HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nauck, M. A. Articles by Meier, J. J. Search for Related Content PubMed PubMed Citation Articles by Nauck, M. A. Articles by Meier, J. J. Social Bookmarking                What's this?

Gastric Inhibitory Polypeptide and Glucagon-Like Peptide-1 in the Pathogenesis of Type 2 Diabetes

¹ From the Diabeteszentrum Bad Lauterberg, Bad Lauterberg, Germany
² Medizinische Universitätsklinik I, St. Josef-Hospital, Ruhr-Universität Bochum, Bochum, Germany
³ Larry L. Hillblom Islet Research Center, UCLA David Geffen School of Medicine, Los Angeles, California

	ABSTRACT

TOP ABSTRACT INCRETIN HORMONES QUANTIFICATION OF THE INCRETIN... GLP-1 SECRETION INSULINOTROPIC (AND OTHER) GLP-1... GIP SECRETION INSULINOTROPIC GIP ACTIONS GIP/GLP-1 RECEPTOR KNOCKOUT... CONCLUSIONS AND HYPOTHESIS REFERENCES

 
The incretin effect denominates the phenomenon that oral glucose elicits a higher insulin response than does intravenous glucose. The two hormones responsible for the incretin effect, glucose-dependent insulinotropic hormone (GIP) and glucagon-like peptide-1 (GLP-1), are secreted after oral glucose loads and augment insulin secretion in response to hyperglycemia. In patients with type 2 diabetes, the incretin effect is reduced, and there is a moderate degree of GLP-1 hyposecretion. However, the insulinotropic response to GLP-1 is well maintained in type 2 diabetes. GIP is secreted normally or hypersecreted in type 2 diabetes; however, the responsiveness of the endocrine pancreas to GIP is greatly reduced. In 50% of first-degree relatives of patients with type 2 diabetes, similarly reduced insulinotropic responses toward exogenous GIP can be observed, without significantly changed secretion of GIP or GLP-1 after oral glucose. This opens the possibility that a reduced responsiveness to GIP is an early step in the pathogenesis of type 2 diabetes. On the other hand, this provides a basis to use incretin hormones, especially GLP-1 and its derivatives, to replace a deficiency in incretin-mediated insulin secretion in the treatment of type 2 diabetes.

	INCRETIN HORMONES

TOP ABSTRACT INCRETIN HORMONES QUANTIFICATION OF THE INCRETIN... GLP-1 SECRETION INSULINOTROPIC (AND OTHER) GLP-1... GIP SECRETION INSULINOTROPIC GIP ACTIONS GIP/GLP-1 RECEPTOR KNOCKOUT... CONCLUSIONS AND HYPOTHESIS REFERENCES

	QUANTIFICATION OF THE INCRETIN EFFECT

TOP ABSTRACT INCRETIN HORMONES QUANTIFICATION OF THE INCRETIN... GLP-1 SECRETION INSULINOTROPIC (AND OTHER) GLP-1... GIP SECRETION INSULINOTROPIC GIP ACTIONS GIP/GLP-1 RECEPTOR KNOCKOUT... CONCLUSIONS AND HYPOTHESIS REFERENCES

 
The incretin effect is a phenomenon in which oral glucose (or any other way for the administration of glucose to not bypass its absorption from the gut) elicits a much higher insulin secretory response than an intravenous infusion of glucose with similar glycemic rises (14,15) or if the same amount of glucose was given by both routes (16). In the latter case, glucose concentrations were much higher with intravenous rather than oral glucose administration (16). State of the art for exactly quantifying the incretin effect is a comparison of the insulin secretory response after oral and "isoglycemic" intravenous glucose (i.e., an infusion leading to a similar glycemic profile as after oral glucose). It has been noted that the contribution of the incretin effect to insulin responses after oral glucose is greater than that based on the measurement of C-peptide concentrations or insulin secretion rates derived thereof by deconvolution techniques (14,15). This difference points to additional changes in insulin clearance (first-pass hepatic elimination), which are greater after oral than intravenous glucose (14,17).

The quantitative impact of the incretin effect depends on the size of the glucose load and ranges between 20 and 60% of the total insulin secretory response in healthy subjects (14–16,18).

In patients with type 2 diabetes, a reduced or absent incretin effect has been described (14). This finding prompted examinations into the secretion and insulinotropic action of incretin hormones in patients with type 2 diabetes, in their first-degree relatives (a high-risk group for developing diabetes later in life) (19), and in subjects with impaired oral glucose tolerance (who are also at high risk) (20,21). In first-degree relatives, no quantitative difference in the incretin effect was found (62 ± 5% vs. 64 ± 6% contribution to C-peptide responses after 75 g oral glucose) (22). The incretin effect in subjects with impaired glucose tolerance has not been reported but appears to be reduced to a much lesser degree (if at all) than in patients with type 2 diabetes. These observations, however, were based on a small number of subjects (M.A.N., W. Creutzfeldt, unpublished observations).

