Enteroinsular signaling: Perspectives on the role of the gastrointestinal hormones glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide in normal and abnormal glucose metabolism

Current Opinion in Clinical Nutrition and Metabolic Care

Volumn 6, Issue 4, 2003, Pages 461-468

  Vahl, Torsten ^a   D'Alessio, David ^a  

^a UNIVERSITY OF CINCINNATI   (United States)

Author keywords

G1 hormone; Glucagon like peptide 1 (GLP 1); Glucose tolerance; Glucose dependent insulinotropic polypeptide (GIP); Incretin

Indexed keywords

EXENDIN 4; GASTROINTESTINAL HORMONE; GLUCAGON LIKE PEPTIDE 1; HEMOGLOBIN A1C; INCRETIN; LIRAGLUTIDE; POLYPEPTIDE; UNCLASSIFIED DRUG;

DIET RESTRICTION; GASTROINTESTINAL MUCOSA; GLUCOSE HOMEOSTASIS; GLUCOSE METABOLISM; HORMONE RELEASE; HUMAN; INSULIN LIKE ACTIVITY; INSULIN RELEASE; INSULIN SENSITIVITY; INTESTINE FUNCTION; PANCREAS ISLET CELL; PATHOPHYSIOLOGY; REVIEW;

EID: 0842298688     PISSN: 13631950     EISSN: None     Source Type: Journal    
DOI: 10.1097/01.mco.0000078991.96795.84     Document Type: Review

References (68)

1. Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev 1999; 20:876-913.
2. D'Alessio DA. Incretins: glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1. In: Porte JD, Sherwin RS, Baron A, editors. Ellenberg & Rifkins's diabetes mellitus. 6th ed. New York: McGraw-Hill; 2002. pp. 85-96.
3. Schirra J, Katschinski M, Weidmann C, et al. Gastric emptying and release of incretin hormones after glucose ingestion in humans. J Clin Invest 1996; 97:92-103.
4. Rocca AS, Brubaker PL. Vagal control of intestinal proglucagon-derived peptide secretion. 10th Annual Congress of Endocrinology; 1996. pp. 2-21.
5. Rocca AS, Brubaker PL. Role of the vagus nerve in mediating proximal nutrient-induced glucagon-like peptide-1 secretion. Endocrinology 1999; 140:1687-1694.
6. Anini Y, Hansotia T, Brubaker PL. Muscarinic receptors control postprandial release of glucagon-like peptide-1: in vivo and in vitro studies in rats. Endocrinology 2002; 143:2420-2426. This paper provides pharmacological and immunocytochemical support for involvement of a cholinergic pathway in the release of GLP-1 from intestinal L cells.
7. Hansen L, Holst JJ. The effects of duodenal peptides on glucagon-like peptide-1 secretion from the ileum: a duodeno-ijeal loop? Regul Pept 2002; 110:39-45.
8. Blat S, Guerin S, Chauvin A, et al. The vagus is inhibitory of the late postprandial insulin secretion in conscious pigs. Auton Neurosci 2002; 101:68-77. The authors demonstrate that vagotomy does not significantly impair meal induced secretion of GIP and GLP-1. Data such as these cloud a growing consensus supporting neural mediation of GLP-1 secretion.
9. Balks HJ, Hoist JJ, von zur Muhlen A, Brabant G. Rapid oscillations in plasma glucagon-like peptide-1 (GLP-1) in humans: cholinergic control of GLP-1 secretion via muscarinic receptors. J Clin Endocrinol Metab 1997; 82:786-790.
10. Ahren B, Holst JJ, The cephalic insulin response to meal ingestion in humans is dependent on both cholinergic and noncholinergic mechanisms and is important for postprandial glycemia. Diabetes 2001; 50:1030-1038.
11. Reimann F, Gribble FM, Glucose-sensing in glucagon-like peptide-1-secreting cells. Diabetes 2002; 51:2757-2763. This paper makes the case that nutrient responsive enteral endocrine cells may use similar mechanisms of glucose sensing as islet β cells.
12. Ni Z, Anini Y, Fang X, et al. Transcriptional activation of the proglucagon gene by lithium and beta-catenin in intestinal endocrine L cells. J Biol Chem 2003; 278:1380-1387. This paper describes a novel mechanism for the regulation of proglucagon production and provides a potential explanation for the observation that LiCl administration stimulates GLP-1 signaling in the brain.
13. van Gitters GW, Kabir M, Kim SP, et al. Elevated glucagon-like peptide-1-(7-36)-amide, but not glucose, associated with hyperinsulinemic compensation for fat feeding. J Clin Endocrinol Metab 2002; 87:5191-5198. This paper clearly demonstrates the effect of chronic dietary factors to modulate the secretion of GLP-1. Of great interest was the effect of high-fat feeding to increase the expression of the GLP-1 receptor, a response that would tend to further amplify GLP-1 signaling.
14. Anini Y, Brubaker PL. Role of leptin in the regulation of glucagon-like peptide-1 secretion. Diabetes 2003; 52:252-259. This paper presents evidence that the adipocyte hormone leptin stimulates GLP-1 secretion. This is the most convincing evidence to date of endocrine regulation of the L-cell. This provides a mechanism whereby incretin function, and glucose metabolism, is linked to adiposity and energy balance.
15. Boyd KA, O'Donovan DG, Doran S, et al. High-fat diet effects on gut motility, hormone, and appetite responses to duodenal lipid in healthy men. Am J Physiol Gastrointest Liver Physiol 2003; 284:G188-G196. High-fat feeding to healthy men for 14 days did not change the secretion of GLP-1. It is possible that the relatively short period of the high-fat diet, and the absence of weight gain in these individuals, contributed to the absence of an effect.
16. Mentlein R. Dipeptidyl-peptidase IV (CD26): role in the inactivation of regulatory peptides. Regul Pept 1999; 85:9-24.
17. Deacon CF, Plamboeck A, Moller S, Holst JJ. GLP-1-(9-36) amide reduces blood glucose in anesthetized pigs by a mechanism that does not involve insulin secretion. Am J Physiol Endocrinol Metab 2002; 282:E873-E879. The GLP-1 metabolite GLP-1-(9-36) did not affect glucose-stimulated insulin secretion in the pig, but did promote glucose disappearance. This is the first demonstration of the effects of GLP-1-(9-36) on parameters of glucose metabolism in vivo.
