title: Association of the SLC30A8 missense polymorphism R325W with proinsulin levels at baseline and after lifestyle, metformin or troglitazone intervention in the Diabetes Prevention Program.
abstract: OBJECTIVE
  Individuals with impaired glucose tolerance have increased proinsulin levels, despite normal glucose or C-peptide levels. In the Diabetes Prevention Program (DPP), increased proinsulin levels predicted type 2 diabetes and proinsulin levels were significantly reduced following treatment with metformin, lifestyle modification or troglitazone compared with placebo. Genetic and physiological studies suggest a role for the zinc transporter gene SLC30A8 in diabetes risk, possibly through effects on insulin-processing in beta cells. We hypothesised that the risk allele at the type 2 diabetes-associated missense polymorphism rs13266634 (R325W) in SLC30A8 would predict proinsulin levels in individuals at risk of type 2 diabetes and may modulate response to preventive interventions.
  
  
  METHODS
  We genotyped rs13266634 in 3,007 DPP participants and examined its association with fasting proinsulin and fasting insulin at baseline and at 1 year post-intervention.
  
  
  RESULTS
  We found that increasing dosage of the C risk allele at SLC30A8 rs13266634 was significantly associated with higher proinsulin levels at baseline (p = 0.002) after adjustment for baseline insulin. This supports the hypothesis that risk alleles at SLC30A8 mark individuals with insulin-processing defects. At the 1 year analysis, proinsulin levels decreased significantly in all groups receiving active intervention and were no longer associated with SLC30A8 genotype (p = 0.86) after adjustment for insulin at baseline and 1 year. We found no genotype × treatment interactions at 1 year.
  
  
  CONCLUSIONS
  In prediabetic individuals, genotype at SLC30A8 predicts baseline proinsulin levels independently of insulin levels, but does not predict proinsulin levels after amelioration of insulin sensitivity at 1 year.
authors.affiliation: Center for Human Genetic Research and Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston, MA, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Majithia
authors.forename: K A
authors.initials: KA
authors.lastname: Jablonski
authors.forename: J B
authors.initials: JB
authors.lastname: McAteer
authors.forename: K J
authors.initials: KJ
authors.lastname: Mather
authors.forename: R B
authors.initials: RB
authors.lastname: Goldberg
authors.forename: S E
authors.initials: SE
authors.lastname: Kahn
authors.forename: J C
authors.initials: JC
authors.lastname: Florez
mesh_terms: D000328:Adult; D002096:C-Peptide / Q000097:blood; D027682:Cation Transport Proteins / Q000235:genetics*; D002839:Chromans / Q000627:therapeutic use*; D003920:Diabetes Mellitus / Q000097:blood* / Q000188:drug therapy / Q000235:genetics* / Q000628:therapy; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D011384:Proinsulin / Q000097:blood*; D045162:Thiazolidinediones / Q000627:therapeutic use*; D000077288:Troglitazone; D000075703:Zinc Transporter 8
chemical_list: D002096:C-Peptide; D027682:Cation Transport Proteins; D002839:Chromans; D007328:Insulin; C492522:SLC30A8 protein, human; D045162:Thiazolidinediones; D000075703:Zinc Transporter 8; D011384:Proinsulin; D008687:Metformin; D000077288:Troglitazone