Effect of rosiglitazone on glucose and non-esterified fatty acid metabolism in Type II diabetic patients

Aims/hypothesis: We aimed to examine the mechanisms by which rosiglitazone improves glycaemic control in Type II (non-insulin-dependent) diabetic patients. Methods: Altogether 29 diet-treated diabetic patients were assigned at random to rosiglitazone, 8 mg/day (n = 15), or placebo (n = 14) for 12 weeks. Patients received 75 g OGTT and two-step euglycaemic insulin (40 and 160 mU/m²min) clamp with 3-³H-glucose, ¹⁴C-palmitate and indirect calorimetry. Results: After 12 weeks, rosiglitazone reduced fasting plasma glucose (195 ± 11 to 150 ± 7 mg/dl, p < 0.01), mean plasma glucose (PG) during OGTT (293 ± 12 to 236 ± 9 mg/dl, p < 0.01), and HbA_{1 c} (8.7 ± 0.4 to 7.4 ± 0.3 %, p < 0.01) without changes in plasma insulin concentration. Basal endogenous glucose production (EGP) declined (3.3 ± 0.1 to 2.9 ± 0.1 mg/kg FFM · min, p < 0.05) and whole body glucose metabolic clearance rate increased after rosiglitazone (first clamp step: 2.8 ± 0.2 to 3.5 ± 0.2 ml/kg FFM · min, p < 0.01; second clamp step: 6.7 ± 0.6 to 9.2 ± 0.8, p < 0.05) despite increased body weight (86 ± 4 to 90 ± 4 kg, p < 0.01) and fat mass (33 ± 3 to 37 ± 3 kg, p < 0.01). Fasting plasma non-esterified fatty acid (NEFA) (735 ± 52 to 579 ± 49 μEq/l, p < 0.01), mean plasma NEFA during OGTT (561 ± 33 to 424 ± 35, p < 0.01), and basal NEFA turnover (18.3 ± 1.5 to 15.5 ± 1.2 μEq/kg FM · min, p < 0.05) decreased after rosiglitazone. Changes in EPG and mean plasma glucose (PG) during OGTT correlated with changes in basal EGP (r = 0.54; r = 0.58), first EGP (r = 0.36; r = 0.41), first MCR (r = –0.66; r = –0.68), second MCR (r = –0.49; r = –0.54), fasting plasma NEFA (r = 0.53; r = 0.49), and NEFA during OGTT (r = 0.66; r = 0.66). Conclusion/interpretation: Rosiglitazone increases hepatic and peripheral (muscle) tissue insulin sensitivity and reduces NEFA turnover despite increased total body fat mass. These results suggest that the beneficial effects of rosiglitazone on glycaemic control are mediated, in part, by the drug's effect on NEFA metabolism. [Diabetologia (2001) 44: 2210–2219] Received: 20 May 2001 and in revised form: 9 August 2001     

The size of adrenal incidentalomas correlates with insulin resistance. Is there a cause‐effect relationship?

Context Adrenal incidentalomas (AI) have often been associated with a high prevalence of insulin resistance (IR) and cardiovascular risk factors, although direct measurement of insulin sensitivity (IS) has never been carried out. Objective We aimed to investigate whether the morphological and hormonal features of AI correlate with the presence and severity of IR, using the hyperinsulinaemic euglycaemic clamp (HEC). Design and Measurements Forty patients with AI (22 women) with a mean age of 58·5 ± 11·1 years underwent hormonal and morphological evaluation. Nineteen patients with AI without known history of diabetes mellitus (DM) or impaired glucose tolerance (IGT) and 17 matched controls underwent oral glucose tolerance test (OGTT) and hyperinsulinaemic euglycaemic clamp (HEC). Results Diabetes mellitus was observed in 13 patients (33%), while three (8%) had IGT. Thirty‐one of the AI were nonfunctioning (82·5%), whereas two (5%) secreted cortisol (Cushing’s syndrome) and seven (12·5%) showed subclinical secretion of cortisol. The 19 patients with nonfunctioning AI were more insulin resistant than controls (glucose up‐take: 4·58 ± 1·80 vs 5·85 ± 2·48 mg/kg/min respectively; P = 0·01); IS was inversely related to the mass size (r = ?0·57; P = 0·04), free urinary cortisol (r = ?0·68; P = 0·01), serum cortisol after 1‐mg dexamethasone suppression (?0·65; P = 0·02) and percentage of trunk fat mass (?0·77; P = 0·02) and directly related to serum adreno cortico tropic hormone (ACTH) (r = 0·62; P = 0·03). After performing multivariate regression, the mass size was found to be the most powerful predictor of IR. Conclusion Our study showed a high prevalence of insulin resistance in patients with nonfunctioning AI and suggests its possible involvement in AI growth.     

