Decreased Plasma Adiponectin Concentrations Are Closely Related to Hepatic Fat Content and Hepatic Insulin Resistance in Pioglitazone-Treated Type 2 Diabetic Patients

Bajaj, Mandeep S; Suraamornkul, Swangjit; Piper, Paul K; Hardies, L. Jean; Glass, Leonard; Cersósimo, Eugênio; Pratipanawatr, Thongchai; Miyazaki, Yoshinori; DeFronzo, Ralph A.

doi:10.1210/jc.2003-031315

Cited by 331 publications

(284 citation statements)

References 41 publications

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“…In the present study, the relationship between adiponectin and insulin sensitivity exclusively reflected changes of peripheral glucose fluxes in late pregnancy. This contrasts with studies reporting an association between basal and insulin-stimulated hepatic glucose production and adiponectin in situations of severe insulin resistance and may represent a feature that is specific to pregnancy [28,29,49].…”

Section: Functional Significance Of Hypoadiponectinaemiacontrasting

confidence: 58%

Adiponectin in human pregnancy: implications for regulation of glucose and lipid metabolism

et al. 2006

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Aims/hypothesis: Adiponectin is upregulated during adipogenesis and downregulated in insulin-resistant states. The mechanism(s) governing the re-arrangements from adipogenesis to facilitated lipolysis during pregnancy are unknown. Our purpose was to analyse the role of adiponectin relative to the metabolic changes in human pregnancy. Subjects, materials and methods: Lean women (BMI <25 kg/m²) were evaluated longitudinally before conception, and in early (12-14 weeks) and late (34-36 weeks) pregnancy. Insulin sensitivity was measured using the glucose clamp technique. Venous blood and subcutaneous adipose tissue biopsies were obtained at each time point. Results: Adiponectin concentrations were lower in the third trimester than in the pregravid condition (9.9±1.4 vs 13.5±1.8 μg/ml). The hypoadiponectinaemia was reflected by a 2.5-fold decrease in white adipose tissue adiponectin mRNA. These changes were associated with a 25% increase in fat mass (23.7±2.9 vs 18.9±2.9 kg). Insulin infusion decreased high molecular weight adiponectin complexes in pregravid women (9.9±0.6 vs 6.2±0.06) and the suppressive effect of insulin was lost during pregnancy. The pregnancy-mediated changes in adiponectin were strongly correlated with basal insulin levels and insulin sensitivity (p<0.0001). The relationship between adiponectin and insulin sensitivity was related to the decreased insulin regulation of glucose utilisation (r=0.55, p<0.001) but not of endogenous hepatic glucose production. Conclusions/interpretation: These data demonstrate that pregnancy is associated with adiponectin changes in lean women. Hypoadiponectinaemia is reflected by a lower amount of high molecular weight adiponectin and by the ratio of high to low molecular weight multimers. The adiponectin changes relate to decreased insulin sensitivity of glucose disposal rather than alterations of lipid metabolism.

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Section: Functional Significance Of Hypoadiponectinaemiacontrasting

confidence: 58%

Adiponectin in human pregnancy: implications for regulation of glucose and lipid metabolism

et al. 2006

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“…The implications of adiponectin have been investigated extensively in patients with NAFLD [5,6,8] and limitedly in patients with chronic HVC infection [16]. However, the role of adiponectin in the development of HBV-related liver cirrhosis and HCC remains largely unknown.…”

Section: Discussionmentioning

confidence: 99%

“…This protein possesses anti-inflammatory and insulin-sensitizing properties [4]. In humans, circulating adiponectin levels are positively correlated with insulin sensitivity and decreased in obese and type 2 diabetic patients [5][6][7][8][9]. Adiponectin has also been found to antagonize tumor necrosis factor (TNF) a [10] and plays a central role in the attenuation of carbon tetrachlorideinduced liver fibrosis in mice [11].…”

Section: Introductionmentioning

confidence: 99%

High serum adiponectin correlates with advanced liver disease in patients with chronic hepatitis B virus infection

et al. 2008

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Purpose Adiponectin possesses anti-inflammatory and insulin-sensitizing properties. Little is known about the role of adiponectin in hepatitis B-related liver disease.Methods Serum adiponectin and hepatitis B viral factors were cross-sectionally assayed in 280 patients with chronic hepatitis B virus (HBV) infection including 120 patients with chronic HBV infection, 40 patients with cirrhosis, and 120 patients with hepatocellular carcinoma (HCC); 116 healthy adults were used as controls. The dynamics of serum adiponectin level was also studied longitudinally in 25 patients with hepatitis B e antigen (HBeAg) seroconversion (SC). Results We found that serum adiponectin level in patients with chronic HBV infection was similar to that in healthy controls and was significantly lower than patients with cirrhosis and HCC. In univariate analysis, high serum adiponectin level significantly correlated with the presence of HBV-related cirrhosis or HCC, abnormal serum ALT level, and HBV genotype C. Multivariate analysis revealed that high serum adiponectin level significantly correlated with the development of HCC. Serum adiponectin levels remained stationary in patients experiencing HBeAg SC. Conclusions Our findings suggest that HBV infection itself does not affect adiponectin levels. Serum adiponectin level correlates with the progression of HBV-related liver diseases but not with the development of HBeAg SC.

