Evidence for Early Impairment of Glucagon-Like Peptide 1-Induced Insulin Secretion in Human Type 2 (Non Insulin-Dependent) Diabetes

Abstract

To investigate a possible role of an enteroinsular axis involvement in the pathogenesis of type 2 diabetes, plasma glucagon-like peptide 1 (GLP-1) 7-36 amide response to nutrient ingestion was evaluated in type 2 diabetics affected by different degrees of β-cell dysfunction.

Methods: 14 patients on oral hypoglycaemic treatment (group A: HbA1C = 8.1 ± 1.8 %) and 11 age-matched diabetic patients on diet only (group B: HbA1C = 6.4 ± 0.9) participated in the study. 10 healthy volunteers were studied as controls. In the postabsorptive state, a mixed meal (700 kCal) was administered to all subjects, and blood samples were regularly collected up to 180′ for plasma glucose, insulin, glucagon, and GLP-1 determination.

Results: In the control group, the test meal induced a significant increase in plasma GLP-1 at 30′ and 60′ (p < 0.01); the peptide concentrations then returning toward basal levels. β-cell function estimation by HOMA score confirmed a more advanced involvement in group A than in group B (p < 0.01). In contrast, the insulin resistance degree showed a similar result in the two groups (HOMA-R). In group A, first-phase postprandial insulin secretion (0 - 60’) resulted, as expected, in being significantly reduced compared to healthy subjects (p < 0.001). In the same patients the mean fasting GLP-1 value was similar to controls, but the meal failed to increase plasma peptide levels, which even tended to decrease during the test (p < 0.01). In group B, food-mediated early insulin secretion was higher than in group A (p < 0.001), although significantly reduced when compared to controls (p < 0.01). Like group A, no GLP-1 response to food ingestion occurred in group B patients in spite of maintained basal peptide secretion. Whereas the test-meal did not significantly modify plasma glucagon levels in the control group, glucagon concentrations increased at 30’ and 60’ in both diabetic groups (p < 0.01).

Conclusions: 1) The functional integrity of GLP-1 cells results as being seriously impaired even in the condition of mild diabetes; 2) the early peptide failure could contribute to the development of β-cell deterioration which characterizes overt type 2 diabetes.

