Economic evaluation of therapeutic interventions to prevent Type 2 diabetes in Canada.

AIMS: To compare the health and economic outcomes of using acarbose, an intensive lifestyle modification programme, metformin or no intervention to prevent progression to diabetes in Canadian individuals with impaired glucose tolerance (IGT). METHODS: A model was developed to simulate the course of individuals with IGT under each treatment strategy. Patients remain in the IGT state or transition from IGT to diabetes, to normal glucose tolerance (NGT) or to death. Effectiveness and resource use data were derived from published intervention trials. A comprehensive health-care payer perspective incorporating all major direct costs, reported in 2000 Canadian dollars, was adopted. RESULTS: Over a decade, 70 of the 1000 untreated patients are expected to die and 542 develop diabetes. Intensive lifestyle modification is estimated to prevent 117 cases of diabetes, while metformin would prevent 52 and acarbose 74 cases. The proportion of those who return to NGT also increases with any treatment. While lifestyle modification is more effective, it can increase overall costs depending on how it is implemented, whereas acarbose and metformin reduce costs by nearly $1000 per patient. Lifestyle modification was cost effective, varying from CAD $10 000/LYG vs. acarbose. Acarbose costs somewhat more than metformin, but is more effective: CAD $1798/LYG. CONCLUSION: The results of this model suggest that the treatment of IGT in Canada is a cost-effective way to prevent diabetes and may generate savings. While pharmacological treatments tended to be less costly, intensive lifestyle modification, if maintained, led to the greatest health benefits at reasonable incremental costs.     

Metformin for diabetes prevention: insights gained from the Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study

The largest and longest clinical trial of metformin for the prevention of diabetes is the Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study (DPP/DPPOS). In this review, we summarise data from the DPP/DPPOS, focusing on metformin for diabetes prevention, as well as its long-term glycaemic and cardiometabolic effects and safety in people at high-risk of developing diabetes. The DPP (1996–2001) was a RCT of 3234 adults who, at baseline, were at high-risk of developing diabetes. Participants were assigned to masked placebo (n = 1082) or metformin (n = 1073) 850 mg twice daily, or intensive lifestyle intervention (n = 1079). The masked metformin/placebo intervention phase ended approximately 1 year ahead of schedule because of demonstrated efficacy. Primary outcome was reported at 2.8 years. At the end of the DPP, all participants were offered lifestyle education and 88% (n = 2776) of the surviving DPP cohort continued follow-up in the DPPOS. Participants originally assigned to metformin continued to receive metformin, unmasked. The DPP/DPPOS cohort has now been followed for over 15 years with prospective assessment of glycaemic, cardiometabolic, health economic and safety outcomes. After an average follow-up of 2.8 years, metformin reduced the incidence of diabetes by 31% compared with placebo, with a greater effect in those who were more obese, had a higher fasting glucose or a history of gestational diabetes. The DPPOS addressed the longer-term effects of metformin, showing a risk reduction of 18% over 10 and 15 years post-randomisation. Metformin treatment for diabetes prevention was estimated to be cost-saving. At 15 years, lack of progression to diabetes was associated with a 28% lower risk of microvascular complications across treatment arms, a reduction that was no different among treatment groups. Recent findings suggest metformin may reduce atherosclerosis development in men. Originally used for the treatment of type 2 diabetes, metformin, now proven to prevent or delay diabetes, may serve as an important tool in battling the growing diabetes epidemic. Long-term follow-up, currently underway in the DPP/DPPOS, is now evaluating metformin’s potential role, when started early in the spectrum of dysglycaemia, on later-stage comorbidities, including cardiovascular disease and cancer. Trial registration: ClinicalTrials.gov NCT00038727 and NCT00004992.     

Effect of metformin on patients with impaired glucose tolerance.

