Pioglitazone has anti-inflammatory effects in patients with Type 2 diabetes.

BACKGROUND: Type 2 diabetes is characterized by increased acute phase serum proteins. They are also risk factors for cardiovascular disease. We wanted to study how improvement of glycemic control with pioglitazone or glibenclamide affects their serum concentrations. MATERIALS AND METHODS: A total of 59 patients with Type 2 diabetes (age 57.3+/-1.2 yr, glycosylated hemoglobin (HbA1c) 8.3+/-0.7%, body mass index (BMI) 31.4+/-0.8 kg/m2) participated in the study. They were previously treated either with diet alone or in combination with one oral antihyperglycemic medicine. After a 1-week lead-in period on diet only, the patients were randomized to pioglitazone or glibenclamide. Blood samples for alpha-1-acid glycoprotein (A1GP), Creactive protein (CR P) and serum amyloid A (SAA) were taken before the treatments and during the therapy after 20 and 52 weeks. RESULTS: Baseline A1GP correlated with CR P (r=0.70, p<0.001) and fasting glucose (r=0.32, p<0.02). Baseline CR P correlated with HbA1c (r=0.26, p<0.05) and insulin (r=0.37, p<0.01). The anti-hyperglycemic effect was comparable with HbA1c levels decreasing both in the pioglitazone (from 8.18+/-0.09% to 7.63+/-0.17%, p<0.01) and glibenclamide (from 8.35+/-0.12% to 7.77+/-0.16%, p<0.01) groups. Pioglitazone treatment was associated with a reduction in A1GP at 20 weeks (p<0.001) and at 52 weeks (p<0.05) as compared to baseline. The significance remained also after comparison to glibenclamide therapy (p<0.001 and p<0.05, 20 and 52 weeks respectively). CR P was also more reduced in the pioglitazone group at 20 weeks of treatment (p<0.05). CONCLUSIONS: Inflammatory factors and markers of hyperglycemia are associated in patients with Type 2 diabetes. Pioglitazone treatment results in reduced A1GP concentration suggesting an anti-inflammatory effect.

Improved glycaemia in type 1 diabetes results in decreased levels of soluble adhesion molecules with no change in serum adiponectin or most acute phase proteins.

AIMS: To investigate how reduction of hyperglycaemia affects acute phase serum proteins in poorly controlled type 1 diabetic patients. METHODS: 24 patients (age 31.7 +/- 2.0 years, HbA1c 9.3 +/- 0.2%, BMI 24.2 +/- 0.7 kg/m2, diabetes duration 15.3 +/- 1.7 years) participated in the study. The treatment was optimised for 16 weeks. Blood samples were taken at baseline and at the end of the study. 16 healthy age- and BMI-matched subjects were chosen for a control group. RESULTS: At baseline, the patients had higher C-reactive protein (CRP) (1.09, median [range 0.24-18.82] mg/l vs. 0.66 [0.18-2.46] mg/l, p < 0.02), mean adiponectin (16.06 +/- 1.31 vs. 8.85 +/- 0.93 mg/l, p < 0.001), ceruloplasmin (306 +/- 16.1 vs. 205.4 +/- 5.5 mg/l, p < 0.001), fibrinogen (3.41 +/- 0.26 vs. 2.38 +/- 0.07 g/l, p < 0.001), soluble intercellular adhesion molecule-1 (sICAM-1) (255.4 +/- 10.3 vs. 194 +/- 10.6 microg/l, p < 0.001), soluble vascular adhesion molecule-1 (sVCAM-1) (533.4 +/- 21.8 vs. 422.9 +/- 20.7 microg/l, p < 0.01) and interleukin-6 (2.89 +/- 0.49 vs. 1.35 +/- 0.30 ng/l, p < 0.01) concentrations than the controls. During intensified treatment, HbA1c decreased (to 8.5 +/- 0.2%, p < 0.001). This resulted in reduced sE-selectin (from 44.6 +/- 2.6 to 38.8 +/- 2.6 microg/l, p < 0.01), alpha-1-acid-glycoprotein (A1GP) (from 622.9 +/- 47.9 to 525.7 +/- 27.9 mg/l, p < 0.01), sICAM-1 (from 255.4 +/- 10.3 to 240.8 +/- 9.1 microg/l, p < 0.05) and IL-6 (from 2.9 +/- 0.5 to 2.1 +/- 0.4 ng/l, p < 0.01). Serum amyloid A (SAA) and CRP did not change 12.00 (0.7-222.0) vs. 12.00 (1.6-277.0) mg/l for SAA and 1.09 (0.24-18.82) vs. 1.09 (0.18-23.08) mg/l for CRP, baseline vs. treatment, respectively. CONCLUSIONS: Poorly controlled type 1 diabetic patients have increased values of adiponectin, CRP, ceruloplasmin, fibrinogen, sICAM-1, sVCAM-1 and IL-6. Reduction of hyperglycaemia results in decreased sE-selectin, A1GP, sICAM-1 and IL6, while other inflammatory factors including CRP, SAA and adiponectin are not affected.

Inflammation affects lipid metabolism during recovery from hyperinsulinaemia.

