Changes in HbA1c and circulating and adipose tissue androgen levels in overweight-obese women with polycystic ovary syndrome in response to electroacupuncture.

AIM: Insulin sensitivity is ~40% lower in women with polycystic ovary syndrome (PCOS) than in controls. We tested the hypothesis that 5 weeks of electroacupuncture treatment improves glucose regulation and androgen levels in overweight/obese women with PCOS. MATERIAL AND METHODS: Seventeen women with PCOS, aged 18 to 38 years, with a body mass index (BMI) ≥25 kg/m2 and diagnosed with PCOS were included in this experimental and feasibility study and subjected to five weeks of electroacupuncture treatments three times/week. The primary outcome was changes in whole-body glucose homeostasis measured by euglycemic hyperinsulinemic clamp before and after the intervention. Secondary outcome were changes in HbA1c, circulating catecholamines, adipocyte size and adipose tissue expression of sex steroids and nerve growth factor (NGF). RESULTS: No significant change in glucose homeostasis was observed, but HbA1c decreased by 9.5% (p = 0.004), circulating testosterone decreased by 22% (p = 0.0007) and dihydrotestosterone decreased by 12% (p = 0.007). The two vagal activity markers of plasma serotonin levels and the dopamine metabolite homovanillic acid decreased by 21% (p = 0.027) and 20% (p = 0.011), respectively. Adipose tissue concentrations of testosterone decreased by 18% (p = 0.049), and androstenedione decreased by 13% (p = 0.035), and mature NGF/proNGF ratio, a marker of sympathetic activity, increased (p = 0.04). These changes occurred without changes in anthropometrics. CONCLUSION: Five weeks of electroacupuncture treatment improves HbA1c and circulating and adipose tissue androgens in women with PCOS. This effect is mediated, at least in part, via modulation of vagal activity and adipose tissue sympathetic activity. Based on these findings, we have recently initiated a randomized controlled study (NTC02647827).

Central nervous system lipocalin-type prostaglandin D2-synthase is correlated with orexigenic neuropeptides, visceral adiposity and markers of the hypothalamic-pituitary-adrenal axis in obese humans.

Lipocalin-type prostaglandin D2-synthase (L-PGDS) is the main producer of prostaglandin D2 (PGD2) in the central nervous system (CNS). Animal data suggest effects of central nervous L-PGDS in the regulation of food intake and obesity. No human data are available. We hypothesised that a role for CNS L-PGDS in metabolic function in humans would be reflected by correlations with known orexigenic neuropeptides. Cerebrospinal fluid (CSF) and serum samples were retrieved from 26 subjects in a weight loss study, comprising a 3-week dietary lead-in followed by 12-weeks of leptin or placebo treatment. At baseline, CSF L-PGDS was positively correlated with neuropeptide Y (NPY) (ρ = 0.695, P < 0.001, n = 26) and galanin (ρ = 0.651, P < 0.001) as well as visceral adipose tissue (ρ = 0.415, P = 0.035). Furthermore, CSF L-PGDS was inversely correlated with CSF leptin (ρ = -0.529, P = 0.005) and tended to correlate inversely with s.c. adipose tissue (ρ = -0.346, P = 0.084). As reported earlier, leptin treatment had no effect on weight loss and did not affect CSF L-PGDS or NPY levels compared to placebo. After weight loss, the change of CSF L-PGDS was significantly correlated with the change of CSF NPY levels (ρ = 0.604, P = 0.004, n = 21). Because of the correlation between baseline CSF L-PGDS levels and visceral adipose tissue, we examined associations with hypothalamic-pituitary-adrenal (HPA) axis components. Baseline CSF L-PGDS was correlated with corticotrophin-releasing hormone (ρ = 0.764, P < 0.001) and ß-endorphin (ρ = 0.491, P < 0.001). By contrast, serum L-PGDS was not correlated with any of the measured variables either at baseline or after treatment. In summary, CSF L-PGDS was correlated with orexigenic neuropeptides, visceral fat distribution and central HPA axis mediators. The importance of these findings is unclear but could suggest a role for CSF L-PGDS in the regulation of visceral obesity by interaction with the neuroendocrine circuits regulating appetite and fat distribution. Further interventional studies will be needed to characterise these interactions in more detail.