AIMS: To evaluate the effect of metformin on glucose metabolism, insulin sensitivity and rate of conversion diabetes in people with impaired glucose tolerance (IGT). METHODS: Seventy subjects with IGT were randomized under double-blind conditions to receive either placebo (n = 37) or metformin (n = 33) at a dosage of 250 mg three times daily for a duration of 12 months. Glycaemic control, plasma insulin and other biochemical indexes were assessed before and after 3, 6 and 12 months. RESULT: At 12 months the conversion rate to diabetes was 16.2% in the placebo group compared to 3.0% for the metformin group (P = 0.011). Of subjects treated with metformin for 12 months, 84.9% became normoglycaemic compared to 51.4% of those receiving the placebo. Significant improvements in fasting glucose, glucose tolerance and insulin sensitivity were found at 12 months and at intermediate clinic assessments. CONCLUSIONS: Metformin can improve glucose metabolism in IGT patients and may be a treatment option in their management of IGT subjects.     

The prevention of type 2 diabetes: what is the evidence?

The prevalence of diabetes is increasing in epidemic proportion worldwide. Because of the morbidity and mortality associated with the disease, it is becoming a major burden for the health care system. With a better understanding of the pathogenesis of type 2 diabetes, the concept of primary prevention has emerged. A number of studies demonstrated that both lifestyle modification program and pharmacological interventions in subjects with impaired glucose tolerance (IGT) can prevent or delay the progression to diabetes. The Diabetes Prevention Study (DPS) and the Diabetes Prevention Program (DPP) convincingly showed that an intensive lifestyle modification program is highly effective in decreasing the risk of diabetes in a high risk population (risk reduction of 58%). Four other smaller studies have made similar observations. The DPP study showed that metformin can reduced the risk of diabetes by 31% in subjects with IGT. The STOP-NIDDM trial confirmed the efficacy of acarbose in decreasing the risk of diabetes by 36% in similar high risk population. The TRIPOD study showed that troglitazone can reduce the incidence of diabetes by 55% in Hispanic women with a history of gestational diabetes. And more recently, the XENDOS study showed that in very obese population on intensive lifestyle modification program, xenical treatment was associated with a 37% reduced incidence of diabetes compared to placebo. Three studies suggested that bariatric surgery in morbidly obese subjects with or without IGT can reduce the incidence of diabetes to near zero. Eight of 10 studies showed that treatment with inhibitors of the renin-angiotensin aldosterone system in high risk population for cardiovascular disease (CVD) were associated with a significant reduction in the subsequent development of diabetes as a secondary outcome. The WOSCOPS study and the HERS study examined the effect of pravastatin and estrogen/progestin respectively on cardiovascular events and observed that these pharmacological interventions were associated with a 30% and 35% reduction in the incidence of diabetes as secondary outcome. There are 3 major trials currently in progress examining the effect of rosiglitazone/ramipril (the DREAM study), nateglinide/valsartan (the NAVIGATOR study) and pioglitazone (the ACT NOW study) on the development of diabetes in IGT subjects as a primary outcome. We also have 3 studies studying the prevention of diabetes as secondary outcomes: the ONTARGET-TRANSCEND study examining telmisartan with or without ramipril, and the ORIGIN study testing glargine insulin/omega 3. The evidence is overwelming-diabetes can be prevented or delayed in high risk population through lifestyle modification or pharmacological interventions. This new information now has to be translated in the real world into well defined strategies for screening and treating high risk population. Prevention of the disease is our only chance to alleviate the ever growing burden of diabetes mellitus in the world.     

Taurine in women with a history of gestational diabetes

Taurine is the most abundant amino acid in the human body and seems to play an important role in increasing glucose-mediated insulin secretion, as well as in programming beta-cell maturation during the prenatal life in utero. To test the hypothesis that plasma taurine is related to glucose tolerance, insulin sensitivity and insulin secretion in subjects with history of beta-cell dysfunction such as women with history of gestational diabetes (GDM), we studied 72 non-diabetic women with history of GDM (n=43), impaired glucose tolerance (IGT; n=7), and normal glucose tolerance (NGT; n=22) as previously classified by a 100g-3h-OGTT performed between the 24th and the 28th gestational week. Insulin sensitivity (ISIogtt, calculated through Matsuda-DeFronzo index) and a proxy for insulin secretion (basal plasma C-peptide/fasting plasma glucose; CP/glucose) were measured during and after pregnancy. Plasma taurine was measured after a median period of 6 years (2-11 years) from index pregnancy, when glucose tolerance was retested by a 75 g-2h-OGTT. Plasma taurine was significantly lower in women who had experienced GDM and was unrelated to ISIogtt. Moreover, plasma taurine was inversely related to previous gestational area-under-curve of glucose and directly related to post-gestational CP/glucose, as well to CP/glucose measured during pregnancy (p<0.05 for both). The relative risk of altered glucose metabolism during previous pregnancies (IGT+GDM) was higher as plasma taurine decreased, even after adjusting for age, time-lag from pregnancy, body mass index and family history of diabetes (OR: 0.980; CI 95%: 0.963-0.999, p=0.003). In conclusion plasma taurine seems to be a fair marker of altered glucose metabolism during past pregnancies in women with antecedent GDM and appears to be inversely related to the previous as well as to the actual insulin secretion in these subjects.     

