Effects of pioglitazone in familial combined hyperlipidaemia

OBJECTIVES: Familial combined hyperlipidaemia (FCH) is associated with insulin resistance. We hypothesized that pioglitazone treatment of FCH patients might increase insulin sensitivity, but may also improve serum lipid levels, body fat distribution, intramyocellular lipids (IMCL) and endothelial function. DESIGN: Double blind, randomized, cross-over study. SUBJECTS: Seventeen FCH patients. INTERVENTIONS: Sixteen weeks of pioglitazone treatment (30 mg) compared with 16 weeks of placebo. MAIN OUTCOME MEASUREMENTS: Insulin sensitivity was measured using the hyperinsulinaemic euglycaemic clamp procedure, body fat distribution and IMCL using magnetic resonance techniques and endothelial function using flow-mediated vasodilatation. RESULTS: Pioglitazone improved insulin sensitivity (M value 37.7 +/- 3.6 micromol min(-1) kg(-1) vs. 33.0 +/- 3.3 micromol min(-1) kg(-1) during placebo, P < 0.05) and LDL composition by increasing the K value (-0.11 +/- 0.06 vs. -0.20 +/- 0.06 during placebo, P < 0.05). However, pioglitazone did not affect other serum lipid levels. Endothelial function, body fat distribution and IMCL were also not affected. In addition, pioglitazone was associated with a decrease in liver enzymes (alkaline phosphatase). CONCLUSION: Pioglitazone treatment of FCH patients without type 2 diabetes mellitus increases insulin sensitivity, decreases liver enzymes and improves LDL composition but has a neutral effect on total serum lipid levels. The change in insulin sensitivity might be too small to induce changes in endothelial function, body fat distribution and IMCL.     

Long-term effects of pioglitazone and metformin on insulin sensitivity in patients with Type 2 diabetes mellitus.

AIM: Despite their comparable glycaemic effects in patients with Type 2 diabetes mellitus (T2DM), pioglitazone and metformin may have different effects on insulin sensitivity because they have different mechanisms of action. We studied the changes in insulin sensitivity, as assessed by the Quantitative Insulin Sensitivity Check Index (QUICKI), in patients with T2DM who used metformin or pioglitazone as monotherapy or in combination therapy with sulphonylurea. METHODS: Data in this report are from two multicentre, randomized, double-blind, double-dummy studies conducted in Europe (monotherapy) or in Europe and Canada (combination therapy study). Patients were randomized to 52 weeks of treatment consisting of a 12-week forced titration period and a 40-week maintenance period. HbA(1c), fasting plasma glucose (FPG) and fasting serum insulin (FSI) were quantified from a single blood sample at weeks 0, 8, 16, 24, 32, 42 and 52. Insulin sensitivity was assessed with QUICKI, which is calculated from FSI and fasting blood glucose (FBG) concentrations using the formula 1/(log(10) FSI + log(10) FBG). Time course effects of the treatments were compared by repeated measures analysis of covariance. RESULTS: As monotherapy, pioglitazone and metformin increased QUICKI compared with baseline (baseline vs. end point [mean +/- sem]; pioglitazone [0.303 +/- 0.001 vs. 0.321 +/- 0.001; P < 0.001] and metformin [0.304 +/- 0.001 vs. 0.315 +/- 0.001; P < 0.001]). Pioglitazone increased insulin sensitivity more than metformin from week 4 through week 52. There were significant increases in QUICKI from baseline in both combination therapy groups (baseline vs. end point; pioglitazone + sulphonylurea [0.305 +/- 0.001 vs. 0.319 +/- 0.001; P < 0.001] and metformin + sulphonylurea [0.306 +/- 0.001 vs. 0.317 +/- 0.001; P < 0.001]). Overall, pioglitazone + sulphonylurea significantly increased insulin sensitivity more than metformin + sulphonylurea. CONCLUSION: Pioglitazone differed from metformin in its effects on insulin sensitivity despite both drugs having comparable glycaemic effects.     

Sustained effects of pioglitazone vs. glibenclamide on insulin sensitivity, glycaemic control, and lipid profiles in patients with Type 2 diabetes.

