Regulation of glucose homeostasis by Doc2b and Munc18 proteins.

dc.contributor.advisorThurmond, Debbie C.
dc.contributor.authorRamalingam, Latha
dc.contributor.otherElmendorf, Jeffrey S.
dc.contributor.otherMirmira, Raghavendra G.
dc.contributor.otherRoach, Peter J.
dc.date.accessioned2014-10-03T15:13:23Z
dc.date.available2014-10-03T15:13:23Z
dc.date.issued2014-01
dc.degree.date2014en_US
dc.degree.disciplineDepartment of Biochemistry & Molecular Biologyen
dc.degree.grantorIndiana Universityen_US
dc.degree.levelPh.D.en_US
dc.descriptionIndiana University-Purdue University Indianapolis (IUPUI)en_US
dc.description.abstractGlucose homeostasis is maintained through the coordinated actions of insulin secretion from pancreatic beta cells and insulin action in peripheral tissues. Dysfunction of insulin action yields insulin resistance, and when coupled with altered insulin secretion, results in type 2 diabetes (T2D). Exocytosis of intracellular vesicles, such as insulin granules and glucose transporter (GLUT4) vesicles is carried out by similar SNARE (soluble NSF attachment receptor) protein isoforms and Munc18 proteins. An additional regulatory protein, Doc2b, was implicated in the regulation of these particular exocytosis events in clonal cell lines, but relevance of Doc2b in the maintenance of whole body glucose homeostasis in vivo remained unknown. The objective of my doctoral work was to delineate the mechanisms underlying regulation of insulin secretion and glucose uptake by Doc2b in effort to identify new therapeutic targets within these processes for the prevention and/or treatment of T2D. Towards this, mice deficient in Doc2b (Doc2b-/- knockout mice) were assessed for in vivo alterations in glucose homeostasis. Doc2b knockout mice were highly susceptible to preclinical T2D, exhibiting significant whole-body glucose intolerance related to insulin secretion insufficiency as well as peripheral insulin resistance. These phenotypic defects were accounted for by defects in assembly of SNARE complexes. Having determined that Doc2b was required in the control over whole body glycemia in vivo, whether Doc2b is also limiting for these mechanisms in vivo was examined. To study this, novel Doc2b transgenic (Tg) mice were engineered to express ~3 fold more Doc2b exclusively in pancreas, skeletal muscle and fat tissues. Compared to normal littermate mice, Doc2b Tg mice had improved glucose tolerance, related to concurrent enhancements in insulin mumsecretion from beta cells and insulin-stimulated glucose uptake in the skeletal muscle. At the molecular level, Doc2b overexpression promoted SNARE complex assembly, increasing exocytotic capacities in both cellular processes. These results unveiled the concept that intentional elevation of Doc2b could provide a means of mitigating two primary aberrations underlying T2D development.en_US
dc.identifier.urihttps://hdl.handle.net/1805/5190
dc.identifier.urihttp://dx.doi.org/10.7912/C2/1877
dc.language.isoen_USen_US
dc.subjectDiabetesen_US
dc.subjectSNARE proteinsen_US
dc.subjectexocytosisen_US
dc.subject.lcshExocytosis -- Research -- Analysis -- Methodologyen_US
dc.subject.lcshBlood sugar -- Researchen_US
dc.subject.lcshDiabetes -- Pathophysiologyen_US
dc.subject.lcshDiabetes -- Researchen_US
dc.subject.lcshBlood sugar -- Analysisen_US
dc.subject.lcshHomeostasis -- Researchen_US
dc.subject.lcshInsulin resistanceen_US
dc.subject.lcshGlucoseen_US
dc.subject.lcshGlucose -- Synthesisen_US
dc.subject.lcshProteins -- Researchen_US
dc.subject.lcshProteins -- Metabolism -- Disordersen_US
dc.subject.lcshGluconeogenesisen_US
dc.subject.lcshTransgenic mice -- Researchen_US
dc.subject.lcshNon-insulin-dependent diabetesen_US
dc.subject.lcshPancreatic beta cellsen_US
dc.titleRegulation of glucose homeostasis by Doc2b and Munc18 proteins.en_US
dc.typeThesisen
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