Hepatic 11ß-hydroxysteroid dehydrogenase type 1 activity in obesity and type 2 diabetes using a novel triple tracer cortisol technique.

AIMS/HYPOTHESIS: Dysregulation of 11ß-hydroxysteroid dehydrogenase (11ß-HSD) enzyme activities are implicated in the pathogenesis of obesity and insulin resistance. The aim of the study was to determine whether hepatic 11ß-HSD type 1 (11ß-HSD-1) enzyme activity differs in people with and without obesity and type 2 diabetes. METHODS: We measured hepatic 11ß-HSD-1 activity in the overnight fasted state in 20 lean non-diabetic participants (LND), 21 overweight/obese non-diabetic participants (OND) and 20 overweight/obese participants with type 2 diabetes (ODM) using a non-invasive approach. One mg doses of [9,12,12-(2)H3]cortisol (D cortisol) and [4-(13)C]cortisone ([(13)C]cortisone) were ingested, while [1,2,6,7-(3)H]cortisol ([(3)H] cortisol) was infused intravenously to enable concurrent measurements of first-pass hepatic extraction of ingested D cortisol and hepatic conversion of ingested [(13)C]cortisone to C13 cortisol derived from the ingested cortisone (a measure of 11ß-HSD-1 activity in the liver) using an isotope dilution technique. One-way ANOVA models and Kruskal-Wallis tests were used to test the hypothesis. RESULTS: Plasma D cortisol and C13 cortisol concentrations were lower in OND than in LND (p < 0.05) over 6 h of the study. There was no difference (p = 0.15) in C13 and D cortisol concentrations between OND and ODM and between LND and ODM for the same study period. Hepatic conversion of [(13)C]cortisone to C13 cortisol was similar between groups. CONCLUSIONS/INTERPRETATION: Hepatic conversion of [(13)C]cortisone to C13 cortisol did not differ between the groups studied. We conclude that hepatic 11ß-HSD-1 activity is similar in individuals who are overweight/obese or who have type 2 diabetes.

Acute hyperglycemia reduces myocardial blood flow reserve and the magnitude of reduction is associated with insulin resistance: a study in nondiabetic humans using contrast echocardiography.

The effect of acute hyperglycemia per se on coronary perfusion in humans is undefined. We evaluated the effects of short-term hyperglycemia on myocardial blood flow reserve (MBFR) in healthy nondiabetic volunteers. Twenty-one nondiabetic volunteers (76 % females, mean ± SD, age 48 ± 5 years) had noninvasive MBFR assessment while exposed to pancreatic clamp with somatostatin and replacement glucagon and growth hormone infusions, with frequent interval plasma glucose (PG) monitoring. Insulin was infused at 0.75 mU/kg/min to mimic postprandial plasma insulin concentrations, and glucose was infused to maintain euglycemia (PG 93.9 ± 7.3 mg/dl) followed by hyperglycemia (PG 231.5 ± 18.1 mg/dl). Myocardial contrast echocardiography (MCE) was performed during each glycemic steady state using continuous infusion of Definity at rest and during regadenoson (Lexiscan 5 ml (400 µg) intravenous bolus) infusion to quantify myocardial blood flow (MBF) and determine MBFR. Insulin resistance (IR) was assessed by glucose infusion rate (GIR; mg/kg/min) at euglycemia. Median stress MBF, MBFR, and ß reserve were significantly reduced during acute hyperglycemia versus euglycemia (stress MBF 3.9 vs 5.4, P = 0.02; MBFR 2.0 vs 2.7, P < 0.0001; ß reserve 1.45 vs 2.4, P = 0.007). Using a median threshold GIR of 5 mg/kg/min, there was a correlation between GIR and hyperglycemic MBFR (r = 0.506, P = 0.019). MBFR, as determined noninvasively by MCE, is significantly decreased during acute hyperglycemia in nondiabetic volunteers, and the magnitude of this reduction is modulated by IR.

11ß-hydroxysteroid dehydrogenase types 1 and 2 activity in subcutaneous adipose tissue in humans: implications in obesity and diabetes.

CONTEXT: The role of 11ß-hydroxysteroid dehydrogenase types 1 (11ß-HSD-1) and 2 (11ß-HSD-2) enzymes in sc adipose tissue is controversial. OBJECTIVE: The objective of the study was to determine the activity of 11ß-HSD-1 and -2 enzymes in the abdominal and leg sc adipose tissue in obesity and diabetes. DESIGN: 11ß-HSD-1 and -2 enzyme activities in abdominal and leg sc adipose tissue were measured by infusing [2,2,4,6,6,12,12-(2)H7] cortisone (D7 cortisone) and [9,12,12-(2)H3] cortisol (D3 cortisol) via microdialysis catheters placed in sc fat depots. SETTING: The study was conducted at the Mayo Clinic Clinical Research Unit. PARTICIPANTS: Lean nondiabetic (n = 13), overweight/obese nondiabetic (n = 15), and overweight/obese participants with type 2 diabetes mellitus (n = 15) participated in the study. MAIN OUTCOME MEASURES: The conversion of infused D7 cortisone to D7 cortisol (via 11ß-HSD reductase activity) and D3 cortisol to D3 cortisone (via 11ß-HSD dehydrogenase activity) in sc adipose tissue. RESULTS: Enrichment of D7 cortisone and D3 cortisol were similar in the effluents from both sites in all groups. D3 cortisone enrichment did not differ in the three cohorts, indicating that 11ß-HSD-2 enzyme activity (conversion of cortisol to cortisone) occurs equally in all groups. However, D7 cortisol enrichment was detectable in abdominal sc fat of overweight/obese participants with type 2 diabetes mellitus only, implying 11ß-HSD-1 reductase activity (conversion of cortisone to cortisol) occurs in obese subjects with type 2 diabetes. CONCLUSIONS: There is conversion of cortisone to cortisol via the 11ß-HSD-1 enzyme pathway in abdominal sc fat depots in overweight/obese participants with type 2 diabetes mellitus. This observation has significant implications for developing tissue-specific 11ß-HSD-1 inhibitors in type 2 diabetes mellitus.

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 approximately 5 mmol/l, insulin raised to approximately 180 pmol/l, C-peptide suppressed with somatostatin, glucagon replaced at approximately 75 pg/ml, and glycerol maintained at approximately 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 micromol x kg(-1) x min(-1)) or metformin (22 +/- 2 vs. 24 +/- 3 micromol x kg(-1) x 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 micromol x kg(-1) x min(-1)) and gluconeogenesis (n = 11; 4.5 +/- 0.9 vs. 0.8 +/- 1.2 micromol x kg(-1) x min(-1)). Metformin did not alter either suppression of glucose production (5.8 +/- 1.0 vs. 5.0 +/- 0.8 micromol x kg(-1) x min(-1)) or gluconeogenesis (n = 9; 3.7 +/- 0.8 vs. 2.6 +/- 0.7 micromol x kg(-1) x 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.