AIMS: This study compared the effects of 52 weeks' treatment with pioglitazone, a thiazolidinedione that reduces insulin resistance, and glibenclamide, on insulin sensitivity, glycaemic control, and lipids in patients with Type 2 diabetes. METHODS: Patients with Type 2 diabetes were randomized to receive either pioglitazone (initially 30 mg QD, n = 91) or micronized glibenclamide (initially 1.75 mg QD, n = 109) as monotherapy. Doses were titrated (to 45 mg for pioglitazone and 10.5 mg for glibenclamide) to achieve glycaemic targets during the next 12 weeks: fasting blood glucose of < or = 7 mmol/l and 1-h postprandial blood glucose of < or = 10 mmol/l. Patients were maintained on the titrated dose for 40 weeks. RESULTS: Pioglitazone significantly increased insulin sensitivity compared with glibenclamide, as assessed by homeostasis model assessment (17.0% vs. -13.0%; P < 0.001), quantitative insulin sensitivity check index (0.011 vs. -0.007; P < 0.001) and fasting serum insulin (-1.3 pmol/l vs. 23.8 pmol/l; P = 0.007). The glibenclamide group had significantly lower HbA1c than the pioglitazone group after 12 weeks of therapy (7.8% vs. 8.3%, P = 0.015), but significantly higher HbA1c after 52 weeks of therapy (7.8% vs. 7.2%, P = 0.001). Pioglitazone significantly (vs. glibenclamide) increased mean HDL-C (P < 0.001), decreased mean triglycerides (P = 0.019), and decreased mean atherogenic index of plasma (AIP; P = 0.001) and mean total cholesterol/HDL-C (P = 0.004), without significantly elevating mean total cholesterol or mean LDL-C compared with glibenclamide. CONCLUSIONS These data suggest that the effects of pioglitazone are more sustained than those of glibenclamide for improving insulin sensitivity in patients with Type 2 diabetes, and that 52 weeks' treatment with pioglitazone has favourable effects on glycaemic control and lipoprotein profile.     

The impact of pioglitazone on glycemic control and atherogenic dyslipidemia in patients with type 2 diabetes mellitus

BACKGROUND: To evaluate the glycemic control, lipid effects, and safety of pioglitazone in patients with type 2 diabetes mellitus. DESIGN AND METHODS: Patients (n = 197) with type 2 diabetes mellitus, a hemoglobin A1c (HbA1c) > or = 8.0%, fasting plasma glucose (FPG) > 7.7 mmol/l (140 mg/dl), and C-peptide > 0.331 nmol/l (1 ng/ml) were enrolled in this 23-week multi-center (27 sites), double-blind clinical trial and randomized to receive either a placebo or pioglitazone HCl 30 mg (pioglitazone), administered once daily, as monotherapy. Patients were required to discontinue all anti-diabetic medications 6 weeks before receiving study treatment. Efficacy parameters included HbA1c fasting plasma glucose (FPG), serum C-peptide, insulin, triglycerides (Tg), and cholesterol (total cholesterol [TC], high-density lipoprotein-cholesterol [HDL-C], low-density lipoprotein-cholesterol [LDL-C]). Adverse event rates, serum chemistry, and physical examinations were recorded. RESULTS: Compared with placebo, pioglitazone significantly (P= 0.0001) reduced HbA1c (-1.37% points), FPG (-3.19 mmol/l; -57.5 mg/dl), fasting C-peptide (-0.076+/-0.022 nmol/l), and fasting insulin (-11.88+/-4.70 pmol/l). Pioglitazone significantly (P < 0.001) decreased insulin resistance (HOMA-IR; -12.4+/-7.46%) and improved beta-cell function (Homeostasis Model Assessment (HOMA-BCF); +47.7+/-11.58%). Compared with placebo, fasting serum Tg concentrations decreased (-16.6%; P = 0.0178) and HDL-C concentrations increased (+12.6%; P= 0.0065) with pioglitazone as monotherapy. Total cholesterol and LDL-C changes were not different from placebo. The overall adverse event profile of pioglitazone was similar to that of placebo, with no evidence of drug-induced elevations of serum alanine transaminase (ALT) concentrations or hepatotoxicity. CONCLUSIONS: Pioglitazone improved insulin resistance and glycemic control, as well as Tg and HDL-C - which suggests that pioglitazone may reduce cardiovascular risk for patients with type 2 diabetes.     

Effects of pioglitazone on beta-cell function in metabolic syndrome patients with impaired glucose tolerance

OBJECTIVE: To determine the potential effects of pioglitazone on beta-cell function in metabolic syndrome patients with impaired glucose tolerance and probe into the possible mechanisms. RESEARCH DESIGN AND METHODS: Twenty-two subjects were treated with pioglitazone 30 mg/day for 4 months. At baseline and after treatment, each subject underwent an IVGTT. The acute insulin response (AIRg), the glucose disappearance rates (coefficients K) and the ratio of Deltainsulin/Deltaglucose (DeltaI/DeltaG) were calculated according to IVGTT results. Hyperglycemic clamp study was conducted to determine the second-phase insulin response, insulin sensitivity index (ISI) and glucose infusion rate (GIR). Euglycemic-hyperinsulinemic clamp study was made to measure the glucose disposal rate (GDR). Plasma glucose, free fatty acids (FFAs), serum insulin and proinsulin levels were measured. RESULTS: AIRg unchanged (P = 0.25) after treatment, whereas the values of coefficients K (P < 0.01) and DeltaI/DeltaG increased (P < 0.05). The second-phase insulin response and GIR were both demonstrated marked increments (P < 0.01 and P < 0.01, respectively). Pioglitazone therapy also resulted in improvement of ISI value (P < 0.05). And the increment of GDR during the euglycemic-hyperinsulinemic clamp was also significant (P < 0.01). Furthermore, a decrease in fasting proinsulin level was observed (P < 0.001). And plasma glucose, FFAs and serum insulin levels all declined. The increase of DeltaI1/DeltaG1 was positively correlated with the improvement of GDR (r = 0.536, P = 0.089). And a positive relationship was observed between the change in the second-phase insulin response and change in K value (r = 0.682, P = 0.021). CONCLUSIONS: Short-term pioglitazone therapy improved beta-cell dysfunction, the mechanism might involve the attenuation of insulin resistance.     

