title: The risk allele load accelerates the age-dependent decline in beta cell function.
abstract: OBJECTIVE
  Among the novel type 2 diabetes risk loci identified by genome-wide association studies, TCF7L2, HHEX, SLC30A8 and CDKAL1 appear to affect beta cell function. In the present study we examined the effect of these genes' risk alleles on the age-dependent decline in insulin secretion.
  
  
  METHODS
  The SNPs rs7903146 (TCF7L2), rs7754840(CDKAL1), rs7923837 (HHEX) and rs13266634 (SLC30A8) were genotyped in 1,412 non-diabetic patients, who were subsequently grouped according to their number of risk alleles. All participants underwent an OGTT. Insulin secretion was assessed by validated indices and proinsulin conversion by calculating AUC(proinsulin)/AUC(insulin).
  
  
  RESULTS
  The number of risk alleles revealed a Gaussian distribution, with most participants carrying four risk alleles. Stratification into groups with low (LAL, up to three alleles), median (MAL, four alleles) and high (HAL, five to eight alleles) allele load resulted in MAL and HAL participants displaying significantly lower insulin secretion and proinsulin conversion than LAL participants (p <or= 0.0014 and p = 0.0185, respectively). In the overall cohort, age was negatively associated with insulin secretion and proinsulin conversion (both p < 0.0001). MAL and HAL participants showed a significantly more pronounced decline in insulin secretion with increasing age than LAL participants (p <or= 0.0325; analysis of covariance), and after stratification for BMI this relationship was maintained in obese, but not non-obese, participants. Proinsulin conversion decreased with increasing age in MAL and HAL, but not LAL, participants (p <or= 0.0003 vs p = 0.2).
  
  
  CONCLUSIONS
  The risk allele load significantly accelerates the age-dependent decline in beta cell function, and this might be of particular importance in obese people.
authors.affiliation: Medical Clinic, Department of Internal Medicine IV (Diabetology, Endocrinology, Nephrology, Angiology, and Clinical Chemistry), Eberhard Karls University, Otfried-Müller-Strasse 10, 72076, Tübingen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Haupt
authors.forename: H
authors.initials: H
authors.lastname: Staiger
authors.forename: S A
authors.initials: SA
authors.lastname: Schäfer
authors.forename: K
authors.initials: K
authors.lastname: Kirchhoff
authors.forename: M
authors.initials: M
authors.lastname: Guthoff
authors.forename: F
authors.initials: F
authors.lastname: Machicao
authors.forename: B
authors.initials: B
authors.lastname: Gallwitz
authors.forename: N
authors.initials: N
authors.lastname: Stefan
authors.forename: H-U
authors.initials: HU
authors.lastname: Häring
authors.forename: A
authors.initials: A
authors.lastname: Fritsche
mesh_terms: D000328:Adult; D000375:Aging / Q000235:genetics*; D000704:Analysis of Variance; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D004247:DNA / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D015894:Genome, Human; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D005951:Glucose Tolerance Test; D006801:Humans; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment
chemical_list: D001786:Blood Glucose; D004247:DNA