Does GIP have therapeutic potential for the treatment of human diabetes? A number of small but important human studies suggested that the β cell response to GIP may be diminished or markedly attenuated in some but not all subjects with type 2 diabetes. For example see Effect of porcine gastric inhibitory polypeptide on beta-cell function in type I and type II diabetes mellitus. Metabolism. 1987 Jul;36(7):677-82 and Glucose dependent insulinotropic polypeptide (GIP) infused intravenously is insulinotropic in the fasting state in type 2 (non-insulin dependent) diabetes mellitus. Horm Metab Res. 1989 Jan;21(1):23-6. and Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993 Jan;91(1):301-7. and The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7-37) in normal and diabetic subjects. Regul Pept. 1994 Apr 14;51(1):63-74 and The effects of glucose-dependent insulinotropic polypeptide infused at physiological concentrations in normal subjects and type 2 (non-insulin-dependent) diabetic patients on glucose tolerance and B-cell secretion. Diabetologia. 1987 Sep;30(9):707-12
Comparison of the actions of infused GLP-1 and GIP in human subjects with type 2 diabetes irrespective of the etiology of the disease demonstrates that although the initial early phase of insulin secretion in response to GIP is preserved in diabetic subjects, the later phase from 20-120 minutes is characterized by a completely defective insulin response to GIP, even when higher concentrations of GIP are infused in study subjects, whereas the insulin secretory response to GLP-1 is preserved. See Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients. Diabetologia. 2002 Aug;45(8):1111-9 and The pathophysiology of diabetes involves a defective amplification of the late-phase insulin response to glucose by glucose-dependent insulinotropic polypeptide-regardless of etiology and phenotype. J Clin Endocrinol Metab. 2003 Oct;88(10):4897-903
The loss of GIP responsivity in human subjects may not simply be a reflection of the diabetic state. Studies of "normal" first degree relatives of human patients with type 2 diabetes revealed a significant defect in GIP-stimulated insulin secretion compared to control subjects. Hence, it seems likely that diminished GIP responsivity may be one predisposing genetic factor that contributes to diminished β cell function and the development of clinical glucose intolerance and ultimately, diabetes. See Reduced Insulinotropic Effect of Gastric Inhibitory Polypeptide in First-Degree Relatives of Patients With Type 2 Diabetes. Diabetes. 2001 Nov;50(11):2497-2504.
Nevertheless, there remains interest in the possibility that GIP analogues resistant to DP IV may exhibit therapeutic potential, as described in NH2-terminally modified gastric inhibitory polypeptide exhibits amino-peptidase resistance and enhanced antihyperglycemic activity. Diabetes. 1999 Apr;48(4):758-65. Furthermore, improvement of glycemic control following treatment with a sulfonylurea, glyburide, for 4 weeks, was associated with improvement in the acute insulinotropic response to GIP administration in 5 subjects as described in The effect of glyburide on beta-cell sensitivity to glucose-dependent insulinotropic polypeptide. Diabetes Care. 1993 Jan;16(1):110-4.
GIP action has also been studied in women with a history of gestational diabetes. Both GLP-1 and GIP secretion were normal in women with a history of GDM, the insulin secretory response to GIP administration was similar and fairly normal after GIP bolus administration or during the hyperglycaemic clamp experiment. Hence in this subset of diabetes, there does not appear to be evidence for loss of GIP responsivity as an early defect in women with GDM who frequently progress to DM. See Secretion of incretin hormones and the insulinotropic effect of gastric inhibitory polypeptide in women with a history of gestational diabetes. Diabetologia. 2005 Jul 12; [Epub ahead of print]