Tissue kallikrein deficiency, insulin resistance, and diabetes in mouse and man.

The kallikrein-kinin system has been suggested to participate in the control of glucose metabolism. Its role and the role of angiotensin-I-converting enzyme, a major kinin-inactivating enzyme, are however the subject of debate. We have evaluated the consequence of deficiency in tissue kallikrein (TK), the main kinin-forming enzyme, on the development of insulin resistance and diabetes in mice and man. Mice with inactivation of the TK gene were fed a high-fat diet (HFD) for 3 months, or crossed with obese, leptin-deficient (ob/ob) mice to generate double ob/ob-TK-deficient mutants. In man, a loss-of-function polymorphism of the TK gene (R53H) was studied in a large general population cohort tested for insulin resistance, the DESIR study (4843 participants, 9 year follow-up). Mice deficient in TK gained less weight on the HFD than their WT littermates. Fasting glucose level was increased and responses to glucose (GTT) and insulin (ITT) tolerance tests were altered at 10 and 16 weeks on the HFD compared with standard on the diet, but TK deficiency had no influence on these parameters. Likewise, ob-TK⁻/⁻ mice had similar GTT and ITT responses to those of ob-TK⁺/⁺ mice. TK deficiency had no effect on blood pressure in either model. In humans, changes over time in BMI, fasting plasma glucose, insulinemia, and blood pressure were not influenced by the defective 53H-coding TK allele. The incidence of diabetes was not influenced by this allele. These data do not support a role for the TK-kinin system, protective or deleterious, in the development of insulin resistance and diabetes.

The lactase persistence genotype is associated with body mass index and dairy consumption in the D.E.S.I.R. study.

OBJECTIVE: The T allele of a functional polymorphism (rs4988235: LCT-13910 C>T), close to the lactase gene, correlates with lactase persistence (LP) in adults. The LP genotype (TT+TC) has been associated with a higher BMI in European populations in cross-sectional studies. In the French D.E.S.I.R. cohort, a high consumption of dairy products was associated with a lower body weight gain over 9-years, and with a lower incidence of high plasma glucose levels and/or the metabolic syndrome. Our aim was to test in this study, the association of rs4988235 with BMI and related metabolic diseases, in interaction with dairy product consumption. METHODS: Among 5212 subjects from D.E.S.I.R., 3575 Caucasians born in mainland France were genotyped and followed over 9years. RESULTS: Those with the LP genotype (frequency: 78.5%) had a higher dairy product consumption, at inclusion and at year-9 (P<0.001). They also had a higher BMI at both time points (difference=0.3kg/m(2), P=0.05), but this effect was restricted to medium/high dairy product consumers (difference=0.5kg/m(2), P=0.006). This genotype was also associated with the metabolic syndrome (IDF definition), but this association disappeared after adjustment for BMI. In the whole population, the C allele was associated with a higher prevalence of impaired fasting glycemia and/or type 2 diabetes. CONCLUSIONS: The lactase persistence genotype was shown to be associated with a higher BMI in a longitudinal study, mainly in those consuming high amounts of dairy products. The association of the C allele, responsible for lactase non-persistence, with the risk of hyperglycemia needs to be replicated.

Dairy products and the metabolic syndrome in a prospective study, DESIR.

OBJECTIVE: In previous cross-sectional analyses of the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort, we have found inverse associations between dairy product consumption and metabolic syndrome (MetS) traits. We have now analyzed in a prospective way the influence of dairy product and calcium consumption at inclusion on the 9-year cumulative incidence of the MetS and associated traits in the French prospective study with a 9-year follow-up, DESIR. METHODS: After exclusion of diabetic subjects and those being on a diet at inclusion, 3417 men and women who completed a food frequency at baseline could be studied. Logistic regression models were used to study associations between dairy products and dietary calcium density at baseline and incident MetS and impaired fasting glycemia/type 2 diabetes (IFG/T2D) after adjusting for gender, age, and lifestyle parameters (alcohol, smoking, physical activity, fat intake). An additional model adjusting for the same covariates and for body mass index (BMI) was also used. Associations between dairy products and continuous variables were studied by repeated measures analysis of covariance, using the same covariates. RESULTS: Total dairy product consumption, dairy (except cheese) consumption, and dietary calcium density were inversely associated with incident MetS and IFG/T2D. Cheese consumption was negatively associated with incident MetS but not with glycemic disorders. All parameters were associated with lower diastolic blood pressure and triglycerides (average over the 9-year period) and with a lower BMI gain in the same period. Higher total dairy and cheese intake and calcium density were associated with a lower increase in waist circumference and triglycerides during the 9-year follow-up. CONCLUSION: In the French general population, these results show beneficial effects of dairy product consumption on the metabolic syndrome and glycemic disorders. Therefore, dairy product consumption could be protective against cardiovascular risk.

