Plasma adiponectin levels in women with polycystic ovary syndrome: Impact of Metformin treatment in a case–control study

ObjectiveAn interaction between adiponectin, steroid synthesis or action and measures of insulin resistance (IR) have been reported in the pathogenesis of polycystic ovary syndrome (PCOS). The present study was done to determine plasma adiponectin concentration (PAC) in women with and without PCOS and to assess its correlation to the hormonal and metabolic parameters including measures of IR. The effect of Metformin for 6 months in PCOS was also evaluated.PatientsIn total, 72 selected women were classified as follows: 17 obese (body mass index (BMI)) > 25 kg/m² with PCOS; 19 normal weight (BMI) 18–22.9 kg/m² with PCOS; 17 obese (BMI) > 25 kg/m² without PCOS and 19 normal weight (BMI) 18–22.9 kg/m² without PCOS.InterventionsBlood samples were collected from all women with PCOS between 0800 and 1100 h, after an overnight fast.Main outcome measuresSerum level of LH, FSH, TSH, total T4, testerosterone, 17-α-hydroxyprogesterone (17OHP), DHEAS, insulin, adiponectin and glucose. Measures of IR included fasting serum insulin (FSI), glucose-to-insulin ratio, and homeostasis model assessment (HOMA).Result and conclusionWaist–hip ratio (WHR), insulin, and HOMA index were significantly higher in the lower adiponectin group than in the higher adiponectin group. By using stepwise multiple regression analysis, in model 1 (including BMI, FSI, fasting plasma glucose (FPG) with other variables such serum as testerosterone and DHEAS), the weight and contributions from other variables, namely FSI and FPG were significant independent determinants of fasting PAC (adjusted r² = 0.66); and in model 2 (including BMI, HOMA, FPG only as an index of IR with other variables such as serum testerosterone and DHEAS), BMI, and HOMA were significant independent determinants of fasting PAC (adjusted r² = 0.59). FPG, HOMA index and FSI were significantly lower after Metformin treatment in both obese and non-obese PCOS while adiponectin levels increased significantly.     

Pioglitazone-induced improvements in insulin sensitivity occur without concomitant changes in muscle mitochondrial function

AimsPioglitazone (Pio) is known to improve insulin sensitivity in skeletal muscle. However, the role of Pio in skeletal muscle lipid metabolism and skeletal muscle oxidative capacity is not clear. The aim of this study was to determine the effects of chronic Pio treatment on skeletal muscle mitochondrial activity in individuals with type 2 diabetes (T2D).Materials and MethodsTwenty-four participants with T2D (13 M/11F 53.38 ± 2.1 years; BMI 36.47 ± 1.1 kg/m²) were randomized to either a placebo (CON, n = 8) or a pioglitazone (PIO, n = 16) group. Following 12 weeks of treatment, we measured insulin sensitivity by hyperinsulinemic–euglycemic clamp (clamp), metabolic flexibility by calculating the change in respiratory quotient (ΔRQ) during the steady state of the clamp, intra- and extra-myocellular lipid content (IMCL and EMCL, respectively) by ¹H magnetic resonance spectroscopy (¹H-MRS) and muscle maximal ATP synthetic capacity (ATPmax) by ³¹P-MRS.ResultsFollowing 12 weeks of PIO treatment, insulin sensitivity (p < 0.0005 vs. baseline) and metabolic flexibility (p < 0.05 vs. CON) significantly increased. PIO treatment significantly decreased IMCL content and increased EMCL content in gastrocnemius, soleus and tibialis anterior muscles. ATPmax was unaffected by PIO treatment.ConclusionsThese results suggest that 12 weeks of pioglitazone treatment improves insulin sensitivity, metabolic flexibility and myocellular lipid distribution without any effect on maximal ATP synthetic capacity in skeletal muscle. Consequently, pioglitazone-induced enhancements in insulin responsiveness and fuel utilization are independent of mitochondrial function.     