BACKGROUND: Inflammation is an established contributor in atherosclerosis and several other common diseases including diabetes. Therefore the study was to investigate how inflammatory factors affect lipid metabolism during recovery from hyperinsulinaemia in healthy individuals. MATERIALS AND METHODS: A total of 22 healthy subjects [aged 27.7 +/- 1.8 years; body mass index (BMI) 24.1 +/- 0.8 kg m(-2)] participated in the study. After a 4-h euglycaemic hyperinsulinaemia (55.9 +/- 2.2 mU L(-1)) insulin infusion was stopped and baseline blood samples were taken. Glucose infusion at a decreasing rate continued for 120 min to maintain euglycaemia throughout the study. RESULTS: The free fatty acid (FFA) concentration at the 120-min time-point was associated with baseline alpha-1-acid glycoprotein (A1GP) (r = 0.57, P < 0.01), C-reactive protein (CRP) (r = 0.54, P < 0.02) and serum amyloid A (r = 0.53, P < 0.02); in total they accounted for 54% of the variation in FFA concentration at the 120-min time-point. Baseline A1GP was also associated with the triglyceride concentration at the 120-min time-point (r = 0.66, P < 0.001). Insulin sensitivity was the most important factor associated with glucose disposal at the 120-min time-point, thus explaining 30% of the variation (P < 0.01). Interleukin-6 (positive correlation) and fibrinogen (negative correlation) increased the proportion to 48% (P < 0.01). There was no significant change in the most acute-phase proteins between baseline and the 120-min time-point. CONCLUSION: Inflammation is an important contributor to lipid and glucose metabolism during recovery from hyperinsulinaemia.

Association of serum adiponectin concentration to lipid and glucose metabolism in healthy humans.

BACKGROUND: Adiponectin is a recently discovered plasma protein with many associations to glucose and lipid metabolism. Due to its central role in cardiovascular diseases and insulin resistance, we studied the relationship between serum adiponectin and factors reflecting glucose and lipid metabolism. METHODS AND RESULTS: Thirty healthy participants (20M/10F, age 32.0 +/- 2.1 years, BMI 25.8 +/- 0.9 kg/m (2) and HbA (1c) 5.2 +/- 0.1 %) were studied four times at approximately one week intervals. The effects of a 4-hour euglycemic hyperinsulinemia (40 mU/m (2)/min), saline infusion (control), oral glucose, and oral fat load on serum adiponectin were studied. No significant correlation was found between serum adiponectin and insulin sensitivity before (r = 0.25) or after adjustment for age, BMI and gender (r = 0.04). Adiponectin concentration correlated inversely with HbA (1c) (r = - 0.43, p < 0.05), insulin concentration (r = - 0.38, p < 0.05) and triglyceride concentration (r = - 0.42, p < 0.05) but positively with HDL cholesterol (r = 0.38, p < 0.05). Metabolic procedures had no effect on serum adiponectin. CONCLUSIONS: Our findings favor the interpretation that adiponectin is not causally related to insulin sensitivity in healthy participants. The strongest associations of adiponectin in healthy participants are to be found to lipid metabolism. Serum levels of adiponectin are very stable and not acutely affected by hyperinsulinemia, oral glucose or fat load.

Plasma IL-6 concentration is inversely related to insulin sensitivity, and acute-phase proteins associate with glucose and lipid metabolism in healthy subjects.

AIM: It has been shown that atherosclerosis is an inflammatory disease. Recent data suggest that inflammation precedes type 2 diabetes. Hence, we wanted to study the interrelationship between IL-6, insulin sensitivity, lipids and numerous acute-phase proteins. METHODS: Twenty-one healthy individuals [16 males/5 females, age 27.9+/-1.8 years, body mass index (BMI) 24.1+/-0.8 kg/m(2)] participated in the study. Each patient went through a 4-h hyperinsulinaemic (40 mU/m(2)/min) euglycaemic clamp and 4-h saline infusion. Blood samples were taken before and at the end of the infusions. RESULTS: Plasma interleukin (IL)-6 concentration correlated inversely with insulin sensitivity (M-value) (r=-0.49, p<0.05). Moreover, the plasma levels of IL-6 associated with c-peptide (r=0.49, p<0.05), fat% (r=0.43, p<0.05) and diastolic blood pressure (r=0.46, p<0.05). alpha-1-acid glycoprotein was related to HbA1(c) (r=0.47, p<0.05), insulin (r=0.55, p<0.01), diastolic blood pressure (r=0.58, p<0.01), systolic blood pressure (r=0.58, p<0.01) and triglycerides (r=0.58, p<0.01). Haptoglobin was correlated with insulin (r=0.46, p<0.05), total cholesterol (r=0.61, p<0.01), BMI (r=0.58, p<0.01), fat% (r=0.63, p<0.01) and lipid oxidation during clamp (r=0.43, p<0.05). Diastolic blood pressure decreased during the clamp (from 78.3+/-1.9 to 72.1+/-2.0 mmHg, p=0.001). Insulin infusion did not affect the serum levels of most acute-phase proteins. CONCLUSIONS: Our study suggests that low grade inflammation, as reflected by IL-6, A1GP and haptoglobin contributes to the regulation of insulin sensitivity, lipid metabolism and blood pressure in normal human physiology.