Effects of pioglitazone in nondiabetic patients with arterial hypertension: a double-blind,placebo-controlled study

Hypertension is often associated with insulin resistance, dyslipidemia and obesity, which indicate a prediabetic state and increased risk of cardiovascular disease. Pioglitazone treatment of patients with type 2 diabetes reduces insulin resistance and improves lipid profiles. The present double-blind placebo-controlled study is the first study to report effects of pioglitazone in non-diabetic patients with arterial hypertension. Following a one week run-in, 60 patients were randomized to receive either pioglitazone (45 mg/day) or placebo for 16 weeks. Insulin sensitivity (M-value) increased by 1.2 +/- 1.7 mg/min/kg with pioglitazone compared with 0.4 +/- 1.4 mg/min/kg (P = 0.022) with placebo. HOMA index was decreased (-22.5 +/- 45.8) by pioglitazone but not by placebo (+0.8 +/- 26.5; P < 0.001). Decreases in fasting insulin and glucose were significantly (P = 0.002 and P = 0.004, respectively) greater with pioglitazone than placebo. Body weight did not change significantly with either treatment. HDL-cholesterol was increased and apolipoprotein B was decreased to a significantly greater extent with pioglitazone. There was a significantly (P = 0.016) greater decrease from baseline in diastolic blood pressure with pioglitazone. These changes would suggest improved glucose metabolism and a possible reduction in risk of cardiovascular disease with pioglitazone treatment of non-diabetic patients with arterial hypertension.     

Effect of pioglitazone in combination with insulin therapy on glycaemic control, insulin dose requirement and lipid profile in patients with type 2 diabetes previously poorly controlled with combination therapy

AIM: The aim of this randomized placebo-controlled study was to evaluate the safety and efficacy of pioglitazone administered alone or in combination with metformin in reducing insulin dosage requirements for improved glycaemic control in patients with type 2 diabetes previously poorly controlled with combination therapy. METHODS: In this multicentre, double-blind study, 222 patients with haemoglobin A1c (HbA(1c))>8.0% at screening treated with combination therapy initially were given titrated insulin therapy (to fasting plasma glucose <140 mg/dl) and then were randomly assigned to 20-week treatment with pioglitazone or placebo in combination with insulin, with or without concurrent metformin therapy. More than 98% of patients were taking metformin prior to and during the study. RESULTS: Pioglitazone significantly reduced (p < 0.05) insulin dose requirements 2 weeks after treatment initiation. At study end relative to baseline, pioglitazone reduced daily insulin dosages by 12.0 units (p < 0.001), a 21.5% (12.0/55.8 units at baseline) group mean average reduction. Relative to placebo, pioglitazone reduced daily insulin dosages by 12.7 units [95% confidence interval [CI]: -17.5, -8.0], while improving mean HbA(1c) levels [adjusted mean HbA(1c) change: pioglitazone, -1.6% vs. placebo, -1.4% (not statistically different)]. Pioglitazone also significantly increased high-density lipoprotein cholesterol levels [adjusted mean difference: +4.5 (95% CI: 2.6-6.5) mg/dl], decreased triglyceride levels [-43.9 (-69.2, -18.6) mg/dl], shifted low-density lipoprotein (LDL) particle concentrations from small [pattern B, -13.6% (-17.7%, -9.5%)] to large [pattern A, +15.1% (10.8%, 19.5%)] and increased mean LDL particle size [+3.8 (2.6, 4.9) A]. More pioglitazone-treated patients experienced oedema (9.0 vs. 4.5%) and weight gain (9.1 vs. 2.7%) than placebo patients. CONCLUSIONS: Pioglitazone in combination with insulin therapy improved glycaemic control, reduced insulin dose requirements and improved lipid profiles in patients with type 2 diabetes previously poorly controlled with combination therapy.     

Compared to glibenclamide, repaglinide treatment results in a more rapid fall in glucose level and beta-cell secretion after glucose stimulation