Association of adiponectin with peripheral muscle status in elderly patients with heart failure

BackgroundReduced peripheral muscle mass was demonstrated in patients with chronic heart failure (HF). Adipokines may have potent metabolic effects on skeletal muscle. The associations between adipokines, peripheral muscle mass, and muscle function have been poorly investigated in patients with HF.MethodsWe measured markers of fat and bone metabolism (adiponectin, leptin, 25-hydroxy vitamin D, parathyroid hormone, osteoprotegerin, RANKL), N-terminal pro B-type natriuretic peptide (NT-pro-BNP) in 73 non-cachectic, non-diabetic, male patients with chronic HF (age: 68 ± 7 years, New York Heart Association class II/III: 76/26%, left ventricular ejection fraction 29 ± 8%) and 20 healthy controls of similar age. Lean mass as a measure of skeletal muscle mass was measured by dual energy X-ray absorptiometry (DEXA), while muscle strength was assessed by hand grip strength measured by Jamar dynamometer.ResultsSerum levels of adiponectin, parathyroid hormone, osteoprotegerin, RANKL, and NT-pro-BNP were elevated in patients with chronic HF compared to healthy controls (all p < 0.0001), while no difference in serum levels of leptin, testosterone or SHBG was noted. Levels of 25-hydroxy vitamin D were reduced (p = 0.002) in HF group. Peripheral lean mass and hand grip strength were reduced in patients with HF compared to healthy subjects (p = 0.006 and p < 0.0001, respectively). Using backward selection multivariable regression, serum levels of increased adiponectin remained significantly associated with reduced arm lean mass and muscle strength.ConclusionsOur findings may indicate a cross-sectional metabolic association of increased serum adiponectin with reduced peripheral muscle mass and muscle strength in non-cachectic, non-diabetic, elderly HF patients.     

Effects of three antidiabetics on insulin and leptin in Chinese type 2 diabetes

AimsThis study was to investigate the effects of some different antidiabetics on circulating insulin and leptin levels in type 2 diabetes with or without overweight in a Chinese population.Methods80 type 2 diabetes men with overweight (body mass index BMI > 24 kg/m²) and 35 type 2 diabetes men with normal body weight (BMI ≤ 24 kg/m²) and 56 control subjects were enrolled in the study. We measured blood glucose, insulin, leptin, total cholesterol, LDL-C, HDL-C, triglycerides, fasting glucose, postprandial glycose, HbA1c and BMI before and after the administration of antidiabetic drugs.ResultsCompared with normal body weight, the levels of plasma insulin and leptin in overweight type 2 diabetes men were higher, after 3 months treatment, a significant increase in insulin and leptin levels was observed in overweight type 2 diabetes men in gliclazide group. Levels of leptin and insulin decreased in metformin and rosiglitazone groups, respectively.ConclusionsWe conclude that surfonylureas treatment leads to increased insulin and leptin levels in overweight type 2 diabetes men, metformin, or rosiglitazone treatment can reduce insulin and leptin levels, respectively, and effect of metformin on plasma leptin and insulin levels is more significant than that of rosiglitazone.     

Metformin decreases plasma resistin concentrations in pediatric patients with impaired glucose tolerance: a placebo-controlled randomized clinical trial

The objective was to determine the effect of metformin on the concentrations of resistin and other markers of insulin resistance or inflammation (C-reactive protein, cytokines, body weight, HbA1c, among others) in minors with glucose intolerance. Patients aged 4 to 17 years with glucose intolerance were studied. They were randomized to receive 850 mg of either metformin or placebo twice daily for 12 weeks, during which all followed an iso-caloric diet and an exercise program. High sensitivity C-reactive protein, TNF-alpha, IL-6, IL1-beta, resistin, leptin, adiponectin, glucose, insulin, HbA1c, lipid profile and transaminases were measured at the beginning and at the end of the period. Fifty-two patients were included, 11.9 ± 2.6 years old; 28 (12 males/16 females) received metformin and 24 placebo (11 males/13 females). Baseline characteristics were similar between groups (except for body mass index, which in the metformin group was slightly higher). Percentage weight loss was greater in the metformin group (?5.86% vs 2.75%, P < .05). At study end, there were statistically significant differences in resistin concentrations, even after adjusting for confounding variables (F = 7.714; P < .006). Also, metformin was associated with a significant decrease in HOMA-IR index (P = .032) and HbA1c levels (P = .001), but no change was observed in the concentration of other markers of inflammation. Metformin resulted in significant reductions of plasma resistin levels in minors with glucose intolerance. This change is independent of its effects on body weight. In contrast, metformin did not alter the concentration of inflammatory markers.     

