No abstract

The effect of pioglitazone (PIO) on plasma adiponectin concentration, endogenous glucose production (EGP), and hepatic fat content (HFC) was studied in 11 type 2 diabetic patients (age, 52 ؎ 2 yr; body mass index, 29.6 ؎ 1.1 kg/m 2 ; HbA 1c , 7.8 ؎ 0.4%). HFC (magnetic resonance spectroscopy) and basal plasma adiponectin concentration were quantitated before and after PIO (45 mg/d) for 16 wk. Subjects received a 3-h euglycemic insulin (100 mU/m 2 ⅐min) clamp combined with 3-[ 3 H] glucose infusion to determine rates of EGP and tissue glucose disappearance (Rd) before and after PIO. PIO reduced fasting plasma glucose (10.0 ؎ 0.7 to 7.2 ؎ 0.6 mmol/liter, P < 0.01) and HbA 1c (7.8 ؎ 0.4 to 6.5 ؎ 0.3%, P < 0.01) despite increased body weight (83.0 ؎ 3.0 to 86.4 ؎ 3.0 kg, P < 0.01). PIO improved Rd (6.6 ؎ 0.6 vs. 5.2 ؎ 0.5 mg/kg⅐min, P < 0.005) and reduced EGP (0.23 ؎ 0.04 to 0.05 ؎ 0.02 mg/kg⅐min, P < 0.01) during the 3-h insulin clamp. After PIO treatment, HFC decreased from 21.3 ؎ 4.2 to 11.0 ؎ 2.4% (P < 0.01), and plasma adiponectin increased from 7 ؎ 1 to 21 ؎ 2 g/ml (P < 0.0001). Plasma adiponectin concentration correlated negatively with HFC (r ‫؍‬ ؊0.60, P < 0.05) and EGP (r ‫؍‬ ؊0.80, P < 0.004) and positively with Rd before (r ‫؍‬ 0.68, P < 0.02) pioglitazone treatment; similar correlations were observed between plasma adiponectin levels and HFC (r ‫؍‬ ؊0.65, P < 0.03) and Rd after (r ‫؍‬ 0.70, P ‫؍‬ 0.01) pioglitazone treatment. EGP was almost completely suppressed after pioglitazone treatment; taken collectively, plasma adiponectin concentration, before and after pioglitazone treatment, still correlated negatively with EGP during the insulin clamp (r ‫؍‬ ؊0.65, P < 0.001). In conclusion, PIO treatment in type 2 diabetes causes a 3-fold increase in plasma adiponectin concentration. The increase in plasma adiponectin is strongly associated with a decrease in hepatic fat content and improvements in hepatic and peripheral insulin sensitivity. The increase in plasma adiponectin concentration after thiazolidinedione therapy may play an important role in reversing the abnormality in hepatic fat mobilization and the hepatic/muscle insulin resistance in patients with type 2 diabetes. (J Clin Endocrinol Metab 89: 200 -206, 2004)

