Circulating vaspin is unrelated to insulin sensitivity in a cohort of nondiabetic humans

Objective: To study the association of vaspin with glucose metabolism. Design: Cross-sectional and intervention study. Subjects and methods: The association of serum vaspin with metabolic and anthropometric characteristics was investigated in 108 volunteers. Euglycemic–hyperinsulinemic clamps (EHC) were performed in 83 of the participants. Changes of circulating vaspin levels were additionally studied in a crossover study using 300 min EHC with lipid versus saline infusion (n=10). Results: Neither glucose tolerance status nor insulin sensitivity, both as measured using EHCs and using homeostasis model assessment for insulin resistance (HOMA-IR), was significantly associated with serum vaspin in the cross-sectional study. Furthermore, there was no effect of short-term lipid-induced insulin resistance due to a 300 min intravenous lipid challenge on circulating vaspin. However, circulating vaspin levels were significantly elevated in women using oral contraceptives (OC), both compared to women without OC intake (1.17±0.26 vs 0.52±0.09 ng/ml, P=0.02) and males (1.17±0.26 vs 0.29±0.04 ng/ml, P=0.01). After exclusion of OC using females and stratification according to body mass index (BMI), a significant sexual dimorphism in subjects with a BMI <25 kg/m2 was observed (males 0.21±0.04 ng/ml versus females 0.70±0.16 ng/ml, P=0.009). Conclusion: Our results support the existence of a sexual dimorphism regarding circulating vaspin. The lack of an association of serum vaspin with HOMA-IR and M value indicates, however, no major role for vaspin concerning insulin sensitivity in nondiabetic humans

Lack of Association between the Tagging SNP A+930→G of SOCS3 and Type 2 Diabetes Mellitus: Meta-Analysis of Four Independent Study Populations

BACKGROUND: The suppressor of cytokine signalling 3 (SOCS3) provides a link between cytokine action and their negative consequences on insulin signalling. Thus SOCS3 is a potential candidate gene for type 2 diabetes (T2DM). METHODOLOGY/PRINCIPAL FINDINGS: Based on HapMap we identified the polymorphism A+930-->G (rs4969168) as a haplotype tagging SNP (htSNP) sufficiently covering the genetic variation of the whole gene. We therefore examined the association between rs4969168 within SOCS3 and T2DM in three independent study populations; one prospective case-cohort study and two cross-sectional study populations. Due to the low frequency of individuals being homozygous for the polymorphism a dominant model of inheritance was assumed. The case-cohort study with 2,957 individuals (764 of them with incident T2DM) showed no effect of the polymorphism on diabetes risk (hazard ratio (95%CI): 0.86 (0.66-1.13); p = 0.3). Within the MeSyBePo-study population 325 subjects had T2DM from a total of 1,897 individuals, while the second cross-sectional cohort included 851 cases of T2DM within a total of 1653 subjects. According to the results in the prospective study, no association with T2DM was found (odds ratio (95%CI): 0.78 (0.54-1.12) for MesyBepo and 1.13 (0.90-1.42) for the Leipzig study population). There was also no association with metabolic subtraits such as insulin sensitivity (p = 0.7), insulin secretion (p = 0.8) or the hyperbolic relation of both, the disposition index (p = 0.7). In addition, no evidence for interaction with BMI or sex was found. We subsequently performed a meta-analysis, additionally including the publicly available data from the T2DM-subcohort of the WTCCC (n = 4,855). The overall odds ratio within that meta-analysis was 0.96 (0.88-1.06). CONCLUSIONS/SIGNIFICANCE: There is no strong effect of the common genetic variation within the SOCS3 gene on the development of T2DM

Prolonged treatment with vitamin D in postmenopausal women with primary hyperparathyroidism

Introduction/background: Vitamin D deficiency further increases circulating parathyroid hormone (PTH) levels in patients with primary hyperparathyroidism (pHPT), with potential detrimental effects on bone mass. Methods: This was an observational clinical study in consecutive conservatively treated postmenopausal women (n=40) with pHPT and coexistent 25-hydroxyvitamin D deficiency (25OHD ≤50 nmol/l (≤20 ng/ml)). Patients who showed an increase in serum 25OHD above the threshold of vitamin D deficiency (>50 nmol/l; n=28) using treatment with various commonly prescribed vitamin D preparations were, for the purposes of statistical analyses, allocated to the treatment group. Patients who were retrospectively identified as having received no treatment with vitamin D and/or remained vitamin D deficient were considered as non-responders/controls (n=12). Adjusted calcium (adjCa), PTH and 25OHD concentrations were monitored in all subjects up to 54 months (mean observation period of 18±2 months). Results: Prolonged increased vitamin D intake, regardless of the source (serum 25OHD, increase from 32.2±1.7 nmol/l at baseline to 136.4±11.6 nmol/l, P0.73). In contrast, serum PTH remained unchanged (15.8±2.6 vs 16.3±1.9 pmol/l, P=0.64) in patients who remained vitamin D deficient, with a significant difference between groups in changes of PTH (P=0.0003). Intrapartial correlation analyses showed an independent negative correlation of changes in 25OHD with PTH levels (r ic=−0.41, P=0.014). Conclusions: Prolonged treatment with vitamin D in various commonly prescribed preparations appeared to be safe and significantly reduced PTH levels by 21%