	GLP-1 SECRETION

TOP ABSTRACT INCRETIN HORMONES QUANTIFICATION OF THE INCRETIN... GLP-1 SECRETION INSULINOTROPIC (AND OTHER) GLP-1... GIP SECRETION INSULINOTROPIC GIP ACTIONS GIP/GLP-1 RECEPTOR KNOCKOUT... CONCLUSIONS AND HYPOTHESIS REFERENCES

 
Plasma GLP-1 concentrations rise after meals or oral glucose, sucrose, or fat loads (2,23–25). Typical basal (fasting) concentrations are 5 pmol/l, and peak concentrations of 15–40 pmol/l are observed 1 h after nutrient ingestion. These numbers refer to the total amount of GLP-1 that has been secreted, including intact (biologically active) GLP-1 (7-36 amide or 7-37) and the dipeptidyl peptidase 4 (DPP4)-degraded form (9-36 amide or 9-37), which is devoid of insulinotropic activity (26–29).

In type 2 diabetic patients, contradicting information has been published regarding the secretion of GLP-1 in response to oral glucose. Both elevated and reduced postchallenge responses have been described in earlier studies (30,31). In recent years, larger cohorts have been studied with more elaborate methods. Uniformly, a slight reduction in GLP-1 response has been found in comparison to nondiabetic subjects, especially during the second hour after the nutrient stimulus (32,33). Vilsbøll et al. (32) also examined the plasma concentrations of intact, biologically active GLP-1 and confirmed a reduced response in patients with type 2 diabetes. The percent contribution of intact GLP-1 relative to total GLP-1 was similar in patients with type 2 diabetes and healthy control subjects. In line with this observation, DPP4 activity in plasma has not been found to be different between patients with type 2 diabetes and healthy control subjects.

Toft-Nielsen et al. (33) also described a slightly reduced GLP-1 secretion in obese subjects with impaired glucose tolerance. Although ATP-dependent K⁺ channels have been described in GLP-1–producing L-cells (34), there is no clear influence of sulfonylurea pretreatment on GLP-1 secretion. It is not known whether improving metabolic control would normalize GLP-1 responses to nutrient ingestion (e.g., whether the GLP-1 secretion abnormality is a primary or secondary phenomenon).

In first-degree relatives of patients with type 2 diabetes, GLP-1 secretion after oral glucose (22) and meals (35) was unchanged relative to healthy control subjects.

The question arises whether small differences (by 5 pmol/l) (32,33) in the late phase of nutrient-induced GLP-1 secretion are of sufficient importance to have consequences for glucose metabolism. The answer probably is not because of multiple reasons. First, even in healthy subjects, antagonizing the action of exogenous GLP-1 (0.3 pmol · kg^–1 · min^–1, leading to increments in plasma GLP-1 concentrations of 12 pmol/l) by using exendin (9-39), a GLP-1 receptor antagonist (36,37), had only minor effects on insulin levels. Second, using the same antagonist to block GLP-1 actions after a liquid mixed meal enhanced rather than reduced insulin responses (38). The GLP-1 increment induced by the meal was 30 pmol/l in this study. The paradoxical rise in insulin is most likely explained by an acceleration in gastric emptying prompted by the GLP-1 antagonist (9). Third, the effect of infusing GLP-1 at a dose of 0.5 pmol · kg^–1 · min^–1, leading to increments in plasma GLP-1 concentrations of 25–40 pmol/l, on both glucose profiles and insulin secretion were minor in patients with type 2 diabetes (39).

Based on these studies, a minor reduction in GLP-1 secretion as demonstrated in patients with type 2 diabetes cannot be expected to have a significant impact on insulin secretion and glucose metabolism.

	INSULINOTROPIC (AND OTHER) GLP-1 ACTIONS

TOP ABSTRACT INCRETIN HORMONES QUANTIFICATION OF THE INCRETIN... GLP-1 SECRETION INSULINOTROPIC (AND OTHER) GLP-1... GIP SECRETION INSULINOTROPIC GIP ACTIONS GIP/GLP-1 RECEPTOR KNOCKOUT... CONCLUSIONS AND HYPOTHESIS REFERENCES

 
Soon after the discovery of GLP-1, it became clear that GLP-1 is active in patients with type 2 diabetes, in contrast to the insulinotropic action of GIP, which is clearly reduced or even lost (31), and that the activity of GLP-1 infused at pharmacological concentrations would be sufficient to fully normalize fasting (40–45) and postprandial (42,46) glucose concentrations. Notably, in patients with type 2 diabetes in good metabolic control on treatment with diet/exercise with or without oral antidiabetic drugs, there was no significant difference in the insulin secretory response to glucose clamped at 8.5 mmol/l in comparison to age- and weight-matched healthy subjects (31). However, in other cohorts, the insulinotropic response to GLP-1 was somewhat impaired in patients with type 2 diabetes (39), and with higher fasting glucose concentrations, the responsiveness to GLP-1 is clearly reduced (33).

