Metabolic profiling of polycystic ovary syndrome reveals interactions with abdominal obesity.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common reproductive disorder associated with metabolic disturbances including obesity, insulin resistance and diabetes mellitus. Here we investigate whether changes in the metabolic profile of PCOS women are driven by increased tendency to obesity or are specific features of PCOS related to increased testosterone levels. DESIGN AND METHODS: We conducted an NMR metabolomics association study of PCOS cases (n=145) and controls (n=687) nested in a population-based birth cohort (n=3127). Subjects were 31 years old at examination. The main analyses were adjusted for waist circumference (WC) as a proxy measure of central obesity. Subsequently, metabolite concentrations were compared between cases and controls within pre-defined WC strata. In each stratum, additional metabolomics association analyses with testosterone levels were conducted separately among cases and controls. RESULTS: Overall, women with PCOS showed more adverse metabolite profiles than the controls. Four lipid fractions in different subclasses of very low density lipoprotein (VLDL) were associated with PCOS, after adjusting for WC and correction for multiple testing (P<0.002). In stratified analysis the PCOS women within large WC strata (⩾98 cm) had significantly lower high density lipoprotein (HDL) levels, Apo A1 and albumin values compared with the controls. Testosterone levels were significantly associated with VLDL and serum lipids in PCOS cases with large WC but not in the controls. The higher testosterone levels, adjusted for WC, associated adversely with insulin levels and HOMA IR in cases but not in the controls. CONCLUSIONS: Our findings show that both abdominal obesity and hyperandrogenism contribute to the dyslipidaemia and other metabolic traits of PCOS which all may negatively contribute to the long-term health of women with PCOS.

Effect of metformin therapy on circulating amino acids in a randomized trial: the CAMERA study.

AIMS: To investigate whether metformin therapy alters circulating aromatic and branched-chain amino acid concentrations, increased levels amino acid concentrations, increased levels of which have been found to predict Type 2 diabetes. METHODS: In the Carotid Atherosclerosis: Metformin for Insulin Resistance (CAMERA) study (NCT00723307), 173 individuals without Type 2 diabetes, but with coronary disease, were randomized to metformin (n=86) or placebo (n=87) for 18 months. Plasma samples, taken every 6 months, were analysed using quantitative nuclear magnetic resonance spectroscopy. Ten metabolites consisting of eight amino acids [three branched-chain (isoleucine, leucine, valine), three aromatic (tyrosine, phenylalanine, histidine) and two other amino acids (alanine, glutamine)], lactate and pyruvate were quantified and analysed using repeated-measures models. On-treatment analyses were conducted to investigate whether amino acid changes were dependent on changes in weight, fat mass or insulin resistance estimated using homeostasis model assessment (HOMA-IR). RESULTS: Tyrosine decreased [-6.1 µmol/l (95% CI -8.5, -3.7); P<0.0001], while alanine [42 umol/l (95% CI 25, 59); P<0.0001] increased in the metformin-treated group compared with the placebo-treated group. Decreases in phenylalanine [-2.0 µmol/l (95% CI -3.6, -0.3); P=0.018] and increases in histidine [2.3 µmol/l (95% CI 0.1, 4.6); P=0.045] were also observed in the metformin group, although these changes were less statistically robust. Changes in these four amino acids were not accounted for by changes in weight, fat mass or HOMA-IR values. Levels of branched-chain amino acids, glutamine, pyruvate and lactate were not altered by metformin therapy. CONCLUSIONS: Metformin therapy results in a sustained and specific pattern of changes in aromatic amino acid and alanine concentrations. These changes are independent of any effects on weight and insulin sensitivity. Any causal link to metformin's unexplained cardiometabolic benefit requires further study.

Metabolic phenotyping of diabetic nephropathy.

Diabetic nephropathy is the most serious complication of type 1 diabetes. There is no treatment to protect the kidneys from poorly controlled diabetes, and therefore prevention of the initial metabolic insults is currently the only effective approach to reducing the high mortality related to diabetic nephropathy. Metabolic phenotyping brings us one step closer to understanding the unique set of regulatory perturbations that predispose to kidney injury and paves the way for multiparametric risk assessment.

Triglyceride-cholesterol imbalance across lipoprotein subclasses predicts diabetic kidney disease and mortality in type 1 diabetes: the FinnDiane Study.

BACKGROUND: Circulating cholesterol (C) and triglyceride (TG) levels are associated with vascular injury in type 1 diabetes (T1DM). Lipoproteins are responsible for transporting lipids, and alterations in their subclass distributions may partly explain the increased mortality in individuals with T1DM. DESIGN AND SUBJECTS: A cohort of 3544 individuals with T1DM was recruited by the nationwide multicentre FinnDiane Study Group. At baseline, six very low-density lipoprotein VLDL, one intermediate-density lipoprotein IDL, three low-density lipoprotein LDL and four higher high-density lipoprotein HDL subclasses were quantified by proton nuclear magnetic resonance spectroscopy. At follow-up, the baseline data were analysed for incident micro- or macroalbuminuria (117 cases in 5.3 years), progression from microalbuminuria (63 cases in 6.1 years), progression from macroalbuminuria (109 cases in 5.9 years) and mortality (385 deaths in 9.4 years). Univariate associations were tested by age-matched cases and controls and multivariate lipoprotein profiles were analysed using the self-organizing map (SOM). RESULTS: TG and C levels in large VLDL were associated with incident albuminuria, TG and C in medium VLDL were associated with progression from microalbuminuria, and TG and C in all VLDL subclasses were associated with mortality. Large HDL-C was inversely associated with mortality. Three extreme phenotypes emerged from SOM analysis: (i) low C (<3% mortality), (ii) low TG/C ratio (6% mortality), and (iii) high TG/C ratio (40% mortality) in all subclasses. CONCLUSIONS: TG-C imbalance is a general lipoprotein characteristic in individuals with T1DM and high vascular disease risk.