Adiponectin in relation to insulin sensitivity and insulin secretion in the development of type 2 diabetes: a prospective study in 64-year-old women.

OBJECTIVES: To examine how serum adiponectin levels predict the incidence of type 2 diabetes, from different prediabetic states, in relation to insulin sensitivity and ß-cell function during 5.5 years of follow-up. METHODS: In a population-based cohort of 64-year-old Caucasian women, we assessed glucose tolerance, insulin sensitivity as homeostasis model assessment, insulin secretion as acute insulin response, lifestyle factors and serum concentrations of adiponectin and high-sensitivity C-reactive protein. After 5.5 years of follow-up, 167 women with normal glucose tolerance (NGT) and 174 with impaired glucose tolerance (IGT) at baseline were re-examined and incidence of diabetes was assessed. RESULTS: A total of 69 new cases of diabetes were detected during follow-up. Diabetes incidence was independently predicted by low levels of serum adiponectin, insulin resistance and insulin secretion, cigarette smoking, impaired fasting glucose (IFG) and IGT at baseline. Serum adiponectin below 11.54 g L(-1) was associated with an odds ratio of 3.6 (95% confidence interval 1.4-8.6) for future type 2 diabetes. At baseline, a high serum adiponectin concentration correlated positively with high levels of insulin sensitivity and insulin secretion. Women with incident diabetes had lower serum adiponectin levels in the NGT, IFG and IGT groups at baseline compared to those who did not develop diabetes during follow-up. CONCLUSIONS: Low adiponectin concentrations were associated with future diabetes independently of insulin secretion and sensitivity, as well as IGT, IFG, smoking and abdominal obesity.

The lipocalins retinol-binding protein-4, lipocalin-2 and lipocalin-type prostaglandin D2-synthase correlate with markers of inflammatory activity, alcohol intake and blood lipids, but not with insulin sensitivity in metabolically healthy 58-year-old Swedish men.

The lipocalins retinol-binding protein (RBP)-4, lipocalin-2 and lipocalin-type prostaglandin D-synthase (L-PGDS) have been suggested to mediate obesity-associated insulin resistance and other metabolic co-morbidities. The role of lipocalins is however controversial and it is unclear whether they have a physiological role in regulation of insulin sensitivity and metabolic function in clinically healthy humans. Therefore, we examined the correlations between serum levels of RBP-4, L-PGDS and lipocalin-2 and insulin sensitivity and other metabolic parameters in non-diabetic subjects selected to display variations in insulin sensitivity. 100 clinically healthy 58-year-old Swedish men were selected by stratified sampling among 818 screened subjects to represent quintiles of varying degrees of insulin sensitivity. Insulin sensitivity was measured by the euglycaemic hyperinsulinaemic clamp method. Serum levels of lipocalins and cytokines were determined using antibody-based techniques. Serum lipids were measured by standardized laboratory methods. None of the measured lipocalins showed any correlations with insulin sensitivity. However, we found that lipocalin-2 and L-PGDS were correlated with each other, but not with RBP-4. Lipocalin-2 and L-PGDS were positively correlated with soluble TNF- receptors 1 and 2 and negatively with alcohol consumption and serum HDL. Further, lipocalin-2 was correlated with interleukin-6 whereas RBP-4 was negatively correlated with TNF-α. □These results suggest that RBP-4, lipocalin-2 and L-PGDS do not regulate insulin sensitivity in healthy men. Rather the expression levels of lipocalin-2 and L-PGDS, but not RBP-4, seemed to reflect inflammatory activity and were inversely correlated with alcohol intake and serum HDL levels.

Association between impaired glucose tolerance and carotid atherosclerosis: a study in 64-year-old women and a meta-analysis.