Plasma soluble tumour necrosis factor‐α receptor 2 is elevated in obesity: specific contribution of visceral adiposity

Objective We examined the obesity phenotype most strongly associated with increased plasma concentrations of sTNFR2, and compared which of the two markers, TNF‐α or sTNFR2, better predicts indices of plasma glucose‐insulin homeostasis. Design, patients and measurements Plasma sTNFR2 levels were measured in a sample of 287 healthy nondiabetic men [age: 43·9 ± 8·0 years (mean ± SD)], covering a wide range of adiposity values (BMI: 29·0 ± 4·4 kg/m²; waist girth: 100·0 ± 11·7 cm). Results Plasma sTNFR2 levels correlated positively and significantly with BMI (r = 0·36; P < 0·0001), fat mass (r = 0·42; P < 0·0001), waist girth (r = 0·38; P < 0·0001) as well as with visceral (r = 0·37; P < 0·0001) and subcutaneous adipose tissue (AT) (r = 0·40; P < 0·0001) areas measured by computed tomography. Two subgroups (n = 27 in each group) of overweight men (BMI ≥25 kg/m²) were individually matched for similar BMI values, but with markedly different levels of visceral AT (< or ≥130 cm²) and then compared with a control group of 46 lean subjects (with both BMI <25 kg/m² and visceral AT <130 cm²). This analysis revealed that men characterized by high levels of visceral AT had significantly higher concentrations of sTNFR2 compared with obese men with low visceral AT (1861 ± 457 pg/ml vs. 1722 ± 400; P < 0·05) and with lean controls (1570 ± 291 pg/ml; P < 0·001). Whereas subjects classified across tertiles of TNF‐α levels showed no difference in glucose tolerance and insulin levels, subjects in the upper tertile of plasma sTNFR2 levels were characterized with the highest plasma insulin concentrations during the OGTT and had the highest area under the curve of insulin concentrations. Conclusions These results indicate that sTNFR2 levels are more closely related to abdominal AT accumulation than to total adiposity. Furthermore, plasma concentrations of sTNFR2 are independently related to plasma glucose‐insulin homeostasis beyond the known contribution of visceral adiposity.     

Association between androgens,intima‐media thickness and the metabolic syndrome in obese adolescent girls

Background While an association between androgens and the metabolic syndrome (MS) is well established in obese women, studies concerning this relationship are scarce in obese adolescent girls. Therefore, we analysed the relationships between androgens, MS and intima‐media thickness (IMT) in this age‐group. Methods In 160 obese girls (aged 12–18 years, mean BMI: 32·6 ± 5·0 kg/m²), androgens [testosterone, dehydroepiandrosterone sulphate (DHEA‐S), androstenedione], SHBG and the components of MS (waist circumference, blood pressure (BP), lipids, uric acid, insulin, glucose, 2 h glucose in oral glucose tolerance test (oGTT)) were studied. Furthermore, IMT was determined in a subgroup of 71 randomly chosen girls. Results Testosterone correlated significantly to systolic BP (r = 0·20), diastolic BP (r = 0·24), 2 h glucose in oGTT (r = 0·30), triglycerides (r = 0·19), uric acid (r = 0·17), waist circumference (r = 0·25) and IMT (r = 0·54). These relationships (except for waist circumference and uric acid) were independent of BMI and insulin resistance index homeostasis model assessment. In contrast to testosterone, DHEA‐S, androstenedione and SHBG showed no or weaker correlations to any parameter of MS. The 48 girls with MS demonstrated significantly higher testosterone (1·8 ± 0·7 nmol/l; P = 0·025) and DHEA‐S (4·7 ± 2·3 μmol/l; P = 0·008) concentrations as compared with the 112 girls without MS (mean testosterone 1·5 ± 0·7 nmol/l, mean DHEA‐S 3·6 ± 2·3 μmol/l). Conclusions Testosterone was significantly related to MS and its components in obese adolescent girls independently of BMI and insulin resistance. As IMT was significantly associated with testosterone, this supports the clinical relevance of this finding.     

Value of the intravenous and oral glucose tolerance tests for detecting subtle impairments in insulin sensitivity and beta-cell function in former gestational diabetes

Objective Women with former gestational diabetes mellitus (fGDM) often show defects in both insulin sensitivity and beta‐cell function but it is not clear which defect plays the major role or which appears first. This might be because fGDM women are often studied as a unique group and not divided according to their glucose tolerance. Different findings might also be the result of using different tests. Our aim was to study insulin sensitivity and beta‐cell function with two independent glucose tolerance tests in fGDM women divided according to their glucose tolerance. Design and patients A total of 108 fGDM women divided into normal glucose tolerance (IGT; N = 82), impaired glucose metabolism (IGM; N = 20) and overt type 2 diabetes (T2DM; N = 6) groups, and 38 healthy control women (CNT) underwent intravenous (IVGTT) and oral glucose tolerance tests (OGTT). Measurements Insulin sensitivity and beta‐cell function were assessed by both the IVGTT and the OGTT. Results Both tests revealed impaired insulin sensitivity in the normotolerant group compared to controls (IVGTT: 4·2 ± 0·3 vs. 5·4 ± 0·4 10^?4 min^?1 (µU/ml)^?1; OGTT: 440 ± 7 vs. 472 ± 9 ml min^?1 m^?2). Conversely, no difference was found in beta‐cell function from the IVGTT. However, some parameters of beta‐cell function by OGTT modelling analysis were found to be impaired: glucose sensitivity (106 ± 5 vs. 124 ± 7 pmol min^?1 m^?2 mm ^?1, P = 0·0407) and insulin secretion at 5 mm glucose (168 ± 9 vs. 206 ± 10 pmol min^?1 m^?2, P = 0·003). Conclusions Both insulin sensitivity and beta‐cell function are impaired in normotolerant fGDM but the subtle defect in beta‐cell function is disclosed only by OGTT modelling analysis.     

