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Editorials EDITORIAL (SEE SOLOMON ET AL., P. 1561)

GIP: An Inconsequential Incretin or Not?

he “incretin effect” refers to the en- control subjects (4). Rather, it appears tion. A total of 29 older obese men and hancement of secretion in that ␤-cell insulin secretory responses to women with either NGT (n ϭ 16) or new- T response to an oral load rel- incretin are impaired in pa- ly-diagnosed (n ϭ 13) ative to that of an isoglycemic intravenous tients with type 2 diabetes. With GLP-1 participated in a 3-month weight loss and glucose challenge (1). In humans, the in- this defect is modest and can be overcome exercise intervention. At baseline and af- cretin effect is mediated by two with infusions that achieve higher GLP-1 ter the intervention, oral glucose toler- hormones, -like peptide 1 levels. In contrast, even infusions that ance tests were performed to measure (GLP-1) and glucose-dependent insulino- achieve supraphysiological GIP concen- nutrient-induced insulin secretion and tropic polypeptide (GIP), which are se- trations fail to elicit a significant insulin GIP responses and hyperinsulinemic- creted from enteroendocrine cells in secretory response in patients with type 2 euglycemic glucose clamps were per- response to nutrients entering the gut. diabetes (5). Thus, GLP-1 infusions formed to measure insulin action. They GLP-1 secretion from L-cells, found in quickly normalize blood glucose levels in observed that the lifestyle intervention, highest density in the distal ileum but also patients with type 2 diabetes, whereas which decreased body weight by around throughout the small and large intestine, GIP infusions do not (6). These observa- 5 kg and increased VO2max in both groups, is stimulated by glucose, amino acids, and tions created considerable enthusiasm for significantly improved glucose tolerance fat. GIP, in contrast, is produced by the the development of pharmaceutical in the type 2 diabetes group but not in the K-cells in the proximal duodenum; its se- agents for the treatment of type 2 diabetes NGT group. Insulin action increased by cretion is also stimulated by glucose, but that work through the incretin axis, and ϳ46% in the NGT group, but signifi- is particularly enhanced by fat (2). Both particularly for those that enhance GLP-1 cantly less so (ϳ26%) in the type 2 dia- GLP-1 and GIP are derived from prohor- activity. Unfortunately, native GLP-1 is betic group. Insulin secretion decreased mones ( and pro-GIP, re- not suitable as a therapy for the treatment in the NGT group in proportion to their spectively) and secreted as active of type 2 diabetes because of its short half- improvement in insulin action, but in- hormones. The effects of both GLP-1 and life. In circulation, both GLP-1 and GIP creased in the type 2 diabetes group in GIP are mediated by specific G protein– are rapidly inactivated by dipeptidylpep- contrast. Similarly, incremental GIP re- coupled receptors present on the plasma tidase-4 (DPP-4), a ubiquitous serine pro- sponses to the glucose challenge in- membrane of ␤-cells and other target tis- tease that cleaves the two NH2-terminal creased significantly in those with type 2 sues. GLP-1 and GIP increase insulin se- amino acids from active hormones ren- diabetes, and tended to go down in those cretion from ␤-cells in a glucose- dering them inactive. As a consequence of with NGT. In the group as a whole, dependent manner. In rodents, GLP-1 the action of DPP-4 as well as rapid clear- changes in GIP were highly correlated to and GIP also enhance ␤-cell mass by in- ance by the kidneys, the half-life of GLP-1 changes in insulin secretion corrected for creasing rates of proliferation and de- in circulation is 1–2 min and that of GIP the degree of insulin resistance following creasing rates of apoptosis. Many around 7 min. Two approaches have been the intervention. A similar relation be- physiological effects of GLP-1 and GIP do successfully employed to enhance the in- tween insulin secretion and GIP was pre- not overlap, however. GLP-1 suppresses cretin effect. The