In contrast to GLP-1 actions at pharmacological plasma concentrations (such as seen during the infusion of 1.2 pmol · kg^–1 · min^–1) (31,40), significant insulinotropic responses at doses mimicking a physiological "replacement" of postprandial GLP-1 increments have failed to significantly stimulate insulin secretion in patients with type 2 diabetes in some (31) but not in all (47) studies. This adds further evidence against the small differences in GLP-1 secretion typical for patients with type 2 diabetes being of pathophysiological importance.

GLP-1 is fully effective in subjects with impaired glucose tolerance (45,48). GLP-1 effects in first-degree relatives of patients with type 2 diabetes have not been studied.

	GIP SECRETION

TOP ABSTRACT INCRETIN HORMONES QUANTIFICATION OF THE INCRETIN... GLP-1 SECRETION INSULINOTROPIC (AND OTHER) GLP-1... GIP SECRETION INSULINOTROPIC GIP ACTIONS GIP/GLP-1 RECEPTOR KNOCKOUT... CONCLUSIONS AND HYPOTHESIS REFERENCES

 
The secretion of GIP in response to oral glucose or mixed meals has been examined in numerous studies. Using different radioimmunological methods, most studies agree that GIP responses, on average, are higher in patients with type 2 diabetes than in healthy control subjects (49–53). Creutzfeldt et al. (52) suggested a bimodal distribution with GIP hypo- as well as hyper-secretors among 141 type 2 diabetic patients studied. The overall differences between diabetic and healthy subjects, however, were minor on average, and other studies have not detected significant differences between healthy controls and type 2 diabetic patients (32,33). In subjects with impaired oral glucose tolerance, GIP responses appear to be normal (33). In first-degree relatives of patients with type 2 diabetes studied during a 24-h period with regular meals, the GIP response after breakfast and lunch was significantly greater than in control subjects without diabetic relatives. The 24-h integrated incremental GIP response was also significantly greater (35). In our own study of first-degree relatives, no significant difference (but a similar trend) was detected (22).

	INSULINOTROPIC GIP ACTIONS

TOP ABSTRACT INCRETIN HORMONES QUANTIFICATION OF THE INCRETIN... GLP-1 SECRETION INSULINOTROPIC (AND OTHER) GLP-1... GIP SECRETION INSULINOTROPIC GIP ACTIONS GIP/GLP-1 RECEPTOR KNOCKOUT... CONCLUSIONS AND HYPOTHESIS REFERENCES

 
Earlier studies used GIP of the porcine sequence and glycemic conditions that were less controlled than during a hyperglycemic clamp. The amino acid sequence difference between porcine and human GIP caused differential affinity to GIP antisera, and thus it was difficult to exactly compare plasma concentrations of endogenous (human) GIP and infused (porcine) GIP (54,55). Nevertheless, all studies found only minor insulinotropic effects of exogenous GIP in patients with type 2 diabetes (31,56–61) (Table 1). If a healthy control group was compared under similar glycemic conditions, insulin secretory responses to exogenous GIP were shown to be greatly reduced in patients with type 2 diabetes (31,59,60), even when extremely high doses of GIP leading to far supraphysiological plasma concentrations were used (61). GIP at a dose leading to a "physiological replacement" of postprandial plasma concentrations (0.8 pmol · kg^–1 · min^–1) was without significant effect on parameters of insulin secretion (31).

If the impaired insulinotropic response to GIP in normal glucose tolerant first-degree relatives of patients with type 2 diabetes is of pathophysiological importance, the subgroup with a subnormal stimulation of insulin secretion by GIP (Fig. 1) should be at especially high risk to progress to diabetes. We are currently following up our cohort (60) to assess their glucose tolerance status. After 4 years, only in a few subjects was a deterioration in glucose tolerance noted, and there was no clear difference related to their previous insulinotropic response with GIP infused during a hyperglycemic clamp (M.A.N., B.B., J.J.M., unpublished observations).

View larger version (46K): [in this window] [in a new window]   FIG. 1. Effect of an intravenous infusion of GIP during hyperglycemic clamp experiments (145 mg/dl; 8 mmol/l) in healthy control subjects without diabetic relatives (•), in type 2 diabetic patients (•), and in first-degree relatives of type 2 diabetic patients () on insulin (A and C) and C-peptide (B and D) concentrations. P values were the result of repeated-measures ANOVA (A: by group; B: with time; A and B: interaction of group assignment and time). *Significant differences at specific time points (P 0.05, Duncan’s post hoc test). In the right panels, individual insulin (C) and C-peptide (D) responses in first-degree relatives of patients with type 2 diabetes are shown. Dashed lines are 95% confidence intervals for responses in healthy control subjects. Approximately half of the relatives have subnormal insulin and C-peptide responses. Modified from Meier et al. (60).

