Glucagon-like peptide-1 mediates the therapeutic actions of DPP-IV inhibitors
- 2.1k Downloads
KeywordsDipeptidyl peptidase-IV Gastric inhibitory polypeptide Gastroenteropancreatic peptide hormones Glucagon-like peptide-1 Incretin Incretin effect Oral hypoglycaemic agents Pharmacokinetics Proteolytic processing
gastric inhibitory peptide
Our opponents in this debate, Nauck and El-Ouaghlidi, have challenged the standard view that the therapeutic actions of the dipeptidyl peptidase-IV (DPP-IV) inhibitors are mediated by glucagon-like peptide-1 (GLP-1) . Based on the findings that exogenously administered GLP-1 is rapidly and extensively degraded by DPP-IV , and that this degradation appears to be mediated by DPP-IV , it was proposed that DPP-IV inhibitors could enhance the survival of intact, biologically active GLP-1 and thus be of use in the treatment of type 2 diabetes mellitus [2, 4]. Although the kinetic studies performed by Mentlein et al. clearly demonstrated that DPP-IV may have substrates in addition to GLP-1 [5, 6], the effect of this enzyme on GLP-1 was considered to be of particular importance because: (1) GLP-1 is extremely susceptible to rapid degradation by DPP-IV, as compared with the majority of other substrates; (2) DPP-IV degradation is the primary route of GLP-1 inactivation; (3) GLP-1 is perhaps the most potent and efficacious insulinotropic hormone in the body , whereas gastric inhibitory peptide (GIP), the other major incretin hormone, has no insulinotropic effects in patients with type 2 diabetes ; and (4) DPP-IV inhibitors have no metabolic effect in mice with a targeted deletion of the GLP-1 and GIP receptor genes .
The authors of the previous article have listed five arguments that have caused them to doubt that GLP-1 is the only, or at least the major, mediator of the remarkable hypoglycaemic effects of DPP-IV inhibitors observed in clinical studies [10, 11, 12]. We would certainly agree that there are other potential substrates for DPP-IV whose extended survival might contribute to the therapeutic effects of these inhibitors; nonetheless, we believe that the protection of GLP-1 against degradation is the major mechanism involved. In the remainder of this paper, we shall respond to each of the five arguments in turn.
DDP-IV inhibition causes little increase in endogenous GLP-1
It should be noted that insulin levels are not elevated during inhibitor treatment [10, 11]; consequently, this situation should not be compared with infusion studies resulting in elevated insulin levels. The insulinotropic actions of GLP-1 appear to be due to an increase in the insulinogenic index, such that the same degree of insulin secretion is produced at lower glucose levels. The doses of exogenous GLP-1 required to elicit this effect have yet to be established.
DPP-IV inhibitors have little effect on gastric emptying
It is argued that, at doses that affect blood glucose, GLP-1 invariably inhibits gastric emptying , whereas a similar deceleration has not been observed in studies employing DPP-IV inhibitors—a conclusion that is difficult to deduce from the reference given for the latter statement . The impression given by the statement that gastric deceleration accompanies the hypoglycaemic effects of GLP-1 is opposite to what was actually reported in the supporting reference, as similar glucose lowering was obtained with all doses of GLP-1 tested, whereas gastric emptying was inhibited in a dose-dependent manner . In other words, the dose–response relationship was shifted to the right. Despite this, we agree that the evidence to date suggests that the effect of the inhibitors on gastric emptying is either weak or absent. This may be related to the observation that there was no change in body weight over 1 year’s inhibition of DPP-IV . Based on the fact that inhibitor treatment merely doubles peripheral concentrations of intact GLP-1, and given the dose–response relationship for gastric emptying defined by Meier et al. , DPP inhibitors would not be expected to have a major effect on gastric emptying, despite a rather pronounced effect on glucose levels. The most important difference between DPP inhibitors and exogenous GLP-1 may be related to the fact that infusions of GLP-1 affect the islets via the endocrine pathway, whereas endogenously produced GLP-1 is likely to influence gastric motility by interacting with afferent sensory neurons in the gastrointestinal tract (Figs. 1, 2). This interaction may take place at a stage at which newly secreted GLP-1 is not yet, or is only partially, degraded by DPP-IV (i.e. before its entry into the capillaries of the gastrointestinal tract or prior to its passage through the liver). It follows that DPP-IV inhibition may not greatly influence this activation, since there is little or no change in local concentrations of intact GLP-1, whereas higher concentrations of exogenous GLP-1 may access and activate the same sensory neurons as endogenous GLP-1 does .
GLP-1 and incretin mimetics cause nausea/vomiting while DPP-IV inhibitors do not
It has been established that nausea will be elicited when circulating concentrations of active GLP-1 exceed 60 pmol/l. Such concentrations may be reached initially after subcutaneous injection of GLP-1 or GLP-1 mimetics, but are never seen when DPP-IV inhibitors are used. It is possible that interaction with receptors in the area postrema—an area of the blood–brain barrier with leaky fenestrated capillaries—is the pathway for this side-effect [24, 25], which would therefore be affected by circulating concentrations of GLP-1.