Association between habitual dietary intake and lipoprotein subclass profile in healthy young adults.

BACKGROUND AND AIMS: Nutritional epidemiology is increasingly shifting its focus from studying single nutrients to the exploration of the whole diet utilizing dietary pattern analysis. We analyzed associations between habitual diet (including macronutrients, dietary patterns, biomarker of fish intake) and lipoprotein particle subclass profile in young adults. METHODS AND RESULTS: Complete dietary data (food-frequency questionnaire) and lipoprotein subclass profile (via nuclear magnetic resonance spectroscopy) were available for 663 subjects from the population-based FinnTwin12 study (57% women, age: 21-25 y). The serum docosahexaenoic to total fatty acid ratio was used as a biomarker of habitual fish consumption. Factor analysis identified 5 dietary patterns: "Fruit and vegetables", "Meat", "Sweets and desserts", "Junk food" and "Fish". After adjustment for sex, age, body mass index, waist circumference, physical activity, smoking status and alcohol intake, the "Junk food" pattern was positively related to serum triglycerides (r = 0.12, P = 0.002), a shift in the subclass distribution of VLDL toward larger particles (r = 0.12 for VLDL size, P < 0.001) and LDL toward smaller particles (r = -0.15 for LDL size, P < 0.001). In addition, higher scores on this pattern were positively correlated with concentrations of small, dense HDL (r = 0.16, P < 0.001). Habitual fish intake associated negatively with VLDL particle diameter ("Fish" pattern and biomarker) and positively with HDL particle diameter (biomarker). CONCLUSIONS: Our results suggest that in young adults, higher habitual fish consumption is related to favorable subclass distributions of VLDL and HDL, while junk food intake is associated with unfavorable alterations in the distribution of all lipoprotein subclasses independent of adiposity and other lifestyle factors.

Lipoprotein subclass profiles in individuals with varying degrees of glucose tolerance: a population-based study of 9399 Finnish men.

OBJECTIVES: We investigated serum concentrations of lipoprotein subclass particles and their lipid components determined by proton nuclear magnetic resonance spectroscopy in a population-based study. DESIGN AND METHODS: A total of 9399 Finnish men were included in the study: 3034 men with normal fasting glucose and normal glucose tolerance; 4345 with isolated impaired fasting glucose (IFG); 312 with isolated impaired glucose tolerance (IGT); 1058 with both IFG and IGT; and 650 with newly diagnosed type 2 diabetes (New DM). Lipoprotein subclasses included chylomicrons (CM) and largest VLDL particles, other VLDL particles (five subclasses), intermediate-density lipoprotein (IDL), LDL (three subclasses) and HDL (four subclasses). The phospholipid, triglyceride (TG), cholesterol, free cholesterol and cholesterol ester levels of the lipoprotein particles were measured. RESULTS: Abnormal glucose tolerance (especially IGT and New DM) was significantly associated with increased concentrations of VLDL subclass particles and their components (with the exception of very small VLDL particles). After further adjustment for total TGs and HDL cholesterol, increased lipid concentrations in the CM/largest VLDL particles and in most of the other VLDL particles remained significant in individuals with isolated IGT, IFG+IGT and New DM. There was a consistent trend towards a decrease in large and an increase in small HDL particle concentrations in individuals with hyperglycaemia even after adjustment for serum total TGs and HDL cholesterol. CONCLUSIONS: Abnormal glucose tolerance modifies the concentrations of lipoprotein subclass particles and their lipid components in the circulation and is also related to compositional changes in these particles.

Association between liver insulin resistance and cardiovascular risk factors.

OBJECTIVES: The objective of this study was to examine the associations between indices of liver insulin resistance (IR) and whole-body insulin sensitivity and different cardiovascular disease (CVD) risk factors. DESIGN AND SUBJECTS: A total of 8750 nondiabetic men (age 57.2 ± 7.1 years, body mass index 26.8 ± 3.8 kg m(-2) ) were included in this study from the population-based cross-sectional Metabolic Syndrome In Men (METSIM) cohort. Liver IR index and Matsuda insulin sensitivity index (ISI) were used as markers of liver IR and whole-body insulin sensitivity, respectively. Pearson correlation analysis was performed to examine the associations between these indices and various CVD risk factors. RESULTS: Total cholesterol (r = -0.088 vs. r = 0.020; P < 0.0019), high-sensitivity C-reactive protein (CRP) (r = 0.284 vs. r = -0.219; P < 0.0019) and total triglycerides (r = 0.507 vs. r = -0.477; P < 0.05) were more highly correlated with liver IR index than with Matsuda ISI. By contrast, Matsuda ISI was nominally more highly correlated with systolic and diastolic blood pressure (r = -0.234 and r = -0.275 vs. r = 0.202 and r = 0.239, respectively) compared to liver IR index. Furthermore, the variance explained by liver IR index was larger than that explained by Matsuda ISI for the majority of CVD risk factors measured. CONCLUSIONS: Liver IR index correlated more strongly than Matsuda ISI with levels of total cholesterol, CRP and triglycerides. Therefore, liver IR might be a significant indicator of CVD risk amongst men.