Metabolic effects of metformin in patients with impaired glucose tolerance.

AIMS: To assess the effect of metformin on insulin sensitivity, glucose tolerance and components of the metabolic syndrome in patients with impaired glucose tolerance (IGT). METHODS: Forty first-degree relatives of patients with Type 2 diabetes fulfilling WHO criteria for IGT and participating in the Botnia study in Finland were randomized to treatment with either metformin 500 mg b.i.d. or placebo for 6 months. An oral glucose tolerance test (OGTT) and a euglycaemic hyperinsulinaemic clamp in combination with indirect calorimetry was performed at 0 and 6 months. The patients were followed after stopping treatment for another 6 months in an open trial and a repeat OGTT was performed at 12 months. RESULTS: Metformin treatment resulted in a 20% improvement in insulin-stimulated glucose metabolism (from 28.7 +/- 13 to 34.4 +/- 10.7 micromol/kg fat-free mass (FFM)/min) compared with placebo (P = 0.01), which was primarily due to an increase in glucose oxidation (from 16.6 +/- 3.6 to 19.1 +/- 4.4 micromol/kg FFM; P = 0.03) These changes were associated with a minimal improvement in glucose tolerance, which was maintained after 12 months. CONCLUSIONS: Metformin improves insulin sensitivity in subjects with IGT primarily by reversal of the glucose fatty acid cycle. Obviously large multicentre studies are needed to establish whether these effects are sufficient to prevent progression to manifest Type 2 diabetes and associated cardiovascular morbidity and mortality. Diabet. Med. 18, 578-583 (2001)     

Long-term beneficial effects of glipizide treatment on glucose tolerance in subjects with impaired glucose tolerance

AIMS: To assess the efficacy and long-term effects of glipizide treatment on glucose and insulin metabolism in individuals with impaired glucose tolerance (IGT). METHODS: Thirty-seven first-degree relatives of patients with type 2 diabetes fulfilling WHO criteria for IGT were randomized to treatment with either glipizide 2.5 mg once daily or matching placebo for 6 months. A 75 g, 2-h oral (OGTT) and 60 min intravenous glucose tolerance test (IVGTT) were performed at baseline and after 6 months. The subjects were followed up for another 12 months after discontinuation of treatment and a repeat OGTT was performed at 18 months. RESULTS: Thirty-three subjects fulfilled the study. Markers of insulin sensitivity - i.e. fasting insulin and HOMA(IR)-index - improved in the glipizide group (P = 0.04 and 0.02 respectively) as well as HDL cholesterol (P = 0.05) compared with placebo group after 6 months. At 18 months, both fasting and 2 h glucose concentrations were significantly lower in the glipizide group compared with the placebo group (P = 0.04 and 0.03 respectively). The prevalence of type 2 diabetes was 29.4% in the placebo group and 5.9% in the glipizide group at 18 months. This equals an 80% relative risk reduction in the active treatment group. CONCLUSIONS: Short-term treatment with glipizide improves glucose and insulin metabolism in subjects with IGT primarily by improving insulin sensitivity mediated by lowering glucose toxicity, thereby providing the beta cells rest. Larger studies are needed to establish whether these effects are sufficient to prevent progression to manifest type 2 diabetes and associated cardiovascular morbidity in subjects at increased risk of developing type 2 diabetes.     

Rosiglitazone improves insulin sensitivity, glucose tolerance and ambulatory blood pressure in subjects with impaired glucose tolerance.

AIMS: To determine the effects of rosiglitazone on insulin sensitivity, glucose tolerance and ambulatory blood pressure when administered to subjects with persistent impaired glucose tolerance (IGT). METHODS: Eighteen subjects with persistent IGT were randomized to receive rosiglitazone 4 mg twice daily or matching placebo for 12 weeks. Evaluation at baseline and at the end of treatment included measurement of whole body insulin sensitivity during a euglycaemic hyperinsulinaemic clamp and deriving an insulin sensitivity index. Changes in glucose and insulin concentration were determined after oral glucose tolerance test (OGTT) and mixed meal tolerance tests, and 24-h ambulatory blood pressure was monitored. RESULTS: Rosiglitazone significantly improved the insulin sensitivity index by 2.26 micro g/kg per min per pmol/l relative to placebo (P = 0.0003). Four of nine subjects receiving rosiglitazone reverted to normal glucose tolerance and 5/9 remained IGT, although four of these had improved 2-h glucose values. In the placebo group, 1/9 subjects progressed to Type 2 diabetes and 8/9 remained IGT. Following OGTT and meal tolerance test, glucose and insulin area under curve were reduced over 3 and 4 h, respectively. Compared with placebo, ambulatory blood pressure decreased significantly in the rosiglitazone group by 10 mmHg systolic (P = 0.0066) and 8 mmHg diastolic (P = 0.0126). CONCLUSIONS: Consistent with its effects in patients with Type 2 diabetes, rosiglitazone substantially improved whole body insulin sensitivity and the glycaemic and insulinaemic responses to an OGTT and meal tolerance test in subjects with persistent IGT. Furthermore, rosiglitazone reduced systolic and diastolic ambulatory blood pressure in these subjects.     