Key words

GLP-1 - Enteroinsular Axis - Diabetes

References

• 1 United Kingdom Prospective Diabetes Study Group (UKPDS 34) . Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes.  Lancet. 1998;  352 854-865
• 2 Jones L C, Clark A. B-cell neogenesis in type 2 diabetes.  Diabetes. 2001;  50 (Suppl. 1) S186-S187
• 3 Weyer C, Bogardus C, Mott D M, Pratley R E. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus.  J Clin Invest. 1999;  104 787-794
• 4 Pimenta W, Korytkowski M, Mitrakou A, Jenssen T, Yki-Jarvinen H, Evron W, Dailey G, Gerich J. Pancreatic β-cell dysfunction as the primary genetic lesion in NIDDM. Evidence from studies in normal glucose-tolerant individuals with a first-degree NIDDM relative.  JAMA. 1995;  273 (23) 1855-1861
• 5 United Kingdom Prospective Diabetes Study Group (UKPDS 13) . Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non insulin-dependent diabetes followed for three years.  BMJ. 1995;  310 83
• 6 Rudenski A S, Hadden D R, Atkinson A B, Kennedy L, Matthews D R, Merrett J D, Pockaj B, Turner R C. Natural history of pancreatic islet b-cell function in type 2 diabetes mellitus studied over six years by homeostasis model assessment.  Diab Med. 1988;  5 36-41
• 7 Sempoux C, Guiot Y, Dubois D, Moulin P, Rahier J. Human type 2 diabetes. Morphological evidence for abnormal B-cell function.  Diabetes. 2001;  50 (Suppl. 1) S172-S177
• 8 Kreymann B, Williams G, Ghatei M A, Bloom S R. Glucagon-like peptide 1 (7-36): a physiological incretin in man.  Lancet. 1987;  ii 1300-1304
• 9 Drucker D J. Glucagon-like peptides.  Diabetes. 1998;  47 59-169
• 10 Fehmann H C, Habener J F. Insulinotropic glucagon-like peptide 1 (7-37)/(7-36 amide). A new incretin hormone.  Trends Endocrinol Metab. 1992;  3 158-163
• 11 Edwards C MB, Todd J F, Mahmoudi M, Wang Z, Wang R M, Ghatei M A, Bloom S R. Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans. Studies with the antagonist exendin 9-39.  Diabetes. 1999;  48 86-93
• 12 Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non insulin-dependent) diabetes.  Diabetologia. 1986;  29 46-52
• 13 Tronier B, Dejgard A, Andersen T, Madsbad S. Absence of incretin effect in obese type 2 and diminished effect in lean type 2 and obese subjects.  Diabetes Res Clin Pract. 1985;  (Suppl. 1) S568
• 14 Lugari R, Dell'Anna C, Ugolotti D, Dei Cas A, Marani B, Iotti M, Orlandini A, Zandomeneghi R, Gnudi A. Effect of nutrients ingestion on glucagon-like peptide 1 (GLP-1) 7-36 amide secretion in human type 1 and type 2 diabetes.  Horm Met Res. 2000;  32 424-428
• 15 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.  Diabetes Care. 1998;  21 (1) S5-S19
• 16 Haffner S M, Miettinen H, Stern M P. The homeostasis model in the San Antonio heart study.  Diabetes Care. 1997;  20 (7) 1087-1092
• 17 Hermans M P, Levy J C, Morris R J, Turner R C. Comparison of insulin sensitivity tests across a range of glucose tolerance from normal to diabetes.  Diabetologia. 1999;  42 678-687
• 18 Bonora E, Targher G, Alberiche M, Bonadonna R C, Saggiani F, Zenere M B, Monauni T, Muggeo M. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity.  Diabetes Care. 2000;  23 57-63
• 19 United Kingdom Prospective Diabetes Study Group (UKPDS 33). Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes.  Lancet. 1998;  352 837-853
• 20 Luzi L, DeFronzo R A. Effect of loss of first-phase insulin secretion on hepatic glucose production and tissue glucose disposal in humans.  Am J Physiol. 1989;  257 E241-E246
• 21 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, Seino Y. Glucose intolerance caused by a defect in the enteroinsular axis: A study in gastric inhibitory polypeptide receptor knockout mice.  PNAS. 1999;  96 (26) 14 843-14 847
• 22 Scrocchi L A, Brown T J, Ma Klusky N, Brubaker P L, Auerbach A B, Joyner A L, Drucker D J. Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene.  Nat Med. 1996;  2 (11) 1254-1258
• 23 Ahren B, Larsson H, Holst J J. Reduced gastric inhibitory polypeptide but normal glucagon-like peptide 1 response to oral glucose in postmenopausal women with impaired glucose tolerance.  Eur J Endocrinol. 1997;  137 127-131
• 24 Byrne M M, Gliem K, Wank U, Arnold R, Katschinski M, Polonsky K S, Goke B. Glucagon-like peptide 1 improves the ability of the β-cell to sense and respond to glucose in subjects with impaired glucose tolerance.  Diabetes. 1998;  47 1259-1265
• 25 Broderick C L, Heisserman J A, Miller A R. Effect of sub-chronic administration of GLP1 (7-37) on β-cell failure in Zucker diabetic rats.  Diabetologia. 1995;  38 (1) A171
• 26 Holz G G, Kuhtreiber W M, Habener J F. Pancreatic β-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide 1 (7-37).  Nature. 1993;  361 362-365
• 27 Gutniak M, Orskov C, Holst J J, Ahren B, Efendic S. Antidiabetogenic effect of glucagon-like peptide 1 (7-36 amide) in normal subjects and in patients with diabetes mellitus.  N Engl J Med. 1992;  326 1316-1322
• 28 Nauck M A. Glucagon-like peptide 1: a potent gut hormone with a possible therapeutic perspective.  Acta Diabetol. 1998;  35 117-129
• 29 Rachman J, Barrow B A, Levy J C, Turner R C. Near-normalisation of diurnal glucose concentrations by continuous administration of glucagon-like peptide 1 (GLP-1) in subjects with NIDDM.  Diabetologia. 1997;  40 205-211
• 30 Nauck M A, Heimesaat M M, Orskov C, Holst J J, 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 Invest. 1993;  91 301-307
• 31 Lefebvre P J, Scheen A J. The postprandial state and risk of cardiovascular disease.  Diabet Med. 1998;  15 (4) S63-S68
• 32 Ceriello A. The post-prandial state and cardiovascular disease: relevance to diabetes mellitus.  Diabetes Res Rev. 2000;  16 (2) 125-132