(Pro3) GIP (Rat)
A Specific GIP-R Antagonist

[D-Ala²] GIP
Resistance to DPIV

Chemical ablation of gastric inhibitory polypeptide receptor action by daily (Pro3)GIP administration improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure in obesity-related diabetes

Glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide [GIP]) is an important incretin hormone secreted by endocrine K-cells in response to nutrient ingestion. In this study, we investigated the effects of chemical ablation of GIP receptor (GIP-R) action on aspects of obesity-related diabetes using a stable and specific GIP-R antagonist, (Pro3)GIP. Young adult ob/ob mice received once-daily intraperitoneal injections of saline vehicle or (Pro3)GIP over an 11-day period. Nonfasting plasma glucose levels and the overall glycemic excursion (area under the curve) to a glucose load were significantly reduced (1.6-fold; P < 0.05) in (Pro3)GIP-treated mice compared with controls. GIP-R ablation also significantly lowered overall plasma glucose (1.4-fold; P < 0.05) and insulin (1.5-fold; P < 0.05) responses to feeding. These changes were associated with significantly enhanced (1.6-fold; P < 0.05) insulin sensitivity in the (Pro3)GIP-treated group. Daily injection of (Pro3)GIP reduced pancreatic insulin content (1.3-fold; P < 0.05) and partially corrected the obesity-related islet hypertrophy and beta-cell hyperplasia of ob/ob mice. These comprehensive beneficial effects of (Pro3)GIP were reversed 9 days after cessation of treatment and were independent of food intake and body weight, which were unchanged. These studies highlight a role for GIP in obesity-related glucose intolerance and emphasize the potential of specific GIP-R antagonists as a new class of drugs for the alleviation of insulin resistance and treatment of type 2 diabetes.

Gault VA, et al. Diabetes. 2005 Aug;54(8):2436-46.  

Yamada Y., et al. Diabetes 55:S86-S91, 2006

Effects of (Pro3)GIP on plasma glucose and insulin response to native GIP 4 h after administration. Tests were conducted 4 h after administration of (Pro3)GIP (25 nmol/kg body wt) or saline (0.9% NaCl) in 18-h–fasted ob/ob mice. Plasma glucose and insulin concentrations were measured before and after intraperitoneal administration of glucose (18 mmol/kg body wt) alone or in combination with native GIP (25 nmol/kg body wt). The incremental areas under the glucose or insulin curves (AUC) between 0 and 60 min are shown in the right panels. Values represent means ± SE for eight mice. *P < 0.05 and **P < 0.01 compared with saline group. Gault VA, et al. Diabetes. 2005 Aug;54(8):2436-46.		Scheme illustrating how the GIP-R antagonist, (Pro3)GIP, counters ß-cell hyperplasia, hyperinsulinemia, and insulin resistance leading to improved glucose intolerance and diabetes control. Possible longer-term direct actions of GIP on adipocyte function and fat stores suggested by studies in GIP-R knockout ob/ob mice have been omitted. Gault VA, et al. Diabetes. 2005 Aug;54(8):2436-46.
		Resistin secretion stimulated by [D-Ala2]GIP in WT and Gipr–/– mice. (A–C) Effect of 24 nmol/kg [D-Ala2]GIP or Ex-4 on resistin secretion in 10-week-old (A) WT, (B) Glp1r–/–, and (C) Gipr–/– mice following an oral glucose load (n = 5–15 per group). Mice were fasted overnight, after which PBS or peptide was administered immediately prior to oral glucose loading. Mice were euthanized at 45 minutes following peptide/glucose administration, and cardiac blood was obtained. *P < 0.05, ***P < 0.001 versus PBS and Ex4. Hansotia T et al. Clin. Invest. 117:143-152 (2007)
Bioassay of GIP1–42 (•) and [D-Ala2]GIP1–42 () in conscious Wistar rats, compared with a saline control (). A: Whole blood glycemia measured from tail vein samples. B: Immunoreactive (IR) plasma insulin levels from tail vein samples. Peptides (8 nmol/kg in 500 µl saline) were injected subcutaneously at time 0, immediately following an OGTT (1 g/kg). Each data point represents the mean ± SE of eight animals. *P < 0.05 vs. saline control; #P < 0.05 between peptides. Hansotia T et al. Clin. Invest. 117:143-152 (2007)
Importance of the NH2-terminus of GIP for receptor binding and activation. A: Competitive radioligand binding studies on wtGIPR cells. •, GIP1–42 (EC50, 171 ± 24 pmol/l; IC50, 3.56 ± 0.81 nmol/l); , GIP3–42 (IC50, 58.4 ± 18.8 nmol/l); , [Ala1-Tyr2]GIP1–42 (IC50, 67.0 ± 20.3 nmol/l). B: cAMP production in receptor-transfected CHO-K1 cells (wtGIPR). Each data point represents the mean ± SE of four to six independent experiments. Hansotia T et al. Clin. Invest. 117:143-152 (2007)		Bioassay of GIP1–42 (•) and [D-Ala2]GIP1–42 () in conscious obese (fa/fa) VDF Zucker rats versus saline injection (). A: Whole blood glycemia measured from tail vein samples. B: Immunoreactive (IR) plasma insulin levels from tail vein samples. Peptides (8 nmol/kg in 500 µl saline) were injected subcutaneously at time 0, immediately following an OGTT (1 g/kg). Each data point represents the mean ± SE of six to eight animals; *P < 0.05 vs. saline control; #P < 0.05 between peptides. Hansotia T et al. Clin. Invest. 117:143-152 (2007)