first approach, inject- viously reported in subjects with glucagon secretion, slows gastric empty- able GLP-1 agonists that are resistant to impaired glucose tolerance by this group ing, and has central nervous system ef- DPP-4, is exemplified by and of investigators, although in this earlier fects to regulate appetite, whereas GIP the recently approved human GLP-1 an- study insulin action was not directly mea- does not. GIP, on the other hand, has di- alog . The second approach, sured (9). These results suggest that im- rect effects on adipocytes to promote tri- orally available, small molecule inhibitors proved ␤-cell–compensatory responses glyceride storage (1). The incretin system, of DPP-4, includes the approved agents to insulin resistance following a lifestyle therefore, facilitates integrated physiolog- and as well as sev- intervention are, at least in part, mediated ical responses to meals of different size eral other agents in development (7). Un- by enhanced GIP secretion and action. and composition allowing ingested nutri- like GLP-1 agonists, DPP-4 inhibitors What is not clear from this study or ents to be optimally metabolized. increase active levels of both GLP-1 and the group’s earlier work is whether the The incretin effect is an important de- GIP. Because studies indicate GIP has enhanced insulin secretion with the life- terminant of glucose tolerance. In patients minimal effects in type 2 diabetes, most of style intervention can be directly attrib- with type 2 diabetes, the incretin effect is the therapeutic benefit of this class has uted to GIP, because insulin secretory markedly diminished and is less than half been ascribed to the actions of GLP-1. responses to GIP were not directly mea- that observed in subjects with normal glu- Consequently, little attention has been sured. Thus, it is possible that a common cose tolerance (NGT) (3). This defect does paid to the physiology and pharmacolog- mechanism altered by the lifestyle inter- not appear to be due to impairments in ical potential of GIP, even though this was vention could account for parallel im- incretin secretion, because most the first incretin hormone identified. provements in insulin and GIP secretion, studies have found comparable circulat- In this issue of Diabetes Care, So- without there necessarily being a direct ing concentrations of GLP-1 and GIP in lomon et al. (8) examines the contribu- link between the two processes. Never- response to nutrient challenges in sub- tions of GIP to changes in insulin theless, other recent data support the no- jects with type 2 diabetes and nondiabetic secretion following a lifestyle interven- tion that incretin responses to GIP could care.diabetesjournals.org DIABETES CARE, VOLUME 33, NUMBER 7, JULY 2010 1691 Editorial be modulated in type 2 diabetes. For ex- enhanced incretin effect contribute to the tide in patients with type-2 diabetes ample, a recent study by Højberg et al. durable effect of thiazolidinedione drugs? mellitus. J Clin Invest 1993;91:301–7 (10) demonstrated that 4 weeks of inten- We don’t know, but GIP may not be the 6. Rachman J, Barrow BA, Levy JC, Turner sive insulin treatment markedly im- inconsequential incretin hormone in type RC. Near-normalisation of diurnal glu- proved insulin secretory responses to 2 diabetes we thought it was after all. cose concentrations by continuous ad- ministration of glucagon-like peptide-1 infused GIP in patients with poorly con- (GLP-1) in subjects with NIDDM. Diabe- trolled type 2 diabetes. Interestingly, the RICHARD E. PRATLEY, MD tologia 1997;40:205–211 same intervention did not increase GIP 7. Pratley RE, Gilbert M. Targeting incretins secretion, but did improve insulin secre- From the Diabetes and Translational Medicine Unit, Division of Endocrinology and in type 2 diabetes: role of GLP-1 receptor tory responses to a standard mixed meal Metabolism, Department of Medicine, University agonists and DPP-4 inhibitors. Rev Diabet in patients with type 2 diabetes, consis- of Vermont College of Medicine, University of Stud 2008;5:73–94 tent with an enhancement in incretin ac- Vermont, Burlington, Vermont. 