title: Clinical and genetic determinants of progression of type 2 diabetes: a DIRECT study.
abstract: OBJECTIVE
  To identify the clinical and genetic factors that explain why the rate of diabetes progression is highly variable between individuals following diagnosis of type 2 diabetes.
  
  
  METHODS
  We studied 5,250 patients with type 2 diabetes using comprehensive electronic medical records in Tayside, Scotland, from 1992 onward. We investigated the association of clinical, biochemical, and genetic factors with the risk of progression of type 2 diabetes from diagnosis to the requirement of insulin treatment (defined as insulin treatment or HbA1c ≥8.5% [69 mmol/mol] treated with two or more noninsulin therapies).
  
  
  RESULTS
  Risk of progression was associated with both low and high BMI. In an analysis stratified by BMI and HbA1c at diagnosis, faster progression was independently associated with younger age at diagnosis, higher log triacylglyceride (TG) concentrations (hazard ratio [HR] 1.28 per mmol/L [95% CI 1.15-1.42]) and lower HDL concentrations (HR 0.70 per mmol/L [95% CI 0.55-0.87]). A high Genetic Risk Score derived from 61 diabetes risk variants was associated with a younger age at diagnosis and a younger age when starting insulin but was not associated with the progression rate from diabetes to the requirement of insulin treatment.
  
  
  CONCLUSIONS
  Increased TG and low HDL levels are independently associated with increased rate of progression of diabetes. The genetic factors that predispose to diabetes are different from those that cause rapid progression of diabetes, suggesting a difference in biological process that needs further investigation.
authors.affiliation: Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, University of Dundee, DD1 9SY.
authors.forename: Kaixin
authors.initials: K
authors.lastname: Zhou
authors.affiliation: Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, University of Dundee, DD1 9SY.
authors.forename: Louise A
authors.initials: LA
authors.lastname: Donnelly
authors.affiliation: Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, University of Dundee, DD1 9SY.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Morris
authors.affiliation: Department of Clinical Science, Genetic & Molecular Epidemiology Unit, Lund University, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, MA; Department of Public Health & Clinical Medicine, Umeå University, Umeå, Sweden.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Franks
authors.affiliation: Department of Mathematical Sciences, University of Bath, Bath, BA2 7AY.
authors.forename: Chris
authors.initials: C
authors.lastname: Jennison
authors.affiliation: Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, University of Dundee, DD1 9SY.
authors.forename: Colin Na
authors.initials: CN
authors.lastname: Palmer
authors.affiliation: Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, University of Dundee, DD1 9SY.
authors.forename: Ewan R
authors.initials: ER
authors.lastname: Pearson
mesh_terms: D015992:Body Mass Index; D008078:Cholesterol, LDL / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D012606:Scotland / Q000453:epidemiology; D014280:Triglycerides / Q000378:metabolism
chemical_list: D008078:Cholesterol, LDL; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D014280:Triglycerides