	GIP/GLP-1 RECEPTOR KNOCKOUT STUDIES

TOP ABSTRACT INCRETIN HORMONES QUANTIFICATION OF THE INCRETIN... GLP-1 SECRETION INSULINOTROPIC (AND OTHER) GLP-1... GIP SECRETION INSULINOTROPIC GIP ACTIONS GIP/GLP-1 RECEPTOR KNOCKOUT... CONCLUSIONS AND HYPOTHESIS REFERENCES

	CONCLUSIONS AND HYPOTHESIS

TOP ABSTRACT INCRETIN HORMONES QUANTIFICATION OF THE INCRETIN... GLP-1 SECRETION INSULINOTROPIC (AND OTHER) GLP-1... GIP SECRETION INSULINOTROPIC GIP ACTIONS GIP/GLP-1 RECEPTOR KNOCKOUT... CONCLUSIONS AND HYPOTHESIS REFERENCES

 
Although clearly and uniformly a reduced insulinotropic response to exogenous GIP has been described in patients with type 2 diabetes (Table 1), and despite the fact that such a secretory abnormality can be found in 50% of first-degree relatives (60), it must now be considered unlikely that type 2 diabetes is simply accompanied (or even preceded) by an underexpression of endocrine pancreatic GIP receptors as previously postulated by us (63). The reasons are 1) a relatively well-preserved insulin secretory response to acute stimulation with a GIP bolus injection (61,70); 2) an unimpaired incretin effect in subjects characterized by a reduced insulinotropic responsiveness toward GIP during hyperglycemic clamps (22); and 3) the failure of a reduced insulinotropic response to exogenous GIP to predict deteriorations in oral glucose tolerance (M.A.N., B.B., J.J.M., unpublished observations.)

Nevertheless, abnormalities in the response to GIP may theoretically initiate the process leading from normal to impaired glucose tolerance (Fig. 2), as suggested by studies with incretin receptor knockout mice (71). Given the quantitative impact of a normal incretin effect to the overall insulin secretory response to oral glucose (14–16,18,77), and the quantitatively significant reduction of the incretin effect in patients with type 2 diabetes (14) along with the reduced insulinotropic effectiveness of GIP (Table 1), it is very likely that this contributes to the phenotypic abnormalities in ß-cell function typical for type 2 diabetic patients (6,62). Such processes may be the initial trigger to the deterioration of glucose tolerance, or mediate, via "glucose toxicity" or other mechanisms, the loss of glucose control also at later stages of type 2 diabetes (Fig. 2). These aspects require more detailed studies into the secretion and action of incretin hormones in patients with type 2 diabetes, their first-degree relatives, and other high-risk groups. Such knowledge will certainly provide the pathophysiological background required for tailoring incretin-based therapeutics to the needs of patients or subjects at risk to develop type 2 diabetes.

View larger version (41K): [in this window] [in a new window]   FIG. 2. Hypothetical sequence of events concerning the insulinotropic action of GIP in the pathogenesis of type 2 diabetes. GIP may play a role in the initiation of impaired ß-cell function in first-degree relatives of type 2 diabetic patients. However, GIP action may be reversibly impaired at later stages in the development of type 2 diabetes.

	ACKNOWLEDGMENTS

 
Studies reported in this article were in part supported by grant Na 203/6-1 (to M.A.N.) from the Deutsche Forschungsgemeinschaft, Bonn Bad Godesberg, Germany, and by the Deutsche Diabetes-Gesellschaft/Menarini Pharma Deutschland (individual project support to J.J.M.).

	FOOTNOTES

 
This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier.

Address correspondence and reprint requests to Prof. Dr. med. Michael Nauck, Diabeteszentrum Bad Lauterberg, Kirchberg 21, D-37431 Bad Lauterberg im Harz. E-mail: m.nauck{at}diabeteszentrum.de

Received for publication March 9, 2004 and accepted in revised form May 18, 2004

Key Words: DPP4, dipeptidyl peptidase 4 • GIP, glucose-dependent insulinotropic hormone • GLP-1, glucagon-like peptide-1

	REFERENCES

TOP ABSTRACT INCRETIN HORMONES QUANTIFICATION OF THE INCRETIN... GLP-1 SECRETION INSULINOTROPIC (AND OTHER) GLP-1... GIP SECRETION INSULINOTROPIC GIP ACTIONS GIP/GLP-1 RECEPTOR KNOCKOUT... CONCLUSIONS AND HYPOTHESIS REFERENCES

 