BACKGROUND: The more rapid onset of action and the shorter half-life of repaglinide may reduce the post-load glucose excursion and limit sustained insulin secretion compared to sulphonylurea (SU) derivatives. METHODS: We studied 12 patients with type 2 diabetes (age 62 +/- 2 years, BMI 28.3 +/- 1.3 kg m(-2), HbA1c 6.7 +/- 0.2%) on SU monotherapy at submaximal dose. Patients were treated for 3 weeks with repaglinide or glibenclamide in a randomized, crossover trial. At the end of each treatment period, patients underwent a 60-min hyperglycaemic clamp (glucose 12 mmol L(-1)) followed by 4-h observation (60-300 min) with frequent blood sampling for determination of glucose, insulin, proinsulin and C-peptide levels. Before the clamp (5 min for repaglinide, 30 min for glibenclamide), patients ingested their usual morning drug dose. RESULTS: After the end of the hyperglycaemic clamp, mean plasma glucose fell to a level of 5 mmol L(-1) after approximately 150 min with repaglinide, and after approximately 190 min with glibenclamide. While initially quite similar, in the period from 240 to 300 min, insulin, proinsulin and C-peptide levels were lower during repaglinide treatment (insulin 133 +/- 20 vs 153 +/- 25 pmol L(-1) (P < 0.05), proinsulin 14 +/- 3 vs 19 +/- 4 pmol L(-1) (P = 0.06) and C-peptide 0.81 +/- 0.19 vs 1.14 +/- 0.18 nmol L(-1) (P = 0.05) for repaglinide vs glibenclamide, respectively). CONCLUSIONS: Following glucose stimulation, plasma glucose levels, and insulin concentration decrease more rapidly after repaglinide treatment than after glibenclamide. Proinsulin and C-peptide secretion tended to fall more rapidly as well. These findings are consistent with a more rapid onset and shorter duration of beta-cell stimulation associated with repaglinide.     

The effect of gliclazide on plasma insulin, intact and 32/33 split proinsulin in South Asian subjects with Type 2 diabetes mellitus.

AIMS: Previous studies have shown that in Caucasian subjects with Type 2 diabetes mellitus (DM), the sulphonylurea glibenclamide increased insulin secretion without causing an increase in 32/33 split proinsulin secretion. South Asian subjects with Type 2 DM are thought to be more insulin resistant and the effect of sulphonylureas may be different. We therefore investigated the effect of sulphonylurea therapy with gliclazide on beta-cell function in South Asian subjects with newly diagnosed Type 2 DM. METHODS: Glucose, insulin, and intact and 32/33 split proinsulin were measured at diagnostic oral glucose tolerance test (OGTT). After 8-12 weeks on a conventional diet, subjects with a fasting glucose > 6 mmol/l (n = 16) were commenced on gliclazide. RESULTS: At diagnosis, those requiring gliclazide were more hyperglycaemic but there was no difference in weight or fasting insulin concentration than in the diet group. Following diet, in the gliclazide group, weight fell (P < 0.04) with no change in fasting glucose concentration. Fasting intact proinsulin, insulin and 32/33 split proinsulin remained unchanged. After gliclazide therapy weight remained unchanged, but fasting glucose fell (P < 0.003). Fasting insulin and intact proinsulin remained unchanged but 32/33 split proinsulin fell (P < 0.05). Fasting insulin to glucose ratio significantly improved after gliclazide (P < 0.006). CONCLUSIONS: In South Asian subjects treated with gliclazide the reduction in fasting glucose concentrations appears to be due to an improvement in insulin sensitivity as well as in beta-cell function.     

吡格列酮降低非糖尿病患者冠状动脉药物洗脱支架再狭窄的研究

目的:探讨吡格列酮对非糖尿病患者冠状动脉(冠脉)支架内再狭窄的影响及其可能机制。方法:选择置入雷帕霉素洗脱支架的非糖尿病患者128例,并排除糖耐量异常者,随机分成吡格列酮组(71例)和对照组(57例),吡格列酮组在对照组常规治疗的基础上加用吡格列酮(30mg,qd);冠脉支架置入术后6～8个月行选择性冠脉造影术,于治疗前及随访6～8个月复查时先后分别测定血脂、空腹血糖、空腹胰岛素、血清瘦素及血清脂联素,并计算胰岛素抵抗指数(HOMA-IR)。结果:吡格列酮组支架内再狭窄的发生率显著低于对照组(2.82%∶12.28%,P=0.037);冠脉支架术后6～8个月,2组血脂指标、空腹血糖差异无统计学意义,但HOMA-IR、脂联素及脂联素/瘦素比值均差异有统计学意义(均P<0.05)。结论:吡格列酮能够降低非糖尿病患者药物洗脱支架的再狭窄,这种作用独立于调整血糖、血脂之外,改善胰岛素抵抗和血管内皮功能可能是吡格列酮阻止支架内再狭窄的重要机制。     