Lifestyle change after gestational diabetes

AIMS: Gestational diabetes mellitus (GDM) is a predictor for overt diabetes later in life. Thus, during pregnancy GDM patients are instructed to change lifestyle after pregnancy. The purpose of the present study was to assess the lifestyle changes made by these women. METHODS: The study was a mailed survey with structured questions on diet, weight loss, exercise and worry about developing diabetes. One hundred and twenty-one (79%) women agreed to participate 11-42 months after pregnancy. Weight gain or loss was defined as a change >/=5 kg. RESULTS: Among women with body mass index (BMI) >25 kg/m(2), only 18% lost weight and more than 33% gained weight. In total, more women gained than lost weight (P<0.05). Prior to pregnancy, 90 (74%) women followed a diet rich in fat. In contrast, only 57 women (47%) did so at follow-up (P<0.001). Further analysis showed that among these 57 women, only 7% had lost weight since pregnancy compared to 25% of women eating healthy (P<0.05). Eighty-six percent were worried to some extent about the risk for subsequent diabetes. The exercise level did not change after pregnancy. Nineteen women (16%) had overt diabetes mellitus and 22 (18%) impaired glucose tolerance (IGT) at follow-up. CONCLUSIONS: Although the majority of the women were concerned about developing overt diabetes, only a few had changed their lifestyle and/or lost weight after pregnancy. This indicates that lifestyle instruction needs to be much more frequent and intensive in the period after pregnancy in these women.     

Prevention of the manifestation of diabetes in the elderly in the presymptomatic stage

Diabetes Mellitus is thought as the presymptomatic stage to cause various vascular diseases. From the point of view that diabetes is already a disease, this paper discusses the prevention of the manifestation of diabetes in the elderly. STOP-NIDDM study demonstrated that acarbose, an alpha-glucosidase inhibitor, reduced the onset of diabetes in impaired glucose tolerance (IGT) subjects by 24%. On the other hand, the Diabetes Prevention Program (DPP) study for IGT subjects revealed that intensive life style intervention prevented diabetes most powerfully by 58% and metformin treatment also reduced by 31%. Furthermore, HOPE, LIFE, and SCOPE studies against hypertension showed that ACI or ARB reduced diabetes by 20-32%, and the WOSCOT study that pravastatin, a HMG-CoA reductase inhibitor, reduced diabetes by 30%. These accumulated results suggest that the most suitable strategy to prevent diabetes in the elderly is intensive life style intervention, and in cases incapable of exercise and diet therapy, acarbose or metformin are recommended for IGT. When associated with hypertension and/or hyperlipidemia, the subjects have to receive ACI or ARB and statins to prevent diabetes.     

Effects of 1-year treatment with metformin on metabolic and cardiovascular risk factors in non-diabetic upper-body obese subjects with mild glucose anomalies: A post-hoc analysis of the BIGPRO1 trial

