title: Contribution of abnormal insulin secretion and insulin resistance to the pathogenesis of type 2 diabetes in myotonic dystrophy.
abstract: OBJECTIVE
  Myotonic dystrophy (MyD), the most common adult form of muscular dystrophy, is often complicated by diabetes. MyD is dominantly inherited and is due to heterozygosity for a trinucleotide repeat expansion mutation in a protein kinase gene able to induce derangement of RNA metabolism responsible of an aberrant insulin receptor expression.
  
  
  METHODS
  To assess insulin sensitivity and secretion before the onset of diabetes, we studied 10 MyD patients, 10 offspring of type 2 diabetes (OFF), and 10 healthy subjects with no family history of diabetes (control subjects) with dual X-ray energy absorption, euglycemic-hyperinsulinemic clamp (40 mU/[m(2). min]) combined with infusion of [6,6-D(2)]-glucose and oral glucose tolerance test (OGTT).
  
  
  RESULTS
  MyD had reduced lean body mass, but peripheral insulin sensitivity was not different to that of control subjects in contrast to OFF, which showed insulin resistance. Insulin secretion, obtained by deconvolution of OGTT data, was also shown to be comparable with that of OFF and control subjects (index of beta-cell function = Phi; P = 0.91) even if increased parameters of insulin secretion were found during the first 30 min (Phi(30); P = 0.05) of the oral glucose challenge. Fasting plasma proinsulin concentrations (P = 0.01) and the ratio to insulin (P = 0.01) were increased in MyD patients. The proinsulin levels also failed to be suppressed during the clamp and showed exaggerated response after the OGTT. Increased proinsulin levels were shown to be peculiar of MyD patients when compared with OFF.
  
  
  CONCLUSIONS
  In nondiabetic, young MyD patients, insulin sensitivity was preserved, and an increased early secretory response to oral glucose was detected. Abnormal plasma proinsulin levels in the fasting state, during the clamp, and during the OGTT were shown to be secretory dysfunctions peculiar of MyD patients and may be more important than insulin resistance in determining the high risk to develop diabetes in these patients.
authors.affiliation: Section of Nutrition/Metabolism and Unit of Clinical Spectroscopy, Istituto Scientifico H San Raffaele, Milan, Italy. perseghin.gianluca@hsr.it
authors.forename: Gianluca
authors.initials: G
authors.lastname: Perseghin
authors.forename: Andrea
authors.initials: A
authors.lastname: Caumo
authors.forename: Cinzia
authors.initials: C
authors.lastname: Arcelloni
authors.forename: Stefano
authors.initials: S
authors.lastname: Benedini
authors.forename: Roberto
authors.initials: R
authors.lastname: Lanzi
authors.forename: Emanuela
authors.initials: E
authors.lastname: Pagliato
authors.forename: Lucia Piceni
authors.initials: LP
authors.lastname: Sereni
authors.forename: Giulio
authors.initials: G
authors.lastname: Testolin
authors.forename: Alberto
authors.initials: A
authors.lastname: Battezzati
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.forename: Mauro
authors.initials: M
authors.lastname: Comola
authors.forename: Livio
authors.initials: L
authors.lastname: Luzi
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000453:epidemiology*; D002149:Energy Intake; D005260:Female; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006801:Humans; D006946:Hyperinsulinism; D007328:Insulin / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007700:Kinetics; D008297:Male; D009223:Myotonic Dystrophy / Q000097:blood / Q000150:complications* / Q000503:physiopathology; D009679:Nuclear Family
chemical_list: D001786:Blood Glucose; D007328:Insulin