Betty Dicke

Comparison of the Effects of Pioglitazone and Metformin on Hepatic and Extra-Hepatic Insulin Action in People With Type 2 Diabetes

OBJECTIVE—To determine mechanisms by which pioglitazone and metformin effect hepatic and extra-hepatic insulin action. RESEARCH DESIGN AND METHODS—Thirty-one subjects with type 2 diabetes were randomly assigned to pioglitazone (45 mg) or metformin (2,000 mg) for 4 months. RESULTS—Glucose was clamped before and after therapy at ∼5 mmol/l, insulin raised to ∼180 pmol/l, C-peptide suppressed with somatostatin, glucagon replaced at ∼75 pg/ml, and glycerol maintained at ∼200 mmol/l to ensure comparable and equal portal concentrations on all occasions. Insulin-induced stimulation of glucose disappearance did not differ before and after treatment with either pioglitazone (23 ± 3 vs. 24 ± 2 μmol · kg−1 · min−1) or metformin (22 ± 2 vs. 24 ± 3 μmol · kg−1 · min−1). In contrast, pioglitazone enhanced (P < 0.01) insulin-induced suppression of both glucose production (6.0 ± 1.0 vs. 0.2 ± 1.6 μmol · kg−1 · min−1) and gluconeogenesis (n = 11; 4.5 ± 0.9 vs. 0.8 ± 1.2 μmol · kg−1 · min−1). Metformin did not alter either suppression of glucose production (5.8 ± 1.0 vs. 5.0 ± 0.8 μmol · kg−1 · min−1) or gluconeogenesis (n = 9; 3.7 ± 0.8 vs. 2.6 ± 0.7 μmol · kg−1 · min−1). Insulin-induced suppression of free fatty acids was greater (P < 0.05) after treatment with pioglitazone (0.14 ± 0.03 vs. 0.06 ± 0.01 mmol/l) but unchanged with metformin (0.12 ± 0.03 vs. 0.15 ± 0.07 mmol/l). CONCLUSIONS—Thus, relative to metformin, pioglitazone improves hepatic insulin action in people with type 2 diabetes, partly by enhancing insulin-induced suppression of gluconeogenesis. On the other hand, both drugs have comparable effects on insulin-induced stimulation of glucose uptake.

Effect of prostaglandins E1 and F1α on the activities of cholesteryl ester synthetase and cholesteryl ester hydrolases of pigeon aorta in vitro

The in vitro effects of prostaglandins E1 and F1alpha on the activity of cholesteryl ester synthetase and cholesteryl ester hydrolase activities of the pigeon aorta were examined. It was found that prostaglandin E1 markedly inhibited the cholesteryl ester hydrolase activity in the supernatant fraction and slightly inhibited the cholesteryl ester synthetase activity. Prostaglandin F1alpha, however, modestly stimulated the cholesteryl ester hydrolase activity both in the microsomal and in the supernatant fraction of the aorta. These observations strongly warrant further studies on the role of prostaglandins in atherogenesis.

Presence of cholesterol ester synthetase activity in guinea pig gallbladder epithelium

Abstract This study is the first to demonstrate the presence of cholesteryl ester synthetase activity in the gallbladder epithelium. Using epithelium of the guinea pig gallbladder, the study demonstrated that the enzyme was localized mainly in the particulate fraction. The enzyme required CoA and ATP for activity and displayed a pH optimum of 7.0. The uptake of biliary cholesterol by gallbladder (shown by other investigators) and the presence of cholesteryl ester synthetase activity (demonstrated in this study) suggest that the gallbladder epithelium has an active role which might be important in conditions of cholesterol supersaturation in bile.

On the cholesteryl ester hydrolase activity in the microsomal and supernatant fractions of pigeon aorta.

Cholesteryl ester hydrolase activity was measured in the microsomal and supernatant fractions of the aorta of atherosclerosis-susceptible White Carneau and atherosclerosis-resistant Show Racer pigeons while on their normal cholesterol-free diets. Enzyme activities from both fractions showed fatty acid specificities for the hydrolysis of different cholesteryl esters in the following decreasing order: Linoleate greater than oleate greater than palmitate. At 9 months of age (the period of lipid accumulation) the microsomal enzyme activity in the Show Racer breed was significantly higher (P less than 0.001) than in the White Carneau breed, while the supernatant enzyme was slightly higher (P less than 0.05) in the White Carneaux at this age. In older birds (3 years of age) these differences in enzyme activities disappeared.

Regression of naturally occurring atherosclerotic lesions in pigeon aorta by intestinal bypass surgery

Early changes in cholesteryl ester metabolism of the aorta during the regression of naturally occurring atherosclerotic lesions in pigeon aorta by ileal bypass surgery were examined. Three months after surgery, there was a decrease (50%) in the content of cholesteryl esters in the aorta. Increases in the activity of cholesteryl ester hypdrolase in the lysosomal (P less than 0.05) and the supernatant (P less than 0.01) fractions of the aorta also occurred at this time. There were no differences in the activity of cholesteryl ester synthetase and in the plasma levels of cholesterol and triglycerides between the ileal bypass group and the controls. These results suggest that ileal bypass surgery decreases the level of cholesteryl esters in the aorta, probably because of enhanced cholesteryl ester hydrolysis.

