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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Widenmaier
Scott B
SB
Department of Cellular and Physiological Sciences and the Diabetes Research Group, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Kim
Su-Jin
SJ
Yang
Gary K
GK
De Los Reyes
Thomas
T
Nian
Cuilan
C
Asadi
Ali
A
Seino
Yutaka
Y
Kieffer
Timothy J
TJ
Kwok
Yin Nam
YN
McIntosh
Christopher H S
CH
D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D011924:Rats, Zucker; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists* / Q000737:chemistry
D051017:Apoptosis Regulatory Proteins; D011964:Receptors, Gastrointestinal Hormone; C041086:gastric inhibitory polypeptide receptor; D005947:Glucose