Pancreatic beta-cell function and insulin sensitivity in japanese subjects with impaired glucose tolerance and newly diagnosed type 2 diabetes mellitus

To clarify whether pancreatic beta-cell function and/or insulin resistance contributes to development of glucose intolerance in Japanese subjects, we investigated 551 subjects who underwent a 75-g oral glucose tolerance test (OGTT). Subjects were divided into 3 groups: normal glucose tolerance (NGT, n = 238), impaired glucose tolerance (IGT, n = 211), and newly diagnosed type 2 diabetes mellitus (n = 102). The diabetics were subdivided into 3 subgroups as follows: diabetes with normal fasting glucose (fasting plasma glucose [FPG] < 110 mg/dL), diabetes with impaired fasting glucose (FPG 110 to 125 mg/dL), and diabetes with diabetic fasting glucose (FPG >or= 126 mg/dL). Insulinogenic index as early-phase insulin secretion, homeostasis model assessment (HOMA-beta and HOMA-resistance), and 4 different formulas of insulin sensitivity index were assessed by plasma glucose and insulin concentrations obtained at fasting or during a 75-g OGTT. Both early-phase insulin secretion and insulin sensitivity were low even in the IGT stage compared with NGT. The transition from IGT to diabetes was accompanied by a progressive deterioration of insulin reserve as well as insulin resistance. During the further progression in diabetes, insulinogenic index decreased additionally, whereas declines in insulin sensitivity were relatively small. In conclusion, both impaired insulin secretion and insulin resistance may contribute to the underlying mechanisms of glucose intolerance in Japanese subjects.     

Glucose metabolism after normalization of markers of iron overload by venesection in subjects with hereditary hemochromatosis

Hereditary hemochromatosis (HH) is associated with abnormal glucose metabolism (AGM). We investigated the effect on glucose metabolism of normalization of the markers of iron overload by phlebotomy in subjects with HH. We prospectively studied 11 newly diagnosed subjects with HH and AGM using a standard 75-g oral glucose tolerance test. Basal quantitative insulin sensitivity check index (QUICKI) and stimulated oral glucose insulin sensitivity index (OGIS) insulin sensitivity was calculated from glucose and insulin data, whereas β-cell function was assessed using C-peptide concentration after adjusting for ambient insulin sensitivity. After normalization of ferritin and transferrin saturations by venesection for 12 (range, 8-16) months, subjects were studied again using the same methods. From 11 subjects with AGM at the time that HH was diagnosed, 7 had impaired glucose tolerance (IGT) and 4 had type 2 diabetes mellitus (T2DM). Normalization of the iron stores (ferritin and transferrin) improved the glucose tolerance status of 4 patients with IGT (to normal glucose tolerance), whereas 2 of those with IGT progressed to T2DM. In 5 patients, glucose tolerance status did not change (4 T2DM and 1 IGT). The area under the insulin and the C-peptide curve during the oral glucose tolerance test and the hepatic insulin extraction increased (P = .05), whereas no statistically significant changes occurred in insulin sensitivity. However, the disposition index, a measure of the ability of insulin release to compensate for insulin resistance, improved significantly (P = .02). Normalization of ferritin and transferrin saturation by venesection in subjects with HH and AGM led to improvements in some, but not all, measures of insulin secretion and action. Most patients with AGM had an improvement in glucose tolerance status, probably due to the augmented action of insulin in peripheral tissues.     

Pathophysiologic phenotypes of Japanese subjects with varying degrees of glucose tolerance: using the combination of C-peptide secretion rate and minimal model analysis.