AimMetformin has recently been considered as a possible pharmacological complement to lifestyle measures for preventing type 2 diabetes in high-risk subjects. However, little is known of its effects on metabolic and cardiovascular risk factors in non-diabetic subjects.MethodsThe BIGPRO1 trial was a 1-year multicentre, randomized, double-blind, controlled clinical trial of metformin versus placebo, carried out in the early 1990s, in 457 upper-body obese non-diabetic subjects with no cardiovascular diseases or contraindications to metformin. We compared the changes (1-year minus baseline) in cardiometabolic risk factors between treatment groups in two subsets of trial subjects: those with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) (n = 101); and those who fulfilled the inclusion criteria of the Diabetes Prevention Program (DPP) (n = 51). Comparisons were adjusted for age and gender.ResultsIn the IFG/IGT subset, significant differences in 1-year changes were observed for systolic blood pressure, which decreased markedly more in the metformin group than in the placebo group (P < 0.003), and for fasting plasma glucose, and total and LDL cholesterol, which decreased slightly in the metformin group, but increased in the placebo group (P < 0.04). Similar results were observed in the subset with DPP criteria. Also, there were no significant differences in 1-year changes for weight, waist-to-hip ratio, 2-h post-load blood glucose, fasting and 2-h post-load insulin, HDL cholesterol, triglycerides and fibrinolytic markers between the two treatment groups.ConclusionIn subjects at high risk of developing diabetes, the use of metformin showed beneficial and no untoward effects on cardiometabolic risk factors.     

妊娠糖尿病患者分娩后胰岛素抵抗和胰岛B细胞功能研究

目的研究妊娠糖尿病患者分娩后胰岛素抵抗、胰岛B细胞功能状态,探讨其在分娩后糖耐量异常发生发展中的作用。方法对2008-09-01—2009-07-10中国医科大学附属盛京医院内分泌科根据口服糖耐量试验筛选出8例有妊娠糖尿病史的妇女妊娠后糖耐量正常(NGT)者,另选取8例有妊娠糖尿病病史的妇女妊娠后糖耐量异常(IGT)者与之匹配。应用高胰岛素-正葡萄糖钳夹技术和静脉葡萄糖耐量试验评估胰岛素抵抗和胰岛B细胞功能。结果 NGT组和IGT组体重指数(BMI)及三酰甘油比较差异无统计学意义(P<0.05);IGT组葡萄糖输注速率(GIR)明显低于NGT组(5.70±1.14对7.79±1.75,P<0.05);NGT组胰岛素一时相分泌量高于IGT组(5.32±0.37对4.35±0.46,P<0.05);两组间胰岛素第二时相分泌量(4.35±0.31对4.38±0.56,P>0.05)比较差异无统计学意义。结论妊娠糖尿病患者分娩后糖耐量异常者较糖耐量正常者存在更为明显的胰岛素抵抗及胰岛B细胞功能缺陷。     

Gestational diabetes mellitus in Korea: prevalence and prediction of glucose intolerance at early postpartum

To determine the prevalence of glucose intolerance in Korean women with gestational diabetes mellitus (GDM) between 6 and 8 weeks postpartum and identify which antepartum variables were predictive of postpartum diabetes and impaired glucose tolerance (IGT), we prospectively performed 75 g oral glucose tolerance test (OGTT) between 6 and 8 weeks postpartum in women with GDM. WHO criteria were used for classification of glucose tolerance postpartum. Of 392 women with GDM were detected during the study period, 311 women participated in this study. Of the 311 participants, 119 (38.3%) women were found to have persistent glucose intolerance; 47 (15.1%) had diabetes and 72 (23.2%) had IGT. The prevalence of postpartum IGT and diabetes increased in parallel with the metabolic severity during pregnancy. Multiple logistic regression analysis revealed that pre-pregnancy weight, gestational age at diagnosis of GDM, 2-h glucose and 3-h insulin concentrations of diagnostic OGTT were independently associated with postpartum diabetes. Pre-pregnancy weight, 2-h glucose and 1-h insulin concentrations were independently associated with postpartum IGT. Our results support the importance of postpartum testing in Korean women with GDM, and demonstrated that impaired beta-cell function and pre-pregnancy obesity were associated with glucose intolerance at early postpartum.     