1. Moore B, Edie ES, Abram JH: On the treatment of diabetes mellitus by acid extract of duodenal mucous membrane. Biochem J1 :28 –38,1906
2. Ørskov C, Rabenhøj L, Wettergren A, Kofod H, Holst JJ: Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide 1 in humans. Diabetes43 :535 –539,1994[Abstract]
3. Deacon CF, Nauck MA, Meier J, Hücking K, Holst JJ: Degradation of endogenous and exogenous gastric inhibitory polypeptide in healthy and in type 2 diabetic subjects as revealed using a new assay for the intact peptide. J Clin Endocrinol Metab85 :3575 –3581,2000[Abstract/Free Full Text]
4. Eaton RP, Allen RC, Schade DS, Erickson KM, Standefer J: Prehepatic insulin production in man: kinetic analysis using peripheral connecting peptide behaviour. J Clin Endocrinol Metab51 :520 –528,1980[Abstract]
5. Polonsky KS, Licinio-Paixao J, Given BD, Pugh W, Rue P, Galloway J, Karrison T, Frank B: Use of biosynthetic human C-peptide in the measurement of insulin secretion rates in normal volunteers and type 1 diabetic patients. J Clin Invest77 :98 –105,1986
6. Polonsky KS, Given BD, Hirsch LJ, Tillil H, Shapiro ET, Frank BH, Galloway JA, Van Cauter E: Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. N Engl J Med318 :1231 –1239,1988[Abstract]
7. Creutzfeldt W: The incretin concept today. Diabetologia16 :75 –85,1979[Medline]
8. Holst JJ: Glucagonlike peptide 1: a newly discovered gastrointestinal hormone. Gastroenterology107 :1848 –1855,1994[Medline]
9. Nauck MA: Glucagonlike peptide 1. Curr Opin Endocrinol Diabetes4 :256 –261,1997
10. Nauck MA: Is glucagon-like peptide 1 an incretin hormone? Diabetologia42 :373 –379,1999[Medline]
11. Meier JJ, Nauck MA, Schmidt WE, Gallwitz B: Gastric inhibitory polypeptide: the neglected incretin revisited. Regul Pept107 :1 –13,2002[Medline]
12. Drucker DJ: Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology122 :531 –544,2002[Medline]
13. Nauck MA, Meier JJ, Creutzfeldt W: Incretins and their analogues as new antidiabetic drugs. Drug News Perspect16 :413 –422,2003[Medline]
14. Nauck M, Stöckmann F, Ebert R, Creutzfeldt W: Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia29 :46 –54,1986[Medline]
15. Shuster LT, Go VLW, Rizza RA, O’Brien PC, Service FJ: Incretin effect due to increased secretion and decreased clearance of insulin in normal humans. Diabetes37 :200 –203,1988[Abstract]
16. Tillil H, Shapiro ET, Miller A, Karrison T, Frank BH, Galloway JA, Rubenstein AH, Polonsky KS: Dose-dependent effects of oral and intravenous glucose on insulin secretion and clearance in normal humans. Am J Physiol (Endocrinol Metab)254 :E349 –E357,1988[Abstract/Free Full Text]
17. Gibby OM, Hales CN: Oral glucose decreases hepatic extraction of insulin. Br Med J286 :921 –923,1983
18. Shapiro ET, Tillil H, Miller MA, Frank BH, Galloway JA, Rubenstein AH, Polonsky KS: Insulin secretion and clearance: comparison after oral and intravenous glucose. Diabetes36 :1365 –1371,1987[Abstract]
19. Köbberling J, Tillil H, Lorenz H-J: Genetics of type 2 A- and type 2 B-diabetes mellitus (Abstract). Diabetes Res Clin Pract1 (Suppl. 1) :311 ,1985
20. Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M: Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med344 :1343 –1350,2001[Abstract/Free Full Text]
21. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M: Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet359 :2072 –2077,2002[Medline]
22. Nauck MA, Gabrys B, Holst JJ, Meier JJ, Gallwitz B, Schmidt WE: Quantification of the incretin effect in first-degree relatives of type 2 diabetic patients compared to healthy control subjects (Abstract). Diabetologia44 (Suppl. 1) :A195 ,2001
23. D’Alessio D, Thirlby R, Laschansky E, Zebroski H, Ensinck J: Response of tGLP-1 to nutrients in humans. Digestion54 :377 –379,1993
24. Herrmann C, Göke R, Richter G, Fehmann HC, Arnold R, Göke B: Glucagon-like peptide-1 and glucose-dependent insulin-releasing polypeptide plasma levels in response to nutrients. Digestion56 :117 –126,1995[Medline]
25. Qualmann C, Nauck MA, Holst JJ, Ørskov C, Creutzfeldt W: Glucagon-like peptide 1 (7–36 amide) secretion in response to luminal sucrose from the upper and lower gut: a study using alpha-glucosidase inhibition (acarbose). Scand J Gastroenterol30 :892 –896,1995[Medline]
26. Grandt D, Sieburg B, Sievert J, Schimiczek M, Becker U, Holtmann D: Is GLP-1 (9–36)amide an endogenous antagonist at GLP-1 receptors? (Abstract). Digestion55 :302 ,1994
27. Knudsen LB, Pridal L: Glucagon-like peptide-1-(9–36) amide is a major metabolite of glucagon-like peptide-1-(7–36) amide after in vivo administration to dogs, and it acts as an antagonist on the pancreatic receptor. Eur J Pharmacol318 :429 –435,1996[Medline]
28. Deacon CF, Hughes TE, Holst JJ: GLP-1 [9–36 amide] neither affects insulin release nor antagonises the insulinotropic effects of GLP-1 [7–36 amide] (Abstract). Diabetologia42 (Suppl. 1) :A198 ,1999
29. Vahl TP, Paty BW, Fuller BD, Prigeon RL, D’Alessio DA: Effects of GLP-1-(7–36)NH2, GLP-1-(7–37), and GLP-1-(9–36)NH2 on intravenous glucose tolerance and glucose-induced insulin secretion in healthy humans. J Clin Endocrinol Metab88 :1772 –1779,2003[Abstract/Free Full Text]