18. Kashima Y, Miki T, Shibasaki T, et al. Critical role of cAMP-GEFII-Rim2 complex in incretin-potentiated insulin secretion. J Biol Chem 2001; 276:46046-46053. It has generally been held that a key proximal step in incretin-stimulated insulin release is cAMP activation of PKA. This paper demonstrates an alternative pathway via cAMP-regulated guanine nucleotide exchange factor II that is PKA independent, and accounts for nearly half of the intracellular incretin effect
19. ATP channel closure by PKA would be greater. This mechanism is proposed as an explanation for the glucose dependence of GLP-1 stimulated insulin secretion.
20. V, prolonging β-cell depolarization, calcium influx and insulin secretion.
21. Delgado-Aros S, Kim DY, Burton DD, et al. Effect of GLP-1 on gastric volume, emptying, maximum volume ingested, and postprandial symptoms in humans. Am J Physiol Gastrointest Liver Physiol 2002; 282:G424-G431. It has been known for several years that GLP-1 can inhibit gastric emptying, and in high doses this contributes considerably to its effect to lower blood glucose following a meal. In this paper the authors have used a new technique for assessing gastric volume, single photon emission computed tomography imaging, combined with more traditional scintigraphic methods of measuring gastric emptying in a study of GLP-1 effects on gastric function. Intravenous GLP-1 caused gastric relaxation and increased the maximal tolerated volume of a liquid meal as well as delaying gastric emptying. These data indicate that GLP-1 has differential effects on the regions of the stomach, relaxing the proximal portions to expand reservoir capacity, and increasing tone in the antro-pyloric region to slow emptying.
22. Schirra J, Wank U, Arnold R, et al. Effects of glucagon-like peptide-1(7-36)amide on motility and sensation of the proximal stomach in humans. Gut 2002; 50:341-348. In this study manometric techniques were used to evaluate the effect of GLP-1 on gastric tone. The authors observed that GLP-1 dose-dependently reduced gastric tone, reduced contractions and enhanced capacitance. These data are consistent with the findings reported by Delgado-Aros above, and raise important new questions as to the physiologic role of GLP-1 in regulating gastric function.
23. Vella A, Shah P, Reed AS, et al. Lack of effect of exendin-4 and glucagon-likis peptide-1-(7,36)-amide on insulin action in non-diabetic humans. Diabetologia 2002; 45:1410-1415. This study compared intravenous GLP-1 and the GLP-1 receptor agonist exendin-4 on glucose metabolism in healthy volunteers. Because exendin-4 is resistant to degradation by DPP IV the authors hypothesized that it could have enhanced actions on glucose disappearance and suppression of hepatic glucose uptake. In fact, they observed that neither GLP-1 nor exendin-4 affected these processes significantly compared with a saline control. These results are consistent with a body of work that does not find independent effects of GLP-1 on glucose disposition.
24. Egan JM, Meneilly GS, Habener JF, Elahi D. Glucagon-like peptide-1 augments insulin-mediated glucose uptake in the obese state. J Clin Endocrinol Metab 2002; 87:3768-3773. This study was an extension of previous work by this group demonstrating insulin-independent effects of GLP-1 to increase glucose disappearance in elderly but not young individuals. In this study GLP-1 was given during a hyperglycemic clamp to a group of obese and presumably insulin-resistant individuals. For a comparison they repeated the clamp without GLP-1 but with an infusion of insulin to achieve a comparable level of insulinemia. The results indicate that glucose uptake was greater during GLP-1 infusion. This paper continues a trend whereby different groups find extra-islet effects of GLP-1 on glucose regulation prolonging a debate that has not yet been conclusively decided.
25. Miyawaki K, Yamada Y, Ban N, et al. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med 2002; 8:738-742. In this elegant study a role for GIP in total body fat balance is demonstrated using mice with a targeted disruption of the GIP receptor gene. GIPr -/- mice are resistant to weight gain on a high-fat diet, and absence of the GIPr blunts the weight trajectory of leptin deficient mice with the ob/ob mutation. The effect of GIP on adipogenesis is proposed to act through peripheral fatty acid oxidation.
26. Vilsboll T, Krarup T, Madsbad S, Hoist JJ. Defective amplification of the late phase insulin response to glucose by GIP in obese type II diabetic patients. Diabetologia 2002; 45:1111-1119. The insulinotropic effect of GIP is typically lost in people with diabetes, and this study demonstrates that this defect involves primarily the late, or second, phase of intravenous glucose induced insulin secretion.
27. Meier JJ, Hucking K, Hoist JJ, et al. Reduced insulinotropic effect of gastric inhibitory polypeptide in first-degree relatives of patients with type 2 diabetes. Diabetes 2001; 50:2497-2504.