Gestational diabetes and the incidence of diabetes in the 5 years following the index pregnancy in South Indian women

This study was carried out to examine the incidence of diabetes and the factors associated with this in a cohort of South Indian women 5 years after they were examined for gestational diabetes (GDM). Women (N=630) whose GDM status was determined (Carpenter-Coustan criteria; GDM: N=41) delivered live babies without major anomalies at the Holdsworth Memorial Hospital, Mysore. Of these, 526 women (GDM: N=35) available for follow-up after 5 years underwent a 2-h oral glucose tolerance test and detailed anthropometry. Diabetes was determined using WHO criteria, and Metabolic Syndrome using IDF criteria recommended for south Asian women. The incidence of diabetes (37% versus 2%) and Metabolic Syndrome (60% versus 26%) was considerably higher in women with previous GDM compared to non-GDM women. GDM women who developed diabetes had lower gestational insulin area-under-the-curve (P=0.05). They had larger waist-to-hip ratio, skinfolds, body mass index, and lower 30-min insulin increment at follow-up than other GDM women. In all, history of diabetes in first-degree relatives was independently associated with higher incidence of diabetes (P<0.001). Our findings suggest high diabetes and cardiovascular risks in women with previous GDM. Follow-up of these women after delivery would provide opportunities to modify adverse lifestyle factors.     

Antepartum and early postpartum predictors of type 2 diabetes development in women with gestational diabetes mellitus

OBJECTIVES: This study aimed at identifying ante-partum and early post-partum (one year) clinical and metabolic characteristics capable of predicting the future development of type 2 diabetes in pregnant women of Mediterranea area affected by gestational diabetes mellitus (GDM). MATERIAL AND METHODS: Seventy GDM patients were evaluated: mean age during pregnancy, plasma glucose levels under OGTT (100 gr. glucose), fasting, 1-h post-prandial plasma glucose levels, HbA(1c) at the third trimester, gestational week of GDM diagnosis, insulin therapy, and weight gain were all taken into consideration. Some maternal risk factors such as pre-pregnancy BMI, and maternal and fetal outcome of index pregnancy were also assessed. One year after delivery in the same patients, BMI, fasting and 1-h post-prandial plasma glucose, plasma glucose and insulinemia under OGTT (75 gr. glucose) were measured. We focused our attention on women who presented type 2 diabetes 5 years after pregnancy or IGT and those who, one year after pregnancy, were normal. RESULTS: Five years after pregnancy 49 women were normal, 5 had developed type 1 diabetes and were not considered, 6 had developed IGT, and 10 type 2 diabetes. Analysis of variables during pregnancy showed that those variables predicting type 2 diabetes were pre-pregnancy BMI, gestational week of diagnosis, need for insulin therapy, obesity, and plasma glucose at 60' OGTT. Analysis of variables evaluated one year after pregnancy showed that BMI, fasting and post-prandial plasma glucose, plasma glucose at each point of the OGTT, and plasma insulin at 30' OGTT were predictive of the development of type 2 diabetes. Furthermore, age, post-partum fasting plasma glucose, and plasma glucose under OGTT post-partum were predictive of the development of IGT. Our data show for the first time that, also in a Caucasian Mediterranean population, markers of the future development of diabetes do exist, as reported in literature. They also stress the importance of correct identification of GDM patients, in order to screen those at greater risk of developing diabetes, for whom it is imperative to set up prevention programs.     

High frequency of antithyroid autoantibodies in pregnant women at increased risk of gestational diabetes mellitus

BACKGROUND: Thyroid autoantibodies (ThyAb) and subclinical hypothyroidism occur more frequently in pregnant women with insulin-dependent diabetes mellitus than in healthy pregnant women. Few studies have investigated the presence of ThyAb in women with gestational diabetes mellitus (GDM), and no significant association between diabetes in pregnancy and thyroid function has been reported. OBJECTIVE: To assess the thyroid biochemical profile and estimate the prevalence of ThyAb in a group of pregnant women at increased risk of GDM due to family and personal risk factors, and to investigate the relationship between a positive family history of diabetes or thyroid diseases and the eventual presence of ThyAb during pregnancy. METHODS: Oral glucose tolerance, serum ThyAb and thyroid function were evaluated in 181 pregnant women with increased risk for GDM (study group). Seventeen healthy pregnant women without risk factors for GDM and with a normal glucose tolerance were recruited as controls. RESULTS: The women who developed GDM showed a mean free thyroxine concentration significantly lower than that observed in the healthy pregnant women and in those with impaired gestational glucose tolerance and normal glucose tolerance. Twenty-nine of the 181 women in the study group (16%) were ThyAb positive. However, the risk of being ThyAb positive during pregnancy was three times greater in the women with positive family history of both diabetes mellitus and thyroid disease than in those with no family history of these conditions. CONCLUSIONS: This study showed that women with increased risk of GDM, mostly those with family history of diabetes mellitus and thyroid disease, also have an increased risk of being ThyAb positive during pregnancy. It also highlighted the importance of evaluating thyroid function in pregnant women with impaired glucose tolerance, in view of their increased risk of subclinical hypothyroidism.     