30. Ørskov C, Jeppesen J, Madsbad S, Holst JJ: Proglucagon products in plasma of noninsulin-dependent diabetics and nondiabetic controls in the fasting state and after oral glucose and intravenous arginine. J Clin Invest87 :415 –423,1991
31. Nauck MA, Heimesaat MM, Ørskov C, Holst JJ, Ebert R, Creutzfeldt W: 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 Invest91 :301 –307,1993
32. Vilsbøll T, Krarup T, Deacon CF, Madsbad S, Holst JJ: Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes50 :609 –613,2001[Abstract/Free Full Text]
33. Toft-Nielsen MB, Damholt MB, Madsbad S, Hilsted LM, Hughes TE, Michelsen BK, Holst JJ: Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab86 :3717 –3723,2001[Abstract/Free Full Text]
34. Gribble FM, Williams L, Simpson AK, Reimann F: A novel glucose-sensing mechanism contributing to glucagon-like peptide-1 secretion from the GLUTag cell line. Diabetes52 :1147 –1154,2003[Abstract/Free Full Text]
35. Nyholm B, Walker M, Gravholt CH, Shearing PA, Sturis J, Alberti KGMM, Holst JJ, Schmitz O: Twenty-four-hour insulin secretion rates, circulating concentrations of fuel substrates and gut incretin hormones in healthy offspring of type II (non-insulin-dependent) diabetic parents: evidence of several aberrations. Diabetologia42 :1314 –1323,1999[Medline]
36. Göke R, Fehmann HC, Linn T, Schmidt H, Krause M, Eng J, Göke B: Exendin-4 is a high potency agonist and truncated exendin-(9–39)-amide an antagonist at the glucagon-like peptide 1-(7–36)-amide receptor of insulin-secreting beta-cells. J Biol Chem268 :19650 –19655,1993[Abstract/Free Full Text]
37. Thorens B, Porret A, Buhler L, Deng SP, Morel P, Widmann C: Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9–39) an antagonist of the receptor. Diabetes42 :1678 –1682,1993[Abstract]
38. Edwards CMB, Todd JF, Mahmoudi M, Wang Z, Wang RM, Ghatei MA, Bloom SR: GLP-1 has a physiological role in the control of postprandial glucose in man: studies with the antagonist exendin 9–39. Diabetes48 :86 –93,1999[Abstract]
39. Kjems LL, Holst JJ, Vølund A, Madsbad S: The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects. Diabetes52 :380 –386,2003[Abstract/Free Full Text]
40. Nauck MA, Kleine N, Ørskov C, Holst JJ, Willms B, Creutzfeldt W: Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7–36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia36 :741 –744,1993[Medline]
41. Rachman J, Gribble FM, Barrow BA, Levy JC, Buchanan KD, Turner RC: Normalization of insulin responses to glucose by overnight infusion of glucagon-like peptide 1 (7–36) amide in patients with NIDDM. Diabetes45 :1524 –1530,1996[Abstract]
42. Rachman J, Gribble FM, Levy JC, Turner RC: Near-normalization of diurnal glucose concentrations by continuous administration of glucagon-like peptide 1 (GLP-1) in subjects with NIDDM. Diabetologia40 :205 –211,1997[Medline]
43. Nauck MA, Weber I, Bach I, Richter S, Ørskov C, JJ H, Schmiegl W: Normalization of fasting glycaemia by intravenous GLP-1 ([7–36 amide] or [7–37]) in type 2-diabetic patients. Diabet Med15 :937 –945,1998[Medline]
44. Willms B, Idowu K, Holst JJ, Creutzfledt W, Nauck MA: Overnight GLP-1 normalizes fasting but not daytime plasma glucose values in NIDDM patients. Exp Clin Endocrinol Diabetes106 :103 –107,1998[Medline]
45. Ritzel R, Schulte M, Porksen N, Nauck MS, Holst JJ, Juhl C, Marz W, Schmitz O, Schmiegel WH, Nauck MA: Glucagon-like peptide 1 increases secretory burst mass of pulsatile insulin secretion in patients with type 2 diabetes and impaired glucose tolerance. Diabetes50 :776 –784,2001[Abstract/Free Full Text]
46. Willms B, Werner J, Holst JJ, Ørskov C, Creutzfeldt W, Nauck MA: Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7–36) amide in type 2 (noninsulin-dependent) diabetic patients. J Clin Endocrinol Metab81 :327 –332,1996[Abstract]
47. Meier JJ, Gallwitz B, Salmen S, Goetze O, Holst JJ, Schmidt WE, Nauck MA: Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with type 2 diabetes. J Clin Endocrinol Metab88 :2719 –2725,2003[Abstract/Free Full Text]
48. Byrne MM, Gliem K, Wank U, Arnold R, Katschinski M, Polonsky KS, Göke B: Glucagon-like peptide 1 improves the ability of the beta-cell to sense and respond to glucose in subjects with impaired glucose tolerance. Diabetes47 :1259 –1265,1998[Abstract]
49. Crockett SE, Mazzaferri EL, Cataland S: Gastric inhibitory peptide (GIP) in maturity-onset diabetes mellitus. Diabetes25 :931 .935,1976[Abstract]
50. Ross SA, Brown JC, Dupré J: Hypersecretion of gastric inhibitory polypeptide following oral glucose in diabetes mellitus. Diabetes26 :525 –529,1977[Abstract]
51. Ebert R, Creutzfeldt W: Hypo- and hypersecretion of GIP in maturity-onset diabetics. Diabetologia19 :271 –272,1980
52. Creutzfeldt W, Ebert R, Nauck M, Stockmann F: Disturbances of the entero-insular axis. Scand J Gastroenterol Suppl82 :111 –119,1983[Medline]
53. Jones IR, Owens DR, Luzio S, Williams S, Hayes TM: The glucose dependent insulinotropic polypeptide response to oral glucose and mixed meals is increased in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia32 :668 –677,1989[Medline]
54. Jorde R, Amland PF, Burhol PG, Giercksy K-E: What are "physiological" plasma levels in man after intravenous infusion of porcine GIP? Scand J Gastroenterol20 :268 –271,1985[Medline]
