Person:

Song, Yiqing

Background: Ion channel transient receptor potential membrane melastatin 6 and 7 (TRPM6 and TRPM7) play a central role in magnesium homeostasis, which is critical for maintaining glucose and insulin metabolism. However, it is unclear whether common genetic variation in TRPM6 and TRPM7 contributes to risk of type 2 diabetes. Methods: We conducted a nested case-control study in the Women's Health Study. During a median of 10 years of follow-up, 359 incident diabetes cases were diagnosed and matched by age and ethnicity with 359 controls. We analyzed 20 haplotype-tagging single nucleotide polymorphisms (SNPs) in TRPM6 and 5 common SNPs in TRPM7 for their association with diabetes risk. Results: Overall, there was no robust and significant association between any single SNP and diabetes risk. Neither was there any evidence of association between common TRPM6 and TRPM7 haplotypes and diabetes risk. Our haplotype analyses suggested a significant risk of type 2 diabetes among carriers of both the rare alleles from two non-synomous SNPs in TRPM6 (Val1393Ile in exon 26 [rs3750425] and Lys1584Glu in exon 27 [rs2274924]) when their magnesium intake was lower than 250 mg per day. Compared with non-carriers, women who were carriers of the haplotype 1393Ile-1584Glu had an increased risk of type 2 diabetes (OR, 4.92, 95% CI, 1.05–23.0) only when they had low magnesium intake (less than 250 mg/day). Conclusion: Our results provide suggestive evidence that two common non-synonymous TRPM6 coding region variants, Ile1393Val and Lys1584Glu polymorphisms, might confer susceptibility to type 2 diabetes in women with low magnesium intake. Further replication in large-scale studies is warranted.

OBJECTIVE: Coffee consumption has been inversely associated with type 2 diabetes risk, but its mechanisms are largely unknown. We aimed to examine whether plasma levels of sex hormones and sex hormone–binding globulin (SHBG) may account for the inverse association between coffee consumption and type 2 diabetes risk. RESEARCH DESIGN AND METHODS: We conducted a case-control study nested in the prospective Women's Health Study (WHS). During a median follow-up of 10 years, 359 postmenopausal women with newly diagnosed type 2 diabetes were matched with 359 control subjects by age, race, duration of follow-up, and time of blood draw. RESULTS: Caffeinated coffee was positively associated with SHBG but not with sex hormones. Multivariable-adjusted geometric mean levels of SHBG were 26.6 nmol/l among women consuming ≥4 cups/day of caffeinated coffee and 23.0 nmol/l among nondrinkers (P for trend = 0.01). In contrast, neither decaffeinated coffee nor tea was associated with SHBG or sex hormones. The multivariable-adjusted odds ratio (OR) of type 2 diabetes for women consuming ≥4 cups/day of caffeinated coffee compared with nondrinkers was 0.47 (95% CI 0.23–0.94; P for trend = 0.047). The association was largely attenuated after further adjusting for SHBG (OR 0.71 [95% CI 0.31–1.61]; P for trend = 0.47). In addition, carriers of rs6259 minor allele and noncarriers of rs6257 minor allele of SHBG gene consuming ≥2 cups/day of caffeinated coffee had lower risk of type 2 diabetes in directions corresponding to their associated SHBG. CONCLUSIONS: Our findings suggest that SHBG may account for the inverse association between coffee consumption and type 2 diabetes risk among postmenopausal women.

OBJECTIVE—The purpose of this study was to investigate the role of circulating resistin levels in the development of type 2 diabetes using two prospective cohorts of well-characterized men and women. RESEARCH DESIGN AND METHODS—We conducted two prospective case-control studies nested in the Women's Health Study (WHS) and Physicians’ Health Study II (PHS II). In the WHS, during a median of 10-years of follow-up, 359 postmenopausal women, who were apparently healthy at baseline and later developed type 2 diabetes, were prospectively matched with 359 healthy control subjects. In the PHS II, with 8 years of total follow-up, 170 men, who were apparently healthy at baseline and later developed type 2 diabetes, were matched with 170 healthy control subjects. Control subjects were matched by age, race, and time of blood draw. RESULTS—Resistin levels at baseline were significantly higher in women than in men (P = 0.003) and in case patients than in control subjects for both women (P < 0.001) and men (P = 0.07). After adjustment for matching factors, physical activity, alcohol intake, smoking, and family history of diabetes, the relative risk of type 2 diabetes comparing the highest to the lowest quartile of resistin in women was 2.22 ([95% CI 1.32–3.73]; P({trend}) = 0.002). This association was attenuated after further adjustment for BMI (1.51 [0.86–2.65]; P({trend}) = 0.20) or C-reactive protein (1.18 [0.68–2.07]; P(_{trend}) = 0.60). A similar but weaker pattern was observed in men. CONCLUSIONS—Elevated levels of circulating resistin were significantly related to increased risk of type 2 diabetes, which appears to be partially accounted for by adiposity and the inflammatory process.