Earlier triple therapy with pioglitazone in patients with type 2 diabetes

Aims: This study assessed the efficacy of add‐on pioglitazone vs. placebo in patients with type 2 diabetes uncontrolled by metformin and a sulphonylurea or a glinide. Methods: This multicentre, double‐blind, parallel‐group study randomized 299 patients with type 2 diabetes to receive 30 mg/day pioglitazone or placebo for 3 months. After this time, patients continued with pioglitazone, either 30 mg [if glycated haemoglobin A1c (HbA_1c) ≤6.5%] or titrated up to 45 mg (if HbA_1c >6.5%), or placebo for a further 4 months. The primary efficacy end‐point was improvement in HbA_1c (per cent change). Secondary end‐points included changes in fasting plasma glucose (FPG), insulin, C‐peptide, proinsulin and lipids. The proinsulin/insulin ratio and homeostasis model assessment of insulin resistance (HOMA‐IR) and homeostasis model assessment of β‐cell function (HOMA‐B) were calculated. Results: Pioglitazone add‐on therapy to failing metformin and sulphonylurea or glinide combination therapy showed statistically more significant glycaemic control than placebo addition. The between‐group difference after 7 months of triple therapy was 1.18% in HbA_1c and ?2.56 mmol/l for FPG (p < 0.001). Almost half (44.4%) of the patients in the pioglitazone group who had a baseline HbA_1c level of <8.5% achieved the HbA_1c target of < 7.0% by final visit compared with 4.9% in the placebo group. When the baseline HbA_1c level was ≥ 8.5%, 13% achieved the HbA_1c target of < 7.0% in the pioglitazone group and none in the placebo group. HOMA‐IR, insulin, proinsulin and C‐peptide decreased and HOMA‐B increased in the pioglitazone group relative to the placebo group. Conclusions: In patients who were not well controlled with dual combination therapy, the early addition of pioglitazone improved HbA_1c, FPG and surrogate measures of β‐cell function. Patients were more likely to reach target HbA_1c levels (< 7.0%) with pioglitazone treatment if their baseline HbA_1c levels were < 8.5%, highlighting the importance of early triple therapy.     

Addition of pioglitazone or bedtime insulin to maximal doses of sulfonylurea and metformin in type 2 diabetes patients with poor glucose control: a prospective, randomized trial

PURPOSE: To compare the efficacy of adding pioglitazone or bedtime isophane (NPH) insulin to maximal doses of metformin and an insulin secretagogue in patients with poor glucose control. METHODS: We conducted a nonblinded, open-label, randomized controlled trial involving 62 patients with type 2 diabetes and glycosylated hemoglobin (HbA1C) levels >8.0%. Patients received either pioglitazone or bedtime NPH insulin in addition to their usual diabetes medication for 16 weeks. Outcome measurements of glycemic control, hypoglycemia, blood pressure, lipid levels, microalbuminuria, and quality of life were assessed at baseline and at 16 weeks. RESULTS: HbA1C levels were lowered to a similar degree in each treatment arm (pioglitazone: -1.9% +/- 1.5%; insulin: -2.3% +/- 1.5%; P = 0.32), but hypoglycemia was less common among patients who received pioglitazone than those who received insulin (37% [11/30] vs. 68% [19/28], P=0.02). Pioglitazone, but not insulin, resulted in an increase in high-density lipoprotein (HDL) cholesterol levels. Both treatments had similar effects on weight, other lipid values, blood pressure, and urine microalbumin levels. CONCLUSION: Adding pioglitazone or bedtime insulin for 16 weeks improved glycemic control in type 2 diabetic patients with secondary oral agent failure. Pioglitazone was associated with less hypoglycemia and improved HDL cholesterol levels.     

Relationship between adipose tissue insulin resistance and liver histology in nonalcoholic steatohepatitis: A pioglitazone versus vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis trial follow-up study

The PIVENS (Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis [NASH]) trial demonstrated that pioglitazone and vitamin E improved liver histology to varying degrees, but the mechanisms are unknown. We conducted a study to examine the changes in adipose tissue insulin resistance (Adipo-IR) during the PIVENS trial and its relationship to histological endpoints. Adipo-IR (fasting nonesterified fatty acids [NEFAs] × fasting insulin) was calculated at baseline and after 16 and 96 weeks of therapy. Compared to placebo, the baseline Adipo-IR was not different in either the vitamin E group (P = 0.34) or the pioglitazone group (P = 0.29). Baseline Adipo-IR was significantly associated with fibrosis score (P = 0.02), but not with other histological features or nonalcoholic fatty liver disease (NAFLD) activity score (NAS). After 16 weeks, compared to placebo, the pioglitazone group had a significant reduction in Adipo-IR (-15.7 versus -1.91; P = 0.02), but this effect did not persist at 96 weeks (-3.25 versus -4.28; P = 0.31). Compared to placebo, Adipo-IR in the vitamin E group did not change significantly either after 16 weeks (P = 0.70) or after 96 weeks (P = 0.85). Change in Adipo-IR at week 16 was not associated with changes in any histological parameters at week 96, but improvement in Adipo-IR at week 96 was significantly associated with improvement in ballooning (P = 0.03), fibrosis (P = 0.004), and NAS (P = 0.01). Conclusion: Vitamin E improved liver histology independent of changes in Adipo-IR, and pioglitazone treatment acutely improved Adipo-IR, but this was not sustained. Changes in Adipo-IR were associated with changes in liver histology, including fibrosis. (HEPATOLOGY 2012).     