28. Lynn FC, Pamir N, Ng EH, et al. Defective glucose-dependent insulinotropic polypeptide receptor expression in diabetic fatty Zucker rats. Diabetes 2001; 50:1004-1011.
29. Lynn FC, Thompson SA, Pospisilik JA, et al. A novel pathway for regulation of glucose-dependent insulinotropic polypeptide (GIP) receptor expression in beta cells. FASEB J 2003; 17:91-93. A series of experiments are presented that demonstrate the regulation of GIP receptor expression by nutrient substrates. Glucose is shown to have a dominant effect.
30. Vilsboll T, Krarup T, Deacon CF, et al. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 2001; 50:609-613.
31. Toft-Nielsen MB, Damholt MB, Madsbad S, et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab 2001; 86:3717-3723.
32. Lugari R, Dei Gas A, Ugolotti D, et al. Evidence for early impairment of glucagon-like peptide 1-induced insulin secretion in human type 2 (non insulin-dependent) diabetes. Horm Metab Res 2002; 34:150-154. In this study plasma GLP-1 responses were found to be severely attenuated in groups of type 2 diabetic patients treated with oral agents or diet. These findings are in line with the results of several other recent studies and suggest that there may be some impairment of GLP-1 responses in humans with diabetes.
33. Toft-Nielsen MB, Madsbad S, Hoist JJ. Determinants of the effectiveness of glucagon-like peptide-1 in type 2 diabetes. J Clin Endocrinol Metab 2001; 86:3853-3860.
34. Kjems LL, Hoist JJ, Volund A, Madsbad S. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects. Diabetes 2003; 52:380-386. It is known that GLP-1 augments insulin release in persons with type 2 diabetes. However, it has previously not been known whether people with diabetes have a normal, decreased or even augmented sensitivity to GLP-1. In this study the authors make the case that β-cell sensitivity to GLP-1 is diminished in patients with diabetes.
35. Greenbaum CJ, Prigeon RL, D'Alessio DA. Impaired beta-cell function, incretin effect, and glucagon suppression in patients with type 1 diabetes who have normal fasting glucose. Diabetes 2002; 51:951-957. This paper characterizes β-cell function and glucose tolerance in a group of patients with preclinical autoimmune diabetes. Among several abnormalities these individuals have impairment in the incretin effect.
36. Staffers DA, Kieffer TJ, Hussain MA, et al. Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas. Diabetes 2000; 49:741-748.
37. Xu G, Stoffers DA, Habener JF, Bonner-Weir S. Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes 1999; 48:2270-2276.
38. Zhou J, Wang X, Pineyro MA, Egan JM. Glucagon-like peptide 1 and exendin-4 convert pancreatic AR42J cells into glucagon- and insulin-producing cells. Diabetes 1999; 48:2358-2366.
39. Hui H, Wright C, Perfetti R. Glucagon-like peptide 1 induces differentiation of islet duodenal homeobox-1-positive pancreatic ductal cells into insulin-secreting cells. Diabetes 2001; 50:785-796.
40. Bulotta A, Hui H, Anastasi E, et al. Cultured pancreatic ductal cells undergo cell cycle re-distribution and beta-cell-like differentiation in response to glucagon-like peptide-1. J Mol Endocrinol 2002; 29:347-360. In this paper the temporal effects of GLP-1 on the growth and differentiation of a pancreatic ductal stem cell line are described. The findings support the hypothesis that GLP-1 has a role in islet neogensis.
41. Zhou J, Pineyro MA, Wang X, et al. Exendin-4 differentiation of a human pancreatic duct cell line into endocrine cells: involvement of PDX-1 and HNFSbeta transcription factors. J Cell Physiol 2002; 192:304-314. The authors present data on the effect of GLP-1 on temporal expression of transcription factors that are important in the differentiation of the pancreatic ductal cell line Capan-1 into β-cells. These results emphasize the importance of GLP-1 regulation of the transcription factor PDX islet cell differentiation.
42. Hardikar AA, Wang XY, Williams LJ, et al. Functional maturation of fetal porcine beta-cells by glucagon-like peptide 1 and cholecystokinin. Endocrinology 2002; 143:3505-3514. Fetal pig islet cells demonstrated biochemical maturation and increased differentiation when exposed to GLP-1. Importantly maturation into insulin secreting cells occurred relatively quickly while the differentiation effect required 4 days in culture with GLP-1. Fetal islet cells treated with GLP-1 for 4 days before transplantation to nude mice secreted insulin in response to glucose while transplanted fetal cells that were not treated did not. These results demonstrate the potential utility of GLP-1 in islet based strategies for treating diabetes.