Quantifying the improvement of surrogate indices of hepatic insulin resistance using complex measurement techniques

We evaluated the ability of simple and complex surrogate-indices to identify individuals from an overweight/obese cohort with hepatic insulin-resistance (HEP-IR). Five indices, one previously defined and four newly generated through step-wise linear regression, were created against a single-cohort sample of 77 extensively characterised participants with the metabolic syndrome (age 55.6±1.0 years, BMI 31.5±0.4 kg/m2; 30 males). HEP-IR was defined by measuring endogenous-glucose-production (EGP) with [6–62H2] glucose during fasting and euglycemic-hyperinsulinemic clamps and expressed as EGP*fasting plasma insulin. Complex measures were incorporated into the model, including various non-standard biomarkers and the measurement of body-fat distribution and liver-fat, to further improve the predictive capability of the index. Validation was performed against a data set of the same subjects after an isoenergetic dietary intervention (4 arms, diets varying in protein and fiber content versus control). All five indices produced comparable prediction of HEP-IR, explaining 39–56% of the variance, depending on regression variable combination. The validation of the regression equations showed little variation between the different proposed indices (r2 = 27–32%) on a matched dataset. New complex indices encompassing advanced measurement techniques offered an improved correlation (r = 0.75, P<0.001). However, when validated against the alternative dataset all indices performed comparably with the standard homeostasis model assessment for insulin resistance (HOMA-IR) (r = 0.54, P<0.001). Thus, simple estimates of HEP-IR performed comparable to more complex indices and could be an efficient and cost effective approach in large epidemiological investigations

Molecular links between obesity and insulin resistance

Die hypothalamische Regulation des Körpergewichtes wird durch Signale aus der Peripherie, wie Ghrelin und Insulin, modifiziert. Wir sahen eine direkte Beeinflussung dieser beiden peripheren Signale. Hohe Insulinspiegel bewirkten einen Abfall von Ghrelin. Als eine Folge des Übergewichts kommt es häufig zu Insulinresistenz, einem Risikofaktor für Typ 2 Diabetes mellitus. Insulinresistenz hatte mit einer aktivierten Entzündungsreaktion assoziiert werden können. Beim Menschen kann durch eine Lipidinfusion eine Insulinresistenz induziert werden. Wir konnten zeigen, daß durch eine Vorbehandlung mit dem anti-inflammatorischen Medikament Acetylsalicylsäure, diese lipid-induzierte Insulinresistenz um ca. 30% vermindert werden kann. Dies unterstützt die Annahme, daß die aktivierte Entzündungsreaktion ursächlich mit Insulinresistenz zusammenhängt. Im Rahmen der aktivierten Entzündungsreaktion hatten erhöhte IL-6 Spiegel gezeigt werden können. Da ein Polymorphismus im IL-6 Promotor (C-174G) mit den IL-6 Spiegeln assoziiert werden konnte, hatten wir an einer Fall-Kontroll-Studie innerhalb der EPIC- Potsdam Kohorte (n= 27548) untersucht, ob dieser Polymorphismus mit dem Risiko für Typ 2 Diabetes assoziiert ist. Wir fanden eine Modifikation des BMI Effektes auf das Diabetes Risiko abhängig von diesem Promotorpolymorphismus. Vor einer abschließenden Beurteilung sind jedoch weitere Untersuchungen an noch größeren Kohorten notwendig. Bei Frauen mit polyzystischem Ovarsyndrom hatte ein Zusammenhang zwischen Insulinresistenz und Hyperandrogenämie gezeigt werden können. Noch ist die Richtung dieses Zusammenhangs nicht ganz klar. Wir hatten eine Interaktion zwischen den Testosteronspiegeln und dem CAG Repeat Polymorphismus im Exon 1 des Androgenrezeptors im Hinblick auf Insulinresistenz gesehen. Diese Interaktion würde für einen Effekt der Hyperandrogenämie auf Insulinresistenz sprechen. Wegen des erhöhten Diabetesrisikos wird Frauen mit polyzystischem Ovarsyndrom ein regelmäßiges Diabetes-Screening empfohlen. Wir fanden die Nüchternglukose bei diesen Frauen ungeeignet zum Diabetes-Screening, so daß stets ein oraler Glukosetoleranztest durchgeführt werden sollte. Die Anzahl notwendiger Glukosetoleranztests ließe sich jedoch durch einfache Entscheidungsbäume reduzieren. So erlaubt bereits der sehr einfache Entscheidungsbaum aus BMI und Hüftumfang fast 25% der oralen Glukosetoleranztests einzusparen.The hypothalamic regulation of body weight is modulated by peripheral signals like ghrelin and insulin. We found a direct interaction between these two peripheral signals. High insulin caused a decrease in ghrelin concentration. Insulin resistance, a risk factor of type 2 diabetes, is a common consequence of obesity. Insulin resistance has been associated with activated inflammatory processes. In humans, insulin resistance can be induced by lipid infusion. We found that pretreatment with the anti-inflammatory drug acetylsalicylic acid diminishes this lipid-induced insulin resistance by about 30%. This further supports the assumption that the activated inflammation causes insulin resistance. Increased levels of IL-6 have been described during these activated inflammatory processes. Since a polymorphism within the IL-6 promoter (C-174G) has been associated with the IL-6 levels we further addressed in a nested case-control study within the EPIC-Potsdam cohort (n= 27548), whether this polymorphism is associated with diabetes risk. We found a modification of the BMI effect on insulin resistance by this polymorphism. However, before the impact of this interaction on diabetes risk can be fully interpreted further studies with even larger cohorts are necessary. In women with the polycystic ovary syndrome a relation between insulin resistance and hyperandrogenemia has been shown. However, it is not yet clear whether insulin resistance causes hyperandrogenemia or vice versa. We described an interaction between testosterone levels and the CAG repeat polymorphism within the exon 1 of the androgen receptor with respect to insulin resistance. Such an interaction points to the assumption of a causal effect of hyperandrogenemia on insulin resistance. Due to the increased diabetes risk in polycystic ovary syndrome a regular screening for diabetes is recommended. We found fasting glucose inappropriate for such a diabetes screening. Therefore, regular oral glucose tolerance tests are necessary. The number of oral glucose tolerance tests necessary to detect all the women with impaired glucose metabolism could be reduced by a screening approach using decision trees. Even a simply to perform decision tree based on BMI and waist circumference only would reduce the number of oral glucose tolerance tests by about 25%

