Download PDF
Horm Metab Res 2002; 34(3): 150-154
DOI: 10.1055/s-2002-23199
Original Clinical
© Georg Thieme Verlag Stuttgart · New York

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

R.  Lugari 1 , A.  Dei Cas 1 , D.  Ugolotti 1 , L.  Finardi 1 , A.  L.  Barilli 1 , C.  Ognibene 2 , A.  Luciani 2 , R.  Zandomeneghi 2 , A.  Gnudi 1
  • 1Department of Endocrinology, University of Parma, Parma, Italy
  • 2Department of Internal Medicine, University of Modena, Modena, Italy
These results were accepted for the 37th Annual Meeting of the European Society for the Study of Diabetes (E.A.S.D.), 9 - 13 September 2001, Glasgow, U.K.
Further Information

Publication History

3 July 2001

30 October 2001

Publication Date:
26 March 2002 (online)

Also available at
    Permissions and Reprints

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
    CrossrefPubMedGoogle Scholar
  • 2 Jones L C, Clark A. B-cell neogenesis in type 2 diabetes.  Diabetes. 2001;  50 (Suppl. 1) S186-S187
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 9 Drucker D J. Glucagon-like peptides.  Diabetes. 1998;  47 59-169
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 12 Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non insulin-dependent) diabetes.  Diabetologia. 1986;  29 46-52
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.  Diabetes Care. 1998;  21 (1) S5-S19
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 28 Nauck M A. Glucagon-like peptide 1: a potent gut hormone with a possible therapeutic perspective.  Acta Diabetol. 1998;  35 117-129
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 31 Lefebvre P J, Scheen A J. The postprandial state and risk of cardiovascular disease.  Diabet Med. 1998;  15 (4) S63-S68
    CrossrefPubMedGoogle Scholar
  • 32 Ceriello A. The post-prandial state and cardiovascular disease: relevance to diabetes mellitus.  Diabetes Res Rev. 2000;  16 (2) 125-132
    CrossrefPubMedGoogle Scholar

Dr. Roberta Lugari

Cattedra di Endocrinologia

Via Gramsci 14 · 43100 Parma · Italy

Phone: + 39 (521) 290 778 ·

Fax: + 39 (521) 982 943

Email: endoparm@ipruniv.cce.unipr.it