The effect of pioglitazone on splanchnic glucose uptake (SGU), endogenous glucose production (EGP), and hepatic fat content was studied in 14 type 2 diabetic patients (age 50 ؎ 2 years, BMI 29.4 ؎ 1.1 kg/m 2 , HbA 1c 7.8 ؎ 0.4%). Hepatic fat content (magnetic resonance spectroscopy) and SGU (oral glucose load-insulin clamp technique) were quantitated before and after pioglitazone (45 mg/day) therapy for 16 weeks. Subjects received a 7-h euglycemic insulin (100 mU ⅐ m ؊2 ⅐ min ؊1 ) clamp, and a 75-g oral glucose load was ingested 3 h after starting the insulin clamp. Following glucose ingestion, the steady-state glucose infusion rate during the insulin clamp was decreased appropriately to maintain euglycemia. SGU was calculated by subtracting the integrated decrease in glucose infusion rate during the 4 h after glucose ingestion from the ingested glucose load. 3-[ 3 H]glucose was infused during the initial 3 h of the insulin clamp to determine rates of EGP and glucose disappearance (R d ). Pioglitazone reduced fasting plasma glucose (10.0 ؎ 0.7 to 7.5 ؎ 0.6 mmol/l, P < 0.001) and HbA 1c (7.8 ؎ 0.4 to 6.7 ؎ 0.3%, P < 0.001) despite increased body weight (83 ؎ 3 to 86 ؎ 3 kg, P < 0.001). During the 3-h insulin clamp period before glucose ingestion, pioglitazone improved R d (6.9 ؎ 0.5 vs. 5.2 ؎ 0.5 mg ⅐ kg ؊1 ⅐ min ؊1 , P < 0.001) and insulinmediated suppression of EGP (0.21 ؎ 0.04 to 0.06 ؎ 0.02 mg ⅐ kg ؊1 ⅐ min ؊1 , P < 0.01). Following pioglitazone treatment, hepatic fat content decreased from 19.6 ؎ 3.6 to 10.4 ؎ 2.1%, (P < 0.005), and SGU increased from 33.0 ؎ 2.8 to 46.2 ؎ 5.1% (P < 0.005). Pioglitazone treatment in type 2 diabetes 1) decreases hepatic fat content and improves insulin-mediated suppression of EGP and 2) augments splanchnic and peripheral tissue glucose uptake. Improved splanchnic/peripheral glucose uptake and enhanced suppression of EGP contribute to the improvement in glycemic control in patients with type 2 diabetes. Diabetes 52:1364 -1370, 2003 T he splanchnic tissues play a pivotal role in the maintenance of normal glucose homeostasis (1). Hyperglycemia, plasma free fatty acid (FFA) concentration, and route of glucose administration all exert independent effects on splanchnic glucose uptake (SGU). When glucose is administered intravenously, the resultant hyperglycemia enhances SGU in proportion to the increase in plasma glucose concentration such that the splanchnic glucose clearance remains unchanged (2,3). This mass-action effect of hyperglycemia to augment SGU is dependent upon maintained portal insulin levels (2-5,8). Insulin per se does not increase SGU (2,5). Studies by DeFronzo and colleagues (3,5) in humans and by Cherrington and colleagues (6,7) in dogs have shown that the gastrointestinal/portal route of glucose administration has a specific enhancing effect on SGU. Thus, following glucose ingestion, the fractional, as well as absolute rate of glucose uptake by the splanchnic tissues is significantly greater than the combined effects of hyperinsulinemia plus hyperglycemia created...

Pioglitazone treatment improves insulin resistance (IR), glucose metabolism, hepatic steatosis, and necroinflammation in patients with nonalcoholic steatohepatitis (NASH). Because abnormal lipid metabolism/elevated plasma free fatty acids (FFAs) are important to the pathophysiology of NASH, we examined the impact of pioglitazone therapy on adipose tissue insulin resistance (Adipo-IR) during the treatment of patients with NASH. To this end, we assessed glucose/lipid metabolism in 47 patients with impaired glucose tolerance/type 2 diabetes mellitus and NASH and 20 nondiabetic controls. All individuals underwent a 75-g oral glucose tolerance test (OGTT) in which we measured glucose tolerance, IR, and suppression of plasma FFAs. We also measured Adipo-IR index (fasting, FFAs ؋ insulin), hepatic fat by magnetic resonance spectroscopy, and liver histology (liver biopsy). Patients were randomized (double-blind) to diet plus pioglitazone (45 mg/day) or placebo for 6 months, and all measurements were repeated. We found that patients with NASH had severe Adipo-IR and low adiponectin levels. Fasting FFAs were increased and their suppression during the OGTT was impaired. Adipo-IR was strongly associated with hepatic fat (rϭ 0.54) and reduced glucose clearance both fasting (rϭ0.34) and during the OGTT (rϭ0.40, all P <0.002).