43. Abraham EJ, Leech CA, Lin JC, et al. Insulinotropic hormone glucagon-like peptide-1 differentiation of human pancreatic islet-derived progenitor cells into insulin-producing cells. Endocrinology 2002; 143:3152-3161. Nestin expression is a characteristic of undifferentiated islet progenitor cells. Nestin-positive cells express the GLP-1 receptor and on treatment with GLP-1 increase intracellular calcium and synthesize and secrete insulin. Nestin positive cells also make proglucagon and secrete GLP-1. The authors propose that GLP-1 may be involved in an autocrine loop that promotes the development of stem cells into islets.
44. Buteau J, Foisy S, Rhodes CJ, et al. Protein kinase Czeta activation mediates glucagon-like peptide-1-induced pancreatic beta-cell proliferation. Diabetes 2001; 50:2237-2243.
45. Gomez E, Prrtchard C, Herbert TP. cAMP-dependent protein kinase and Ca2+ influx through L-type voltage-gated calcium channels mediate Raf-independent activation of extracellular regulated kinase in response to glucagon-like peptide-1 in pancreatic beta-cells. J Biol Chem 2002; 277:48146-48151. GLP-1 activates ERK in a glucose-dependent manner. In the β-cell line MIN6, this process is dependent on activation of PKA CAM kinase and increased flux through voltage gated calcium channels. These data suggest that GLP-1 effects on β-cell growth may be dependent on increases in glucose, similar to GLP-1 stimulated insulin secretion.
46. Buteau J, Foisy S, Joly E, Prentki M. Glucagon-like peptide 1 induces pancreatic beta-cell proliferation via transactivation of the epidermal growth factor receptor. Diabetes 2003; 52:124-132. Evidence is presented for a novel mechanism by which GLP-1 stimulates the proliferation of β-cells.
47. MacDonald PE, El-Kholy W, Riedel MJ, et al. The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion. Diabetes 2002; 51:S434-S442. An excellent review of the current literature on GLP-1 stimulation of the β cell.
48. Li Y, Hansotia T, Yusta B, et al. Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis. J Biol Chem 2003; 278:471-478. A demonstration of the anti-apoptotic actions of GLP-1 in vivo. Mice given the β-cell toxin streptozotocin had less apotosis when receiving exendin-4.
49. Farilla L, Hui H, Bertolotto C, et al. Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats. Endocrinology 2002; 143:4397-4408. Treatment of Zucker diabetic fatty rats with a 2-day continuous infusion of GLP-1 improved insulin secretion and glucose tolerance 48 h later. GLP-1 treatment of these animals both increased β-cell proliferation and suppressed apoptosis.
50. Wang Q, Brubaker PL. Glucagon-like peptide-1 treatment delays the onset of diabetes in 8 week-old db/db mice. Diabetologia 2002; 45:1263-1273. Administration of exendin-4 to db/db mice for 2 weeks caused a significant improvement in their glucose tolerance. This effect was due to several important factors among them an increases in insulin synthesis, glucose and insulin stimulated insulin secretion, and β-cell mass.
51. Trumper A, Trumper K, Horsch D. Mechanisms of mitogenic and anti-apoptotic signaling by glucose-dependent insulinotropic polypeptide in beta(INS-1)-cells. J Endocrinol 2002; 174:233-246. This paper presents a series of experiments in the INS β-cell line that serve to demonstrate the important pathways of signal transduction activated by the GIP receptor. A useful overview of GIP signaling.
52. Ehses JA, Pelech SL, Pederson RA, McIntosh CH. Glucose-dependent insulinotropic polypeptide activates the Raf-Mek1/2-ERK1/2 module via a cyclic AMP/cAMP-dependent protein kinase/Rap1-mediated pathway. J Biol Chem 2002; 277:37088-37097. This paper focuses on the regulation of growth initiating pathways by GIP. The results suggest a role for cAMP and PKA in this process. The authors provide a nuanced and edifying discussion of GIP, and incretin, action on the β cell.
53. Pamir N, Lynn FC, Buchan AM, et al. Glucose-dependent insulinotropic polypeptide receptor null mice (GIPR-/-) exhibit compensatory changes in the enteroinsular axis. Am J Physiol Endocrinol Metab 2003; 284:E931-939 [epub ahead of print]. Mice with a targeted deletion of the GIP receptor have impaired insulin synthesis, insulin secretion and glucose tolerance. However, β-cell sensitivity to GLP-1 is enhanced in these animals. These results are congruent with a previous study by this group indicating that GLP-1 receptor knockout mice have increased sensitivity to GIP. Together these results present the interesting possibility that the incretins are able to compensate one for the other.
54. Ling Z, Wu D, Zambre Y, et al. Glucagon-like peptide 1 receptor signaling influences topography of islet cells in mice. Virchows Arch 2001; 438:382-387.
55. Miyawaki K, Yamada Y, Yano H, et al. 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 A 1999; 96:14843-14847.
56. Sakuraba H, Mizukami H, Yagihashi N, et al. Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese type II diabetic patients. Diabetologia 2002; 45:85-96.
57. Butler AE, Janson J, Bonner-Weir S, et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003; 52:102-110.