Evidence against a rate-limiting role of proinsulin processing for maximal insulin secretion in subjects with impaired glucose tolerance and beta-cell dysfunction

In subjects with impaired glucose tolerance (IGT) insulin secretion is impaired. Increased proinsulin/insulin (PI/I) ratios suggest that there is also reduced processing of proinsulin to insulin in this condition. The PI/I ratio in the insulin secretory granule is ideally assessed by plasma measurements in response to acute stimulation of insulin secretion. In the present study we tested the hypothesis that maximal stimulation of insulin secretion results in exhaustion of the proinsulin conversion pathway to insulin. We therefore determined the PI/I ratio in 11 normal glucose-tolerant subjects (NGT) and 11 subjects with IGT in response to glucose (squarewave hyperglycemic clamp, 10 mmol/L), glucagon-like peptide-1 (GLP-1; primed-continuous infusion), and arginine given during the continued GLP-1 infusion. In IGT, insulin levels were significantly lower during the first phase (144 +/- 20 vs. 397 +/- 119 pmol/L; P = 0.02), at the end of the GLP infusion (2142 +/- 350 vs. 5430 +/- 1091 pmol/L; P: = 0.002), and in response to arginine (3983 +/- 375 vs. 8663 +/- 1430 pmol/L; P = 0.005). In response to glucose, the minimum PI/I ratio was significantly higher in IGT (3.4 +/- 0.6%) than in NGT (1.4 +/- 0.5%; P = 0.02), suggesting defective proinsulin processing in this condition. In subjects with IGT, the PI/I ratio decreased significantly after GLP-1 priming (1.7 +/- 0.2%; P = 0.02) and after arginine given during GLP-1 (1.4 +/- 0.2%; P = 0.007) and was not significantly different from those values in NGT (1.3 +/- 0.2% and 1.3 +/- 0.2%, respectively; both P = NS). In conclusion, during maximal stimulation of insulin secretion in subjects with IGT, the PI/I ratio in plasma decreased significantly and was not different from that in normal controls. This strongly argues against the hypothesis that defective processing of proinsulin to insulin represents a major component of the beta-cell dysfunction in IGT.     

Insulin resistance and beta-cell dysfunction in normoglycaemic European women with a history of gestational diabetes

OBJECTIVE: Women with previous gestational diabetes (GDM) are at increased risk of subsequent type 2 diabetes. To characterize early metabolic abnormalities associated with this increased risk, we studied normoglycaemic women with a history of GDM. PATIENTS AND MEASUREMENTS: We performed an insulin-modified, frequently sampled intravenous glucose tolerance test (FSIVGTT) in 34 normoglycaemic European women with previous GDM and 44 European control women, deriving measures of insulin sensitivity, glucose effectiveness, glucose disappearance rate and acute insulin response to glucose. RESULTS: Post-GDM women were more obese than controls [body mass index (BMI), geometric mean (95% confidence interval); 25.3 kg/m2 (23.8-27.1 kg/m2) vs. 23.1 kg/m2 (21.9-24.3 kg/m2), P = 0.03]. Evidence of insulin resistance was provided by their lower insulin sensitivity as measured by FSIVGTT [0.6 x 10-4/min/pmol/l (0.3-1.2 x 10-4/min/pmol/l) vs. 1.5 x 10-4/min/pmol/l (1.2-1.8 x 10-4/min/pmol/l), P = 0.01] and by homeostatic model assessment [72% (49-107%) vs. 153% (113-206%), P = 0.004]; and by their higher fasting triglycerides [1.0 mmol/l (0.7-1.5 mmol/l) vs. 0.7 mmol/l (0.6-0.8 mmol/l), P = 0.001]. Though there was no difference between groups in fasting NEFA levels, acute NEFA suppression was diminished in the post-GDM group (P = 0.01). Concomitant beta-cell dysfunction in the post-GDM women was revealed by their lower disposition index [0.05/min (0.02-0.10/min) vs. 0.11/min (0.09-0.14/min), P = 0.02] compared to controls. The differences in insulin sensitivity, but not those of beta-cell function, were partly, though not completely, attributable to differences in regional and total adiposity. CONCLUSIONS: European normoglycaemic women with previous GDM display both glucoregulatory and antilipolytic insulin resistance, reduced beta-cell function and dyslipidaemia. These metabolic abnormalities are likely to contribute to their increased risk of future type 2 diabetes.     

Comparison of pioglitazone and metformin efficacy using homeostasis model assessment.

AIMS: To compare clinical efficacy of two different insulin sensitizers, pioglitazone and metformin, and to reveal factors that influence the clinical efficacy. METHODS: Seventy-eight Japanese subjects with Type 2 diabetes mellitus poorly controlled with sulphonylureas [38 men and 40 women, aged 57 +/- 9 years, body mass index 25.2 +/- 1.4 kg/m2, and HbA1c 8.3 +/- 0.6% (means +/- SD)] were randomly assigned to groups for the addition of either pioglitazone or metformin and followed up for 4 months. A decrease in HbA1c levels was compared with baseline factors including homeostasis model assessment of insulin sensitivity (HOMA-R) and beta-cell function (HOMA-beta) with 71 subjects who completed the study. RESULTS: The overall decrease in HbA1c levels was similar for the pioglitazone (-1.2 +/- 0.2%) and metformin (-1.3 +/- 0.1%) groups. In the pioglitazone group, the decrease in HbA1c levels was negatively correlated with baseline HOMA-R (r=-0.698, P<0.0001) and HOMA-beta (r=-0.680, P<0.0001). In contrast, the decrease was positively correlated with baseline HOMA-beta (r=0.556, P=0.0004) in the metformin group. Multivariate analysis revealed that either HOMA-R or HOMA-beta was a main determinant of the decrease in HbA1c levels in the pioglitazone group. In the metformin group, baseline levels of fasting glucose were also included as an independent determinant in addition to HOMA-beta. The subjects with greater HOMA-R (> or =4.0) or HOMA-beta (> or =40%) displayed better response to pioglitazone than to metformin, and vice versa. CONCLUSIONS: In Type 2 diabetic subjects poorly controlled with sulphonylureas, addition of pioglitazone or metformin resulted in a comparable reduction in HbA1c levels. Subjects with greater insulin resistance or preserved beta-cell function displayed better response to pioglitazone, whereas subjects with reduced beta-cell function displayed better response to metformin.     