Diurnal variation and effect of insulin on circulating high molecular weight (HMW) adiponectin and NF-κB activity in human endothelial cells

ObjectiveTo study the diurnal variation and the effect of insulin on adiponectin multimers and nuclear factor-kappaB (NF-κB) activity in human endothelial cells.Methods and resultsWe utilized a prolonged insulin–glucose infusion in six healthy human subjects. HMW and total adiponectin levels were higher in the morning and lower at night; NF-κB activities in serum treated human microvascular endothelial cells (HMEC-1) cells were lower in the morning and higher at night. Hyperinsulinemic induction significantly decreased HMW and total adiponectin levels but increased NF-κB activity in serum treated HMEC-1 cells (P < 0.05, P < 0.01). There were no significant changes to MMW and LMW adiponectin levels (P > 0.05).ConclusionCircadian rhythm of HMW adiponectin and NF-κB activity are altered by hyperinsulinemia providing novel insights adiponectin and NF-κB biology, which may be pertinent to insulin resistant states, e.g. obesity and type 2 diabetes mellitus.     

The correlation of plasma omentin-1 with insulin resistance in non-obese polycystic ovary syndrome

ObjectivesAberrant circulating adipokines are considered to be related to the pathological mechanism of polycystic ovary syndrome (PCOS). This study aims to evaluate the relationship between plasma omentin-1 levels, metabolic and hormonal parameters in the setting of non-obese Chinese women with PCOS.Material and methodsThis was a case-controlled, cross-sectional study of 153 non-obese (BMI < 25 kg/m²) PCOS and 114 age-matched healthy non-obese control individuals. Levels of plasma omentin-1, fasting blood glucose, insulin and sexual hormones and ovary volume were analyzed in all subjects.ResultsPlasma omentin-1 levels of non-obese PCOS individuals were significantly lower than in healthy non-obese controls. Body Mass Index (BMI), homeostasis model of assessment for insulin resistance index (HOMA-IR), levels of testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), LH/FSH ratio and ovary volume (OV) were significantly higher in subjects with PCOS than controls. In the HOMA-IR stratified subgroups, PCOS individuals with insulin resistance had lower omentin-1 than those without insulin resistance after BMI adjustment. Omentin-1 was negatively correlated with BMI, HOMA-IR and fasting insulin. Multiple linear regressions revealed that BMI contributed to omentin-1 levels. Ovary volume was negatively correlated to HOMA-IR but had no correlation with omentin-1.ConclusionsPlasma omentin-1 concentrations were decreased in the non-obese PCOS group. Insulin resistance could further decrease plasma omentin-1 in non-obese individuals with PCOS independent of BMI status.     

The effect of pioglitazone as add-on therapy to metformin or sulphonylurea compared to a fixed-dose combination of metformin and glibenclamide on diabetic dyslipidaemia