Insulin sensitivity and secretion in children and adolescents with hypothalamic obesity following treatment for craniopharyngioma

Background Craniopharyngioma (CP), a tumour occurring in the hypothalamic–pituitary area, results in morbid obesity in 25–60% of affected children. It has been suggested that abnormalities of insulin secretion and/or insulin action due to hypothalamic injury may be associated with weight gain and the metabolic syndrome in this population. Aim To evaluate: (i) insulin secretion (IS) and insulin sensitivity (Si); (ii) features of the metabolic syndrome (MS) and (iii) factors involved in risk for diabetes and heart disease in obese youth treated for CP. Methods Obese subjects treated for CP were compared to BMI‐matched control subjects. All subjects underwent anthropometric, blood pressure, resting energy expenditure and body fat assessment. Cholesterol and inflammatory markers, oral glucose tolerance test (OGTT) and frequent sampling intravenous glucose tolerance test (FSIGT), with calculation of IS and Si, were performed. Results Fifteen CP subjects and 15 controls (C) were studied. There were no differences between CP and C for age, gender, BMI or pubertal status. MS was present in 10/15 CP and 3/15 C (P = 0·03), including impaired glucose tolerance (IGT) in 6/15 CP and 0/15 C (P = 0·02). Measures of IS, including first and second phase IS, and insulin area‐under‐the‐curve (AUC_ins) during OGTT, were significantly higher in CP. Si, measured by frequent sampled intravenous glucose tolerance test (Si‐FSIGT), was significantly lower in CP subjects (0·96 ± 0·34 vs. 1·67 ± 0·7; P = 0·01). AUC_ins was negatively correlated with Si‐FSIGT (r = ?0·62; P = 0·003). Conclusion Children with CP and hypothalamic obesity have more features of MS, increased IS and IGT prevalence and lower Si compared with BMI‐matched controls.     

Evaluation of glycaemic status in young people with clinical insulin resistance; fasting glucose,fasting insulin or an oral glucose tolerance test?

Objective It is important to identify young people with prediabetes for early intervention. However, it is unclear how to best screen overweight and obese young people for prediabetes. The objective of this study was to compare fasting indices with an oral glucose tolerance test (OGTT) in diagnosing prediabetes. Design Retrospective review. Patients A total of 224 young people, aged 12·0 years (range: 3·2–17·3 years), with clinical features of insulin resistance, who had an OGTT between 2000 and 2007 at a tertiary children’s hospital, Sydney, Australia. Measurements Oral glucose tolerance test. Results A total of 168 (75%) participants had normal glucose tolerance, 45 (20%) had prediabetes and 11 (5%) had type 2 diabetes; 29 of those with prediabetes and 10 with type 2 diabetes were identified by fasting glucose criteria alone. Young people with normal fasting glucose and fasting insulin ≤180 pmol/l had lower insulin resistance (homeostasis model assessment median 1·9 vs. 4·2, P < 0·001), higher insulin sensitivity index (2·4 vs. 1·0, P < 0·001) and a lower early insulin response (insulinogenic index 2·5 vs. 4·1, P < 0·001) compared to those with normal fasting glucose and higher fasting insulin levels. If a fasting insulin cut point (≤180 pmol/l) was used in addition to fasting glucose to determine the need for an OGTT, 114 (68%) young people with normal glucose tolerance would have avoided the test. By contrast, the diagnosis of impaired glucose tolerance, identified by an OGTT, would have been missed in three children. Conclusion Fasting glucose and insulin levels should be measured in young people with insulin resistance before undertaking a time‐ and resource‐intensive OGTT.     

Increases in muscle blood flow after a mixed meal are impaired at all stages of type 2 diabetes

Objective In type 2 diabetes, although the impairment of postprandial muscle blood flow response is well established, information on the effect of this impairment on glucose uptake and lipid metabolism is controversial. Design Postprandial forearm blood flow responses and metabolic parameters were assessed in a cross‐sectional study of subjects at various stages of insulin resistance. Patients Eleven healthy subjects (CONTROLS), 11 first‐degree relatives of type‐2 diabetics (RELATIVES), 10 patients with impaired glucose tolerance (IGT), 10 diabetic patients with postprandial hyperglycaemia (DMA), and 13 diabetic patients with both fasting and postprandial hyperglycaemia (DMB). Measurements All subjects received a meal. Blood was drawn from a forearm deep vein and the radial artery at specific time‐points during a period of 360 min for measurements of glucose, insulin, triglycerides and nonesterified‐fatty acids. Forearm muscle blood flow was measured with strain‐gauge plethysmography. Glucose uptake and ISI Index were calculated. Results Peak‐baseline muscle blood flow was higher in CONTROLS (3·32 ± 0·4) than in RELATIVES (0·53 ± 0·29), IGT (0·82 ± 0·2), DMA (1·44 ± 0·34), DMB (1·23 ± 0·35 ml/min/100 ml tissue), P < 0·001. Glucose uptake (AUC_0?360,μmol/100 ml tissue) was higher in CONTROLS (1023 ± 132) than in RELATIVES (488 ± 42), IGT (458 ± 43), DMA (347 ± 63), DMB (543 ± 53), P < 0·001. ISI index, postprandial triglycerides and nonesterified‐fatty acids behaved in a similar way. Peak‐baseline muscle blood flow correlated positively with glucose uptake (r = 0·440, P = 0·001) and ISI index (r = 0·397, P = 0·003), and negatively with postprandial triglycerides (r = ?0·434, P = 0·001) and nonesterified‐fatty acids (r = ?0·370, P = 0·005). Conclusions These results suggest that increase in muscle blood flow after a meal is impaired at all stages of type‐2 diabetes. This defect influences glucose uptake and is associated with impaired lipid metabolism in the postprandial state.     

