Lack of germline mutations in the preproglucagon gene region coding for glucagon-like peptide 1 in Type 2 diabetic (NIDDM) patients

 

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Summary:

Glucagon-like peptide 1 (GLP-1) has antidiabetic effects and many facets of Type 2 diabetes could theoretically be the consequence of a reduction in or lack of GLP-1 function. Exogenous GLP-1 is exquisitely effective in Type 2 diabetic patients, making receptor defects unlikely. GLP-1 responses after meals as detected by radioimmunoassay are not overtly reduced in Type 2 diabetic patients. Therefore, a sequence analysis of exon 2 of the preproglucagon gene coding for the GLP-1 protein was initiated in order to exclude potential germline mutations. 24 Type 2 diabetic patients and in 14 control subjects with normal oral glucose tolerance (WHO criteria) were studied. In all specimens of peripheral blood leukocyte DNA examined, no germline mutations of the GLP-1 sequence were identified, thus excluding mutations in the GLP-1 sequence as a major contributor to the pathophysiological appearance of the Type 2 diabetic phenotype. Rare mutations, however, cannot be excluded due to the small number of Type 2 diabetic patients examined.

References

• 1 Bell G I, Sanchez-Pescador R, Laybourn P J, Najarian R C. Exon duplication and divergence in the human preproglucagon gene.  Nature. 304 368-371 1983; 
  CrossrefPubMedGoogle Scholar
• 2 Cox N J, Xiang K-S, Fajans S. Bell GI: Mapping diabetes-susceptibility genes. Lessons learned from search for DNA marker for maturity-onset diabetes of the young.  Diabetes. 41 401-407 1992; 
  PubMedGoogle Scholar
• 3 Fehmann H C, Gherzi R, Göke B. Regulation of islet hormone gene expression by incretin hormones.  Exp Clin Endocrinol Diabetes. 103 Suppl 2 56-65 1995; 
  PubMedGoogle Scholar
• 4 Gutniak M K, Holst J J, Ørskov C, Åhren B, Efendic S. Antidiabetogenic effect of glucagon-like peptide-1 (7-36)amide in normal subjects and patients with diabetes mellitus.  N Engl J Med.. 326 1316-1322 1992; 
  CrossrefPubMedGoogle Scholar
• 5 Holst J J, Orskov C, Vagn-Nielsen O, Schwartz T W. Truncated glucagon-like peptide 1, an insulin-releasing hormone from the distal gut.  FEBS Letters.. 211 169-174 1987; 
  CrossrefPubMedGoogle Scholar
• 6 Kolligs F, Fehmann H C, Göke R, Göke B. Reduction of the incretin effect in rats by the glucagon-like peptide 1 receptor antagonist exendin (9-39) amide.  Diabetes. 44 16-19 1995; 
  PubMedGoogle Scholar
• 7 Komatsu R, Matsuyama T, Namba M. et al. . Glucagonostatic and insulinotropic action of glucagonlike peptide I-(7-36)-amide.  Diabetes. 38 902-905 1989; 
  CrossrefPubMedGoogle Scholar
• 8 Kreymann B, Williams G, Ghatei MA, Bloom SR. Glucagon-like peptide-1 [7-36]: a physiological incretin in man.  Lancet. 2 1300-1304 1987; 
  PubMedGoogle Scholar
• 9 Mojsov S, Weir G C, Habener J F. Insulinotropin: glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas.  J Clin Invest. 79 616-619 1987; 
  CrossrefPubMedGoogle Scholar
• 10 Nathan D M, Schreiber E, Fogel H, Mojsov S, Habener J F. Insulinotropic action of glucagon-like peptide 1 (7-37) in diabetic and non-diabetic subjects.  Diabetes Care. 15 270-276 1992; 
  PubMedGoogle Scholar
• 11 Nauck M A, Bartels E, Ørskov C, Ebert R, Creutzfeldt W. Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-1-(7-36) amide infused at near-physiological insulinotropic hormone and glucose concentrations.  J Clin Endocrinol Metab. 76 912-917 1993a; 
