While the role of endogenous GIP in diabetes pathophysiology (reviewed below) remains unclear, there is considerable interest in combining GLP-1 together with GIP as co-agonist therapy for diabetes and obesity as reviewed here Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease Mol Metab. 2020 Sep 25:101090. doi: 10.1016/j.molmet.2020.101090
Although several GIP-GLP-1 co-agonists failed to impress in clinical testing data for trizepatide (LY3298176)has shown compelling reduction of blood glucose and body weight in both preclinical LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept Mol Metab. 2018 Dec;18:3-14. doi: 10.1016/j.molmet.2018.09.009 and clinical studies. Several of the key dose rangong studies and clinical trials are highlighted here Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial Lancet. 2018 Nov 17;392(10160):2180-2193. An overview of the Phase 3 Tirzepatide SURPASS program for Type 2 diabetes was presented by Eli Lilly on Nov 20 2020.
Although mechanisms remain incompletely understood, genetic variation within the GIP gene may influence the susceptibility of developing type 2 diabetes. Carriers of the risk allele rs12453394-A residing at 17q21.32 exhibited a small but significant risk of developing T2D Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes Nature Communications 9, Article number: 321(2018 doi:10.1038/s41467-017-02380-9
Similarly, variations in the human GIP gene may influence plasma levels of GIP and in turn, control of postprandial glycemia. Chang and colleagues identified SNPs in the 5-regions of several genes, including 3 variants in the GIP gene, with significant allelic differences in representation among populations of different ancestry. Transfection of reporter plasmids containing these GIP promoter variants into heterologous cells revealed reduced transcriptional activity. Analysis of a population of 123 Han-Chinese east-asian women who underwent glucose tolerance testing during week 23-29 of pregnancy revealed correlations between Gip genotpes and 1 h postglucose levels of GIP in patients with different Gip SNP variants. See Identification of Metabolic Modifiers That Underlie Phenotypic Variations in Energy-Balance Regulation Diabetes. 2011 Feb 7.
Evidence that plasma GIP levels may be partly genetically determined was provided by Almgren et al. Fasting GIP , 2-hour GIP , and 2-hour GLP-1 showed heritabilities of approximately 15%; intriguingly, two independent loci were significantly associated with fasting GIP concentration: GIPR and GLP2R. The minor alleles of rs1800437 and rs2287019 (P = 4.0 × 10–11) in the GIPR locus were associated with lower fasting (P = 4.1 × 10–15) and 2-hour (P = 1.6 × 10–17) GIP concentrations. rs17681684 within the GLP2R was associated with GIP specifically in the fasting state where each A allele associated with 5.5% increased GIP levels. No association with 2-hour GIP could be detected. The SLC5A1 locus was also associated with 2-hour GIP. Each G allele of rs17683011 associated with 12.2% increased 2-hour GIP levels. Four SNPs in strong LD (r2 = 0.95-1, D′ = 1), near the ABO gene, were associated with both fasting (P = 6.5 × 10–4) and 2-hour (P = 9.0 × 10–14) GIP concentration but not with GLP-1. The T allele of the rs927332 variant within F13A1 was suggestively associated with increased fasting GIP (P = 2.5 × 10–5) and significantly associated with increased 2-hour GIP . Finally, a rare C allele of rs150112597 in HOXD1 (minor allele frequency = 0.005) was found to be associated with 28% reduced 2-hour GIP concentration See Genetic determinants of circulating GIP and GLP-1 concentrationsJCI Insight. 2017 Nov 2;2(21). pii: 93306.