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“…During the week prior to the start of PIO or FENO, all subjects received: (1) baseline measurements of FPG, plasma AD, NEFA, insulin (mean of three values drawn at 15 min intervals), fasting plasma lipids and HbA 1c ; (2) measurement of liver fat content with magnetic resonance spectroscopy [16,25]; and (3) quantification of hepatic and peripheral tissue insulin sensitivity with a hyperinsulinaemic-euglycaemic clamp [29] in combination with 3-[ 3 H]glucose. All studies were started at 06.00 hours following a 10 h overnight fast.…”

Section: Methodsmentioning

confidence: 99%

“…Plasma AD levels are reduced in obese humans [22], the offspring of diabetic parents [23] and patients with type 2 diabetes [22] and are increased two-to threefold following thiazolidinedione treatment [24]. We [25] and others [19] have previously reported that PPAR-γ (thiazolidinedione) treatment causes a threefold increase in plasma AD concentration, which is closely related to the decrease in hepatic fat content and enhanced hepatic and peripheral insulin sensitivity in type 2 diabetic patients. Injection of recombinant AD in mice enhances adenosine 5′-monophosphate-activated protein kinase (AMPK) activity, increases fatty acid oxidation and reduces triacylglycerol content in muscle, improves muscle sensitivity to insulin and decreases basal hepatic glucose output [26,27].…”

Section: Introductionmentioning

confidence: 93%

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

et al. 2007

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Aims/hypothesis The aim of the study was to examine the effects of pioglitazone (PIO), a peroxisome proliferatoractivated receptor (PPAR)-γ agonist, and fenofibrate (FENO), a PPAR-α agonist, as monotherapy and in combination on glucose and lipid metabolism. Subjects and methods Fifteen type 2 diabetic patients received FENO (n=8) or PIO (n=7) for 3 months, followed by the addition of the other agent for 3 months in an openlabel study. Subjects received a 4 h hyperinsulinaemiceuglycaemic clamp and a hepatic fat content measurement at 0, 3 and 6 months. Results Following PIO, fasting plasma glucose (FPG) (p<0.05) and HbA 1c (p<0.01) decreased, while plasma adiponectin (AD) (5.5±0.9 to 13.8±3.5 μg/ml [SEM], p<0.03) and the rate of insulin-stimulated total-body glucose disposal (R d ) (23.8 ± 3.8 to 40.5 ± 4.4 μmol kg −1 min −1 , p < 0.005) increased. After FENO, FPG, HbA 1c , AD and R d did not change. PIO reduced fasting NEFA (784±53 to 546± 43 μmol/l, p<0.05), triacylglycerol (2.12±0.28 to 1.61± 0.22 mmol/l, p<0.05) and hepatic fat content (20.4±4.8 to 10.2±2.5%, p<0.02). Following FENO, fasting NEFA and hepatic fat content did not change, while triacylglycerol decreased (2.20± 0.14 to 1.59± 0.13 mmol/l, p<0.01).Addition of FENO to PIO had no effect on R d , FPG, HbA 1c , NEFA, hepatic fat content or AD, but triacylglycerol decreased (1.61±0.22 to 1.00±0.15 mmol/l, p<0.05). Addition of PIO to FENO increased R d (24.9±4.4 to 36.1± 2.2 μmol kg −1 min −1 , p<0.005) and AD (4.1±0.8 to 13.1± 2.5 μg/ml, p<0.005) and reduced FPG (p<0.05), HbA 1c (p<0.05), NEFA (p<0.01), hepatic fat content (18.3±3.1 to 13.5±2.1%, p<0.03) and triacylglycerol (1.59±0.13 to 0.96±0.9 mmol/l, p<0.01). Muscle adenosine 5′-monophosphate-activated protein kinase (AMPK) activity did not change following FENO; following the addition of PIO, muscle AMPK activity increased significantly (phosphorylated AMPK:total AMPK ratio 1.2±0.2 to 2.2±0.3, p<0.01). Conclusions/interpretation We conclude that PPAR-α therapy has no effect on NEFA or glucose metabolism and that addition of a PPAR-α agonist to a PPAR-γ agent causes a further decrease in plasma triacylglycerol, but has no effect on NEFA or glucose metabolism.

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Decreased Plasma Adiponectin Concentrations Are Closely Related to Hepatic Fat Content and Hepatic Insulin Resistance in Pioglitazone-Treated Type 2 Diabetic Patients

Cited by 331 publications

References 41 publications

Adiponectin in human pregnancy: implications for regulation of glucose and lipid metabolism

Adiponectin in human pregnancy: implications for regulation of glucose and lipid metabolism

High serum adiponectin correlates with advanced liver disease in patients with chronic hepatitis B virus infection

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

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