We tried to characterize the clinical features associated with glucose metabolism in the development of diabetes. Study subjects were glucose-tolerant subjects without a family history of diabetes (normal glucose tolerance [NGT]1 group, n = 15) and with a first-degree diabetes relative (NGT2, n = 9), 12 subjects with impaired glucose tolerance (IGT), and 13 subjects with type 2 diabetes mellitus (DM). The first phase C-peptide secretion (CS1), insulin sensitivity (Si), and glucose effectiveness (Sg) were assessed by the combination of C-peptide 2-compartment model and minimal model analyses. Using these parameters, each group was characterized: CS1 was decreased in NGT2 and IGT compared with NGT1 and further decreased in DM; Si was not different among NGT1, NGT2, and IGT, whereas Si was decreased in DM; CS1 x Si value was decreased in NGT2 compared with NGT1 and decreased in IGT, DM, progressively; Sg was decreased in IGT and DM compared with NGT1 and NGT2. CS1 x Si and Sg values could segregate each group distinctively, although it had a large variety of phenotypes. CS1 x Si value and Sg are assumed to represent the contributions of insulin-dependent and independent mechanisms to glucose tolerance, respectively, and thus, both mechanisms should play an important role in the characterization of pathophysiologic phenotypes of the subjects with various degrees of glucose tolerance.     

Comparison of the effects of pioglitazone and metformin on insulin resistance and hormonal markers in patients with impaired glucose tolerance and early diabetes.

Impaired glucose tolerance (IGT) is associated with cardiovascular risk factors, but the effects of pioglitazone and metformin on IGT are not well described. We tested the hypothesis that each drug would exhibit antiatherogenic and anti-inflammatory effects in subjects with IGT and early diabetes. The study design was a prospective, randomized, open label, cross-over study. Blood tests, including a 75-g oral glucose tolerance test (OGTT), were performed at baseline and after each treatment. Pioglitazone 15 mg/day or metformin 500-750 mg/day was given for 3 months. Biochemical markers to assess insulin resistance as well as lipid, inflammatory, neurohumoral, and hemostatic factors were included. Twenty-five subjects (17 male, 8 female; age [mean+/-SD]: 61+/-9 years; 84% hypertensive) completed the protocol. Of 25 subjects, 14 were diagnosed as IGT and 11 as diabetes with 75-g OGTT. Pioglitazone significantly reduced fasting glucose (p<0.05), and homeostasis model assessment of insulin resistance (HOMA-IR) (p<0.05) and metformin (p<0.01) reduced cholesterol. Both drugs significantly reduced aldosterone (both p<0.05) and von Willebrand factor (vWF) (both p<0.05). Plasma adiponectin was increased only by pioglitazone (p<0.001). Neither drug affected BP levels. In conclusion, pioglitazone was superior to metformin for the improvement of insulin resistance and adiponectin, and both drugs were equally effective in reducing vWF and aldosterone in subjects with IGT and early diabetes. Early intervention with pioglitazone or metformin therapy may reduce the incidence of future cardiovascular disease in subjects with impaired glucose tolerance or early diabetes.     

Blood pressure increase with impaired glucose tolerance in young adult american blacks

Hypertension and non-insulin-dependent diabetes mellitus are more prevalent in blacks than whites. The convergence of these 2 disorders augments the expression and severity of cardiovascular disease. The purpose of this study was to determine whether alterations in glucose metabolism are related to an increase in blood pressure (BP). This study was conducted on 304 nondiabetic blacks (mean age=32 years). Measurements in all subjects included BP, anthropometric measures, oral glucose tolerance test, insulin clamp to measure insulin sensitivity, and plasma lipids. The sample was stratified according to plasma glucose on oral glucose tolerance test to normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and diabetes mellitus (DM). A 2-way ANOVA was performed to determine differences between the metabolic groups. With the use of American Diabetic Association criteria, 20.4% of the samples were classified as IGT and 5.9% were diabetic. A significant increase in BP existed from NGT to IGT to DM, which was stronger in women than men (systolic blood pressure in women: NGT=122, IGT=127, and DM=140 mm Hg, P<0.001) with a significant linear trend (P<0.001). With the use of body mass index as a covariate, the group difference in BP remained significant (P=0.006). Measures of insulin sensitivity demonstrated significant metabolic group differences (P<0.001) with a linear trend (P<0.001) of decreasing insulin sensitivity from NGT to DM. These results indicate that early alterations in glucose metabolism effects an upward shift in BP. The higher BP in IGT and DM may be due to vascular endothelial cell resistance to insulin action.     

