Cost-sparing effect of twice-weekly targeted endurance training in type 2 diabetics: a one-year controlled randomized trial

OBJECTIVE: We evaluated the effects of targeted, moderate endurance training on healthcare cost, body composition and fitness in type 2 diabetes patients routinely followed within the French healthcare system. DESIGN AND METHODS: A total of 25 type 2 diabetic patients was randomly assigned to one of two groups: 13 underwent a training programme (eight sessions, followed by training twice a week for 30-45 minutes at home at the level of the ventilatory threshold [V(T)]); and 12 received their usual routine treatment. Both groups were followed for one year to evaluate healthcare costs, exercise effectiveness and a six-minute walking test. RESULTS: The training prevented loss of maximum aerobic capacity, which decreased slightly in the untrained group (P=0.014), and resulted in a higher maximum power output (P=0.041) and six-minute walking distance (P=0.020). The Voorrips activity score correlated with both V(O2max) (r=0.422, P<0.05) and six-minute walking distance (r=0.446, P<0.05). Changes in V(O2max) were negatively correlated with changes in body weight (r=0.608, P<0.01). Training decreased the insulin-resistance index (HOMA-IR) by 26% (P<0.05). Changes in percentages of fat were correlated to changes in waist circumference (r=0.436, P<0.05). The total healthcare cost was reduced by 50% in the trained group (euro 1.65+/-1 per day versus euro 3.00+/-1.47 per day in the untrained group; P<0.02) due to fewer hospitalizations (P=0.05) and less use of sulphonylureas (P<0.05). CONCLUSION: Endurance training at V(T) level prevented the decline in aerobic working capacity seen in untrained diabetics over the study period, and resulted in a marked reduction in healthcare costs due to less treatments and fewer hospitalizations.     

Efficacy, dose-response relationship and safety of once-daily extended-release metformin (Glucophage XR) in type 2 diabetic patients with inadequate glycaemic control despite prior treatment with diet and exercise: results from two double-blind, placebo-controlled studies

AIM: The efficacy, dose-response relationships and safety of an extended-release formulation of metformin (Glucophage) XR) were evaluated in two double-blind, randomized, placebo-controlled studies of 24 and 16 weeks' duration, in patients with inadequate glycaemic control despite diet and exercise. Protocol 1 provided an evaluation of metformin XR at a commonly used dosage. Protocol 2 evaluated different dosages of metformin XR. METHODS: In Protocol 1, 240 patients were randomized to receive metformin XR 1000 mg once daily. or placebo in a 2:1 ratio for 12 weeks (patients could receive metformin XR 1500 mg during weeks 12-24 if required). In Protocol 2, 742 patients were randomized to receive metformin XR 500 mg once daily, 1000 mg once daily, 1500 mg once daily, 2000 mg once daily, 1000 mg twice daily or placebo for 16 weeks. The primary endpoint in each study was the change from baseline in HbA(1C) at 12 weeks (Protocol 1) or 16 weeks (Protocol 2). RESULTS: Metformin XR reduced HbA(1C) in Protocol 1, with mean treatment differences for 1000 mg once daily vs. placebo of -0.7% at 12 weeks and -0.8% at 24 weeks (p < 0.001 for each). In Protocol 2, a clear dose-response relationship was evident at doses up to 1500 mg, with treatment differences vs. placebo of -0.6% (500 mg once daily), -0.7% (1000 mg once daily), -1.0% (1500 mg once daily) and -1.0% (2000 mg once daily). The efficacy of metformin XR 2000 mg once daily and 1000 mg twice daily were similar (mean treatment differences vs. placebo in HbA(1C) were -1.0% and -1.2%, respectively). More patients achieved HbA(1C) < 7.0% with metformin XR vs. placebo in Protocol 1 (29% vs. 14% at 12 weeks) and with once-daily metformin XR in Protocol 2 (up to 36% vs. 10% at 16 weeks). No significant changes in fasting insulin or body weight occurred. Total and low-density lipoprotein (LDL)-cholesterol improved (p < 0.05-p < 0.001) in metformin XR groups in Protocol 2. Metformin XR was well tolerated; gastrointestinal side effects were more common with metformin XR vs. placebo, but few patients withdrew for this reason (1.3% vs. 1.3% in Protocol 1 and 1.6% vs. 0.9% in Protocol 2). CONCLUSIONS: Once-daily metformin XR presents an effective and well-tolerated therapeutic option for delivering metformin in a convenient manner, which supports good compliance with therapy.     