55. Sarson DL, Wood SM, Kansal PC, Bloom SR: Glucose-dependent insulinotropic polypeptide augmentation of insulin: physiology or pharmacology? Diabetes33 :389 –393,1984[Abstract]
56. Amland PF, Jorde R, Aanderup S, Burhol PG, Giercksky K-E: Effects of intravenously infused porcine GIP on serum insulin, plasma C-peptide, and pancreatic polypeptide in non-insulin-dependent diabetes in the fasting state. Scand J Gastroenterol20 :315 –320,1985[Medline]
57. Jorde R, Burhol PG: The insulinotropic effect of gastric inhibitory polypeptide in non-insulin dependent diabetes. Ital J Gastroenterol19 :76 –78,1987
58. Jones IR, Owens DR, Moody AJ, Luzio SD, Morris T, Hayes TM: 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. Diabetologia30 :707 –712,1987[Medline]
59. Krarup T, Saurbrey N, Moody AJ, Kühl C, Madsbad S: Effect of porcine gastric inhibitory polypeptide on ß-cell function in type 1 and type 2 diabetes mellitus. Metabolism36 :677 –682,1987[Medline]
60. Meier JJ, Hücking K, Holst JJ, Deacon CF, Schmiegel WH, Nauck MA: Reduced insulinotropic effect of gastric inhibitory polypeptide in first-degree relatives of patients with type 2 diabetes. Diabetes50 :2497 –2504,2001[Abstract/Free Full Text]
61. Vilsbøll T, Krarup T, Madsbad S, Holst JJ: Defective amplification of the late phase insulin response to glucose by GIP in obese type II diabetic patients. Diabetologia45 :1111 –1119,2002[Medline]
62. Cerasi E, Luft R: The plasma insulin response to glucose infusion in healthy subjects and in diabetes mellitus. Acta Endocrinol (Copenh)55 :278 –304,1967[Medline]
63. Holst JJ, Gromada J, Nauck MA: The pathogenesis of NIDDM involves a defective expression of the GIP receptor. Diabetologia40 :984 –986,1997[Medline]
64. Lynn FC, Pamir N, Ng EH, McIntosh CH, Kieffer TJ, Pederson RA: Defective glucose-dependent insulinotropic polypeptide receptor expression in diabetic fatty Zucker rats. Diabetes50 :1004 –1011,2001[Abstract/Free Full Text]
65. Chang AM, Jakobsen G, Sturis J, Smith MJ, Bloem CJ, An B, Galecki A, Halter JB: The GLP-1 derivative NN2211 restores beta-cell sensitivity to glucose in type 2 diabetic patients after a single dose. Diabetes52 :1786 –1791,2003[Abstract/Free Full Text]
66. Gromada J, Dissing S, Bokvist K, Renström E, Froekjaer-Jensen J, Wulff BS, Rorsman P: Glucagon-like peptide I increases cytoplasmic cacium in insulin-secreting ßTC3-cells by enhancement of intracellular calcium mobilization. Diabetes44 :767 –774,1995[Abstract]
67. Gromada J, Bokvist K, Ding WG, Holst JJ, Nielsen JH, Rorsman P: Glucagon-like peptide 1 (7–36) amide stimulates exocytosis in human pancreatic beta-cells by both proximal and distal regulatory steps in stimulus-secretion coupling. Diabetes47 :57 –65,1998[Abstract]
68. Gromada J, Holst JJ, Rorsman P: Cellular regulation of islet hormone secretion by the incretin hormone glucagon-like peptide 1. Pflügers Arch - Eur J Physiol435 :583 –594,1998
69. Lynn FC, Thompson SA, Pospisilik JA, Ehses JA, Hinke SA, Pamir N, McIntosh CH, Pederson RA: A novel pathway for regulation of glucose-dependent insulinotropic polypeptide (GIP) receptor expression in beta cells. Faseb J17 :91 –93,2003[Abstract/Free Full Text]
70. Meier JJ, Nauck MA, Siepmann N, Greulich M, Holst JJ, Deacon CF, Schmidt WE, Gallwitz B: Similar insulin secretory response to a gastric inhibitory polypeptide bolus injection at euglycemia in first-degree relatives of patients with type 2 diabetes and control subjects. Metabolism52 :1579 –1585,2003[Medline]
71. Miyawaki K, Yamada Y, Yano H, Niwa H, Ban N, Ihara Y, Kubota A, Fujimoto S, Kajikawa M, Kuroe A, Tsuda K, Hashimoto H, Yamashita T, Jomori T, Tashiro F, Miyazaki J-i, Seino Y: Glucose intolerance caused by a defect in the entero-insular axis: A study in gastric inhibitory polypeptide receptor knockout mice. Proc Natl Acad Sci U S A96 :14843 –14847,1999[Abstract/Free Full Text]
72. Scrocchi LA, Brown TJ, MaClusky N, Brubaker PL, Auerbach AB, Joyner AL, Drucker DJ: Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene. Nat Med2 :1254 –1258,1996[Medline]
73. Scrocchi LA, Marshall BA, Cook SM, Brubaker PL, Drucker DJ: Identification of glucagon-like peptide 1 (GLP-1) actions essential for glucose homeostasis in mice with disruption of GLP-1 receptor signaling. Diabetes47 :632 –639,1998[Abstract]
74. Pederson RA, Satkunarajah M, McIntosh CH, Scrocchi LA, Flamez D, Schuit F, Drucker DJ, Wheeler MB: Enhanced glucose-dependent insulinotropic polypeptide secretion and insulinotropic action in glucagon-like peptide 1 receptor -/- mice. Diabetes47 :1046 –1052,1998[Abstract]
75. Hansotia T, Baggio LL, Tsukiyama K, Miyawaki K, Yamada Y, Thorens B, Seino Y, Drucker DJ: Combined genetic disruption of incretin signalling produces abnormalities in glucose homeostasis and body weight in GLP-1R^–/–:GIPR^–/– double mutant mice (Abstract). Diabetes51 (Suppl. 2) :A66 ,2002
76. Hansotia T, Baggio L, Yamada Y, Tsukiyama S, Preitner F, Thorens B, Seino Y, Drucker D: Combined genetic disruption of dual incretin receptor signalling pathways reveals novel glucose lowering properties of DPP IV inhibitors in mice (Abstract). Diabetes52 (Suppl. 1) :A77 ,2003
77. Nauck MA, Homberger E, Siegel EG, Allen RC, Eaton RP, Ebert R, Creutzfeldt W: Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab63 :492 –498,1986[Abstract]