Genetic variability at the six transmembrane protein of prostate 2 locus and the metabolic syndrome: the data from an epidemiological study on the Insulin Resistance Syndrome (DESIR) study.

CONTEXT: The six-transmembrane protein of prostate 2 (STAMP2) has been shown to be involved in insulin resistance in animal models, but in humans, its role is far from understood. Our hypothesis was that genetic variation of STAMP2 could be associated with insulin resistance phenotypes such as the metabolic syndrome (MetS) in humans. OBJECTIVE: Our objective was to search for associations between STAMP2 polymorphisms and the MetS in humans. SUBJECTS AND METHODS: Nine single-nucleotide polymorphisms (SNPs) were tested for associations with the International Diabetes Federation-defined MetS and its constituent parameters in 5212 French Caucasians from the prospective study, Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR), with a 9-yr follow-up. Methods included logistic regression and analysis of covariance adjusting for confounding variables and testing for interactions. RESULTS: None of the SNPs was significantly associated with the prevalence or the incidence of the MetS. The rs12386756 was marginally associated with two parameters of the MetS [triglycerides (P = 0.04) and fasting glucose (P = 0.05)]. An interaction effect between this SNP and fat intake was observed on high-density lipoprotein-cholesterol levels (P = 0.01) and systolic blood pressure (P = 0.03) that is consistent with an interrelation between STAMP2 and nutrition. Three SNPs were associated with insulin levels, but these SNPs were not associated with other features of the MetS. CONCLUSION: These findings suggest that the common polymorphisms of STAMP2 are unlikely to significantly contribute to the risk of the MetS in the general population, but relationships with insulin and interactions with fat intake need to be replicated.

Associations of the -344 T>C and the 3097 G>A polymorphisms of CYP11B2 gene with hypertension, type 2 diabetes, and metabolic syndrome in a French population.

BACKGROUND: Aldosterone can affect both blood pressure (BP) and glucose metabolism. We assessed the association of two polymorphisms -344 T>C and the 3097 G>A in the aldosterone synthase gene (CYP11B2) with prevalent and incident hypertension (HT), type 2 diabetes (T2D), and the metabolic syndrome (MetS). METHODS: We studied the 5,212 participants to D.E.S.I.R. (Data from Epidemiologic Study on the Insulin Resistance syndrome), a cohort from French general population. Genotyping was done by a TaqMan assay. Analysis of covariance, multivariate logistic regression (adjusted for age, MetS components) and haplotype analysis were performed. RESULTS: The prevalences and 9-year incidences were 16.7 and 36.1% for HT, 2.6 and 6.2% for T2D, and 19.3 and 25.1% for the MetS. Risk for incident HT was reduced with the AA genotype of 3097 G>A, adjusted odds ratios (OR): 0.67; p = 0.04. The prevalence of HT was lower in women carrying the C allele of -344 T>C, OR 0.75; p = 0.03 for the TC genotype and 0.69; p = 0.03 for the CC genotype. In men, incident T2D was associated with both polymorphisms, adjusted OR for -344 T>C: 1.63; p = 0.04 for TC genotype and 2.12; p = 0.008 for CC genotype; for the 3097 G>A: the AA genotype was associated with a lower risk, OR 0.23; p = 0.02. In men, incident MetS was associated with 3097 G>A, OR: 0.57; p = 0.02 for AA genotype. Significant associations between haplotype combinations and the prevalence or incidence of the three diseases were also found. CONCLUSION: The -344 T>C and 3097 G>A polymorphisms in the CYP11B2 are associated with T2D, hypertension and the MetS in European subjects with gender variations.

Association of ADIPOQ genetic variants and plasma adiponectin isoforms with the risk of incident renal events in type 2 diabetes.