Meal-stimulated levels of GLP-1 fall in response to DPP-IV inhibition
It is argued that feedback inhibition of L-cell secretion during inhibitor treatment, as demonstrated by Deacon et al. , leaves “little potential for plasma concentrations of endogenously secreted GLP-1 to rise into the therapeutically relevant range.” There are several comments to be made here. First, all studies have shown that the peripheral concentration of intact GLP-1 does increase (by a factor of 2) during inhibitor treatment, in spite of decreased L-cell secretion. Second—given that the hepatoportal receptors may be of importance—concentrations of active GLP-1 in the portal plasma will be increased due to the inhibition of endothelial DPP-IV in the capillaries of the intestines and to the dilution factor discussed above. Third, we should bear in mind that, for both GLP-1 and GIP secretion, the measurements of feedback inhibition reported to date are based on acute studies. In contrast, the effects of DPP-IV inhibitors develop slowly, and early effects on glucose levels may be inconspicuous compared with those that only become apparent after 4–12 weeks. Concentrations of active GLP-1 and GIP may change over this period, in agreement with the hypothesis that the secretion of GLP-1 is decreased in type 2 diabetes, presumably as a consequence of the diabetic state [27, 28]. Incretin secretion or sensitivity to their effects might improve with gradual improvements in metabolism. For example, it has been reported that high glucose levels downregulate the GIP receptor , while the response to GIP has been seen to improve following antihyperglycaemic therapy with glyburide to reduce fasting glucose levels in diabetic patients .
DPP-IV inhibition has delayed effects on glucose homeostasis
As mentioned above and by our opponents, the effects of the inhibitors develop slowly, whereas the effects of GLP-1 are immediate. It is currently unknown why this is so, but it seems probable that this is related to increased secretion over time, and possibly to an enhanced effect of the incretin hormones, sensitivity to which is greatly reduced in untreated diabetes [8, 31].
We conclude that all the arguments put forward by our opponents can, in fact, be turned around to support the hypothesis that the main effects of DPP-IV inhibitors are mediated by GLP-1. We would like to add that this discussion has, perhaps, focused too much on insulin secretion, and that one of the more important therapeutic effects of GLP-1 may be the inhibition of glucagon secretion, as also seems to be the case for the DPP-IV inhibitors—once again, a striking similarity [11, 32]. Our opponents suggest that pancreatic neuropeptides may be alternative mediators, and this certainly remains a possibility. However, the importance of pancreatic innervation for postprandial insulin secretion in humans remains unclear. We conclude that the evidence available to date is consistent with the hypothesis that the protection of GLP-1 is a major contributor to the effects of DPP-IV inhibition.
- 1.Nauck MA, El-Ouaghlidi (2005) The therapeutic actions of DPP-IV are not mediated by glucagon-like peptide-1. Diabetologia DOI 10.1007/s00125-005-1704-8
- 2.Deacon CF, Nauck MA, Toft-Nielsen M (1995) Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes 44:1126–1131Google Scholar
- 3.Deacon CF, Johnsen AH, Holst JJ (1995) Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Metab 80:952–957Google Scholar
- 4.Holst JJ, Deacon CF (1998) Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. Diabetes 47:1663–1670Google Scholar
- 5.Mentlein R, Gallwitz B, Schmidt WE (1993) Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem 214:829–835Google Scholar
- 6.Mentlein R (1999) Dipeptidyl-peptidase IV (CD26)—role in the inactivation of regulatory peptides. Regul Pept 85:9–24Google Scholar
- 7.Vilsboll T, Holst JJ (2004) Incretins, insulin secretion and Type 2 diabetes mellitus. Diabetologia 47:357–366Google Scholar
- 8.Vilsboll T, Krarup T, Madsbad S, Holst JJ (2002) Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients. Diabetologia 45:1111–1119Google Scholar
- 9.Hansotia T, Baggio LL, Delmeire D et al (2004) Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors. Diabetes 53:1326–1335Google Scholar
- 10.Ahren B, Simonsson E, Larsson H et al (2002) Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in type 2 diabetes. Diabetes Care 25:869–875Google Scholar
- 11.Ahren B, Landin-Olsson M, Jansson PA, Svensson M, Holmes D, Schweizer A (2004) Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. J Clin Endocrinol Metab 89:2078–2084Google Scholar
- 12.Ahren B, Gomis R, Standl E, Mills D, Schweizer A (2004) Prolonged efficacy of LAF237 in patients with type 2 diabetes (T2DM) inadequately treated with metformin. Diabetes 53:7L-BGoogle Scholar
