With Type 2 Diabetes
I am learning how the disease
affects my body.

GIP works to maintain Glycemic control

Despite their best efforts, people with T2D struggle to manage their A1C¹

In people with T2D, insulin resistance leads to a decline in beta cell function, resulting in hyperglycemia.^2,3

PROGRESSIVE NATURE OF T2D

Graph on decline in beta-cell function — While many people with T2D try to their part with diet and exercise, hyperglycemia can still persist, leading to complication if not addressed early.^4-6

^*Adapted from Freeman JS. A physiologic and pharmacological basis for implementation of incretin hormones in the treatment of type 2 diabetes mellitus. Mayo Clin Proc.2010;85(suppl12):S6.

GIP may help maintain blood glucose level in 2 important ways^5,7,8

Enhances glucose-dependent insulin secretion from beta cells
Improves insulin sensitivity based on preclinical data

GIP And The Incretin Effect

GIP has a greater contribution to the incretin effect than GLP-1 in healthy humans.

Incretins enhance glucose-dependent insulin secretion from beta cells.⁵

THE INCRETIN HORMONES GIP AND GLP-1 DRIVE THE INCRETIN EFFECT (augmentation of insulin release after nutrition ingestion)

Image on Incretin Hormones regulating metabolism — GIP is responsible for nearly two-thirds of the incretin effect in healthy humans, contributing more to insulin secretion than GLP-1.⁹

Adapted from Nauck and Meier, Meier JJ. GIP and GLP-1; stepsiblings rather than monozygotic twins within the incretin family. Diabetes. 2019;68:899

Estaban Jodar, MD, Discusses GIP and the Incretin Effect

Welcome to this educational activity on GIP and the incretin effect. My name is Esteban Jodar, I am endocrinologist at the University Hospital Quironsalud Madrid and full professor of endocrinology in the School of Medicine in the Universidad Europea here in Madrid, Spain. Here you can see my disclosures.

Incretin hormones are gut peptides, gut hormones in fact, that are secreted after nutrient intake when these nutrients reach the gut and produce changes in volume and also in density. Their secretion stimulates insulin secretion together with hyperglycemia. GIP, glucose dependent insulinotropic polypeptide, is produced in the upper gut by K-cells and GLP-1, glucagon-like peptide Type 1, is produced in the lower gut by L-cells.

In this figure, the estimate of the contribution to the incretin effect is showed. The enhanced insulin secretion rate related to the incretin effect in normal population is mainly related to GIP, which is responsible for the majority of this effect.

Oral glucose leads to a greater stimulation of insulin secretion than intravenous glucose infusion, even when the same plasma glucose concentration profiles are achieved, which is called isoglycemia. This difference between the insulin secretory response to an intravenous glucose infusion and an oral glucose load is known as the incretin effect.

In fact, incretins are responsible for most of the insulin release following nutrient ingestion. GIP and GLP-1 are responsible for this effect, which enhances the secretion of insulin after a meal. Together they are responsible for a two- to three-fold higher insulin secretory response to oral as compared to intravenous glucose administration.

Here, you can see the incretin effect in healthy subjects in the left panel, as compared to the reduced incretin effect in people with Type 2 diabetes on the right panel. The figure illustrates plasma insulin concentrations after an intake of 50 grams of oral glucose, and with isoglycemic intravenous glucose infusions. In people with Type 2 diabetes shown in the right, the difference in insulin secretion between an oral glucose load and intravenous glucose infusion is diminished indicating an impaired incretin effect.

Both GIP and GLP-1 bind to the receptors on pancreatic beta cells, although endogenous GIP in healthy people generates a more significant effect on insulin mediated glucose clearance compared with endogenous GLP-1. In fact, GIP is responsible for nearly two-thirds of the incretin effect in healthy humans, contributing more to insulin secretion than GLP-1.

Here we can see the effects of placebo GLP-1 receptor blockade and GIP receptor blockade in healthy individuals showing the bigger effect of GIP as compared to GLP-1 on the postprandial increase in insulin secretion.

In summary, incretins enhance glucose-dependent insulin secretion from beta cells. Endogenous GIP and GLP-1 differ in their relative contribution to the incretin effect in healthy humans. GIP is responsible for nearly two-thirds of the incretin effect in healthy humans, contributing more to insulin secretion than GLP-1.

GIP And Insulin Senstivity

People with T2D have a diminished incretin effect^3,10

Graph on difference in insulin secretion in response to oral vs IV glucose in healthy individuals

Graph on difference in insulin secretion in response to oral vs IV glucose in people with T2Dm

In healthy people, there is a substantial difference in insulin secretion when glucose is given orally to intravenously. The incretin effect is diminished in people with T2D, likely contributing to dysglycemia.¹⁰

Based on preclinical studies.
^*Adapted from Nauck MA, Meier JJ. Incretin hormones; their role in health and disease. Diabetes Obes Metab. 2018;20(suppl 1):5-21. 2018 John Wiley & Sons Ltd; used with permission.