Background and aimsDiabetic dyslipidaemia contributes to the increased risk of cardiovascular disease in patients with Type 2 diabetes. This paper examines the effectiveness of adding pioglitazone to metformin or a sulphonylurea (SU) compared with a fixed-dose combination of metformin and glibenclamide on diabetic dyslipidaemia in patients with Type 2 diabetes.Methods and resultsPatients (n = 250) treated with metformin (≤3 g/day) or an SU as monotherapy at a stable dose for ≥3 months were randomised to receive either pioglitazone (15–30 mg/day) in addition to their metformin or SU, or a fixed-dose combination tablet containing metformin (400 mg) and glibenclamide (2.5 mg) [up to 3 tablets daily] for 6 months. Addition of pioglitazone tended to increase plasma high-density lipoprotein-cholesterol (HDL-C) [0.04 mmol/L; P = 0.051] at 6 months and significantly reduced plasma triglycerides (−0.25 mmol/L; P = 0.013) compared with baseline. Patients treated with metformin/glibenclamide for 6 months had reduced HDL-C (−0.09 mmol/L; P < 0.01) and no change in plasma triglyceride levels (0.03 mmol/L; P = 0.733). Both treatment regimes resulted in a similar level of glycaemic control.ConclusionThe beneficial effects of pioglitazone on diabetic dyslipidaemia may help combat the increased cardiovascular morbidity and mortality observed in patients with Type 2 diabetes while providing stable glycaemic control.     

FNDC5 and irisin in humans: I. Predictors of circulating concentrations in serum and plasma and II. mRNA expression and circulating concentrations in response to weight loss and exercise

ObjectiveIn mouse, PGC1-α overexpression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. One prior study has shown that FNDC5 induces browning of subcutaneous fat in mice and mediates beneficial effects of exercise on metabolism, but a more recent study using gene expression arrays failed to detect a robust increase in FNDC5 mRNA in human muscles from exercising subjects. No prior study has reported on the physiological regulation and role of circulating irisin and FNDC5 in humans.Materials/MethodsA. FNDC5 gene expression studies: We first examined tissue distribution of FNDC5 in humans. B. Cross-sectional studies: Predictors of FNDC5 mRNA expression levels were examined in muscle tissues from 18 healthy subjects with a wide range of BMI. Assays were optimized to measure circulating FNDC5 and irisin levels, and their associations with anthropometric and metabolic parameters were analyzed in two cross-sectional studies that examined 117 middle-aged healthy women and 14 obese subjects, respectively. C. Interventional studies: The effect of weight loss on FNDC5 mRNA and/or circulating irisin levels was examined in 14 obese subjects before and after bariatric surgery. The effect of acute and chronic exercise was then assessed in 15 young healthy adults who performed intermittent sprint running sessions over an 8 week period.ResultsTissue arrays demonstrated that in humans, the FNDC5 gene is predominantly expressed in muscle. Circulating irisin was detected in the serum or plasma of all subjects studied, whereas circulating FNDC5 was detected in only a distinct minority of the subjects. Cross-sectional studies revealed that circulating irisin levels were positively correlated with biceps circumference (used as a surrogate marker of muscle mass herein), BMI, glucose, ghrelin, and IGF-1. In contrast, irisin levels were negatively correlated with age, insulin, cholesterol, and adiponectin levels, indicating a possible compensatory role of irisin in metabolic regulation. Multivariate regression analysis revealed that biceps circumference was the strongest predictor of circulating irisin levels underlying the association between irisin and metabolic factors in humans at baseline. Both muscle FNDC5 mRNA levels and circulating irisin levels were significantly downregulated 6 months after bariatric surgery. Circulating irisin levels were significantly upregulated 30 min after acute exercise and were correlated mainly with ATP levels and secondarily with metabolites related to glycolysis and lipolysis in muscle.ConclusionsSimilar to mice, the FNDC5 gene is expressed in human muscle. Age and muscle mass are the primary predictors of circulating irisin, with young male athletes having several fold higher irisin levels than middle-aged obese women. Circulating irisin levels increase in response to acute exercise whereas muscle FNDC5 mRNA and circulating irisin levels decrease after surgically induced weight loss in parallel to decrease in body mass. Further studies are needed to study the regulation of irisin levels and its physiological effects in humans and to elucidate the mechanisms underlying these effects.     