  CrossrefPubMedGoogle Scholar
• 12 Nauck M A, Heimesaat M M, Ørskov 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. 91 301-307 1993b; 
  CrossrefPubMedGoogle Scholar
• 13 Nauck M A, Kleine N, Ørskov C, Holst J J, 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.  Diabetologia. 36 741-744 1993c; 
  CrossrefPubMedGoogle Scholar
• 14 Nauck M A, Niedereichholz U, Ettler R. et al. . Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans.  Am J Physiol. 273 E981-988 1997; 
  PubMedGoogle Scholar
• 15 Ørskov C. Glucagon-like peptide-1, a new hormone of the entero-insular axis.  Diabetologia. 35 701-711 1992; 
  PubMedGoogle Scholar
• 16 Ørskov C, Holst J J, Nielsen O V. Effect of truncated glucagon-like peptide-1 [proglucagon-(78-107) amide] on endocrine secretion from pig pancreas, antrum, and nonantral stomach.  Endocrinology. 123 2009-2013 1988; 
  PubMedGoogle Scholar
• 17 Ørskov C, Jeppesen J, Madsbad S, Holst J J. Proglucagon products in plasma of noninsulin-dependent diabetics and nondiabetic controls in the fasting state and after oral glucose and intravenous arginine.  J Clin Invest. 87 415-423 1991; 
  CrossrefPubMedGoogle Scholar
• 18 Ørskov C, Knuhtsen S, Baldissera F G, Poulsen S S, Nielsen O V, Holst J J. Glucagon-like peptides GLP-1 and GLP-2, predicted products of the glucagon gene, are secreted separately from pig small intestine but not pancreas.  Endocrinology. 119 1467-1475 1986; 
  PubMedGoogle Scholar
• 19 Sauerwald A, Hahn S, Schmiegel W, Nauck M. Fehlen von Mutationen im Proglucagon-Exon, das für GLP-1 codiert, bei Patienten mit Typ II-Diabetes.  Diabetes Stoffw.. 6 (Suppl. 1) 97 1997; 
  PubMedGoogle Scholar
• 20 Stoffel M, Espinosa R d, Le Beau M M, Bell G I. Human glucagon-like peptide-1 receptor gene. Localization to chromosome band 6p21 by fluorescence in situ hybridization and linkage of a highly polymorphic simple tandem repeat DNA polymorphism to other markers on chromosome 6.  Diabetes. 42 1215-1218 1993; 
  CrossrefPubMedGoogle Scholar
• 21 Turner R C, Hattersley A T, Shaw J TE, Levy J C. Type II diabetes: Clinical aspacts of molecular biological studies.  Diabetes. 44 1-10 1995; 
  PubMedGoogle Scholar
• 22 Turton M D, O'Shea D, Gunn I. et al. . A role for glucagon-like peptide-1 in the central regulation of feeding.  Nature. 379 69-72 1996; 
  CrossrefPubMedGoogle Scholar
• 23 Valverde I, Villanueva Penacarrillo M L. In vitro insulinomimetic effects of GLP-1 in liver, muscle and fat.  Acta Physiol Scand.. 157 359-360 1996; 
  CrossrefPubMedGoogle Scholar
• 24 Vionnet N, Hani E H, Lesage S. et al. . Genetics of NIDDM in France. Studies with 19 candidate genes in affected sib pairs.  Diabetes. 46 1062-1068 1997; 
  PubMedGoogle Scholar
• 25 Walsh P S, Metzger D A, Higuchi R. Chelex 100 as a medium for simple extraction of DNA for PCR-based typing from forensic material.  BioTechniques. 10 506-513 1991; 
  PubMedGoogle Scholar
• 26 Wang Z, Wang R M, Owji A A, Smith D M, Ghatei M A, Bloom S R. Glucagon-like peptide-1 is a physiological incretin in rat.  J Clin Invest.. 95 417-421 1995; 
  CrossrefPubMedGoogle Scholar
• 27 Willms B, Werner J, Holst J J, Ørskov C, Creutzfeldt W, Nauck M A. 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 Metab.. 81 327-332 1996; 
  CrossrefPubMedGoogle Scholar

Prof. Dr. med. Michael Nauck

Medizinische Universitätsklinik

Knappschaftskrankenhaus

In der Schornau 23-25

D-44892 Bochum

Phone: 0234-299-3412

Fax: 0234-299-3409

Email: Michael.Nauck@ruhr-uni-bochum.de