8. Solomon TP, Haus JM, Kelly KR, Rocco tion (11). It has been known for some Corresponding author: Richard E. Pratley, richard. M, Kashyap SR, Kirwan JP. Improved time that expression of the GIP receptor [email protected]. pancreatic ␤-cell function in type 2 dia- DOI: 10.2337/dc10-0704 on pancreatic ␤-cells is downregulate by betic patients after lifestyle-induced © 2010 by the American Diabetes Association. weight loss is related to glucose-depen- hyperglycemia. Thus, the enhanced in- Readers may use this article as long as the work is cretin response to GIP following normal- properly cited, the use is educational and not for dent insulinotropic polypeptide. Diabetes Care 2010;33:1561–1566 ization of glucose levels in the study by profit, and the work is not altered. See http:// creativecommons.org/licenses/by-nc-nd/3.0/ for 9. Kelly KR, Brooks LM, Solomon TP, Kashyap Højberg et al. could be due to up- details. SR, O’Leary VB, Kirwan JP. The glucose-de- regulation of the GIP receptor on the pendent insulinotropic polypeptide and ␤-cells of these individuals. New insights glucose-stimulated insulin response to exer- into the mechanisms by which this might Acknowledgments— No potential conflicts cise training and diet in obesity. Am J occur have recently been reported by of interest relevant to this article were Physiol Endocrinol Metab 2009;296: Gupta et al. (12) in preclinical models of reported. E1269–1274 diabetes. This group observed that the 10. Højberg PV, Vilsbøll T, Rabøl R, Knop FK, GIP receptor contains a functional perox- ●●●●●●●●●●●●●●●●●●●●●●● Bache M, Krarup T, Holst JJ, Madsbad S. isome proliferator–activated receptor-␥ References Four weeks of near-normalisation of blood (PPAR-␥) response element in the pro- 1. Drucker DJ. The biology of incretin hor- glucose improves the insulin response to glucagon-like peptide-1 and glucose-de- moter region of the gene. Interventions mones. Cell Metab 2006;3:153–165 ␥ 2. Rijkelijkhuizen JM, McQuarrie K, Girman pendent insulinotropic polypeptide in pa- that decreased or increased PPAR- activ- tients with type 2 diabetes. Diabetologia ity (including exposure to a thiazo- CJ, Stein PP, Mari A, Holst JJ, Nijpels G, Dekker JM. Effects of meal size and com- 2009;52:199–207 lidinedione) resulted in corresponding position on incretin, alpha-cell, and beta- 11. Højberg PV, Vilsbøll T, Zander M, Knop changes in GIP receptor expression. Col- cell responses. Metabolism 2010;59:502– FK, Krarup T, Vølund A, Holst JJ, Mads- lectively, these data and the results of the 511 bad S. Four weeks of near-normalization present study suggest that it is possible to 3. Nauck M, Sto¨ckmann F, Ebert R, of blood glucose has no effect on post- normalize the incretin effect in type 2 di- Creutzfeldt W. Reduced incretin effect in prandial GLP-1 and GIP secretion, but abetes through interventions that de- type 2 (non-insulin-dependent) diabetes. augments pancreatic B-cell responsive- crease hyperglycemia, improve insulin Diabetologia 1986;29:46–52 ness to a meal in patients with Type 2 resistance, or both. Whether treating pa- 4. Meier JJ, Nauck MA. Is secretion of gluca- diabetes. Diabet Med 2008;25:1268– tients with type 2 diabetes with a thiazol- gon-like peptide-1 reduced in type 2 dia- 1275 12. Gupta D, Peshavaria M, Monga N, Jetton idinedione will enhance incretin effects betes mellitus? Nat Clin Pract Endocrinol Metab. 2008;4:606–607 TL, Leahy JL. Physiologic and pharmaco- mediated by GIP is not known, but is an 5. Nauck MA, Heimesaat MM, Orskov C, logic modulation of GIP receptor expres- intriguing possibility given that thiazol- Holst JJ, Ebert R, Creutzfeldt W. Pre- sion in ss-cells by PPAR␥ signaling: idinediones and DPP-4 inhibitors are now served incretin activity of glucagon-like possible mechanism for the GIP resistance being studied in combination for the peptide 1 [7–36 amide] but not of syn- in type 2 diabetes. Diabetes 2010;59: treatment of type 2 diabetes. Could an thetic human gastric inhibitory polypep- 1445–1450

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