Comparative effects of pioglitazone and metformin on oxidative stress markers in newly diagnosed type 2 diabetes patients: A randomized clinical trial

AimsRecent studies have suggested that pioglitazone exerts anti-oxidant properties which may countervail oxidative stress (OS). We aimed to elucidate the effects of pioglitazone on OS modulation and to compare its effects with metformin.MethodsData from the randomized clinical trial (registration no.NCT01521624) were used. Newly diagnosed type 2 diabetes patients were assigned to pioglitazone 30 mg daily (n = 30), metformin 1000 mg daily (n = 50), or no medication (n = 49). Recommendations for exercise and dietary modifications were provided for three groups. Serum concentrations of advanced oxidation protein products(AOPP), advanced glycation end products(AGE), ferritin reducing ability of plasma(FRAP), and enzymatic activities of paraoxonase(PON), lecithin-cholesterol asyltransferase(LCAT), and lipoprotein lipase(LPL) were measured at baseline and after three months.ResultsIn comparison with no medication, pioglitazone proved to be superior in OS amelioration (p < 0.05 in all analyses). Compared with metformin, both medications were equally effective in decrement of AOPP and AGE, along with increment of PON (p = 0.688, 0.140, and 0.273, respectively). FRAP concentrations increased significantly with metformin (p = 0.012). On the other hand, pioglitazone yielded better efficacy in restoration of LCAT and LPL enzymatic activities (p = 0.037, and < 0.001, respectively).ConclusionsSimilar to metformin, three months treatment with Pioglitazone is beneficial in terms of OS alleviation and anti-oxidant capacity restoration.     

Effects of acute hyperinsulinaemia on total and high-molecular-weight adiponectin concentration in metabolically healthy but obese postmenopausal women: A Montreal–Ottawa New Emerging Team (MONET) study

AimThe aim of this study was to determine the differences and changes in total and high-molecular-weight (HMW) adiponectin levels among metabolically healthy but obese (MHO) postmenopausal women in response to acute hyperinsulinaemia.MethodIn this cross-sectional study, 55 non-diabetic overweight and obese postmenopausal women underwent a hyperinsulinaemic–euglycaemic clamp test to evaluate insulin sensitivity. Subjects within the upper tertile of insulin sensitivity were described as ‘MHO’ (n = 18), whereas those within the lowest tertile were considered ‘at risk’ (n = 18). Plasma total and HMW adiponectin levels were measured by ELISA at 0 (baseline), 90, 160 and 180 min during the clamp.ResultsAt baseline and at all time points during the clamp, MHO individuals had significantly higher total and HMW adiponectin levels than at-risk subjects (AUC: total adiponectin = 2506 ± 1010 vs 1616 ± 830; HMW adiponectin = 909 ± 307 vs 604 ± 349; P < 0.05). In addition, a significant reduction in total adiponectin was observed at 160 min and 180 min in at-risk and MHO subjects, respectively, while HMW adiponectin significantly decreased at 160 min in at-risk subjects, and at 90 min as well as 160 min in MHO women.ConclusionMHO postmenopausal women had higher levels of plasma total and HMW adiponectin than at-risk subjects at baseline and during the clamp. Furthermore, significant decreases in total and HMW adiponectin were observed at certain time points in both the MHO and at-risk subjects.     

Association between circulating irisin levels and the promotion of insulin resistance during the weight maintenance period after a dietary weight-lowering program in obese patients

ObjectiveWeight regain is associated with the promotion of insulin resistance. The newly discovered myokine irisin, which was proposed to be involved in the management of insulin sensitivity, could play a role in this process. This study aimed to investigate the association between irisin and reduced insulin sensitivity induced by weight regain.Materials/MethodsInsulin sensitivity was evaluated according to the homeostasis model assessment of insulin resistance (HOMA-IR) in 136 obese patients who followed an eight-week hypocaloric diet (30% reduced energy expenditure) to lose weight and was re-evaluated four or six months after treatment. Irisin plasma levels, as well as the levels of leptin, adiponectin, ghrelin and TNF-α, were quantified in a sub-cohort (n = 73) from the initially studied patients at baseline (T0), at the diet endpoint (T1) and after the follow-up period (T2).ResultsAfter a successful dietary intervention to lose weight, 50% of the patients who regained the lost weight during the follow-up period were categorized as insulin resistant (HOMA-IR ≥ 2.5) compared with only 25% of patients who maintained the weight loss (p = 0.018). Importantly, in addition to the well-studied hormones leptin and adiponectin, irisin plasma levels were statistically associated with several risk factors for insulin resistance. Indeed, the increased risk of insulin resistance during the follow-up period was related to high irisin levels at baseline (odds ratio = 4.2; p = 0.039).ConclusionsCirculating irisin predicts the insulin resistance onset in association with weight regain. Therefore, irisin could be secreted as an adaptive response to counteract the deleterious effect of excess adiposity on glucose homeostasis.     