A subsequent study identified a specific genetic variant in the Gipr, the A allele of rs10424928, as a modifier of b-cell function and BMI. Human carriers of the A allele exhibited reduced insulin secretion in response to oral glucose, but normal insulin secretion in response to intravenous glucose. Furthermore, infusion of GIP into non-diabetic subjectes demonstrated that the TA/AA genotype exhibited reduced insulin secretion in response to GIP, but normal insulin secretion in response to GLP-1. The relative levels of islet Gipr mRNA transcripts were also significantly lower in islets from non-diabetic subjects. Nevertheless, GIP levels (fasting and post-glucose challenge) were lower in carriers of the TA/AA genotype. Intriguingly, BMI and waist circumference was also significantly reduced, and despite impaired beta cell function, the risk of diabetes was not increased in subjects with the A allele. The authors speculate that the detrimental effect of this "reduced functional Gipr allele" in the b-cell is offset by the benefical effect on body weight, and presumably, insulin sensitivity. GIP (1 nM) was also shown to increase islet osteopontin expression under conditions of 5 mM glucose and they raise the possibility that the cytoprotective actions of GIP may be mediated in part through osteopontin. See Pleiotropic Effects of GIP on Islet Function Involves Osteopontin Diabetes 2011 Sep;60(9):2424-33
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 suboptimally controlled 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
Kim and colleagues examined the actions of a 3 hr GIP infusion in subjects with type 2 diabetes. GIP increased plasma levels of both insulin and glucagon, reduced levels of GLP-1, and resulted in increased levels of blood glucose after a meal. Exogenous glucose-dependent insulinotropic polypeptide worsens post-prandial hyperglycemia in type 2 diabetes Diabetes. 2009 Mar 10. [Epub ahead of print]
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 available evidence suggests that a component of the defective GIP response in diabetic subjects may be attributable to metabolic abnormalities, perhaps hyperglycemia alone, and as such may be partially reversible following treatment of the diabetes. A small study of 8 obese diabetic subjects, HbA1c 8.6 +/- 1.3%, demonstrated that 4 weeks of intensive therapy with insulin for 4 weeks significantly improved beta cell responsiveness to both GLP-1 and GIP (but not glucose alone) by a factor of three to four-fold. See Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes Diabetologia. 2008 Nov 27. [Epub ahead of print] . Similarly, analysis of GIP responsivity in human diabetic subjects (n=12) treated with a sulfonylurea 1 hr prior to infusion of GIP demonstrated that the SU enahnced the insulin secretory response to GIP infusion. Whether this cooperation would also be observed in more prolonged studies is not clear. See KATP channel closure ameliorates the impaired insulinotropic effect of glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. J Clin Endocrinol Metab. 2008 Dec 2. [Epub ahead of print]
In contrast, Mentis and colleagues assessed whether a 6 hr infusion of GIP alone or superimposed upon GLP-1 administration provided any acute benefit in terms of glucose lowering or insulin secretion in 12 overweight fasted patients with T2DM. Patients received a 6h infusion of either placebo, or GIP, GLP-1, and GIP plus GLP-1 after an overnight fast on different days. Adding GIP on top of GLP-1 did not provide any further glucose lowering, and actually increased plasma levels of glucagon that were reduced by GLP-1; whether GIP may have more benefit in situations of more sustained peptide administration and/or better control of glucose requires further study GIP Does Not Potentiate the Antidiabetic Effects of GLP-1 in Hyperglycemic Patients with Type 2 Diabetes Diabetes. 2011 Feb 17. [Epub ahead of print]
Similarly, Christensen and colleagues infused GIP to infuse high normal physiological values ranging from 75-100 pM for 90 minutes in 12 subjects with T2DM, mean age 62, BMI 29, A1c 6.5% under conditions of insulin induced hypoglycemia, fasting, or hyperglycemia (12 mM), conditions achieved using clamps. Under all 3 conditions, GIP increased levels of circulating glucagon, although the extent of glucagon induction was greated during hypoglycemia