In anorexia nervosa, even a small increase in abdominal fat is responsible for the appearance of insulin resistance

Context The aim of treatment in patients affected by anorexia nervosa (AN) is weight recovery. However, during weight gain, anorectic patients’ body composition is changed, with an increase in abdominal fat, particularly in the visceral compartment. Objective We hypothesized that changes in body composition, particularly in abdominal fat, are responsible for the variability in insulin sensitivity (IS) in different stages of AN. Design and Measurements We compared 20 anorectic patients in the acute stage, 19 in the weight‐recovery stage and 21 controls. All subjects underwent an oral glucose tolerance test, hyperinsulinaemic euglycaemic clamp and dual energy X‐ray absorptiometry to measure body composition. Results The percentage of trunk fat was higher in weight recovery than in the acute phase (47·7 ± 8·4%vs 34·6 ± 7·6%; P ≤ 0·01) and in the control group (33·4 ± 7·6; P < 0·01 vs weight recovery). Although the recovery group gained weight, their body mass index (BMI) was not statistically different from that of the acute group (14·4 ± 1·1 vs 13·6 ± 1·8 kg/m²). Insulin sensitivity was lower in the weight‐recovery group than the acute group (4·7 ± 1·5 vs 7·8 ± 1·6 mg/kg/min; P < 0·01) and controls (7·7 ± 1·4 mg/kg/min; P < 0·01). A linear negative correlation was found between IS and the percentage of abdominal fat in the weight‐recovery and acute groups (r = ?0·51; P = 0·04 and r = ?0·53; P = 0·04 respectively), while IS did not correlate with BMI. Conclusion Although weight‐recovery represents the main aim of treatment in AN, refeeding is associated with an increase in abdominal fat which might be responsible of the onset of insulin resistance. As BMI and weight‐recovery were associated with impaired IS, they cannot be considered the only aim of treatment of AN.     

High prevalence of subclinical hypercortisolism in patients with bilateral adrenal incidentalomas: a challenge to management

Objective The prevalence of subclinical hypercortisolism (SH) in unilateral incidentalomas (UI) has been extensively studied; however, patients with bilateral incidentalomas (BI) have not been thoroughly investigated. We therefore aimed to describe the characteristics of patients with BI compared to their unilateral counterparts. The surgical outcome in a small number of patients is reported. Design Observational retrospective study in a single secondary/tertiary centre. Patients One hundred and seventy‐two patients with adrenal incidentalomas (41 with BI). Measurements Morning cortisol (F), ACTH, dehydroepiandrosterone sulphate (DHEA‐S), midnight F, 24‐h urine collection for cortisol (UFC), low‐dose dexamethasone suppression test (LDDST), fasting glucose, insulin, and oral glucose tolerance test (OGTT). Primarily, SH was defined as F‐post‐LDDST>70 nmol/l and one more abnormality; several diverse cut‐offs were also examined. Results No difference was noted in age, body mass index, or prevalence of diabetes and impaired glucose tolerance between patients with UI and those with BI. Patients with BI had higher F‐post‐LDDST (119·3 ± 112·8 vs 54·3 ± 71·5 nmol/l, P < 0·001) and lower DHEA‐S (1·6 ± 1·5 vs 2·5 ± 2·3 μmol/l, P = 0·003) but similar UFC, ACTH and midnight F levels, compared to UI. SH was significantly more prevalent in BI (41·5%vs 12·2%, P < 0·001). Fourteen patients were operated on; four underwent bilateral interventions. In 10 patients, unilateral adrenalectomy on the side of the largest lesion resulted in significant improvement in F‐post‐LDDST (P = 0·008) and a decrease in midnight F (P = 0·015) levels. Conclusions Subclinical hypercortisolism is significantly more prevalent in bilateral incidentaloma patients, posing great dilemmas for its optimum management.     

Adipokines in type 1 diabetes after successful pancreas transplantation: normal visfatin and retinol‐binding‐protein‐4, but increased total adiponectin fasting concentrations