Branched chain and aromatic amino acids change acutely following two medical therapies for type 2 diabetes mellitus

ObjectiveElevated circulating levels of branched chain and aromatic amino acids (BCAA/AAAs) are associated with insulin resistance and incident type 2 diabetes (T2D). BCAA/AAAs decrease acutely during an oral glucose tolerance test (OGTT), a diagnostic test for T2D. It is unknown whether changes in BCAA/AAAs also signal an early response to commonly used medical therapies for T2D.Materials and MethodsA liquid chromatography–mass spectrometry approach was used to measure BCAA/AAAs in 30 insulin sensitive (IS) and 30 insulin resistant (IR) subjects before and after: 1) one dose of a sulfonylurea medication, glipizide, 5 mg orally; 2) two days of twice daily metformin 500 mg orally; and 3) a 75-g OGTT. Percent change in BCAA/AAAs was determined after each intervention.ResultsFollowing glipizide, which increased insulin and decreased glucose in both subject groups, BCAA/AAAs decreased in the IS subjects only (all P < 0.05). Following metformin, which decreased glucose and insulin in only the IR subjects, 4 BCAA/AAAs increased in the IR subjects at or below P = 0.05, and none changed in the IS subjects. Following OGTT, which increased glucose and insulin in all subjects, BCAA/AAAs decreased in all subjects (P < 0.05).ConclusionsBCAA/AAAs changed acutely during glipizide and metformin administration, and the magnitude and direction of change differed by the insulin resistance status of the individual and the intervention. These results indicate that BCAA/AAAs may be useful biomarkers for monitoring the early response to therapeutic interventions for T2D.     

Association of ADIPOQ variants, total and high molecular weight adiponectin levels with coronary artery disease in diabetic and non-diabetic Brazilian subjects

ObjectiveTo investigate the association of ADIPOQ variants, total and high molecular weight adiponectin (HMW) adiponectin levels with the prevalence of diabetes mellitus and coronary artery disease (CAD) diagnosed by coronary angiography in Brazilian subjects with high cardiovascular risk.Methods603 subjects undergoing coronary angiography were studied in regard to their glycemic status and presence of CAD (lesions > 0%). We evaluated baseline concentrations of total and HMW adiponectin and three ADIPOQ variants: ? 11391G > A (rs17300539), + 45T > G (rs2241766) and + 276G > T (rs1501299).ResultsThe G-allele of rs2241766 was associated with higher levels of total and HMW adiponectin, and the A-allele of rs17300539 was associated with higher levels of HMW adiponectin. Lower levels of total and HMW adiponectin were independently associated with CAD. The G-allele of rs2241766 (OR 2.45, 95% C.I. 1.05–6.04, p = 0.04) and the G-allele of rs1501299 (OR 1.89, 95% C.I. 1.04–3.45, p = 0.03) were associated with CAD, and these associations were independent of circulating levels of adiponectin.ConclusionsIn Brazilian subjects with high cardiovascular risk, CAD was associated with lower total and HMW adiponectin levels. The rs2241766 and rs1501299 polymorphisms were associated with CAD. The rs2241766 variant was associated with total and HMW adiponectin levels, while rs17300539 was associated with HMW adiponectin levels.     