In middle-aged siblings of patients with type 2 diabetes mellitus normal glucose tolerance is associated with insulin resistance and with increased insulin secretion. The SPIDER study

OBJECTIVES: To evaluate the frequency of impaired glucose tolerance (IGT) and of Type 2 diabetes mellitus (Type 2 DM) in siblings of patients with Type 2 DM, and to assess insulin release and insulin sensitivity in siblings with normal glucose tolerance (NGT), compared with NGT spouses of probands without family history of Type 2 DM. DESIGN AND METHODS: We evaluated 87 families including 103 Type 2 DM patients (87 probands), and we carried out an oral glucose tolerance test (OGTT) in 130 siblings and in 60 spouses. Among NGT subjects, 12 siblings and 16 spouses underwent a low-dose insulin-glucose infusion test (LDIGIT) to evaluate C-peptide release and insulin sensitivity. RESULTS: After the OGTT, 24 siblings were classified as having Type 2 DM, 31 as IGT, and only 14 spouses as IGT (P=0.0012 vs siblings). NGT siblings (n=75) showed higher insulin levels at 120 min than NGT spouses (n=46) at OGTT, in spite of identical blood glucose levels; at LDIGIT, NGT siblings secreted more C-peptide and showed a lower insulin sensitivity than NGT spouses. CONCLUSIONS: These data indicate that middle-aged siblings of probands with Type 2 DM have a high frequency of IGT and Type 2 DM, and that NGT siblings have increased insulin resistance and increased insulin secretion when compared with adequate controls.     

Effects of low intensity exercise therapy on early phase insulin secretion in overweight subjects with impaired glucose tolerance and type 2 diabetes mellitus

This study was designed to evaluate effects of exercise therapy on early phase insulin secretion in overweight subjects with impaired glucose tolerance (IGT) and type 2 diabetes mellitus (DM). The subjects consisted of overweight subjects with normal glucose tolerance (NGT, n=10), IGT (n=10) and DM (n=10) (age: 51.1+/-8.2, 56.3+/-8.8 and 58.5+/-6.2 years, respectively). All of these patients performed exercise therapy at lactate threshold intensity for 12 weeks. Before intervention, area under the glucose curve (AUC(PG)) was higher in DM, IGT and NGT groups, and area under the insulin curve (AUC(IRI)) and the early phase insulin secretion as calculated by insulinogenic index was higher in the NGT group than in either the IGT or DM groups (p<0.05). After exercise therapy, the insulin sensitivity, AUC(PG) and AUC(IRI) improved in three groups (p<0.05, respectively). The insulinogenic index increased in IGT and DM groups (p<0.05, respectively), but the changes in the insulinogenic index showed no significant differences between IGT and DM groups. These results suggest that the ss-cell function in subjects with IGT and DM could therefore improve after exercise therapy. Moreover, AUC(PG), AUC(IRI) and insulin sensitivity were also improved no relation to NGT, IGT and DM.     

A pilot study to examine the feasibility of insulin glargine in subjects with impaired fasting glucose, impaired glucose tolerance or new-onset type 2 diabetes.

OBJECTIVE: People with early type 2 diabetes and pre-diabetes (impaired glucose tolerance [IGT] and/or impaired fasting glucose [IFG]) are at risk of hyperglycaemia-related complications, including cardiovascular disease. Insulin, traditionally reserved as late treatment in type 2 diabetes, may also be a useful therapy in this population. We examined the short-term efficacy and tolerability of insulin glargine (glargine) in individuals with early or pre-type 2 diabetes. RESEARCH DESIGN AND METHODS: In this multicentre, double-blind, placebo-controlled, randomized, parallel group, 12-day study, subjects with IGT/IFG (n=9), newly diagnosed type 2 diabetes (n=9) or normal glucose tolerance (n=3) (confined to a clinical research unit taking a prescribed diet) were randomized to once-daily glargine (n=16) or placebo (saline; n=5) at bedtime. Dose was titrated to achieve target fasting blood glucose (FBG) 80-95 mg/dL. RESULTS: Over the treatment period, mean FBG decreased in glargine-treated subjects (from 100.0+/-18.8 to 85.6+/-18.4 mg/dL), but was unchanged in placebo-treated subjects (from 112.5+/-10.6 to 111.3+/-17.5 mg/dL). Mean eight-point blood glucose value decreased by 9.7 mg/dL in the glargine group, but increased by 8.1 mg/dL in the placebo group. Mean post-exercise blood glucose was similar before and after glargine treatment, but increased after placebo treatment. Five subjects receiving glargine experienced 16 mild symptomatic hypoglycaemia episodes; however, no hypoglycaemia occurred during exercise. Mean body weight decreased in both the glargine (-0.44 kg) and placebo (-0.25 kg) groups, in line with dietary restrictions. CONCLUSIONS: The results of this pilot study suggest that glargine can be used by people with IFG, IGT or new-onset type 2 diabetes for management of hyperglycaemia with low risk of hypoglycaemia. However titration of insulin in people on dietary restrictions should be more cautious as they may be more prone to hypoglycaemia. Further studies are warranted to determine the clinical benefits of this approach.     