GIP And Adipose Tissue

Excess weight negatively influences insulin sensitivity.^7,8,11

In general, people who have overweight or have obesity can be burdened with insulin resistance, leading to a decline in beta cell function. The result is hyperglycemia, a known cause of microvascular and macrovascular complications. ^2,3,6

Within Adipocytes, GIP May Improve Insulin Sensitivity^7,8,11

Preclinical studies suggest that, in adipocytes, GIP may regulate lipid metabolism and improve insulin sensitivity.^7,8,11

T2D is associated with impaired lipid partitioning. Dysregulated lipid storage and metabolism in adipose tissue contribute to disease pathophysiology.^8,12,13

GIP May Help Adipose Tissue Function Normally, Storing And Releasing Lipids As Needed^8,13

Preclinical studies suggest that GIP enhances the uptake of TG and free fatty acids into adipocytes, which may lower plasma TG levels. The coupling of lipid intake, with its appropriate storage in adipose tissue, is important for maintaining metabolic health and glycemic control. ^11,14-16

GIP may have a greater impact on Weight-related mechanism than you know^*

^*Based on preclinical trials

CV=cardiovascular; GIP=glucose-dependent insulinotropic polypeptide; GLP-1=glucagon-like peptide-1; T2D=type 2 diabetes.

References

American Diabetes Association. Standards of medical care in diabetes-2021, Diabetes Care. 2021;44(suppl 1):S1-S232.
Davidson JA, Parkin CG. Is hyperglycemia a causal factor in cardiovascular disease? Does proving this relationship really matter? Yes. Diabetes Care. 2009;32(suppl 2):S331-S333. doi:10.2337/dc09-S333
Freeman JS. A physiologic and pharmacological basis for implementation of incretin hormones in the treatment of type 2 diabetes mellitus. Mayo Clin Proc. 2010;85(suppl 12):S5-S14. doi:10.4065/mcp.2010.0467
DeFronzo RA. Overview of newer agents: where treatment is going. Am J Med. 2010;123(suppl 3):S38-S48. doi:10.1016/j.amjmed.2009.12.008
Nauck MA, Meier JJ. The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. Lancet Diabetes Endocrinol. 2016;4(6):525-536. doi:10.1016/S2213-8587(15)00482-9
Laiteerapong N, Ham SA, Gao Y, et al. The legacy effect in type 2 diabetes: impact of early glycemic control on future complications (The Diabetes & Aging Study). Diabetes Care. 2019;42(3):416-426 doi:10.2337/dc17-1144
Mohammad S, Ramos LS, Buck J, Levin LR, Rubino F, McGraw TE. Gastric inhibitory peptide controls adipose insulin sensitivity via activation of cAMP-response element-binding protein and p110 ß isoform of phosphatidylinositol 3-kinase. J Biol Chem. 2011;286(50):43062-43070. doi:10.1074/jbc.M111.289009
Nauck MA, Meier JJ. Incretin hormones; Their role in health and disease, Diabetes Obes Metab. 2018 Feb;20 Suppl 1:5-21. DeFronzo, R.A. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis; the missing links. The Claude Bernard Lecture 2009. Diabetologia 53, 1270-1287 (2010).
Nauck MA, Meier JJ. GIP and GLP-1: stepsiblings rather than monozygotic twins within the incretin family. Diabetes. 2019;68(5):897-900. doi:10.2337/dbi19-0005
Nauck MA, Meier JJ. Incretin hormones: their role in health and disease. Diabetes Obes Metab. 2018;20(suppl 1):5-21 doi:10.1111/dom. 13129
Finan B, Müller TD, Clemmensen C, et al. Reappraisal of GIP pharmacology for metabolic diseases. Trends Mol Med. 2016;22(5):359-376. doi:10.1016/j.molmed.2016.03.005
Gastaldelli A. Insulin resistance and reduced metabolic flexibility: cause or consequence of NAFLD? Clin Sci (Lond). 2017;131(22):2701-2704. doi:10.1042/CS20170987
Jorge-Galarza E, Medina-Urrutia A, Posadas-Sánchez R, et al. Adipose tissue dysfunction increases fatty liver association with pre diabetes and newly diagnosed type 2 diabetes mellitus. Diabetol Metab Syndr. 2016;8:73. doi:10.1186/s13098-016-0189-6
Asmar M, Simonsen L, et al. Glucose-dependent insulinotropic polypeptide may enhance fatty acid re-esterification in subcutaneous abdominal adipose tissue in lean humans. Diabetes. 2010;59(9):2160-2163. doi:10.2337/db10-0098
Asmar M, Tangaa W, Madsbad S, et al. On the role of glucose-dependent insulintropic polypeptide in postprandial metabolism in humans. Am J Physiol Endocrinol Metab. 2010;298(3):E614-E621. doi:10.1152/ajpendo.00639.2009
Frayn KN, Karpe F. Regulation of human subcutaneous adipose tissue blood flow. Int J Obes, 2014;38:1019-1026. doi:10.1038/ijo.2013.200

With Type 2 DiabetesI am learning how the diseaseaffects my body.

GIP works to maintain Glycemic control

GIP may have a greater impact on Weight-related mechanism than you know*Read the latest

With Type 2 Diabetes
I am learning how the disease
affects my body.

GIP may have a greater impact on Weight-related mechanism than you know^*