Measurement of muscle insulin sensitivity in obese men

AimsIn 2007, a novel estimate of skeletal muscle insulin sensitivity was derived from the oral glucose tolerance test (OGTT). The aim of this investigation is to assess whether and to what extent the proposed index of skeletal muscle insulin sensitivity derived from the OGTT was associated with muscle insulin sensitivity measured using the hyperinsulinemic-euglycaemic clamp technique.MethodsForty-six middle-aged, abdominally obese men (age 44 ± 8 years, waist circumference 107.4 ± 6.2) were studied. Each participant participated in a 2-hour, 75-g OGTT and a 3-hour hyperinsulinemic-euglycaemic clamp protocol.ResultsThe OGTT-derived index of muscle insulin sensitivity correlated with muscle insulin sensitivity measured with the insulin clamp (r = 0.55, P < 0.01), however, the standard error of estimate (SEE) when predicting muscle insulin sensitivity by the OGTT-derived index was 5.3 (50%).ConclusionOur findings suggest that despite a statistically significant association between the two methods, the OGTT approach lacks precision and is not a useful method for estimating skeletal muscle insulin sensitivity in abdominally obese men.     

Adiponectin is expressed in the pancreas of high-fat-diet-fed mice and protects pancreatic endothelial function during the development of type 2 diabetes

AimAdiponectin levels in skeletal muscle and adipose tissue have been reported to be involved in insulin resistance in rats fed with a high-fat diet (HFD). Our objective was to explore whether adiponectin is also expressed in the pancreas and what its potential role is during the development of type 2 diabetes (T2D) in outbred CD-1 mice.MethodsMale 4-week-old outbred CD-1 mice were fed an HFD to induce a polygenic model of human T2D. Adiponectin expression was examined in mouse pancreas by quantitative real-time polymerase chain reaction (qPCR), western blots and immunofluorescence analyses. Human umbilical vein endothelium cells (HUVECs) were transfected with an adiponectin-expressing lentivirus to determine the effect of adiponectin on angiogenic function in vitro.ResultsFeeding mice an HFD for 9 weeks resulted in constant hyperglycaemia, obesity, impaired glucose tolerance and insulin resistance. Additional hyperinsulinaemia emerged in mice fed an HFD for 18 weeks. Interestingly, aberrant expression of adiponectin was detectable in the pancreatic vascular endothelial cells (VECs) of mice fed with an HFD, but not in mice fed with regular chow (RC). Expression levels of pancreatic adiponectin varied during the development of T2D. This extraordinary expression of adiponectin in pancreatic VECs played a role in protecting endothelial function against potential damage by HFD. Our in vitro study has demonstrated that adiponectin promotes angiogenic function.ConclusionThese results reveal for the first time that adiponectin is expressed in pancreatic VECs of HFD-fed mice during the development of T2D as a protective adaptation in response to the HFD.     

Efficacy and safety of anti-hyperglycaemic drugs in patients with non-alcoholic fatty liver disease with or without diabetes: An updated systematic review of randomized controlled trials

AimThere are no approved drugs for the treatment of non-alcoholic fatty liver disease (NAFLD). However, many randomized controlled trials (RCT) have examined the effect of anti-hyperglycaemic agents on NAFLD in patients with and without type 2 diabetes mellitus (T2DM), since both T2DM and insulin resistance are closely linked to this burdensome liver disease.MethodsWe systematically searched publication databases using predefined keywords to identify head-to-head or placebo-controlled RCTs (published until September 30, 2019) of NAFLD individuals testing the efficacy of anti-hyperglycaemic drugs to specifically treat NAFLD or non-alcoholic steatohepatitis (NASH). Outcomes of interest included changes in serum liver enzyme levels, liver fat, liver fibrosis, or histologic resolution of NASH.ResultsWe included 29 RCTs involving a total of 2,617 individuals (∼45% had T2DM) that have used metformin (n = 6 studies), glitazones (n = 8 studies), glucagon-like peptide-1 receptor agonists (n = 6 studies), dipeptidyl peptidase-4 inhibitors (n = 4 studies) or sodium-glucose cotransporter-2 inhibitors (n = 7 studies) to treat NAFLD. Although most anti-hyperglycaemic drugs improved serum liver enzyme levels, only glitazones (especially pioglitazone) and liraglutide showed an improvement of histologic features of NAFLD, with a mild beneficial effect also on liver fibrosis for pioglitazone only.ConclusionRCT evidence supports the efficacy of some anti-hyperglycaemic agents (especially pioglitazone) in patients with NAFLD or NASH, though weight gain with pioglitazone may warrant caution. Further well-designed RCTs are needed to better characterize the efficacy and safety of monotherapy and combination therapy with anti-hyperglycaemic agents in patients with NAFLD.     