Metabolic syndrome does not increase the risk of conversion of impaired glucose tolerance to diabetes in Asian Indians--Result of Indian diabetes prevention programme

AIMS: In this study, we assessed for the prevalence of metabolic syndrome (MetS) in the cohort of subjects with impaired glucose tolerance (IGT) in the Indian Diabetes Prevention Programme and studied whether the syndrome enhanced the conversion to diabetes. METHODS: Effectiveness of lifestyle modification (LSM), metformin (Met) and LSM plus Met was tested in a randomised, controlled primary prevention study in subjects with IGT n=502 (M:W 397:105) at a median follow up of 30 months. Baseline prevalence of MetS was calculated using the WHO criteria. Insulin resistance (IR) was calculated using homeostasis model assessment (HOMA) method. RESULTS: MetS was present in 233 subjects (46.4%; 95% CI 41.9-50.9) in the total group, in men (n=168; 42.3%; 95% CI 37.4-47.3) and in women (n=65; 61.9%; 95% CI 51.9-71.2) (men versus women chi(2)=12.8, p=0.0005). Insulin resistance (HOMA-IR>or=4.1) was present in 69.1% with no gender difference. IR increased proportionately with increasing number of abnormalities, in IGT (39.8%), IGT plus one abnormality (56.5%) and IGT plus any two or more abnormalities (69.1%) (Mantel Haenszel chi(2)=22.8, p<0.0001). Incidence of diabetes was similar in subjects with (40.3%) (n=94/233) or without (40.1%) (n=108/269) MetS (p=0.97). Cox's regression analysis confirmed that MetS did not enhance the conversion rate of IGT to diabetes both in the control (HR=0.88, 95% CI 0.53-1.47, p=0.63) and in the total group (HR=1.02, 95% CI 0.78-1.35, p=0.88), after correcting for effects of intervention. CONCLUSION: Prevalence of MetS is high in Asian Indian IGT subjects, especially in women. However, it did not influence the rate of conversion of IGT to diabetes.     

二甲双胍和食物纤维在糖耐量低减人群向2型糖尿病发展中的干预作用

目的　观察二甲双胍和食物纤维预防糖耐量低减 (IGT)人群进展为 2型糖尿病 (DM)的作用。　方法　以口服 75 g葡萄糖耐量试验 (OGTT)确诊 (WHO标准 )的 IGT2 93例中男 2 16例 ,女 77例。入选者年龄 35岁以上 ,体重指数 (BMI)在 19kg/ m2以上。随机分为对照组 72例 ,教育组 5 7例 ,食物纤维组 84例 ,二甲双胍组 80例。对照组进行一般的健康教育 ;教育组进行饮食指导 ,每半年1次 ;食物纤维组除健康教育外 ,每日口服食物纤维 12 g;二甲双胍组每日口服二甲双胍 0 .75 g,分 3次餐后口服。对四组参试者每半年作 1次 OGTT,同时测身高、体重、BMI、12 h尿白蛋白 ,复查日当天不服干预药物或食物纤维。共观察 3年。若 2次 OGTT或最后 1次复查结果为 DM,则判断为已发展为 DM。　结果　 2 93例 IGT在观察中有 2 3例 (7.8% )退出。空腹血糖 (FBS)和服糖后 1h血糖 (1hPBS)在对照组、教育组和食物纤维组均较治疗前略有升高 ,但在二甲双胍治疗组均有下降。四组间FBS比较 F=8.118,P<0 .0 1,四组间 1h PBS比较 F=3.6 97,P=0 .0 12。观察期末对照组 16例 (2 5 .0 % )、教育组 11例 (2 1.6 % )、食物纤维组 13例 (16 .3% )、二甲双胍组 7例 (9.3% )转化为 DM,二甲双胍组在治疗后 DM转化率明显低于对照组 (χ2 =6 .318,P<0 .0     

Beneficial metabolic effects of chronic glipizide in obese African Americans with impaired glucose tolerance: implications for primary prevention of type 2 diabetes