Rosiglitazone improves insulin sensitivity and glucose tolerance in subjects with impaired glucose tolerance

OBJECTIVE: This study was designed to evaluate the effects of rosiglitazone (ROS) on insulin sensitivity, beta-cell function, and glycaemic response to glucose challenge and meal in subjects with impaired glucose tolerance (IGT). METHODS: Thirty patients with IGT (ages between 30 and 75 years and BMI (body mass index) < or = 27 kg/m2) were randomly assigned to receive either placebo (n = 15) or ROS (4 mg/day) (n = 15). All participants underwent a 75-g oral glucose tolerance test (OGTT), meal test, and frequently sampled intravenous glucose tolerance test (FSIGT) before and after the 12-week treatment. RESULTS: After 12 weeks of ROS treatment, there were significant increases in total cholesterol (TC) (4.25 +/- 0.22 vs 4.80 +/- 0.17 mmol/l, P < 0.001), high-density lipoprotein cholesterol (HDL-C) (1.25 +/- 0.07 vs 1.43 +/- 0.06 mmol/l, P < 0.05), and low-density lipoprotein cholesterol (LDL-C) (2.70 +/- 0.15 vs 3.37 +/- 0.17 mmol/l, P < 0.05) without changes in triglyceride concentration, TC/HDL-C and LDL-C/HDL-C ratio. Although the acute insulin response (AIR) to intravenous glucose and disposition index (measured as the ability of pancreatic beta-cell compensation in the presence of insulin resistance) remained unchanged, the insulin sensitivity (SI) and glucose effectiveness (SG) were remarkably elevated (0.38 +/- 0.06 vs 0.54 +/- 0.09 x 10(-5) min(-1)/pmol, P < 0.05; 0.017 +/- 0.002 vs 0.021 +/- 0.001 min(-1), P < 0.05, respectively) in the ROS group. The glucose, insulin, and c-peptide areas under curve (AUC) in response to OGTT and the glucose and insulin AUC during meal were significantly ameliorated in the ROS group. Five out of 15 (33%) and two out of 15 (13%) subjects treated with ROS and placebo, respectively, reversed to normal response during OGTT (P < 0.05). CONCLUSION: Rosiglitazone treatment significantly improved insulin resistance and reduced postchallenge glucose and insulin concentrations in patients with impaired glucose tolerance without remarkable effects on beta-cell secretory function.     

Octreotide therapy of pediatric hypothalamic obesity: a double-blind,placebo-controlled trial

Hypothalamic obesity is a devastating complication in children surviving brain tumors and/or cranial irradiation. These subjects are thought to exhibit autonomic dysregulation of the beta-cell, with insulin hypersecretion in response to oral glucose tolerance testing (OGTT). We report the results of a randomized, double-blind, placebo-controlled trial of octreotide therapy for pediatric hypothalamic obesity. Eighteen subjects [weight, 100.6 +/- 5.6 kg; body mass index (BMI), 37.1 +/- 1.3 kg/m(2)] received octreotide (5-15 microg/kg x d s.c.) or placebo for 6 months. With octreotide, Delta weight (mean +/- SEM) was +1.6 +/- 0.6 vs. +9.1 +/- 1.7 kg for placebo (P < 0.001). Delta BMI was -0.2 +/- 0.2 vs. +2.2 +/- 0.5 kg/m(2), respectively (P < 0.001). OGTT documented Delta insulin response (peak - basal) of -417 +/- 304 pM after octreotide vs. +216 +/- 215 pM after placebo (P = 0.034). Improvement in physical activity by parent report was noted with octreotide, but not placebo (P = 0.03). For the octreotide group, changes in quality of life positively correlated with changes in insulin response (P = 0.041). Complications and adverse events were mild and self-limited. These data demonstrate the beneficial effects of octreotide in pediatric hypothalamic obesity. Octreotide suppressed insulin, and stabilized weight and BMI. Improved quality of life correlated with the degree of insulin suppression. Octreotide was safe and well tolerated.     