Plasma adiponectin levels are related to obesity,inflammation, blood lipids and insulin in type 2 diabetic and non-diabetic Trinidadians

AimsTo determine the relationship between plasma adiponectin levels and obesity, inflammation, blood lipids and insulin resistance in type 2 diabetics (T2DM) and non-diabetics in a patient population in Trinidad.MethodsA cohort study of a total of 126 type 2 diabetic (42 males and 84 females) and 140 (43 males and 97 females) non-diabetic public clinic attendees were assessed between December 2008 and July 2009. Along with clinical history and anthropometry, adiponectin, TNF-α, IL-6, CRP, lipid profile, glucose, and insulin were measured in fasting blood samples and insulin resistance (HOMA-IR) was calculated.ResultsDiabetics had higher (p < 0.05) glucose, insulin, HOMA-IR, triglycerides (TG), VLDL and systolic blood pressure than non-diabetics, but lower (p < 0.05) HDL and adiponectin levels. Adiponectin levels were lower (p < 0.05) in obese than in non-obese individuals regardless of diabetic status. There were significant gender differences in HDL, LDL and TG. Among non-obese persons, adiponectin correlated negatively with triglycerides (r = ?0.280; adiponectin), IL-6 (r = ?0.216; p < 0.005), HOMA-IR (r = ?0.373; p = 000) and positively correlated with HDL (r = 0.355; p = 0.000). Diabetic status (p = 0.025), TNF-α (p = 0.048) and BMI (p = 0.027) were identified as useful predictors of adiponectin by multiple linear regression methods. In addition binary logistic regression analysis found glucose (p = 0.001) and adiponectin (p = 0.047) to be useful indicators of type 2 diabetes.ConclusionsAdiponectin decreases with increasing adiposity and insulin resistance. Adiponectin and TNF-α appear to be related to differences in the insulin mediated glucose turnover.     

Increased systemic and adipose tissue inflammation differentiates obese women with T2DM from obese women with normal glucose tolerance

IntroductionObesity is strongly related to type-2 diabetes (T2DM), but there is a subset of obese individuals that remains relatively insulin sensitive and metabolically healthy. This study determined to what extent differences in metabolic health in obese women are associated with differences in adipose tissue and/or systemic inflammation.MethodsThe subject group consisted of age comparable lean (n = 12) and obese women either with T2DM (n = 28) or normal glucose tolerance (NGT; n = 26). Number of crown like structures (CLS) and adipocyte size were measured in subcutaneous and visceral adipose tissue of the obese women. Circulating cytokine and free fatty acid (FFA) levels, as well as number and activation status of peripheral leukocytes were determined.ResultsObese T2DM subjects showed higher circulating levels of IL-6, FFA and glycerol as compared to obese NGT subjects. Obese T2DM subjects had higher absolute numbers of peripheral leukocytes which were mainly due to an increase of T helper cells. Activation status of circulating cytotoxic T (CD8+CD25 +) and B (CD19+CD38 +) cells was significantly increased in obese NGT subjects as compared to lean but was not different between the two obese groups. Subcutaneous adipose tissue of obese T2DM subjects contained more CLS than adipose tissue of obese NGT subjects.ConclusionObese T2DM subjects show higher FFA levels and adipose tissue macrophage infiltration in addition to higher levels of circulating IL-6 and numbers of CD4 + T cells than obese NGT subjects. Hence, obese T2DM subjects show a higher extent of inflammation at both the systemic and adipose tissue level.