Strategies for diabetes prevention before and after pregnancy in women with GDM

Interventions for lifestyle modification promoting weight loss and pharmacotherapy interventions for improving insulin sensitivity have been shown to be effective in preventing or delaying the onset of type 2 diabetes (T2DM) in high risk populations. Women with gestational diabetes mellitus (GDM) are at high risk for T2DM, but only two trials have assessed the feasibility of diabetes prevention in this population. We present evidence supporting an intervention with lifestyle modification for women with GDM that would begin during pregnancy and continue through the postpartum period, as pharmacotherapy interventions may not be appropriate for pregnant women or women of reproductive age who could again become pregnant. Young women with GDM may not be aware of their diabetes risk and may perceive difficulty in changing behaviors. Thus, novel approaches will be necessary to translate the lifestyle modification programs previously proven effective among older women with impaired glucose tolerance to younger women with a recent history of GDM, particularly those with normal glucose tolerance postpartum. Understanding barriers to increasing physical activity and adopting a healthy diet and finding strategies for the successful integration of lifestyle modification programs into the busy schedules of women with young children remain priorities for future research.     

Glucose tolerance of offspring of mother with gestational diabetes mellitus in a low-risk population.

AIMS: To describe the prevalence of impaired glucose tolerance and obesity in offspring of mothers whose pregnancies were complicated by gestational diabetes mellitus (GDM) in a low-risk population and to investigate the effect on these outcomes of minimal intervention compared with tight control for management of GDM. METHODS: Eighty-nine children (mean age 9.1 years, 93% Caucasian) were recruited through a follow-up study of women previously involved in a randomized controlled trial of minimal intervention (control group) vs. tight glycaemic control (treatment group) for GDM. Fasting blood glucose (FBG) and 2-h glucose tolerance tests (2hGTT) were performed on offspring and body mass index (BMI) calculated. Glucose tolerance and BMI of treatment groups were compared using non-inferiority tests (non-inferiority margin -15%). RESULTS: Of those offspring, 6.9% (5/72) had abnormal glucose metabolism [four children had impaired glucose tolerance (IGT) and one had Type 2 diabetes mellitus (DM) (all Caucasian)]. Of the four children with IGT, three were male, three had normal BMI, and three had a family history of Type 2 diabetes. Of the 71 offspring who underwent 2hGTT, 25/25 (100%) of the control offspring and 46/46 (100%) of the treatment offspring had normal FBG (FBG < 5.7 mmol/l). Twenty-five of 25 (100%) of control and 42/46 (91.3%) of the treatment offspring had normal glucose tolerance (2hGTT < 7.8 mmol/l) (% difference 8.7, 95% CI -5.6, 20.3). BMI < 85th percentile was found in 25/33 (75.8%) of the treatment group and 44/52 (84.6%) of the control group (difference in percentage -8.9, 95% CI -27.2, 7.8). CONCLUSIONS: School-age children of mothers with GDM are at risk of IGT and overweight, even if from a low-risk ethnic population. FBG was not adequate for screening this population. Minimal intervention for glycaemic control in GDM pregnancies appears to be as effective as tight control for preventing IGT in childhood but not for preventing obesity.     

Inhibition of dipeptidyl peptidase IV activity by oral metformin in Type 2 diabetes.