Plasma C5 Glucose–to–2H2O Ratio Does Not Provide an Accurate Assessment of Gluconeogenesis During Hyperinsulinemic-Euglycemic Clamps in Either Nondiabetic or Diabetic Humans

OBJECTIVE—Measurement of plasma C2 glucose enrichment is cumbersome. Therefore, the plasma C5 glucose–to–2H2O rather than the plasma C5-to-C2 glucose ratio commonly has been used to measure gluconeogenesis and glycogenolysis during hyperinsulinemic-euglycemic clamps. The validity of this approach is unknown. RESEARCH DESIGN AND METHODS—Ten nondiabetic and 10 diabetic subjects ingested 2H2O the evening before study. The following morning, insulin was infused at a rate of 0.6 mU · kg−1 · min−1 and glucose was clamped at ∼5.3 mmol/l for 5 h. Plasma C5 glucose, C2 glucose, and 2H2O enrichments were measured hourly from 2 h onward. RESULTS—Plasma C2 glucose and plasma 2H2O enrichment were equal in both groups before the clamp, resulting in equivalent estimates of gluconeogenesis and glycogenolysis. In contrast, plasma C2 glucose and plasma C5 glucose enrichments fell throughout the clamp, whereas plasma 2H2O enrichment remained unchanged. Since the C5 glucose concentration and, hence, the C5 glucose–to–2H2O ratio is influenced by both gluconeogenesis and glucose clearance, whereas the C5-to-C2 glucose ratio is only influenced by gluconeogenesis, the C5 glucose–to–2H2O ratio overestimated (P < 0.01) gluconeogenesis during the clamp. This resulted in biologically implausible negative (i.e., calculated rates of gluconeogenesis exceeding total endogenous glucose production) rates of glycogenolysis in both the nondiabetic and diabetic subjects. CONCLUSIONS—Plasma C5 glucose–to–2H2O ratio does not provide an accurate assessment of gluconeogenesis in nondiabetic or diabetic subjects during a traditional (i.e., 2–3 h) hyperinsulinemic-euglycemic clamp. The conclusions of studies that have used this approach need to be reevaluated.

Effects of pioglitazone and metformin on NEFA-induced insulin resistance in type 2 diabetes

Aims/hypothesisWe sought to determine whether pioglitazone and metformin alter NEFA-induced insulin resistance in type 2 diabetes and, if so, the mechanism whereby this is effected.MethodsEuglycaemic–hyperinsulinaemic clamps (glucose ∼5.3 mmol/l, insulin ∼200 pmol/l) were performed in the presence of Intralipid–heparin (IL/H) or glycerol before and after 4 months of treatment with pioglitazone (n = 11) or metformin (n = 9) in diabetic participants. Hormone secretion was inhibited with somatostatin in all participants.ResultsPioglitazone increased insulin-stimulated glucose disappearance (p < 0.01) and increased insulin-induced suppression of glucose production (p < 0.01), gluconeogenesis (p < 0.05) and glycogenolysis (p < 0.05) during IL/H. However, glucose disappearance remained lower (p < 0.05) whereas glucose production (p < 0.01), gluconeogenesis (p < 0.05) and glycogenolysis (p < 0.05) were higher on the IL/H study day than on the glycerol study day, indicating persistence of NEFA-induced insulin resistance. Metformin increased (p < 0.001) glucose disappearance during IL/H to rates present during glycerol treatment, indicating protection against NEFA-induced insulin resistance in extrahepatic tissues. However, glucose production and gluconeogenesis (but not glycogenolysis) were higher (p < 0.01) during IL/H than during glycerol treatment with metformin, indicating persistence of NEFA-induced hepatic insulin resistance.Conclusions/interpretationWe conclude that pioglitazone improves both the hepatic and the extrahepatic action of insulin but does not prevent NEFA-induced insulin resistance. In contrast, whereas metformin prevents NEFA-induced extrahepatic insulin resistance, it does not protect against NEFA-induced hepatic insulin resistance.

Effect of estrogens on the concentration and composition of arterial sterols and steryl esters in male White Carneau pigeons

The effect of short-term (6 months) administration of conjugated equine estrogen (Premarin) on content and composition of the aortic sterols in male shite Carneau pigeons while they were on a cholesterol-free grain diet was investigated. Estrogen treatment resulted in a 38% increase (P less than 0.05) in free sterol concentration, with a 28.8% concomitant decrease (P less than 0.05) in the percent of cholesteryl esters. The total sterol concentration remained unchanged. This finding suggests that estrogens might influence the synthetic or hydrolytic (or both) processes that control the concentration of cholesteryl esters in the aorta. Fatty acid composition of steryl esters did not change significantly. The cholesterol content of plasma showed a mild reduction (14%) whereas the triglycerides increased significantly (30%).