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PKA activity in the pancreatic beta-...

Kaihara, Kelly Asako.

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PKA activity in the pancreatic beta--cell enhances insulin secretion and improves glycemic control.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	PKA activity in the pancreatic beta--cell enhances insulin secretion and improves glycemic control./
作者:	Kaihara, Kelly Asako.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2012,
面頁冊數:	152 p.
附註:	Source: Dissertation Abstracts International, Volume: 73-11(E), Section: B.
Contained By:	Dissertation Abstracts International73-11B(E).
標題:	Cellular biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3517160
ISBN:	9781267472540

PKA activity in the pancreatic beta--cell enhances insulin secretion and improves glycemic control.
Kaihara, Kelly Asako.

PKA activity in the pancreatic beta--cell enhances insulin secretion and improves glycemic control. - Ann Arbor : ProQuest Dissertations & Theses, 2012 - 152 p.

Source: Dissertation Abstracts International, Volume: 73-11(E), Section: B.

Thesis (Ph.D.)--The University of Chicago, 2012.

This project centers on a novel mouse model of pancreatic beta-cell protein kinase A (PKA) signaling. Activation of PKA in the beta-cell results in enhanced insulin secretion. At the time that this mouse model was generated in 2006, a new class of pharmacological agents had recently been approved for the treatment of Type 2 Diabetes Mellitus (T2DM). These drugs activated beta-cell PKA activity through glucagon-like peptide-1 (GLP-1) signaling to improve insulin secretion and impact positively on glycemic control. However, how much of the improvement in glycemic control was attributed to a beta-cell phenotype was confounded by the many off target effects of GLP-1 upon other tissues. Moreover, GLP-1 activates two downstream targets in the beta-cell through increases in 3',5'-cyclic monophosphate (cAMP) levels: PKA and cAMP-regulated guanine nucleotide exchange factor (cAMP-GEF) known as EPAC. Both have been implicated in the potentiation of insulin secretion however their relative contributions are contested within the field. At this point in time there existed no mouse model of altered beta-cell PKA activity. The overall goal of this project was to determine the sole effects of increased beta-cell PKA activity on insulin secretion at a physiological level. To accomplish this, a mouse model of beta-cell specific constitutively active PKA signaling was generated hereafter referred to as beta-C&agr;R mice. Results demonstrate that PKA activity enhanced both the acute and sustained phases of insulin secretion under hyperglycemic conditions, but after a single glucose challenge, only enhancement at the acute phase was observed. Moreover, beta-cell PKA activity changed the dynamics of insulin release that promoted a 'first burst' of insulin within 2 minutes of a glucose challenge that was not observed in control animals. It is well established that individuals that progress to T2DM show a reduction at the acute phase of insulin release. The novel phenotype in the beta-C&agr;R mice allowed for physiological studies that addressed the consequences of solely increasing the acute phase for regaining glucose control. The data show that increased insulin secretion at the acute phase not only improved glucose homeostasis throughout aging, but also reversed pre-established glucose intolerance, representing a novel strategy for the treatment of T2DM.

ISBN: 9781267472540Subjects--Topical Terms:

3172791
Cellular biology.

PKA activity in the pancreatic beta--cell enhances insulin secretion and improves glycemic control.
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