Sustained hyperglycemia from diabetes causes catastrophic damage to many organs and tissues. An emerging point of view is focused on the rise in blood glucose following a meal. These blood glucose levels can be very high, and the peak concentration is more predictive of end organ damage in diabetes than the more commonly measured fasting glucose levels. Complex physiological mechanisms exist to specifically handle the post-meal glucose load, and a breakdown in these mechanisms causes diabetes. The long term goal of this study is to understand the post-meal regulation of glucose stimulated insulin secretion from pancreatic beta-islet cells. Glucokinase (GK) sets the rate of insulin secretion, and acute post-translational regulation of GK through interaction with nitric oxide synthase (NOS) and reaction with nitric oxide have recently been proposed. However, the mechanisms that control GK interaction with NOS and the physiological role of GK regulation by nitric oxide are not understood.
Specific Aim 1 will quantify the effect of nitrosylation on GK kinetics.
Specific Aim 2 will use a domain swapping strategy to identify the sequence elements in GK essential to complex formation with NOS.
Specific Aim 3 will identify cellular mechanisms used to control GK activation on secretory granules and Specific Aim 4 will test the hypothesis that regulation of GK by NOS is utilized for positive regulation of glucose-stimulated insulin secretion by a known post-meal incretin hormone, glucagon-like peptide 1. These studies will be accomplished using biochemical methods and fluorescence imaging techniques. This research will further understanding of the mechanisms that regulate nutrient-stimulated insulin secretion and are particularly relevant to understanding the pathogenesis of diabetes, since dysfunctional insulin secretion is one of the central abnormalities associated with type 2 diabetes.

Public Health Relevance

Insulin is secreted from the pancreas in response to rising blood glucose levels, and the strength of the secretory response is controlled by hormones. This study will gather information relating to the mechanisms that hormones use to control the rate of insulin secretion, and determine the extent that dysfunction of a particular mechanism contributes to a specific genetic type of diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK077140-05
Application #
8288794
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Appel, Michael C
Project Start
2008-08-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$294,030
Indirect Cost
$98,010
Name
University of Maryland Baltimore
Department
Physiology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Markwardt, Michele L; Seckinger, Kendra M; Rizzo, Mark A (2016) Regulation of Glucokinase by Intracellular Calcium Levels in Pancreatic β Cells. J Biol Chem 291:3000-9
Rizzo, Mark A (2016) Emptying the Pool: Modular Insulin Secretion From the Pancreas. Diabetes 65:542-4
Desmond, Patrick F; Muriel, Joaquin; Markwardt, Michele L et al. (2015) Identification of Small Ankyrin 1 as a Novel Sarco(endo)plasmic Reticulum Ca2+-ATPase 1 (SERCA1) Regulatory Protein in Skeletal Muscle. J Biol Chem 290:27854-67
Costantini, Lindsey M; Baloban, Mikhail; Markwardt, Michele L et al. (2015) A palette of fluorescent proteins optimized for diverse cellular environments. Nat Commun 6:7670
Mauban, Joseph R H; Fairfax, Seth T; Rizzo, Mark A et al. (2014) A method for noninvasive longitudinal measurements of [Ca2+] in arterioles of hypertensive optical biosensor mice. Am J Physiol Heart Circ Physiol 307:H173-81
Mauban, Joseph R H; Zacharia, Joseph; Zhang, Jin et al. (2013) Vascular tone and Ca(2+) signaling in murine cremaster muscle arterioles in vivo. Microcirculation 20:269-77
Haataja, Leena; Snapp, Erik; Wright, Jordan et al. (2013) Proinsulin intermolecular interactions during secretory trafficking in pancreatic β cells. J Biol Chem 288:1896-906
Geraedts, Maartje C P; Takahashi, Tatsuyuki; Vigues, Stephan et al. (2012) Transformation of postingestive glucose responses after deletion of sweet taste receptor subunits or gastric bypass surgery. Am J Physiol Endocrinol Metab 303:E464-74
Markwardt, Michele L; Nkobena, Andongfac; Ding, Shi-Ying et al. (2012) Association with nitric oxide synthase on insulin secretory granules regulates glucokinase protein levels. Mol Endocrinol 26:1617-29
Gade, Padmaja; Ramachandran, Girish; Maachani, Uday B et al. (2012) An IFN-γ-stimulated ATF6-C/EBP-β-signaling pathway critical for the expression of Death Associated Protein Kinase 1 and induction of autophagy. Proc Natl Acad Sci U S A 109:10316-21

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