The rs2274911 polymorphism in GPRC6A gene is associated with insulin resistance in normal weight and obese subjects.

OBJECTIVE: Identification of the novel endocrine role of osteocalcin (OC) and its receptor GPRC6A has given rise to a new branch of research in OC/GPRC6A axis related to glucose metabolism. GPRC6A- and OC-deficient mice share features of the metabolic syndrome, in addition to male infertility. Recently, the polymorphism rs2274911 in GPRC6A was shown to be associated with testicular impairment. We aimed to investigate the role of rs2274911 polymorphism in glucose and lipid metabolism in a cohort of normal weight and obese subjects DESIGN, PATIENTS, SETTINGS: A total of 392 male and females, including 218 obese patients and 174 age-matched normal weight controls, were retrospectively selected. RESULTS: The distribution of rs2274911 alleles and genotypes did not differ either between normal weight and obese subjects or sexes (all P > 0·05). Age- and OC-adjusted multivariate analysis revealed that, in the normal weight group, fasting insulin and HOMA-IR increased in GA (P = 0·016 and P = 0·025) and AA genotypes (P = 0·033 and P = 0·040) compared with GG homozygotes. In the obese group, AA homozygotes had increased fasting glucose (P = 0·041 vs GG). Triglycerides, fasting insulin and HOMA-IR increased in both GA (P = 0·020, P < 0·001 and P = 0·001) and AA genotype (P = 0·021, P = 0·013 and P = 0·013). CONCLUSION: In a cohort of normal weight and obese subjects, we found that the nonrare polymorphism rs2274911 in the GPRC6A gene was associated with insulin resistance features, independently of the metabolic phenotype and OC levels.

Circulating Stem Cells Associate With Adiposity and Future Metabolic Deterioration in Healthy Subjects.

CONTEXT: Obesity and metabolic syndrome are associated with mild leukocytosis, but whether hematopoietic stem/progenitor cells (HSPCs) play a role in metabolic deterioration is unknown. OBJECTIVE: Our objective was to analyze the cross-sectional and longitudinal associations between CD34(+) HSPCs, adiposity, and metabolic syndrome features. DESIGN: This is a cross-sectional study on 242 participants, 155 of whom were followed and included in a longitudinal assessment. SETTING: This study took place in a tertiary referral center for metabolic diseases. PARTICIPANTS: Healthy working individuals attending a cardiovascular screening program (total n = 3158) and having a baseline measure of circulating CD34(+) cells participated. MAIN OUTCOME MEASURES: We collected demographic and anthropometric data, cardiovascular risk factors, and metabolic syndrome parameters. RESULTS: Participants (34.7% males, mean age 45.9 ± 0.5 years) were free from diabetes and cardiovascular disease. Cross-sectionally, absolute CD34(+) cell counts were directly correlated with body mass index and waist circumference, inversely correlated with high-density lipoprotein cholesterol and the quantitative insulin sensitivity check index, and were higher in individuals with the metabolic syndrome. The hematopoietic component contributed most to the association of CD34(+) cells with adiposity. During a 6.3-year follow-up, high absolute levels of CD34(+) cells were associated with increasing waist circumference, declining quantitative insulin sensitivity check index and high-density lipoprotein cholesterol, and with incidence of metabolic syndrome. Relative CD34(+) cell counts showed weaker associations with metabolic parameters than absolute levels, but were longitudinally associated with increasing waist circumference and metabolic syndrome development. CONCLUSIONS: A mild elevation of circulating CD34(+) progenitor cells, reflecting expansion of HSPCs, is associated with adiposity and future metabolic deterioration in healthy individuals.

Synergistic interactions among metabolic syndrome components and homeostasis model assessment of insulin resistance in a middle-aged general population over time.

BACKGROUND: Insulin resistance is considered a hallmark feature of the metabolic syndrome, but how metabolic syndrome components and insulin resistance measures interact over time is unclear. The homeostasis model assessment of insulin resistance (HOMA-IR) is a static index of insulin resistance typically used in epidemiological studies. We explored how HOMA-IR is affected by clustering metabolic syndrome components over time in a population of middle-aged, healthy subjects. METHODS: A total of 1757 subjects aged 41.3±7.5 years (39% males) free from diabetes at baseline were followed-up for a median of 5.7 years. At baseline and at the end of observation, we determined metabolic syndrome components and HOMA-IR. RESULTS: Cross-sectionally, HOMA-IR was synergistically increased by clustering of at least two to three metabolic syndrome components as determined at baseline and at study end by departure from additivity. Some combinations of metabolic syndrome components were associated with a significant synergic increase in HOMA-IR, and some combinations of two components entailed a synergistic risk of developing metabolic syndrome. Over time, the average change in HOMA-IR was more than additively affected by change in the number of metabolic syndrome components. Baseline HOMA-IR values were predictive of incident metabolic syndrome independent from age, sex, and each metabolic syndrome component. CONCLUSIONS: We show synergistic interaction between clustering metabolic syndrome components and insulin resistance, estimated by HOMA-IR, cross-sectionally and over time. This more than additive effect explains the incremental value of HOMA-IR in predicting metabolic risk.

Elevated white blood cell count is associated with prevalence and development of the metabolic syndrome and its components in the general population.

The metabolic syndrome (MS) is characterized by chronic inflammation. We aimed to determine the association of white blood cell (WBC) count with prevalence and development of the MS and its components in the general population. A cohort of 1,329 subjects from the local working population aged 41.3 ± 7.5 years and recruited since 2000-2008 was followed up for 4.0 ± 1.2 years. WBC count and MS components were determined at baseline and follow-up. To determine whether WBC predicted incident MS, we used a logistic regression analysis adjusted for demographics, baseline variables that define MS components, smoke, medications, and follow-up duration. Cross-sectionally in the whole population, WBC count increased in parallel with the number of MS components in the same individual, and the presence of each component was associated with higher WBC count. Baseline WBC count was significantly higher in subjects with prevalent MS. Among subjects without MS at baseline, those who developed MS had significantly higher WBC than those who did not develop MS at follow-up. Development of each MS component was associated with increased WBC count. WBC count remained significantly associated with MS development after correction for several potential confounders (OR for 1 SD increase in WBC 1.26; 95 % CI 1.01-1.58). In conclusion, elevated WBC is intimately linked to the prevalence and future development of the MS in a young population of working subjects.