We examined the long-term metabolic effects of glipizide gastrointestinal therapeutic system (GITS), a potent sulfonylurea (SU), in impaired glucose-tolerant (IGT), first-degree relatives of African American patients with type 2 diabetes. To this end, we assessed glucose homeostasis, beta-cell function, insulin sensitivity (Si), and glucose effectiveness (Sg) in patients with IGT before and at yearly intervals for 24 months of GITS or an identical placebo in a randomized, double-blind manner. Eighteen IGT patients were randomized to receive either glipizide GITS (GITS, 5 mg/d, n = 9; mean age, 43.3 +/- 8.7 years; mean body mass index [BMI], 32.9 +/- 6.3 kg/m(2)) or identical placebo (PLAC, n = 9; mean age, 41.5 +/- 5.7 years; mean BMI, 39 +/- 4.2 kg/m(2)) for 24 months. Each of the subjects underwent oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIGT) at baseline and yearly intervals for 2 years. Si and Sg were determined by Bergman's minimal model method. The ability of beta cell to compensate for peripheral insulin resistance was calculated as the disposition index (DI). Chronic administration of glipizide GITS attenuated serum glucose responses to oral glucose challenge at 12 and 24 months when compared to baseline (0 months). In contrast, serum glucose levels at fasting and during OGTT tended to increase in the IGT/PLAC group at 12 and 24 months when compared to baseline. Serum insulin (P <.05 to 0.01) and serum C-peptide levels progressively increased in the GITS group at 12 and 24 months versus 0 months. In contrast, serum insulin and C-peptide responses remained unchanged in the IGT/PLAC group. During FSIGT, chronic GITS was associated with significant improvement in the blunted acute first insulin release in the IGT patients at 12 and 24 months. These parameters remained blunted in the IGT/PLAC group. We found that Si increased in the IGT/GITS group at 12 months (P <.01) and 24 months(P <.05) versus baseline, but deteriorated in the IGT/PLAC group. Similarly, the DIs significantly (P <.01) increased following GITS therapy at 12 and 24 months when compared to baseline. In contrast, DI did not change from baseline values in the IGT/PLAC group throughout the study period. Chronic GITS partially restored the ability of beta cells to compensate for peripheral insulin resistance (as assessed by DIs). GITS was well tolerated without any symptoms suggestive of either hypoglycemia or significant weight gain. In summary, long-term chronic glipizide GITS administration improved glucose homeostasis by increasing beta-cell responsiveness to glucose, improving Si, as well as significantly improved DI, but not Sg, in high-risk, obese African Americans with IGT. Our study demonstrated that GITS appears to prime beta cells to intravenous glucose stimulation resulting in restoration of physiologic acute first- and second-phase insulin secretion in African Americans with IGT. We conclude that GITS might be considered as a useful agent in the primary prevention of type 2 diabetes in high-risk, obese African American patients with IGT.     

Relative conributions of beta-cell function and tissue insulin sensitivity to fasting and postglucose-load glycemia

We performed hyperglycemic clamps in 283 nondiabetic Caucasians and, with multiple linear regression, determined the contribution of beta-cell function and tissue insulin sensitivity to variations in glycemia and insulinemia during oral glucose tolerance tests (OGTTs). Impaired glucose tolerance (IGT) subjects had reduced insulin sensitivity (P < .02) and beta-cell function (P < .0001). Normal glucose tolerance (NGT) subjects with first-degree type 2 diabetic relatives had reduced first and second phase insulin secretion (both, P < .05), but normal insulin sensitivity (P = .37). Beta-Cell function and insulin sensitivity accounted for one fourth of the variability in glucose tolerance. Fasting plasma glucose in subjects with NGT (n = 185) was a function of both phases of insulin secretion and of insulin sensitivity (all, P < .05), whereas, in IGT subjects (n = 98), it was a function of first phase insulin secretion and insulin sensitivity (P < .01). Two-hour glycemia was a function of second phase secretion and insulin sensitivity (P < .01). Fasting and 2-hour plasma insulin levels were determined by insulin sensitivity (and glycemia) in NGT subjects (P < .001), but by second phase secretion in IGT (P < .001). We conclude that beta-cell function is reduced in subjects with IGT; glycemia and insulinemia are not regulated by the same mechanisms in IGT and NGT; insulin sensitivity does not contribute to insulinemia in IGT; family history of diabetes influences beta-cell function, but not insulin sensitivity in Caucasians.     

Metformin treatment leads to an increase in basal, but not insulin-stimulated, glucose disposal in obese patients with impaired glucose tolerance.

