title: Phenotypic characteristics of early-onset autosomal-dominant type 2 diabetes unlinked to known maturity-onset diabetes of the young (MODY) genes.
abstract: OBJECTIVE
  To investigate whether there are forms of early-onset autosomal-dominant type 2 diabetes that are distinct from typical maturity-onset diabetes of the young (MODY) and to characterize their phenotypic characteristics.
  
  
  METHODS
  The study included 220 affected subjects from 29 families in which early-onset type 2 diabetes occurred in multiple generations and was not linked to known MODY genes (MODY gene-negative families). All individuals underwent an oral glucose tolerance test and other clinical measurements aimed at investigating the underlying metabolic defect and the presence of diabetic complications. For comparison, 79 affected carriers of MODY3 (hepatocyte nuclear factor [HNF]-1 alpha) mutations were similarly examined.
  
  
  RESULTS
  Subjects from MODY gene-negative pedigrees were diagnosed with diabetes at an older age (36 +/- 17 vs. 21 +/- 10 years, P = 0.0001) and were more frequently obese (52 vs. 18%, P = 0.0001) than MODY3 individuals. MODY gene-negative patients who were insulin treated required more exogenous insulin than did MODY3 subjects (0.7 +/- 0.4 vs. 0.45 +/- 0.2 U.kg-1.day-1, P = 0.04), despite similar C-peptide levels. Among subjects not treated with insulin, MODY gene-negative subjects had significantly higher serum insulin levels, both fasting (16.5 +/- 15 vs. 6.5 +/- 5 microU/ml, P = 0.027) and 2 h after a glucose load (53 +/- 44 vs. 11 +/- 10, P = 0.002). They also had higher serum triglycerides (P = 0.02), higher cholesterol levels (P = 0.02), more hypertension (P = 0.0001), and more nephropathy (P = 0.001). Differences persisted when families were matched for age at diagnosis.
  
  
  CONCLUSIONS
  Our findings indicate the existence of forms of early-onset autosomal-dominant type 2 diabetes that are distinct from MODY and are frequently characterized by insulin resistance, similar to later-onset type 2 diabetes. Because of the Mendelian pattern of inheritance, the goal of identifying the genes involved in these forms of diabetes appears to be particularly feasible.
authors.affiliation: Section on Genetics, Joslin Diabetes Center, Boston, MA 02215, USA. adoria@joslin.harvard.edu
authors.forename: A
authors.initials: A
authors.lastname: Doria
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.forename: M
authors.initials: M
authors.lastname: Malecki
authors.forename: S
authors.initials: S
authors.lastname: Scotti
authors.forename: J
authors.initials: J
authors.lastname: Dreyfus
authors.forename: C
authors.initials: C
authors.lastname: O'Keeffe
authors.forename: T
authors.initials: T
authors.lastname: Orban
authors.forename: J H
authors.initials: JH
authors.lastname: Warram
authors.forename: A S
authors.initials: AS
authors.lastname: Krolewski
mesh_terms: D000328:Adult; D017668:Age of Onset; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D002784:Cholesterol / Q000097:blood; D004268:DNA-Binding Proteins / Q000235:genetics; D003920:Diabetes Mellitus / Q000097:blood / Q000235:genetics / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000235:genetics / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000235:genetics; D005190:Family; D005260:Female; D005799:Genes, Dominant; D018149:Glucose Intolerance / Q000235:genetics; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins; D009765:Obesity; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics*; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D007328:Insulin; D009687:Nuclear Proteins; D014157:Transcription Factors; D014280:Triglycerides; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D002784:Cholesterol