58. Tourrel C, Bailbe D, Lacorne M, et al. Persistent improvement of type 2 diabetes in the Goto-Kakizaki rat model by expansion of the beta-cell mass during the prediabetic period with glucagon-like peptide-1 or exendin-4. Diabetes 2002; 51:1443-1452. This paper adds to the evidence that GLP-1 signaling can increase islet mass and may have clinical application in this regard. The Goto-Kakizaki rat, one of the better rat models of type 2 diabetes mellitus, has a decreased islet mass as a primary defect. One week treatment with GLP-1 improved β-cell mass in young Goto-Kakizaki rats. Moreover, this treatment was apparent as improved glucose tolerance in adult animals.
59. Zander M, Madsbad S, Madsen JL, Hoist JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 2002; 359:824-830. The most comprehensive and convincing of the long-term studies using GLP-1 to treat type 2 diabetes.
60. Nauck MA, Heimesaat MM, Behle K, et al. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab 2002; 87:1239-1246. Infusion of GLP-1 to normal volunteers during a stepped hypoglycemic clamp had no effect on the response of glucagon, cortisol, norepinephrine, epinephrine or neuroglycopenic symptoms compared with a control study.
61. Egan JM, Clocquet AR, Elahi D. The insulinotropic effect of acute exendin-4 administered to humans: comparison of nondiabetic state to type 2 diabetes. J Clin Endocrinol Metab 2002; 87:1282-1290. Administration of a 60 min pulse of exendin-4 caused an insulinotropic effect that lasted for several hours in diabetic and nondiabetic humans. This effect was dependent on elevation of plasma glucose.
62. Egan JM, Meneilly GS, Elahi D. Effects of one month bolus subcutaneous administration of exendin-4 in type 2 diabetes. Am J Physiol Endocrinol Metab 2003 [epub ahead of print]. Patients with type 2 diabetes with poor glycemic control were given twice daily exendin-4 for 1 month. Glycemic control was improved based on significantly lower hemoglobin A1c levels. There was no effect of exendin on insulin sensitivity, hepatic glucose production, glucagon levels or fatty acid concentrations. The improvement in glycemic control is likely due to improved insulin secretion.
63. Juhl CB, Hollingdal M, Sturis J, et al. Bedtime administration of NN2211, a long-acting GLP-1 derivative, substantially reduces fasting and postprandial glycemia in type 2 diabetes. Diabetes 2002; 51:424-429. The long acting GLP-1 analogue was given to 11 well controlled patients with diabetes as a single evening injection. There was a significant improvement in fasting and postprandial glycemic and insulin responses up to 12 h after dosing.
64. Reimer MK, Holst JJ, Ahren B. Long-term inhibition of dipeptidyl peptidase IV improves glucose tolerance and preserves islet function in mice. Eur J Endocrinol 2002; 146:717-727. Eight weeks of treatment with a DPP IV inhibitor improved insulin secretion and glucose tolerance in normal and insulin resistant mice. Islet expression of the GLUT-2 glucose transporter was augmented suggesting one mechanism by which DPP IV inhibitors act.
65. Sudre B, Broqua P, White RB, et al. Chronic inhibition of circulating dipeptidyl peptidase IV by FE 999011 delays the occurrence of diabetes in male Zucker diabetic fatty rats. Diabetes 2002; 51:1461-1469. Treatment with a DPP IV inhibitor improved glucose tolerance in fatly Zucker rats and delayed the onset of hyperglycemia in diabetes-prone Zuckers. Treatment increased both plasma GLP-1 levels and islet expression of the GLP-1 receptor.
66. Pospisilik JA, Stafford SG, Demuth HU, et al. Long-term treatment with the dipeptidyl peptidase IV inhibitor P32/98 causes sustained improvements in glucose tolerance, insulin sensitivity, hyperinsulinemia, and beta-cell glucose responsiveness in VDF (fa/fa) Zucker rats. Diabetes 2002; 51:943-950. Zucker diabetic rats had improved glucose tolerance, insulin secretion and insulin sensitivity after 3 months of treatment with a DPP IV inhibitor compared with placebo treated controls,
67. Pospisilik JA, Stafford SG, Demuth HU, et al. Long-term treatment with dipeptidyl peptidase IV inhibitor improves hepatic and peripheral insulin sensitivity in the VDF Zucker rat: a euglycemic-hyperinsulinemic clamp study. Diabetes 2002; 51:2677-2683. Twelve weeks of DPP IV inhibitor treatment improved both hepatic and peripheral insulin sensitivity in Zucker diabetic rats. While the specific mechanism for these effects is not known, the findings here are consistent with studies showing that long-term treatment with a GLP-1 receptor agonist improves insulin sensitivity.
68. Ahren B, Simonsson E, Larsson H, et al. Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in type 2 diabetes. Diabetes Care 2002; 25:869-875. The best demonstration to date of the potential of DPP IV inhibition in the treatment of type 2 diabetes.