Objective In type 1 diabetes mellitus (T1DM), the release of many hormones, not only from beta‐cells, but also from adipocytes (adipokines) may be altered. After successful pancreas–kidney‐transplantation (PKTx), T1DM patients can revert to a nondiabetic metabolism, but it is unclear whether alterations of adipokines are still present after PKTx. Design, patients and measurements Concentrations of adipokines [visfatin, retinol‐binding protein‐4 (RBP‐4), adiponectin, high molecular weight (HMW) adiponectin] were measured at fasting in 10 PKTx and in 19 T1DM. Nondiabetic healthy controls (CON, n = 9) and six nondiabetic patients after kidney transplantation (KTx) were examined as control groups. In PKTx, KTx and CON, indices of insulin sensitivity (OGIS) and beta cell function (adaptation index, AI) were calculated from 75 g oral glucose tolerance test (OGTT) data. Results Fasting serum visfatin (T1DM: 56 ± 4 μg/l, PKTx: 42 ± 6 μg/l, KTx: 39 ± 3 μg/l, CON: 40 ± 3 μg/l) and RBP‐4 (T1DM: 490 ± 26 μg/l, PKTx: 346 ± 39 μg/l, KTx: 401 ± 13 μg/l, CON: 359 ± 36 μg/l) was increased by 40% and 36%, respectively (each P < 0·03) in T1DM only. Levels were positively correlated with HbA1c in all subjects (visfatin: r = 0·43, P < 0·004; RBP‐4: r = 0·46, P < 0·03). Fasting plasma adiponectin was 80% higher in T1DM and in PKTx (T1DM: 18 ± 2 mg/l, PKTx: 18 ± 3 mg/l, KTx: 12 ± 3 mg/l, CON: 10 ± 1 mg/l; P < 0·04) and was positively correlated with diabetes duration (r = 0·37, P < 0·02). HMW/total adiponectin ratio was increased in T1DM (P < 0·02). PKTx displayed a normoglycaemic metabolism as insulin sensitive as CON, but AI was lower than in CON and KT (P < 0·01). Conclusions T1DM after successful PKTx show normal fasting visfatin and RBP‐4 levels and HMW‐adiponectin/adiponectin‐ratio, which are elevated in T1DM, whereas total adiponectin levels are similarly increased in T1DM and PKTx patients.     

Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients

We examined the effect of pioglitazone on abdominal fat distribution to elucidate the mechanisms via which pioglitazone improves insulin resistance in patients with type 2 diabetes mellitus. Thirteen type 2 diabetic patients (nine men and four women; age, 52 +/- 3 yr; body mass index, 29.0 +/- 1.1 kg/m(2)), who were being treated with a stable dose of sulfonylurea (n = 7) or with diet alone (n = 6), received pioglitazone (45 mg/d) for 16 wk. Before and after pioglitazone treatment, subjects underwent a 75-g oral glucose tolerance test (OGTT) and two-step euglycemic insulin clamp (insulin infusion rates, 40 and 160 mU/m(2).min) with [(3)H]glucose. Abdominal fat distribution was evaluated using magnetic resonance imaging at L4-5. After 16 wk of pioglitazone treatment, fasting plasma glucose (179 +/- 10 to 140 +/- 10 mg/dl; P < 0.01), mean plasma glucose during OGTT (295 +/- 13 to 233 +/- 14 mg/dl; P < 0.01), and hemoglobin A(1c) (8.6 +/- 0.4% to 7.2 +/- 0.5%; P < 0.01) decreased without a change in fasting or post-OGTT insulin levels. Fasting plasma FFA (674 +/- 38 to 569 +/- 31 microEq/liter; P < 0.05) and mean plasma FFA (539 +/- 20 to 396 +/- 29 microEq/liter; P < 0.01) during OGTT decreased after pioglitazone. In the postabsorptive state, hepatic insulin resistance [basal endogenous glucose production (EGP) x basal plasma insulin concentration] decreased from 41 +/- 7 to 25 +/- 3 mg/kg fat-free mass (FFM).min x microU/ml; P < 0.05) and suppression of EGP during the first insulin clamp step (1.1 +/- 0.1 to 0.6 +/- 0.2 mg/kg FFM.min; P < 0.05) improved after pioglitazone treatment. The total body glucose MCR during the first and second insulin clamp steps increased after pioglitazone treatment [first MCR, 3.5 +/- 0.5 to 4.4 +/- 0.4 ml/kg FFM.min (P < 0.05); second MCR, 8.7 +/- 1.0 to 11.3 +/- 1.1 ml/kg FFM(.)min (P < 0.01)]. The improvement in hepatic and peripheral tissue insulin sensitivity occurred despite increases in body weight (82 +/- 4 to 85 +/- 4 kg; P < 0.05) and fat mass (27 +/- 2 to 30 +/- 3 kg; P < 0.05). After pioglitazone treatment, sc fat area at L4-5 (301 +/- 44 to 342 +/- 44 cm(2); P < 0.01) increased, whereas visceral fat area at L4-5 (144 +/- 13 to 131 +/- 16 cm(2); P < 0.05) and the ratio of visceral to sc fat (0.59 +/- 0.08 to 0.44 +/- 0.06; P < 0.01) decreased. In the postabsorptive state hepatic insulin resistance (basal EGP x basal immunoreactive insulin) correlated positively with visceral fat area (r = 0.55; P < 0.01). The glucose MCRs during the first (r = -0.45; P < 0.05) and second (r = -0.44; P < 0.05) insulin clamp steps were negatively correlated with the visceral fat area. These results demonstrate that a shift of fat distribution from visceral to sc adipose depots after pioglitazone treatment is associated with improvements in hepatic and peripheral tissue sensitivity to insulin.     