AIMS: This study was initiated to test the hypothesis that metformin treatment leads to enhanced glucose disposal at ambient insulin concentrations. METHODS: Nineteen obese patients with impaired glucose tolerance (IGT) were treated with either metformin or placebo in a randomized, double-blind, placebo-controlled, cross-over study. Insulin secretion and insulin resistance were quantified using the homeostasis model assessment (HOMA) and insulin-stimulated glucose disposal were measured by determining the steady-state plasma glucose (SSPG). RESULTS: The average benefit of metformin was 0.6 mmol/l for glucose (95% confidence interval (CI) 0.2-0.9 P = 0.002), 2.8 pmol/l for insulin (95% CI 0.2-5.4, P = 0.019). Insulin resistance, as quantified by HOMA, was improved by 1.1 (95% CI 0.2-2.0, P = 0.004), without any change in insulin secretion. Basal and insulin-stimulated glucose oxidation were comparable in the placebo and metformin-treated groups at the end of each treatment period, as was the SSPG concentration. However, both systolic and diastolic blood pressures fell significantly following metformin administration as compared to treatment with placebo. CONCLUSIONS: These results indicate that metformin administration to patients with IGT is associated with enhanced glucose disposal at baseline insulin concentrations and a fall in blood pressure. In contrast, neither glucose oxidation nor glucose disposal were increased in association with metformin treatment under conditions of physiological hyperinsulinaemia.     

Prevention of diabetes in women with a history of gestational diabetes: effects of metformin and lifestyle interventions

CONTEXT: A past history of gestational diabetes mellitus (GDM) confers a very high risk of postpartum development of diabetes, particularly type 2 diabetes. OBJECTIVE: The Diabetes Prevention Program (DPP) sought to identify individuals with impaired glucose tolerance (IGT) and intervene in an effort to prevent or delay their progression to diabetes. This analysis examined the differences between women enrolled in DPP with and without a reported history of GDM. DESIGN: The DPP was a randomized, controlled clinical trial. SETTING: The study was a multicenter, National Institutes of Health-sponsored trial carried out at 27 centers including academic and Indian Health Services sites. Patients: A total of 2190 women were randomized into the DPP and provided information for past history of GDM. This analysis addressed the differences between those 350 women providing a past history of GDM and those 1416 women with a previous live birth but no history of GDM. INTERVENTIONS: Subjects were randomized to either standard lifestyle and placebo or metformin therapy or to an intensive lifestyle intervention. MAIN OUTCOMES: The primary outcome was the time to development of diabetes ascertained by semiannual fasting plasma glucose and annual oral glucose tolerance testing. Assessments of insulin secretion and insulin sensitivity were also performed. RESULTS: Whereas entering the study with similar glucose levels, women with a history of GDM randomized to placebo had a crude incidence rate of diabetes 71% higher than that of women without such a history. Among women reporting a history of GDM, both intensive lifestyle and metformin therapy reduced the incidence of diabetes by approximately 50% compared with the placebo group, whereas this reduction was 49 and 14%, respectively in parous women without GDM. These data suggest that metformin may be more effective in women with a GDM history as compared with those without. CONCLUSIONS: Progression to diabetes is more common in women with a history of GDM compared with those without GDM history despite equivalent degrees of IGT at baseline. Both intensive lifestyle and metformin are highly effective in delaying or preventing diabetes in women with IGT and a history of GDM.     

Impaired beta-cell function in the presence of reduced insulin sensitivity determines glucose tolerance status in acromegalic patients

OBJECTIVE: Abnormal glucose tolerance is often demonstrated in acromegalic patients. Although insulin resistance is a common feature of acromegaly, it remains unclear whether the extent of insulin resistance per se determines the abnormal glucose tolerance. In order to elucidate this issue, we investigated insulin sensitivity and beta-cell function in acromegalic patients. DESIGN: Twenty-four acromegalic patients were studied in comparison with 24 healthy control subjects. To estimate insulin sensitivity and beta-cell function, we used correct homeostasis model assessment (HOMA) model, a computer-solved model. We also investigated the effects of surgical success on both parameters. RESULTS: HOMA insulin sensitivity (HOMA-%S) in the acromegalic patients was 74 +/- 51 (SD)%, significantly lower than that in 24 healthy controls (144 +/- 49%). HOMA-%S in 12 normal glucose tolerance (NGT) patients was 54 +/- 31%, not significantly different from that in impaired glucose tolerance (IGT; n = 11) or diabetes mellitus (DM; n = 1) patients (93 +/- 60%). By contrast, HOMA beta-cell function (HOMA-%beta) in the NGT acromegalic patients was 163 +/- 67%, significantly higher than the IGT/DM acromegalic patients (89 +/- 34%) and the healthy controls (72 +/- 19%). In 11 patients who achieved complete normalization of GH excess after surgery, HOMA-%S significantly increased to control ranges (from 76 +/- 26 to 159 +/- 61%) within 2 weeks after the surgical success. CONCLUSIONS: We conclude that insulin sensitivity is reduced to a similar extent in acromegalic patients with normal glucose tolerance and those with impaired glucose tolerance or diabetes. Compensatory hyperfunction of beta-cells appears to counterbalance the reduced insulin sensitivity in the acromegalic patients with normal glucose tolerance but not in those with impaired glucose tolerance or diabetes.     