BACKGROUND: Adiponectin levels are high in cases of diabetic nephropathy, but it remains unclear whether these high levels are a cause or a consequence of the disease. We investigated the possible association of polymorphisms in the adiponectin gene and baseline adiponectin levels with the incidence of renal events in subjects with type 2 diabetes. METHODS: We studied three adiponectin polymorphisms (-11391G > A, +45T > G and +276G > T) in 3086 subjects with type 2 diabetes and high levels of albumin excretion from the diabetes, hypertension, microalbuminuria or proteinuria, cardiovascular events and ramipril (DIABHYCAR) trial. Baseline concentrations of total adiponectin and of adiponectin isoforms were determined in cases with incident renal events and in controls matched for sex, age, body mass index (BMI) and adiponectin genotype. We used another cohort of type 2 diabetes patients-the survie, diabète de type 2 et génétique(SURDIAGENE) study (n = 1004)-for the replication of genetic data. RESULTS: In DIABHYCAR, the -11391A and +45G alleles were associated with a higher incidence of renal events [hazard ratio (HR) = 1.73; 95% confidence interval (CI), 1.10-2.71; and HR = 1.68; 95% CI, 1.14-2.47, respectively]. The haplotype containing susceptibility alleles, -11391A/+45G/+276G, was more frequent in cases with renal events (5.1% vs. 1.9% in those without, P = 0.005). In SURDIAGENE, the -11391A/+45G/+276G haplotype was also associated with renal events (5.6% vs. 1.9% in those without, P = 0.03). In DIABHYCAR, all isoforms were more abundant in subjects carrying the -11391A or +45G alleles. Medium- (MMW) and low-molecular weight (LMW) isoforms were more abundant in cases with renal events. CONCLUSIONS: In subjects with type 2 diabetes and early renal dysfunction, adiponectin gene variants are determinants of the renal risk. The -11391A and +45G alleles may affect renal risk by leading to high circulating adiponectin concentrations, at least those of MMW and LMW isoforms.

Relationships between common polymorphisms of adenosine triphosphate-binding cassette transporter A1 and high-density lipoprotein cholesterol and coronary heart disease in a population with type 2 diabetes mellitus.

Patients with type 2 diabetes mellitus (T2D) have a high coronary risk partly because of low levels of high-density lipoprotein-cholesterol (HDL-C). The adenosine triphosphate-binding cassette transporter A1 (ABCA1) plays a key role in HDL metabolism. We studied the association of common single nucleotide polymorphisms (SNPs) in the ABCA1 gene with HDL-C levels and coronary risk in a cohort of subjects with T2D. We studied 5 SNPs: +69C>T, +378G>C, R219K, I883M, and R1587K. The C allele of +378G>C was significantly associated with lower HDL-C concentrations (P = .04); and the M allele of I883M, with higher HDL-C concentrations (P = .03). No significant association was found between these SNPs and the incidence of new coronary events. Nevertheless, cross-sectional data on entry showed that the frequency of K219 was lower in patients with previous coronary heart disease (angina pectoris and/or myocardial infarction) (odds ratio, OR [95% confidence interval, CI] = 0.80 [0.65-0.98], P = .03, after adjustment for multiple risk factors other than HDL-C). The frequency of K1587 was higher in patients with angina pectoris (OR [95% CI] = 1.27 [1.01-1.58], P = .04, after multiple adjustment). The TT genotype of the C69T SNP was less frequent in subjects with prior myocardial infarction (OR [95% CI] = 0.28 [0.13-0.61], P = .001, after multiple adjustment). These associations persisted after further adjustment for HDL-C levels. In conclusion, common genetic variations of ABCA1 had a moderate influence on HDL-C levels and/or coronary heart disease in patients with T2D. These 2 effects were independent.

The CETP TaqIB polymorphism is associated with the risk of sudden death in type 2 diabetic patients.