Total and high molecular weight (HMW) adiponectin levels and measures of glucose and lipid metabolism following pioglitazone treatment in a randomized placebo-controlled study in polycystic ovary syndrome

Objective Recent studies suggested that the effect of adiponectin on insulin‐stimulated glucose metabolism is mediated primarily by the high molecular weight (HMW) form of adiponectin. In the present study we evaluated total and HMW adiponectin in polycystic ovary syndrome (PCOS) patients and controls and examined possible mechanisms for increased insulin sensitivity during pioglitazone treatment. Study subjects Thirty PCOS patients randomized to pioglitazone, 30 mg/day, or placebo for 16 weeks and 14 weight‐matched healthy females were studied. Design Total and HMW adiponectin levels were measured, and euglycaemic hyperinsulinaemic clamps and indirect calorimetry were performed. Δ‐values denoted changes during pioglitazone treatment (16 weeks – basal). Results Pretreatment adiponectin levels were decreased in PCOS patients vs. controls (P < 0·05), whereas no significant differences were found in HMW adiponectin levels. Following pioglitazone treatment, total and HMW adiponectin increased (all P < 0·05), whereas no significant changes were observed with placebo. Δ‐total adiponectin levels correlated positively with the rate of Δ‐insulin‐stimulated glucose disposal (R_d) (r = 0·89) and Δ‐oxidative glucose metabolism (r = 0·71) and inversely with Δ‐fasting free fatty acid (FFA) levels (r = –0·69) and Δ‐lipid oxidation (r = –0·73) during insulin stimulation (all P < 0·01). Weaker correlations were found between Δ‐HMW adiponectin levels and Δ‐measures of glucose and lipid metabolism during insulin stimulation than with Δ‐total adiponectin. Conclusion A close correlation between increased total adiponectin levels and increased insulin‐stimulated glucose metabolism during pioglitzone treatment supports the hypothesis that the insulin‐sensitizing effect of pioglitazone in PCOS is, at least in part, mediated by adiponectin. Measures of changes in HMW adiponectin did not add further information to this relationship.     

Effect of glucocorticoid replacement therapy on glucose tolerance and intermediary metabolites in hypopituitary adults

BACKGROUND AND OBJECTIVES Excess Impaired glucose tolerance and diabetes mellitus have been reported in hypopituitary adults on conventional replacement therapy Including glucocorticoids. We investigated the effect of the glucocorticoid component on glucose tolerance and intermediary metabolites in hypopituitary adults. DESIGN A 3-hour 75-g oral glucose tolerance test (OGTT) was performed on two study days, at least one week apart. On one study day, the glucocorticoid replacement morning dose was taken 60 minutes before the OGTT, and on the other it was left until after the OGTT. All other pituitary replacement therapies were kept unchanged on the two study days. PATIENTS Eight hypopituitary adults (3 males and 5 females; aged 46–76 years) on conventional replacement therapy were studied. Their duration of hypopituitarism was mean (range) 15 (5–31) years. Their mean body mass index (BMI) was 28·4 (24·1–35·1) kg/m². Their total daily cortisol dose was 26 (15–30) mg. MEASUREMENTS Plasma glucose, insulin, non-esterified fatty acids (NEFA), glycerol and 3-hydroxybutyrate were measured at 30-minute intervals and plasma cortisol levels were measured hourly. RESULTS Fasting glucose and insulin concentrations were similar on the glucocorticoid day (GD) and the non-glucocorticoid day (NGD) (glucose (mean ± SD) 4·9 ± 0·9 vs 4·4 ± 0·5 mmol/l, insulin (median (range) 5 (1-17) vs 2 (1-15) mU/l, respectively). Post-glucose glycaemia was higher on the GD than on the NGD with a significantly higher glucose area under the curve (AUC) (45·0 ± 82 vs 38·9 ± 11·7 mmol/l h, P < 0·05). Post-glucose insulinaemia was also higher on the GD than on the NGD with significantly higher insulin AUC (270 (47-909) vs 207 (46-687)mU/l h, P < 0·02). Impaired glucose tolerance was found in three patients on the GD, one of whom continued to have impaired glucose tolerance on the NGD. The areas under the curves of NEFA, glycerol and 3-hydroxybutyrate were not significantly different on the two days. On the NGD, plasma cortisol levels were undetectable (<50nmol/l) in all patients and on the GD the median (range) peak was 500 (330–740) nmol/l dropping to 125 (60-330) nmol/l at 180 minutes. The difference in glucose AUC between the two days correlated with the maximal plasma cortisol levels (Spearman's p= 0·83, P < 0·01). CONCLUSIONS Glucocorticoid replacement therapy taken pre-prandially In hypopituitary adults induces mild elevations In circulating glucose and insulin levels even with acceptable plasma cortisol concentrations. Optimal regimens for glucocorticoid replacement require more study.     

Fasting concentrations of nesfatin‐1 are negatively correlated with body mass index in non‐obese males

Background We recently identified a novel anorexigenic protein, nesfatin‐1, which is processed from nesfatin/nucleobindin‐2 (NUCB2). However, the clinical importance of this protein has not been determined. Objective To investigate its clinical significance in humans, we have established a new specific enzyme‐linked immunosorbent assay (ELISA) for human nesfatin‐1 in peripheral blood and measured its circulating concentration in healthy subjects. Design The new sandwich‐type ELISA method was validated and then used to measure nesfatin‐1 levels in plasma samples, under overnight fasting conditions, followed by oral glucose tolerance and meal tests. Patients and measurements A total of 43 nonobese males (age: 24·5 ± 0·6 , body mass index (BMI); 21·1 ± 0·3 kg/m²) were recruited to the study for evaluating fasting concentrations of nesfatin‐1. In those, fifteen subjects underwent a 75‐ g oral glucose tolerance test (OGTT) and another 15 underwent a meal test. In addition, fasting concentrations of nesfatin‐1 were measured in nine males with high BMI (age: 32·4 ± 3·7 , BMI; 37·3 ± 3·8 kg/m²). Results Peripheral concentrations of nesfatin‐1 showed a significant negative correlation with BMI, percentage body fat, body fat weight and blood glucose (P < 0·05). Nesfatin‐1 concentrations were not significantly changed during OGTT and meal tests. Fasting nesfatin‐1 levels were significantly lower in subjects with high BMI compared to nonobese subjects (P < 0·05). Conclusions A new specific and sensitive ELISA for nesfatin‐1 was established. Further accumulation of clinical observations is necessary to clarify the role of circulating nesfatin‐1 in various metabolic disorders.     