AIMS: Glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are important insulinotropic hormones that enhance the insulin secretory response to feeding. Their potential for treating Type 2 diabetes is limited by short biological half-life owing to degradation by dipeptidyl peptidase IV (DPP IV). We investigated the acute effects of metformin on DPP IV activity in Type 2 diabetes to elucidate inhibition of DPP IV as a possible mechanism of action. METHODS: Eight fasting subjects with Type 2 diabetes (5M/3F, age 53.1+/-4.2 years, BMI 36.8+/-1.8 kg/m2, glucose 8.9+/-1.2 mmol/l, HbA1c 7.8+/-0.6%) received placebo or metformin 1 g orally 1 week apart in a random, crossover design. RESULTS: Following metformin, DPP IV activity was suppressed compared with placebo (AUC0-6 h 3230+/-373 vs. 5764+/-504 nmol ml/l, respectively, P=0.001). Circulating glucose, insulin and total GLP-1 were unchanged. Metformin also concentration-dependently inhibited endogenous DPP IV activity in vitro in plasma from Type 2 diabetic subjects. CONCLUSION: Oral metformin effectively inhibits DPP IV activity in Type 2 diabetic patients, suggesting that the drug may have potential for future combination therapy with incretin hormones.     

Lifestyle intervention, glucose tolerance, and risk of developing type 2 diabetes mellitus

Diabetes mellitus is rapidly becoming one of the main health issues in the 21st century. Environmental factors such as lifestyle habits (i.e., physical inactivity and dietary intake) and obesity may act as initiating factors or progression factors for type 2 diabetes. Therefore, changes in lifestyle (i.e., diet and physical activity) should have the potential to postpone or prevent the development of type 2 diabetes mellitus in subjects at high risk (for example, those with impaired glucose tolerance [IGT]). Several independent and well-controlled randomized studies have shown the beneficial impact of a lifestyle intervention program on glucose tolerance, insulin resistance, and diabetes risk in populations at risk for developing type 2 diabetes mellitus. After 2 years of a combined diet and physical activity intervention program, according to general public health guidelines, the Study on Lifestyle-intervention and IGT Maastricht (SLIM) revealed an improved glucose tolerance in the intervention group compared to a further deterioration in the control group. The Finnish Diabetes Prevention Study (DPS) and the US Diabetes Prevention Program (DPP) both observed a 58% reduction in diabetes risk after 3 years of intervention in a high-risk population. Although other intervention strategies can reduce the incidence of diabetes, lifestyle changes are the most effective mean of delaying or preventing the development of type 2 diabetes mellitus. For a successful implementation of a diabetes prevention program in a primary healthcare setting, both patients and healthcare professionals should be aware of the (clinical) significance of impaired glucose tolerance and the effectiveness of lifestyle interventions to prevent or postpone type 2 diabetes mellitus and its complications.     

The impact of family history of diabetes on risk factors for gestational diabetes

OBJECTIVE: Familial history of type 2 diabetes (FHD) represents a pathophysiologically unique risk factor for gestational diabetes (GDM), insofar as it encompasses both inherited and lifestyle elements. We thus hypothesized that the risk factors for gestational hyperglycaemia in women with FHD may differ from those in women without FHD. DESIGN/PATIENTS/MEASUREMENTS: GDM risk factors were evaluated in 90 women with FHD and in 83 women without FHD, at the time of oral glucose tolerance testing in late pregnancy. RESULTS: There were no significant differences between the two groups in ethnicity, prepregnancy BMI, the insulin-sensitizing protein adiponectin, glucose tolerance status and area-under-the-glucose-curve (AUC(gluc)). In women with FHD, a multiple linear regression model of established GDM risk factors reconciled 35% of the variance in AUC(gluc), with (i) previous GDM (t = 3.74, P = 0.0003) identified as a positive independent determinant and (ii) log adiponectin (t = -3.48, P = 0.0008) and, unexpectedly, parity (t = -3.19, P = 0.0021) emerging as negative independent covariates of AUC(gluc). In contrast, in women without FHD, the same multivariate model reconciled only 15% of the variance in AUC(gluc), with no significant variables identified. Interestingly, in the entire population (n = 173), parity significantly modified the relationship between FHD and AUC(gluc) (FHD-parity interaction: t = -2.29, P = 0.0235). Indeed, FHD was an independent determinant of AUC(gluc) in nulliparous women (n = 91), but not in parous women (n = 82). CONCLUSION: Established risk factors for GDM are relevant in women with FHD but may not be the principal determinants of gestational hyperglycaemia in women without FHD. Moreover, FHD may be more relevant to risk of GDM in nulliparous women than in parous subjects. These findings highlight the complex relationship between FHD and gestational hyperglycaemia, and may hold implications for selective screening for GDM.     