Initial therapy with the fixed-dose combination of sitagliptin and metformin results in greater improvement in glycaemic control compared with pioglitazone monotherapy in patients with type 2 diabetes

Aims: To evaluate the efficacy and safety of initial therapy with a fixed‐dose combination (FDC) of sitagliptin and metformin compared with pioglitazone in drug‐naÏve patients with type 2 diabetes. Methods: After a 2‐week single‐blind placebo run‐in period, patients with type 2 diabetes, HbA1c of 7.5–12% and not on antihyperglycaemic agent therapy were randomized in a double‐blind manner to initial treatment with a FDC of sitagliptin/metformin 50/500 mg twice daily (N = 261) or pioglitazone 30 mg per day (N = 256). Sitagliptin/metformin and pioglitazone were up‐titrated over 4 weeks to doses of 50/1000 mg twice daily and 45 mg per day, respectively. Both treatments were then continued for an additional 28 weeks. Results: From a mean baseline HbA1c of 8.9% in both groups, least squares (LS) mean changes in HbA1c at week 32 were ?1.9 and ?1.4% for sitagliptin/metformin and pioglitazone, respectively (between‐group difference = ?0.5%; p < 0.001). A greater proportion of patients had an HbA1c of <7% at week 32 with sitagliptin/metformin vs. pioglitazone (57% vs. 43%, p < 0.001). Compared with pioglitazone, sitagliptin/metformin treatment resulted in greater LS mean reductions in fasting plasma glucose (FPG) [?56.0 mg/dl (?3.11 mmol/l) vs. ?44.0 mg/dl (?2.45 mmol/l), p < 0.001] and in 2‐h post‐meal glucose [?102.2 mg/dl (?5.68 mmol/l) vs. ?82.0 mg/dl (?4.56 mmol/l), p < 0.001] at week 32. A substantially greater reduction in FPG [?40.5 mg/dl (?2.25 mmol/l) vs. ?13.0 mg/dl (?0.72 mmol/l), p < 0.001] was observed at week 1 with sitagliptin/metformin vs. pioglitazone. A greater reduction in the fasting proinsulin/insulin ratio and a greater increase in homeostasis model assessment of β‐cell function (HOMA‐β) were observed with sitagliptin/metformin than with pioglitazone, while greater decreases in fasting insulin and HOMA of insulin resistance (HOMA‐IR), and a greater increase in quantitative insulin sensitivity check index (QUICKI) were observed with pioglitazone than with sitagliptin/metformin. Both sitagliptin/metformin and pioglitazone were generally well tolerated. Sitagliptin/metformin led to weight loss (?1.4 kg), while pioglitazone led to weight gain (3.0 kg) (p < 0.001 for the between‐group difference). Higher incidences of diarrhoea (15.3% vs. 4.3%, p < 0.001), nausea (4.6% vs. 1.2%, p = 0.02) and vomiting (1.9% vs. 0.0%, p = 0.026), and a lower incidence of oedema (1.1% vs. 7.0%, p < 0.001), were observed with sitagliptin/metformin vs. pioglitazone. The between‐group difference in the incidence of hypoglycaemia did not reach statistical significance (8.4 and 4.3% with sitagliptin/metformin and pioglitazone, respectively; p = 0.055). Conclusion: Compared with pioglitazone, initial therapy with a FDC of sitagliptin and metformin led to significantly greater improvement in glycaemic control as well as a higher incidence of prespecified gastrointestinal adverse events, a lower incidence of oedema and weight loss vs. weight gain.     

Effects of insulin vs. glibenclamide in recently diagnosed patients with type 2 diabetes: a 4-year follow-up

Aim:  To compare effects of early insulin vs. glibenclamide treatment on beta-cell function, metabolic control and quality of life (QL) in recently diagnosed patients with type 2 diabetes.
Methods:  Forty-nine patients with type 2 diabetes diagnosed 0–2 years before inclusion were randomized to two daily injections of premixed 30% soluble and 70% NPH insulin or glibenclamide at six diabetic clinics in Sweden. C-peptide–glucagon tests were performed yearly after 3 days of withdrawal of treatment.
Results:  Thirty-four patients completed 4 years of study. Daily dose of insulin was increased from 20.4 ± 1.8 U at year 1 to 26.1 ± 2.9 U at year 4 (p = 0.005). Glibenclamide dosage increased from 2.7 ± 0.4 mg at year 1 to 4.5 ± 0.8 mg at year 4 (p = 0.02). Weight increased more in insulin than in glibenclamide treated (+4.4 ± 0.8 vs. +0.3 ± 1.0 kg, p < 0.005). Following short-term withdrawal of treatment, the C-peptide responses to glucagon were significantly higher in the insulin vs. glibenclamide group at years 1 (p < 0.01) and 2 (p < 0.02). HbA1c improved identical during the first year but thereafter deteriorated in the glibenclamide group (p < 0.005 for difference at year 4). Ratios of proinsulin to insulin were higher during treatment in glibenclamide- vs. insulin-treated patients after year 2. QL after 4 years as measured by the MOS 36-item Short-Form Health Survey (SF-36) form was not significantly altered.
Conclusions:  In a 4-year perspective, beta-cell function deteriorated in both groups. However, deterioration occurred faster in the glibenclamide group, indicating that alleviating demands on secretion by insulin treatment is beneficial.