Glucose homeostasis in patients with acromegaly treated with surgery or somatostatin analogues

Objective Long‐acting somatostatin analogues (SSA) are widely used for the treatment of acromegaly; however, they also alter β‐cell function by inhibiting insulin secretion. In this study, we assess the effect of SSA on glucose homeostasis in patients with acromegaly treated with SSAs, compared to patients treated with surgery. Design We studied four groups of patients with acromegaly: at the time of diagnosis (group I, n = 53), after successful transsphenoidal surgery (TSS, group II, n = 30) and under successful SSA treatment (group III, n = 20); 22 patients were studied only before treatment, 19 only post‐treatment, while 31 patients (group IV) were studied before and after the treatment. Measurements Patients underwent an oral glucose tolerance test. Insulin sensitivity and β‐cell insulin secretion were estimated using appropriate mathematical models. Results Control of acromegaly with either TSS or SSA improved insulin sensitivity as evident by significantly lower fasting and postglucose insulin levels and HOMA‐IR. In addition, patients of group III compared to patients of group II demonstrated significantly lower HOMA‐β% (52·5 ± 10·9 vs 189·6 ± 86·7, P < 0·05) and lower first and second phase insulin release (443 ± 83·5 vs 1077 ± 140·8, P < 0·05 and 150 ± 18·2 vs 285 ± 33·3, P < 0·05), respectively. Also, lower fasting glucose levels and a lower prevalence of diabetes were noted in group II compared to group III (5·1 ± 0·2 vs 6·2 ± 0·2 mm , P < 0·05, and 13·3%vs 40%, P < 0·0031, respectively). Conclusions Control of acromegaly with SSA seems to exhibit a negative effect on pancreatic β‐cell function. Whether this has long‐term clinical implications remains to be established. Nevertheless, careful monitoring of glucose metabolism in patients under SSA is beneficial for their optimal management.     

Risk of early progression to prediabetes or diabetes in women with recent gestational dysglycaemia but normal glucose tolerance at 3‐month postpartum

Objective  Both gestational diabetes mellitus (GDM) and milder glucose intolerance in pregnancy identify women who are at risk of developing type 2 diabetes. While some of these women will have prediabetes or diabetes in the early postpartum, most will have normal glucose tolerance (NGT), despite their future diabetic risk. In this context, we sought to evaluate the risk of early progression to dysglycaemia in women with NGT at 3‐month postpartum and identify predictors thereof. Methods  Three hundred and twenty‐five women with varying degrees of gestational dysglycaemia but NGT on oral glucose tolerance test (OGTT) at 3‐month postpartum underwent repeat OGTT at 12‐month postpartum. Results  By 12‐month postpartum, 10% of the study population and 17·1% of those with recent GDM had progressed to dysglycaemia (primarily impaired glucose tolerance). At 3‐month postpartum, compared to nonprogressors, the progressors had (i) higher BMI (P = 0·0023), LDL (P = 0·0017), triglycerides (P = 0·0002), leptin (P = 0·0021) and C‐reactive protein (P = 0·043), and (ii) lower HDL (P = 0·0026) and adiponectin (P = 0·045). Notably, although all women had NGT at the time, each of the following glucose‐related parameters from the OGTT at 3‐month postpartum emerged as a significant independent predictor of progression on logistic regression analyses: area‐under‐the‐glucose‐curve (OR = 1·37, 95%CI: 1·13–1·65; P = 0·0012); sum of the glucose values (OR = 1·16, 95%CI: 1·05–1·29; P = 0·0042); and having a delayed blood glucose peak (occurring >30 min postload) (OR = 2·89, 95%CI: 1·29–6·45; P = 0·0097). Conclusions  A normal OGTT at 3‐month postpartum does not necessarily provide assurance of a low risk of progression to prediabetes. Glucose‐related measures during this OGTT may identify those women at highest risk for early progression.     

Correlation of insulin sensitivity with bone mineral status in obese adolescents with nonalcoholic fatty liver disease