The dipeptidyl peptidase-4 inhibitor PHX1149 improves blood glucose control in patients with type 2 diabetes mellitus

Aim: To determine the efficacy and tolerability of PHX1149, a novel dipeptidyl peptidase‐4 (DPP4) inhibitor, in patients with type 2 diabetes. Methods: This is a multicentre, randomized, double‐blind, placebo‐controlled, 4‐week study in patients with type 2 diabetes with suboptimal metabolic control. Patients with a baseline haemoglobin A_1c (HbA_1c) of 7.3 to 11.0% were randomized 1 : 1 : 1 : 1 to receive once‐daily oral therapy with either PHX1149 (100, 200 or 400 mg) or placebo; patients were on a constant background therapy of either metformin alone or metformin plus a glitazone. Results: Treatment with 100, 200 or 400 mg of PHX1149 significantly decreased postprandial glucose area under the curve AUC_{0–2 h} by approximately 20% (+0.11 ± 0.50, ?2.08 ± 0.51, ?1.73 ± 0.49 and ?1.88 ± 0.48 mmol/l × h, respectively, for placebo and 100, 200 and 400 mg (p = 0.002, 0.008 and 0.004 vs. placebo). Postprandial AUC_{0–2 h} of intact glucagon‐like peptide‐1, the principal mediator of the biological effects of DPP4 inhibitors, was increased by 3.90 ± 2.83, 11.63 ± 2.86, 16.42 ± 2.72 and 15.75 ± 2.71 pmol/l × h, respectively, for placebo and 100, 200 and 400 mg (p = 0.053, 0.001 and 0.002 vs. placebo). Mean HbA_1c was lower in all dose groups; the placebo‐corrected change in the groups receiving 400 mg PHX1149 was ?0.28% (p = 0.02). DPP4 inhibition on day 28 was 53, 73 and 78% at 24 h postdose in the groups receiving 100, 200 and 400 mg PHX1149, respectively. There were no differences in adverse events between PHX1149‐treated and placebo subjects. Conclusions: Addition of the DPP4 inhibitor PHX1149 to a stable regimen of metformin or metformin plus a glitazone in patients with type 2 diabetes was well tolerated and improved blood glucose control.     

Lifestyle behaviors and cardiovascular risk profiles among parous women by gestational diabetes status, 2007–2018

Background and aimsWomen with prior gestational diabetes mellitus (GDM) are at elevated risk of type 2 diabetes mellitus and cardiovascular disease. We compared cardiometabolic risk factors among parous U.S. women ages 20–44 by history of GDM.Methods and resultsUsing data from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018, 3537 parous women were classified by self-reported GDM history. We compared anthropometric measures, glycemia, blood pressure, lipids, lifestyle factors, cardiovascular health, and cardiometabolic disease prevalence by GDM status. NHANES survey design was taken into account. Women without history of GDM were younger and, after adjusting for age, race/ethnicity, and education, had more favorable cardiometabolic risk factor profiles for measures of anthropometry, glycemia, diabetes, many lipids, physical activity, diet, and overall cardiovascular health than women with history of GDM. Many patterns persisted after further adjustment for lifestyle factors. In analyses stratified by race/ethnicity, many patterns persisted, though there were key differences. Hypertension prevalence differed by GDM history only among Hispanic women. In women of other race/ethnicity, there was no difference in healthy eating or body mass index by GDM history. In non-Hispanic Black women, there was no difference in healthy eating by GDM history.ConclusionAmong parous U.S. women ages 20–44, those with history of GDM had less favorable cardiometabolic risk factor profiles than those without history of GDM. This highlights the importance of continued efforts to develop and test multilevel interventions to improve cardiometabolic risk factors among reproductive-age women with a history of GDM.