedside. Diabetes Obes Metab 14 Suppl 3:152-60
Goldfine, Allison B; Gerwien, Robert W; Kolberg, Janice A et al. (2011) Biomarkers in fasting serum to estimate glucose tolerance, insulin sensitivity, and insulin secretion. Clin Chem 57:326-37
Pihlajamäki, Jussi; Lerin, Carles; Itkonen, Paula et al. (2011) Expression of the splicing factor gene SFRS10 is reduced in human obesity and contributes to enhanced lipogenesis. Cell Metab 14:208-18
Jin, Wanzhu; Goldfine, Allison B; Boes, Tanner et al. (2011) Increased SRF transcriptional activity in human and mouse skeletal muscle is a signature of insulin resistance. J Clin Invest 121:918-29
Lopez, Ximena; Cypess, Aaron; Manning, Raquel et al. (2011) Exogenous insulin enhances glucose-stimulated insulin response in healthy humans independent of changes in free fatty acids. J Clin Endocrinol Metab 96:3811-21
Patti, M E; Goldfine, A B (2010) Hypoglycaemia following gastric bypass surgery--diabetes remission in the extreme? Diabetologia 53:2276-9
Bouche, Clara; Lopez, Ximena; Fleischman, Amy et al. (2010) Insulin enhances glucose-stimulated insulin secretion in healthy humans. Proc Natl Acad Sci U S A 107:4770-5
Christen, Thomas; Sheikine, Yuri; Rocha, Viviane Z et al. (2010) Increased glucose uptake in visceral versus subcutaneous adipose tissue revealed by PET imaging. JACC Cardiovasc Imaging 3:843-51
Pihlajamäki, Jussi; Boes, Tanner; Kim, Eun-Young et al. (2009) Thyroid hormone-related regulation of gene expression in human fatty liver. J Clin Endocrinol Metab 94:3521-9

Showing the most recent 10 out of 13 publications