A GIP receptor agonist exhibits beta-cell anti-apoptotic actions in rat models of diabetes resulting in improved beta-cell function and glycemic control

The gastrointestinal hormone GIP promotes pancreatic islet function and exerts pro-survival actions on cultured beta-cells. However, GIP also promotes lipogenesis, thus potentially restricting its therapeutic use. The current studies evaluated the effects of a truncated GIP analog, D-Ala(2)-GIP(1-30...

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Bibliographic Details
Published in:PloS one 2010-03, Vol.5 (3), p.e9590-e9590
Main Authors: Widenmaier, Scott B, Kim, Su-Jin, Yang, Gary K, De Los Reyes, Thomas, Nian, Cuilan, Asadi, Ali, Seino, Yutaka, Kieffer, Timothy J, Kwok, Yin Nam, McIntosh, Christopher H S
Format: Article
Language:English
Subjects:
3T3 Cells
Adipocytes
Adipocytes - cytology
Animal models
Animals
Apoptosis
Apoptosis Regulatory Proteins - chemistry
Body weight
C-Terminus
Cell Biology/Cellular Death and Stress Responses
Cell culture
Cell survival
Diabetes and Endocrinology/Obesity
Diabetes and Endocrinology/Type 2 Diabetes
Diabetes mellitus
Diabetes Mellitus, Experimental - drug therapy
Gastroenterology and Hepatology/Pancreas
Glucose
Glucose - metabolism
Glucose tolerance
Glucose Tolerance Test
Homeostasis
In vivo methods and tests
Insulin
Insulin resistance
Insulin secretion
Insulin-Secreting Cells - metabolism
Lipase
Lipogenesis
Lipoprotein lipase
Mice
Mice, Inbred C57BL
Mice, Knockout
Obesity
Pancreas
Proteins
Rats
Rats, Zucker
Receptors, Gastrointestinal Hormone - agonists
Receptors, Gastrointestinal Hormone - chemistry
Rodents
Secretion
Selectivity
Streptozocin
Survival
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Summary:The gastrointestinal hormone GIP promotes pancreatic islet function and exerts pro-survival actions on cultured beta-cells. However, GIP also promotes lipogenesis, thus potentially restricting its therapeutic use. The current studies evaluated the effects of a truncated GIP analog, D-Ala(2)-GIP(1-30) (D-GIP(1-30)), on glucose homeostasis and beta-cell mass in rat models of diabetes. The insulinotropic and pro-survival potency of D-GIP(1-30) was evaluated in perfused pancreas preparations and cultured INS-1 beta-cells, respectively, and receptor selectivity evaluated using wild type and GIP receptor knockout mice. Effects of D-GIP(1-30) on beta-cell function and glucose homeostasis, in vivo, were determined using Lean Zucker rats, obese Vancouver diabetic fatty rats, streptozotocin treated rats, and obese Zucker diabetic fatty rats, with effects on beta-cell mass determined in histological studies of pancreatic tissue. Lipogenic effects of D-GIP(1-30) were evaluated on cultured 3T3-L1 adipocytes. Acutely, D-GIP(1-30) improved glucose tolerance and insulin secretion. Chronic treatment with D-GIP(1-30) reduced levels of islet pro-apoptotic proteins in Vancouver diabetic fatty rats and preserved beta-cell mass in streptozotocin treated rats and Zucker diabetic fatty rats, resulting in improved insulin responses and glycemic control in each animal model, with no change in body weight. In in vitro studies, D-GIP(1-30) exhibited equivalent potency to GIP(1-42) on beta-cell function and survival, but greatly reduced action on lipoprotein lipase activity in 3T3-L1 adipocytes. These findings demonstrate that truncated forms of GIP exhibit potent anti-diabetic actions, without pro-obesity effects, and that the C-terminus contributes to the lipogenic actions of GIP.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0009590