CiteULike

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				A. N. Pilichiewicz, R. Chaikomin, I. M. Brennan, J. M. Wishart, C. K. Rayner, K. L. Jones, A. J. P. M. Smout, M. Horowitz, and C. Feinle-Bisset Load-dependent effects of duodenal glucose on glycemia, gastrointestinal hormones, antropyloroduodenal motility, and energy intake in healthy men Am J Physiol Endocrinol Metab, September 1, 2007; 293(3): E743 - E753. [Abstract] [Full Text] [PDF]

				N. Rozengurt, S. V. Wu, M. C. Chen, C. Huang, C. Sternini, and E. Rozengurt Colocalization of the {alpha}-subunit of gustducin with PYY and GLP-1 in L cells of human colon Am J Physiol Gastrointest Liver Physiol, November 1, 2006; 291(5): G792 - G802. [Abstract] [Full Text] [PDF]

				M. R. Heitmeier, C. B. Kelly, N. J. Ensor, K. A. Gibson, K. G. Mullis, J. A. Corbett, and T. J. Maziasz Role of Cyclooxygenase-2 in Cytokine-induced {beta}-Cell Dysfunction and Damage by Isolated Rat and Human Islets J. Biol. Chem., December 17, 2004; 279(51): 53145 - 53151. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nauck, M. A. Articles by Meier, J. J. Search for Related Content PubMed PubMed Citation Articles by Nauck, M. A. Articles by Meier, J. J. Social Bookmarking                What's this?