Thiazolidinediones increase hepatic insulin extraction in African Americans with impaired glucose tolerance and type 2 diabetes mellitus. A pilot study of rosiglitazone

Peripheral insulin levels are determined by beta-cell secretion, insulin sensitivity, and hepatic insulin extraction (HIE). We have previously shown that whereas sulfonylureas reduce insulin extraction, metformin enhances HIE. However, the effects of thiazolidinediones (TZDs) on HIE remain uncertain. Thus, we investigated the potential contribution of hepatic insulin clearance to peripheral insulin levels during rosiglitazone therapy in African Americans with impaired glucose tolerance (IGT) and type 2 diabetes mellitus (DM). The study was composed of 12 first-degree relatives with IGT and 17 patients with newly diagnosed type 2 DM. Nineteen healthy relatives with normal glucose tolerance served as controls. Serum glucose, insulin, and C-peptide, and HIE (C-peptide-insulin molar ratios) were measured at t = 0 and 120 minutes during oral glucose tolerance test (OGTT) in all the subjects. The OGTT was performed before and after 3 months of rosiglitazone therapy (4 mg/d x 4 weeks and >8 mg/d x 8 weeks) in patients with IGT and type 2 DM. Insulin resistance index and beta-cell function were calculated in each subject using homeostasis model assessment (HOMA). Rosiglitazone therapy improved but did not normalize the overall glycemic control in the IGT and type 2 DM groups. After rosiglitazone therapy, the mean serum insulin and C-peptide levels at fasting remained unchanged. However, the 2-hour serum glucose and insulin were lower, whereas serum C-peptide was unchanged during 3 months of rosiglitazone treatment. Mean insulin resistance index of HOMA was reduced by 30% (4.12 +/- 1.95 vs 6.33 +/- 3.54, P < .05) in the type 2 DM group and by 21% (3.78 +/- 2.45 vs 4.81 +/- 3.49, P = NS) in the IGT group. Mean HIE values were significantly lower (70%) in the type 2 DM and IGT groups when compared with the normal glucose tolerance group. At 3 months, basal HIE was not significantly changed by rosiglitazone therapy in IGT and type 2 DM groups when compared with the baseline (0 month). However, rosiglitazone therapy was associated with increased HIE at 2 hours during OGTT by 40% and 30% in the IGT and type 2 DM groups, respectively, from the baseline (0 month) values. Furthermore, HIE inversely correlated with the insulin resistance index of HOMA (r = -.46, P < .05). We conclude that rosiglitazone therapy improved overall glucose tolerance and enhanced insulin sensitivity in patients with IGT and type 2 DM. Although basal HIE remained unchanged, rosiglitazone therapy increased postglucose challenge HIE in African Americans with IGT and type 2 DM. We speculate that TZDs increase insulin clearance or HIE after oral glucose challenge. This study suggests that in addition to insulin sensitization, rosiglitazone may be involved in insulin metabolism. The significance of the increased insulin clearance by TZD therapy remains uncertain and deserves further investigation in patients with insulin resistance and glucose intolerance.     

Hypolipidemic effects of metformin in hyperprebetalipoproteinemia.

Metformin's hypolipidemic effects (2.55 g/day for 3 months) have been studied in 19 subjects with Fredrickson's Type IV hyperprebetalipoproteinemia. The majority of patients were above ideal body weight (relative body weight = 118 +/- 2.7 %). Eleven of the subjects presented chemical diabetes, 5 fasting hyperglycemia, and 3 normal glucose tolerance. After treatment with metformin, body weight showed a slight, but significant reduction (--2.4 +/- 0.3 kg). Glucose tolerence was not substantially altered while basal glucose was significantly reduced in the 5 subjects with fasting hyperglycemia. Basal plasma insulin was significantly reduced in all the patients following metformin treatment. Insulin response to OGTT was slightly reduced in the subjects with fasting hyperglycemia. Independent of the patients' glucose tolerance, metformin treatment induced a marked decrease in plasma triglycerides (-- 40 %) and a reduction in plasma cholesterol (-- 12 %). No correlation was found between triglyceride and cholesterol reduction and body weight, glucose, and plasma insulin variations. Like phenformin, metformin acts not only on glucose metabolism and insulin secretion but on lipid metabolism as well.