Search

OBJECTIVE--Insulin clearance is decreased in type 2 diabetes mellitus (T2DM) for unknown reasons. Subjects with metabolic syndrome are hyperinsulinemic and have an increased risk of T2DM. We aimed to investigate [...]

OBJECTIVE--Fibroblast growth factor (FGF)-21 improves insulin sensitivity and lipid metabolism in obese or diabetic animal models, while human studies revealed increased FGF-21 levels in obesity and type 2 diabetes. Given that FGF-21 has been suggested to be a peroxisome proliferator-activator receptor (PPAR) α--dependent regulator of fasting metabolism, we hypothesized that free fatty acids (FFAs), natural agonists of PPARα, might modify FGF-21 levels. RESEARCH DESIGN AND METHODS--The effect of fatty acids on FGF-21 was investigated in vitro in HepG2 cells. Within a randomized controlled trial, the effects of elevated FFAs were studied in 21 healthy subjects (13 women and 8 men). Within a clinical trial including 17 individuals, the effect of insulin was analyzed using an hyperinsulinemic-euglycemic clamp and the effect of PPARγ/activation was studied subsequently in a rosiglitazone treatment trial over 8 weeks. RESULTS--Oleate and linoleate increased FGF-21 expression and secretion in a PPARα-dependent fashion, as demonstrated by small-interfering RNA-induced PPARα knockdown, while palmitate had no effect. In vivo, lipid infusion induced an increase of circulating FGF-21 in humans, and a strong correlation between the change in FGF-21 levels and the change in FFAs was observed. An artificial hyperinsulinemia, which was induced to delineate the potential interaction between elevated FFAs and hyperinsulinemia, revealed that hyperinsulinemia also increased FGF-21 levels in vivo, while rosiglitazone treatment had no effect. CONCLUSIONS--The results presented here offer a mechanism explaining the induction of the metabolic regulator FGF-21 in the fasting situation but also in type 2 diabetes and obesity., Fibroblast growth factor (FGF)-21 is a recently discovered metabolic regulator of fasting metabolism. FGF-21 activates glucose uptake in adipocytes, protects animals from diet-induced obesity when overexpressed in transgenic mice, and [...]

OBJECTIVE--It has been suggested that retinol-binding protein 4 (RBP4) links adiposity, insulin resistance, and type 2 diabetes. However, circulating RBP4 levels are also affected by kidney function. Therefore, the aim of this study was to test whether RBP4 serum levels are primarily associated with kidney function or type 2 diabetes. RESEARCH DESIGN AND METHODS--RBP4 serum concentration was determined by enzyme-linked immunosorbent assay in 126 nondiabetic and 104 type 2 diabetic subjects. The study population was divided according to estimated glomerular filtration rate (eGFR) into the following groups: eGFR >90 ml/min per 1.73 [m.sup.2] (n = 53), 60-90 ml/min per 1.73 [m.sup.2] (n = 90), 30-60 ml/min per 1.73 [m.sup.2] (n = 38), and RESULTS--RBP4 serum concentration was elevated (2.65 vs. 2.01 µmol/l; P < 0.001) and eGFR was reduced (56 vs. 74 ml/min per 1.73 [m.sup.2]; P < 0.001) in type 2 diabetic vs. nondiabetic subjects, respectively. By stratifying for eGFR, no more differences in RBP4 serum concentration were detectable between type 2 diabetic and nondiabetic subjects. A linear regression analysis revealed an influence of eGFR (r = -0.477; P < 0.001) but not A1C (r = 0.093; P = 0.185) on RBP4 serum concentration. CONCLUSIONS--Existing human data showing elevated RBP4 levels in type 2 diabetic patients may be the result of moderate renal insufficiency rather than support for the suggestion that RBP4 links obesity to type 2 diabetes., Retinol-binding protein 4 (RBP4) is a small visceral protein (~21 kDa), mainly synthesized in the liver and catabolized in the kidneys after glomerular filtration (1). To prevent the renal loss [...]

OBJECTIVE--Cereal fiber intake is linked to reduced risk of type 2 diabetes in epidemiological observations. The pathogenic background of this phenomenon is unknown. Based on recent findings, we hypothesized that [...]

Adiponectin affects lipid metabolism and insulin sensitivity. However, adiponectin circulates in three different oligomers that may also have distinct biological functions. We aimed to analyze the role of these oligomers in obesity and lipid metabolism after weight reduction. A total of 17 obese volunteers (15 women and 2 men) participated in a weight reduction program. Individuals were characterized before and after 6 months of a balanced diet. Adiponectin was determined by enzyme-linked immunosorbent assay, and oligomers were detected by nondenaturating Western blot. BMI decreased (35.1 ± 1.2 to 32.8 ± 1.1 kg/[m.sup.2], P < 0.001), which was associated with an improved metabolite profile. Total adiponectin increased from 5.3 ± 0.5 to 6.1 ± 0.6 µg/ml (P = 0.076). High (HMW) and medium molecular weight (MMW) adiponectin oligomers significantly increased during weight reduction (HMW: 0.37 ± 0.07 to 0.4 ± 0.08 µg/ml, P = 0.042; MMW: 2.3 ± 0.2 to 2.9 ± 0.3 µg/ml, P = 0.007), while low molecular weight (LMW) did not significantly change. Body weight inversely correlated with HMW (r = -0.695, P = 0.002) and positively with LMW (r = 0 .579, P = 0.015). Interestingly, HDL cholesterol and HMW were strongly correlated (r = 0.665, P = 0.007). Indeed, HMW and free fatty acids before weight reduction predicted ~60% of HDL changes during intervention. In conclusion, weight reduction results in a relative increase of HMW/MMW adiponectin and a reduction of LMW adiponectin. Total adiponectin and especially HMW adiponectin are related to circulating HDL cholesterol., Obesity is associated with dyslipidemia, hypertension, type 2 diabetes, and atherosclerotic cardiovascular disease (1,2). Adipose tissue was believed to be a fat-storage organ, but it is now acknowledged to be [...]

Various cross-sectional studies suggest that a polymorphism (E23K) within the ATP-sensitive [K.sup.+] channel KCNJ11 gene is associated with type 2 diabetes (1). However, only two prospective studies have addressed the [...]