BACKGROUND AND AIMS: Impaired glucose tolerance (IGT) is regarded as a transient metabolic state leading to type-2 diabetes, and is known to predict future risk of cardiovascular disease. This study was designed to investigate if IGT is associated with subclinical atherosclerosis. METHODS AND RESULTS: In a population-based cohort of 64-year-old women, a group with IGT determined by repeated oral glucose tolerance tests (n=205) was compared with healthy women with normal glucose tolerance (NGT, n=188). Intima-media thickness (IMT) and plaques in the common carotid arteries (CCA) and bulbs were measured by ultrasound. The 95% confidence interval (CI) of the difference between the IGT and NGT groups was -0.03 to 0.03mm. There was no difference in carotid bulb IMT or in the occurrence, size, and characteristics of plaques between the IGT and NGT groups. A meta-analysis was used to calculate summary measures of 12 reviewed studies showing a difference of 0.030 (95% CI 0.012-0.048) mm in carotid IMT between IGT and NGT groups. Heterogeneity in IMT differences between studies was shown. CONCLUSIONS: In our population-based cohort of 64-year-old women, IGT was not associated with increased occurrence of subclinical atherosclerosis. However, a meta-analysis of 12 studies, including our current study, showed that IGT was associated with a small increase in the CCA IMT.

Adiponectin, obesity and atherosclerosis.

The circulating protein adiponectin has been the subject of immense interest ever since it was first discovered in the mid-1990s. The protein is uniquely produced and secreted by mature adipocytes and is believed to have important anti-inflammatory and anti-diabetic effects; low levels have been shown to be predictive of future type 2 diabetes and cardiovascular disease. This review discusses adiponectin in relation to obesity, inflammation, insulin resistance and atherosclerosis.

Adiponectin: saving the starved and the overfed.

The incidence of the metabolic syndrome, type 2 diabetes and cardio- and cerebrovascular disease is increasing in the Western world. The adipocyte derived protein adiponectin is thought to have a protective role against these conditions. But why is it so? Is it reasonable to believe that we have adiponectin to gain protection from welfare related diseases? Humans have had a far deadlier foe throughout history than obesity and sedentariness and that is starvation. During starvation, the body is catabolic in order to provide fuel. Catabolism is also seen in patients with advanced cardiac or renal failure, type 1 diabetes and anorexia. These subjects have higher adiponectin levels than controls. In this article, I will put forward the hypothesis that the adiponectin system evolved in order to help us to survive periods of malnourishment.

Are serum adiponectin concentrations in a population sample of 64-year-old Caucasian women with varying glucose tolerance associated with ultrasound-assessed atherosclerosis?

OBJECTIVE: To examine whether serum adiponectin concentrations were associated with subclinical atherosclerosis assessed as intima media thickness (IMT) in the carotid arteries in Caucasian women with varying degrees of glucose tolerance. RESEARCH DESIGN AND METHODS: From a population-based cohort of 64-year-old Swedish women, 533 subjects with type 2 diabetes (DM2, n=177), impaired glucose tolerance (IGT; n=178) or normal glucose tolerance (NGT, n=178) were recruited. Anthropometrics, usual cardiovascular risk factors were examined and ultrasound examination of the carotid arteries was performed. RESULTS: Women with low adiponectin concentrations were characterized by thick IMT, higher prevalence of DM2, history of previous myocardial infarction, angina pectoris, anti-hypertensive treatment and high body mass index (BMI), waist circumference, plasma insulin, serum triglycerides, fasting glucose, HbA1c, and low serum HDL cholesterol levels. Carotid IMT correlated with HbA1c (r=0.24, P<0.001), waist circumference (r=0.22, P<0.001), plasma insulin (r=0.19, P<0.001), BMI (r=0.18, P<0.001), DM2 (r=0.16, P<0.001), systolic blood pressure (r=0.16, P<0.001), blood glucose (r=0.16, P<0.001), triglycerides (r=0.15, P<0.001), and reversely to adiponectin (r=-0.11, P=0.01), HDL cholesterol (r=-0.13, P=0.004), and alcohol intake (r=-0.087, P<0.05). A more detailed analysis of underlying associations was difficult due to a high co-linearity between these variable. CONCLUSIONS: Low serum adiponectin concentrations were associated with increased carotid artery IMT, and several risk factors for cardiovascular diseases, mainly those constituting the metabolic syndrome.