The effects of GIP infusion at normoglycemia, hypoglycemia and hyperglycemia were examined during 90 minute GIP infusions in 10 healthy male subjects. A very small (1-3 pM) increase in plasma glucagon was seen during the first 30 minutes of the GIP infusion in subjects with euglycemia or insulin-induced hypoglycemia, whereas an even smaller non-significant 1-2 pM decrement in glucagon levels was observed in hyperglycemic clamped subjects. These changes were observed in the context of the hyperinsulinemia infused during the respective clamp conditions. Glucose-Dependent Insulinotropic Polypeptide: A Bifunctional Glucose-Dependent Regulator of Glucagon and Insulin Secretion in Humans Diabetes. 2011 Oct . In human subjects with type 1 diabetes, acute exogenous infusion of GIP in subjects with insulin-induced hypoglycemia augments the glucagon response to hypoglycemia during the recovery phase, associated with an increased in endogenous glucose production and a reduced requirement for exogenous glucose to normalize glycemia. Glucose-Dependent Insulinotropic Polypeptide Augments Glucagon Responses to Hypoglycemia in Type 1 Diabetes Diabetes. 2014 Jul 22. pii: DB_140440
The loss of beta cell GIP responsivity in hyperglycemic 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 DPP-4 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]
Obese subjects with normal glucose tolerance and compensatory hyperinsulinemia and subjects with newly diagnosed type 2 DM were subjected to a 3 monthsupervised program of diet and exercise-induced (1 hr 5 x weekly) weight loss. Metabolic assessments were carried out in the two groups prior to and after the diet/exercise periods. Subjects in both groups lost about 5 kgs over the 3 month experiment, together with reduced plasma lipid parameters and a small 0.7% but non-significant reduction in HbA1c in the obese T2DM group. Obese T2DM subjects exhibited improved oral glucose tolerance, increased C-peptide responses, and enhanced insulin-stimulated glucose disposal after weight loss. Glucose-stimulated levels of GIP increased significantly after weight loss/exercise in the obese T2DM subjects, but not in the obese NGT subjects. Hence, improvement in GIP secretion correlates with improvement in b-cell function in this group of obese subjects after exercise/wt loss Improved Pancreatic Beta-Cell Function In Type 2 Diabetics Following Lifestyle-Induced Weight Loss Is Related To Glucose-Dependent Insulinotropic Polypeptide. Diabetes Care. 2010 Mar 3. [Epub ahead of print
The effects of GIPR activation in human adipocytes have also been examined in vitro. Adipocytes were prepared from subcutaneous abdominal fat depots from 9 subjects (4 non-obese). Stromal vascular cells were expanded in vitro, then differentiated with a cocktail that included T3, dexamethasone, insulin, rosiglitazone, vitamins, and transferrin. Treatment of cells for 1h with 1 nM GIP rapidly induced cytokine (IL-6, IL-1β and IL-1Ra) mRNA expression in the presence or absence of serum, actions sensitive to PKA, orlistat (lipase inhibitor) or IKK-β inhibition . These actions were blocked by treatment of cells with GIP(6-30) and Gipr mRNA transcripts were not detected in undifferenitaed pre-adipocytes. In contrast, GIP treatment had little effect on cytokine secretion, but potentiated the induction of cytokine secretion in the presence of other inflammatory mediators (LPS, IL-1b, TNF-a). Consistent with the inhibitory actions of orlistat on cytokine gene expression, GIP induced lipolysis as measured by glycerol release, in a PKA-dependent manner. Inhibitors of IKK-β/NF-κB, IL-1 receptor activation, Jun N-terminal kinase (JNK), and the Mitogen-Activated Protein Kinase (MAPK) blocked GIP-induced HSL phosphorylation and lipolysis. Acute GIP treatment alone, or with insulin, did not affect glucose uptake, whereas prolonged pretreatment with GIP for 6 h dose-dependently reduced insulin stimulated glucose uptake, in association with impaired insulin-stimulated GLUT4 translocation Glucose-dependent insulinotropic polypeptide induces cytokine expression, lipolysis and insulin resistance in human adipocytes Am J Physiol Endocrinol Metab. 2012 Oct 23.