Aim The aim of this study was to investigate the relationships between bone mineral density (BMD) vs insulin resistance and metabolic risk factors in obese adolescents with nonalcoholic fatty liver disease (NAFLD). Patients and methods Eighty‐two obese adolescents [45 girls and 37 boys, mean age: 12·3 ± 1·7 years, mean body mass index‐standard deviation score (BMI‐SDS): 1·9 ± 0·2] and 30 control subjects (15 girls and 15 boys, mean age: 12·3 ± 1·45 years, mean BMI‐SDS: 0·5 ± 0·7) were enrolled the study. The obese subjects were divided into two groups based on the presence or absence of liver steatosis with high transaminases (NAFLD group and non‐NAFLD group). Insulin resistance was evaluated by homeostasis model assessment (HOMA‐IR) from fasting samples. BMD was determined by dual‐energy X‐ray absorptiometry. Results Fasting insulin levels in the NAFLD group were significantly higher than in the non‐NAFLD obese (32·3 ± 24·0 vs 11·02 ± 2·95 mU/l, P < 0·001) and control groups (8·4 ± 2·4 mU/l, P< 0·001). The NAFLD group had higher values of HOMA‐IR than the non‐NAFLD obese (7·3 ± 0·1 vs 2·3 ± 0·7, P < 0·001) and control groups (1·8 ± 0·5, P < 0·001). BMD‐SDS measurements were lower in the NAFLD group than in the non‐NAFLD (0·56 ± 0·3 vs 1·02 ± 0·9, P < 0·001) and control groups (0·56 ± 0·3 vs 1·37 ± 1·04, P < 0·001). BMD‐SDS was positively correlated with BMI‐SDS (r = 0·530, P = 0·004) and negatively correlated with HOMA‐IR (r = ?0·628, P = 0·017) in the NAFLD obese group. Conclusion This study reports the association between BMD‐SDS and insulin resistance in obese adolescents both with and without NAFLD, although the NAFLD group had a lower BMD‐SDS than the non‐NAFLD group. We suggest that NAFLD has a detrimental effect on bone health in adolescents, and it is correlated with increased insulin resistance.     

Evaluation of proposed oral disposition index measures in relation to the actual disposition index

Aims While the disposition index provides a useful measure of B‐cell function, its calculation requires the performance of a frequently sampled intravenous glucose tolerance test (FSIVGTT). Recently, the demonstration of a hyperbolic relationship between indices of insulin secretion and insulin sensitivity derived from the oral glucose tolerance test (OGTT) has led to the introduction of two novel OGTT‐based measures of B‐cell function analogous to the disposition index: (i) the insulin secretion‐sensitivity index‐2 (ISSI‐2) (defined as the ratio of the area‐under‐the‐insulin‐curve to the area‐under‐the‐glucose curve, multiplied by the Matsuda index) and (ii) insulinogenic index (IGI)/fasting insulin. However, neither of these two measures has been directly compared with the disposition index. Methods Two hundred and thirteen non‐diabetic children (122 boys, 91 girls) underwent both OGTT and FSIVGTT, allowing for the calculation of ISSI‐2, IGI/fasting insulin and the disposition index. Results ISS1‐2 and IGI/fasting insulin were strongly correlated with each other (r = 0.82, P < 0.0001). Both measures correlated with the disposition index, with ISSI‐2 showing a modestly stronger association (ISSI‐2: r = 0.24, P = 0.0003; IGI/fasting insulin: r = 0.21, P = 0.0022). Standardized linear regression analyses confirmed that the relationship between log ISSI‐2 and the disposition index (standardized regression coefficient = 0.224, P = 0.001) was stronger than that between log IGI/fasting insulin and the disposition index (standardized regression coefficient = 0.166, P = 0.015). Conclusions The OGTT‐derived measures ISSI‐2 and IGI/fasting insulin exhibit modest correlations with the disposition index. These relationships require further assessment in other patient populations.     

Circulating leptin concentrations in polycystic ovary syndrome: relation to anthropometric and metabolic parameters

OBJECTIVE To determine the relation between metabolic and anthropometric parameters and circulating leptin concentrations in women with polycystic ovary syndrome (PCOS). DESIGN AND PATIENTS Correlation of fasting serum leptin concentrations with anthropometric measures and multiple metabolic parameters including insulin and glucose responses to a 2-hour 75-g oral glucose tolerance test (OGTT) in 85 women with PCOS (17–36 years, body mass index (BMI) 29.9 ± 0.9 kg/m², mean ± SD) and 18 control women (25–47 years, BMI 25 ± 1.7 kg/m²). Diagnostic criteria for PCOS: characteristic ovarian morphology on ultrasound plus at least two of (1) elevated serum testosterone; (2) elevated serum androstenedione; and (3) reduced serum SHBG concentrations. MEASUREMENTS Concentrations of androgens, lipids, PRL, gonadotrophins, and leptin were measured in the baseline fasting blood sample from an OGTT. Insulin and glucose were measured throughout OGTT. Serum leptin concentrations were measured by radioimmunoassay. RESULTS Log leptin levels in the PCOS group correlated significantly with BMI (r = 0.85, P < 0.0001) and with 8 other parameters including waist/hip ratio (r = 0.51, P = 0.0005). By stepwise regression analysis, only BMI (P < 0.0001) and plasma high density lipoprotein concentration (P = 0.02) were independently correlated with log leptin levels, both positively. There was no effect of fat distribution, as measured by waist/hip ratio, on leptin concentrations. Comparison of control subjects to a BMI-matched subgroup of 55 PCOS subjects revealed significantly higher circulating concentrations of LH, testosterone, DHEAS, progesterone and androstenedione, and higher glucose and insulin responses to OGTT in the PCOS group. Leptin levels were not different between the PCOS subgroup and control group (14.8 ± 1.3 vs 12.1 ± 2.3 μg/l, mean ± SE, P = 0.26) and the relation of BMI to leptin levels determined by linear regression analysis also did not differ between the two groups. CONCLUSIONS Our results indicate that circulating leptin concentrations in women with PCOS, a condition characterized by hyperandrogenaemia, increased LH concentrations and insulin resistance, are strongly related to BMI and not independently affected by circulating levels of insulin, gonadotrophins or sex hormones.