OBJECTIVE: Type 2 diabetic patients have a high risk of coronary heart disease (CHD) and sudden death. This cardiovascular risk can be partly attributed to low levels of HDL cholesterol. The B2 allele of the CETP TaqIB polymorphism has been repeatedly reported to be associated with high HDL cholesterol levels in both healthy and type 2 diabetic subjects, but its association with CHD is unclear. We investigated the association of the CETP TaqIB polymorphism with CHD, and sudden death in particular, in a prospective cohort of type 2 diabetic patients. RESEARCH DESIGN AND METHODS: The CETP TaqIB polymorphism was genotyped in 3,124 type 2 diabetic subjects with high cardiovascular risk: the Noninsulin-Dependent Diabetes, Hypertension, Microalbuminuria, Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR) study. We used Cox regression analysis to estimate the impact of the TaqIB single nucleotide polymorphism on the CHD events (myocardial infarction or sudden death) during follow-up. RESULTS: The incidence of CHD was higher in B1B1 homozygotes than in B2 carriers (P = 0.02). This effect was mainly due to sudden death (hazard ratio [B1B1 vs. B2+] = 1.51 [95% CI = 1.05-2.18]). Although the B1 allele was associated in a dose-dependent fashion with lower HDL cholesterol (P < 0.001), the association with sudden death persisted after adjustment for multiple risk factors, including HDL cholesterol levels. CONCLUSIONS: In type 2 diabetic patients, the CETP TaqIB polymorphism is a good genetic predictor of cardiac mortality. This association is partly independent of the effect on HDL cholesterol levels.

ABCA1 single nucleotide polymorphisms on high-density lipoprotein-cholesterol and overweight: the D.E.S.I.R. study.

The adenosine triphosphate-binding cassette A1 (ABCA1) gene plays a key role in reverse cholesterol transport. Some ABCA1 gene polymorphisms have been associated with high-density lipoprotein-cholesterol (HDL-C) concentrations. The aim of this study was to assess the effect of three polymorphisms, C69T, G378C, and G1051A (R219K), on HDL-C levels and their interaction with BMI in more than 5000 French whites from the D.E.S.I.R. (Data from an Epidemiological Study on the Insulin Resistance syndrome) cohort study. The T allele of the C69T single nucleotide polymorphism (SNP) was associated with higher HDL-C levels in normal-weight men (BMI <25 kg/m(2)). The C allele of the G378C SNP was associated with lower HDL-C in overweight subjects (BMI > or =25 kg/m(2)). For the G1051A SNP, in the normal-weight group, the minor A allele was significantly associated with higher HDL-C levels. In contrast, in overweight people, the minor allele was associated with lower HDL-C levels. After accounting for multiple testing, empiric p values remained significant for the associations between G378C SNP and HDL-C in the overweight group and between G1051A SNP and HDL-C in the normal-weight group. This study suggests that ABCA1 gene polymorphisms modulate HDL-C concentrations, in interaction with BMI, and, thus, they might influence cardiovascular risk in the general population.

The PPARG Pro12Ala polymorphism is associated with a decreased risk of developing hyperglycemia over 6 years and combines with the effect of the APM1 G-11391A single nucleotide polymorphism: the Data From an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study.

Although cross-sectional studies have associated the Pro12Ala polymorphism of PPARG with type 2 diabetes, prospective studies offer more opportunities to investigate genetic variants. Associations between PPARG polymorphisms with insulin resistance parameters and with the 6-year incidence of impaired fasting glucose or type 2 diabetes were tested in 3,914 French Caucasians from the DESIR (Data From an Epidemiological Study on the Insulin Resistance Syndrome) cohort. In subjects normoglycemic at baseline (n = 3,498), the 6-year risk of hyperglycemia was lower in PPARG Ala carriers (odds ratio [OR] vs. ProPro = 0.66 [95% CI 0.44-0.99], P = 0.046 adjusted for sex, age, and BMI). Similar results were found with the PPARG C1431T single nucleotide polymorphism (SNP; adjusted OR = 0.65 [0.44-0.96], P = 0.036). Both alleles are in strong linkage disequilibrium (D' = 0.669, P < 0.001). The baseline mean fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) were lower in Ala carriers compared with ProPro homozygotes (P = 0.001 for both), with smaller increases in mean insulin and HOMA-IR during follow-up (P = 0.007 and 0.018, respectively). No association with insulin levels or HOMA-IR was found with C1431T. In this cohort, the APM1 G-11391A SNP is associated with the development of hyperglycemia. The combined effects of PPARG Pro12Ala and APM1 G-11391A SNPs showed no interaction on the risk of 6-year hyperglycemia. The PPARG Ala allele showed a relatively high protective effect in developing hyperglycemia and hyperinsulinemia during a 6-year period. Cumulative rather than synergistic effects of PPARG Pro12Ala and APM1 SNPs on diabetes risk are suggested.