- 13.Vilsboll T, Krarup T, Deacon CF, Madsbad S, Holst JJ (2001) Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 50:609–613Google Scholar
- 14.Hansen L, Deacon CF, Orskov C, Holst JJ (1999) Glucagon-like peptide-1-(7-36)amide is transformed to glucagon-like peptide-1-(9-36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology 140:5356–5363Google Scholar
- 15.Hansen L, Hartmann B, Bisgaard T, Mineo H, Jørgensen PN, Holst JJ (2000) Somatostatin restrains the secretion of glucagon-like peptide-1 and 2 from isolated perfused porcine ileum. Am J Physiol 278:E1010–E1018Google Scholar
- 16.Deacon CF, Pridal L, Klarskov L, Olesen M, Holst JJ (1996) Glucagon-like peptide 1 undergoes differential tissue-specific metabolism in the anesthetized pig. Am J Physiol 2713:E458–E464Google Scholar
- 17.Holst JJ (2003) Implementation of GLP-1 based therapy of type 2 diabetes mellitus using DPP-IV inhibitors. Adv Exp Med Biol 524:263–279Google Scholar
- 18.Nakagawa A, Satake H, Nakabayashi H et al (2004) Receptor gene expression of glucagon-like peptide-1, but not glucose-dependent insulinotropic polypeptide, in rat nodose ganglion cells. Auton Neurosci 110:36–43Google Scholar
- 19.Nishizawa M, Nakabayashi H, Uchida K, Nakagawa A, Niijima A (1996) The hepatic vagal nerve is receptive to incretin hormone glucagon-like peptide-1, but not to glucose-dependent insulinotropic polypeptide, in the portal vein. J Auton Nerv Syst 61:149–154Google Scholar
- 20.Nakabayashi H, Nishizawa M, Nakagawa A, Takeda R, Niijima A (1996) Vagal hepatopancreatic reflex effect evoked by intraportal appearance of tGLP-1. Am J Physiol 271:E808–E813Google Scholar
- 21.Balkan B, Li X (2000) Portal GLP-1 administration in rats augments the insulin response to glucose via neuronal mechanisms. Am J Physiol Regul Integr Comp Physiol 279:R1449–R1454Google Scholar
- 22.Meier JJ, Gallwitz B, Salmen S et al (2003) 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 Metab 88:2719–2725Google Scholar
- 23.El-Ouaghlidi A, Rehring E, Schweizer A, Holmes D, Nauck MA (2003) The dipeptidyl peptidase IV inhibitor LAF237 does not accentuate reactive hypoglyaemia caused by the sulfonylurea glibenclamide administered before an oral glucose load in healthy subjects (abstract 507-P). Diabetes 52(Suppl 1):A118Google Scholar
- 24.Orskov C, Poulsen SS, Moller M, Holst JJ (1996) Glucagon-like peptide I receptors in the subfornical organ and the area postrema are accessible to circulating glucagon-like peptide I. Diabetes 45:832–835Google Scholar
- 25.Tang-Christensen M, Vrang N, Larsen PJ (2001) Glucagon-like peptide containing pathways in the regulation of feeding behaviour. Int J Obes Relat Metab Disord 25(Suppl 5):S42–S47Google Scholar
- 26.Deacon CF, Wamberg S, Bie P, Hughes TE, Holst JJ (2002) Preservation of active incretin hormones by inhibition of dipeptidyl peptidase IV suppresses meal-induced incretin secretion in dogs. J Endocrinol 172:355–362Google Scholar
- 27.Vaag AA, Holst JJ, Volund A, Beck-Nielsen HB (1996) Gut incretin hormones in identical twins discordant for non-insulin-dependent diabetes mellitus (NIDDM)—evidence for decreased glucagon-like peptide 1 secretion during oral glucose ingestion in NIDDM twins. Eur J Endocrinol 135:425–432Google Scholar
- 28.Toft-Nielsen M-B, Damholt MB, Madsbad S et al (2001) Determinants of the impaired secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetic patients. J Clin Endocrinol Metab 86:3717–3723Google Scholar
- 29.Lynn FC, Thompson SA, Pospisilik JA et al (2003) A novel pathway for regulation of glucose-dependent insulinotropic polypeptide (GIP) receptor expression in beta cells. FASEB J 17:91–93Google Scholar
- 30.Meneilly GS, Bryer-Ash M, Elahi D (1993) The effect of glyburide on beta-cell sensitivity to glucose- dependent insulinotropic polypeptide. Diabetes Care 16:110–114Google Scholar
- 31.Kjems LL, Holst JJ, Volund A, Madsbad S (2003) The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects. Diabetes 52:380–386Google Scholar
- 32.Creutzfeldt WO, Kleine N, Willms B, Orskov C, Holst JJ, Nauck MA (1996) Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I(7-36) amide in type I diabetic patients. Diabetes Care 19:580–586Google Scholar
- 33.Burcelin R, Da Costa A, Drucker D, Thorens B (2001) Glucose competence of the hepatoportal vein sensor requires the presence of an activated glucagon-like peptide-1 receptor. Diabetes 50:1720–1728Google Scholar
- 34.Dardevet D, Moore MC, Neal D, DiCostanzo CA, Snead W, Cherrington AD (2004) Insulin-independent effects of GLP-1 on canine liver glucose metabolism: duration of infusion and involvement of hepatoportal region. Am J Physiol Endocrinol Metab 287:E75–E81Google Scholar