Purpose: To investigate the use of a three-pool relaxation model to measure myelin, myelinated-axon, and mixed water-pool fractions in white matter (WM) during myelination. Materials and Methods:MRI at 1.9 Tesla, and conventional spin-echo imaging were used to acquire T1 and T2 relaxation data in 15 normal children ranging in age from 3 months to 13 years 4 months. Three equations with three unknowns were solved to calculate three water-pool fractions for each child in a frontal association-fiber area and a frontal-parietal projection-fiber area. The temporal trend of the fractions was compared with a theoretical three-pool myelination model. Results:The myelin level in the projection-fiber area rose earlier than in the association-fiber area following the standard caudal-to-rostral trend. The temporal trend of the three-pool fractions followed that predicted by the theoretical myelination model in both brain areas. The myelinatedaxon and mixed pool sizes were significantly different in the two WM areas following early myelination, although their myelin pools were similar. T1 values correlated more highly with the myelinated-axon and mixed pool fractions than with the myelin pool fraction. Conclusion:The three-pool relaxation model provides measurements of water-pool fractions in WM that follow values predicted during myelination. MR IMAGES of the human brain provide excellent contrast between gray matter (GM) and white matter (WM) with a limiting spatial resolution of about 1 mL. Two mechanisms are largely responsible for this high contrast: spin-lattice (T1) and spin-spin (T2) relaxation. The microscopic environment of water in tissue determines the T1 and T2 relaxation times. A single volume element (voxel) in WM contains several distinct microscopic water environments (or water pools) separated by membranes that limit the exchange of water between them. For instance, in the genu of the corpus callosum (CC) there are approximately 100,000 individual axons with differing diameters and myelin content within a volume of 1 mm 3 (1). Interspersed among these axons are oligodendrocytes, other glial cells, extracellular fluid, and vessels. The interplay of within-pool relaxation times and between-pool exchange times of water for these biological pools determines the net relaxation properties in WM (2,3).T1-and T2-weighted images are commonly used for visual assessments of WM (4,5), while MRI relaxometry (calculating T1 and T2) is more appropriate when quantitative measures are desired (6). Several investigators have acquired age-related baseline values for T1 and T2 in normal children and adults (6 -9). MRI relaxometry has also been used to study myelin disorders, hypomyelination (7,10), and demyelination (11). While clinical MRI studies and MRI relaxometry are useful in myelin assessments, neither directly indicate myelin levels. Though changes in myelin content are known to produce changes in MR relaxation properties in WM (3,4,6,12), changes in net relaxation properties of WM arise from multiple water pools, not ...

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.

OBJECTIVES:To study the effect of pioglitazone (PIO) on plasma resistin concentration, endogenous glucose production (EGP), and hepatic fat content (HFC) in patients with type II diabetes (T2DM). SUBJECTS: A total of 13 T2DM patients (age ¼ 5172 y, BMI ¼ 29.771.1 kg/m 2 , HbA 1c ¼ 8.070.5%). METHODS: HFC (magnetic resonance spectroscopy) and basal plasma resistin concentration were quantitated before and after PIO treatment (45 mg/day) for 16 weeks. Subjects received a 3 h euglycemic insulin (100 mU/m 2 /min) clamp with 3-[ 3 H] glucose to determine rates of EGP and tissue glucose disappearance (Rd) before and after PIO. RESULTS: PIO reduced fasting plasma glucose (10.370.7 to 7.670.6 mmol/l, Po0.001) and HbA 1c (8.070.4 to 6.870.3%, Po0.001) despite increased body weight (83.273.4 to 86.373.4 kg, Po0.001). PIO improved Rd (4.970.4 to 6.670.5 mg/ kg/min, Po0.005) and reduced EGP (0.2270.04 to 0.0670.02 mg/kg/min, Po0.01) during the insulin clamp. Following PIO, HFC decreased from 21.173.5 to 11.272.1% (Po0.005), and plasma resistin decreased from 5.370.6 to 3.570.3 ng/ml (Po0.01). Plasma resistin concentration correlated positively with HFC before (r ¼ 0.58, Po0.05) and after (r ¼ 0.55, Po0.05) PIO treatment. Taken collectively, plasma resistin concentration, before and after PIO treatment, correlated positively with hepatic fat content (r ¼ 0.66, Po0.001) and EGP during the insulin clamp (r ¼ 0.41, Po0.05). However, the plasma resistin concentration did not correlate with whole body glucose disposal (Rd) during the insulin clamp either before (r ¼ À0.18, P ¼ NS) or after (r ¼ À0.13, P ¼ NS) PIO treatment. CONCLUSIONS: PIO treatment in T2DM causes a significant decrease in plasma resistin concentration. The decrease in plasma resistin is positively correlated with the decrease in hepatic fat content and improvement in hepatic insulin sensitivity.

Magnetic resonance imaging (MRI) and MRI relaxometry were used to investigate disturbed brain myelination in 18q- syndrome, a disorder characterized by mental retardation, dysmorphic features, and growth failure. T1-weighted and dual spin-echo T2-weighted MR images were obtained, and T1 and T2 parametric image maps were created for 20 patients and 12 controls. MRI demonstrated abnormal brain white matter in all patients. White matter T1 and T2 relaxation times were significantly prolonged in patients compared to controls at all ages studied, suggesting incomplete myelination. Chromosome analysis using fluorescence in situ hybridization techniques showed that all patients with abnormal MRI scans and prolonged white matter T1 and T2 relaxation times were missing one copy of the myelin basic protein (MBP) gene. The one patient with normal-appearing white matter and normal white matter T1 and T2 relaxation times possessed two copies of the MBP gene. MRI and molecular genetic data suggest that incomplete cerebral myelination in 18q- is associated with haploinsufficiency of the gene for MBP.