Changes in dominant groups of the gut microbiota do not explain cereal-fiber induced improvement of whole-body insulin sensitivity

Background Diets high in cereal-fiber (HCF) have been shown to improve whole-body insulin sensitivity. In search for potential mechanisms we hypothesized that a supplemented HCF-diet influences the composition of the human gut microbiota and/or biomarkers of colonic carbohydrate fermentation. Methods We performed a randomized controlled 18-week intervention in group-matched overweight participants. Fecal samples of 69 participants receiving isoenergetic HCF (cereal-fiber 43 g/day), or control (cereal-fiber 14 g/day), or high-protein (HP, 28% of energy-intake, cereal-fiber 14 g/day), or moderately high cereal fiber/protein diets (MIX; protein 23% of energy-intake, cereal-fiber 26 g/day) with comparable fat contents were investigated for diet-induced changes of dominant groups of the gut microbiota, and of fecal short-chain fatty-acids (SCFA) including several of their proposed targets, after 0, 6, and 18-weeks of dietary intervention. In vitro fermentation of the cereal fiber extracts as used in the HCF and MIX diets was analyzed using gas chromatography. Diet-induced effects on whole-body insulin-sensitivity were measured using euglycaemic-hyperinsulinemic clamps and re-calculated in the here investigated subset of n = 69 participants that provided sufficient fecal samples on all study days. Results Gut microbiota groups and biomarkers of colonic fermentation were comparable between groups at baseline (week 0). No diet-induced differences were detected between groups during this isoenergetic intervention, neither in the full model nor in uncorrected subgroup-analyses. The cereal-fiber extract as used for preparation of the supplements in the HCF and MIX groups did not support in vitro fermentation. Fecal acetate, propionate, and butyrate concentrations remained unchanged, as well as potential targets of increased SCFA, whereas valerate increased after 6-weeks in the HP-group only (p = 0.037). Insulin-sensitivity significantly increased in the HCF-group from week-6 (baseline M-value 3.8 ± 0.4 vs 4.3 ± 0.4 mg·kg-1·min-1, p = 0.015; full model 0-18-weeks, treatment-x-time interaction, p = 0.046). Conclusions Changes in the composition of the gut microbiota and/or markers of colonic carbohydrate fermentation did not contribute explaining the observed early onset and significant improvement of whole-body insulin sensitivity with the here investigated HCF-diet

Annual change in insulin sensitivity

The incidence of both type 2 diabetes and cardiac events is reported to be higher during winter, indicating a putative annual periodic change in insulin sensitivity (IS). Annual differences in IS quantified as HOMA-%S and Matsuda-Sensitivity Index - were analyzed using a cosine wave-fitting algorithm in a cross-sectional study group including 2 385 participants. Additionally, semiannual differences in IS were compared. We found periodicity for HOMA-%S and Matsuda-Sensitivity Index (p = 0.02 or 0.006), which was strengthened after restriction to participants without diabetes ( p = 0.009 or 0.004). The rhythm amplitude of 0.08 indicated moderate changes in IS throughout the year. IS was significantly higher when participants were enrolled during the second vs. the first half of the year (HOMA-%S 112.0 +/- 3.0 % vs. 97.4 +/- 2.4 %, p < 0.001). The impact of the half-year on IS, which remained significant after adjustment for confounders, was again moderate and explained only 0.5% of the variation. IS showed a significant moderate annual periodicity, which may affect the interpretation of studies reporting small changes in IS