Variation near the hepatocyte nuclear factor (HNF)-4α gene associates with type 2 diabetes in the Danish population

Aims/hypothesis The hepatocyte nuclear factor (HNF)-4 is an orphan nuclear receptor, which plays crucial roles in regulating hepatic gluconeogenesis and insulin secretion. The gene encoding HNF-4 (HNF4A) is located on chromosome 20q12–q13 in a region that in several studies has shown linkage with type 2 diabetes. Recently, two independent studies identified single nucleotide polymorphisms (SNPs) in a 90-kb region spanning HNF4A, which showed strong association with type 2 diabetes in the Finnish and Ashkenazi Jewish populations. In an attempt to replicate and extend these findings, we selected four SNPs in the same HNF4A region, which in the Finnish and Ashkenazi Jewish populations were associated with type 2 diabetes, and examined their relationships with type 2 diabetes and prediabetic phenotypes in the Danish Caucasian population.Methods The rs1884614, rs2425637, rs1885088 and rs3818247 were analysed in case-control studies of 1387, 1429, 1417 and 1371 type 2 diabetic patients and 4766, 4727, 4665 and 4748 glucose-tolerant subjects respectively. Genotype–quantitative trait analyses comprised 4430, 4394, 4336 and 4413 middle-aged glucose-tolerant subjects from the population-based Inter99 cohort for the rs1884614, rs2425637, rs1885088 and rs3818247 respectively.Results The risk allele of the rs1884614, which is located 4 kb upstream of the HNF4A P2 promoter, was associated with type 2 diabetes (odds ratio [OR]=1.14, p=0.02) and with a subtle increase in post-OGTT plasma glucose levels in glucose-tolerant subjects (additive model, p=0.05).Conclusions/interpretation Consistent with results from studies of Finnish and Ashkenazi Jewish subjects, variation near the P2 region of HNF4A is associated with type 2 diabetes in the Danish population.     

Weight Change and Glycemic Control After Diagnosis of Type 2 Diabetes

BACKGROUND  Limited community-based data describe weight change after diabetes diagnosis. OBJECTIVE  To evaluate weight change patterns and associations in the 1st year after diabetes mellitus type 2 diagnosis. DESIGN  Retrospective cohort study. PARTICIPANTS  Patients aged 21–75 with diabetes mellitus type 2 diagnosed between 1 January 1997 and 31 December 2004, identified from electronic medical records in Kaiser Permanente Northwest, a health maintenance organization. Eligible patients met weight measurement criteria (a baseline and three additional weight measurements) and did not have a condition associated with unintentional weight change (n = 4,135). MEASUREMENTS  We estimated 12-month patient weight trajectories using growth curve analyses, grouped similar trajectories using cluster analysis, and compared characteristics among groups. RESULTS  The four weight trajectory groups were “higher stable weight” (n = 757; 18.3%), “lower stable weight” (n = 2,236; 54.1%), “weight gain” (n = 664; 16.0%), and “weight loss” (n = 478; 11.6%). After adjustments, members of the weight-loss group were more likely than those in the weight-gain group to be older, female, take fewer medications, have had nutritionist visits, and have a lower mean HbA_1c. Those in the weight-loss group were less likely to be in a race group at higher risk for obesity, have depression or dyslipidemia, or have taken >30 days of a sulfonylurea alone or with metformin. CONCLUSIONS  A small-but-substantial group of patients had a mean weight trajectory that included a clinically significant weight loss. Weight-loss trajectories were strongly associated with better glycemic control when compared to weight gain. Patients with certain characteristics may need more support for weight loss. This study was supported by grant no. R21 DK073546–02 (Weight in Secondary Prevention) from the National Institute of Diabetes and Digestive and Kidney Diseases     

最大体重与2型糖尿病发病关系的病例对照研究

目的探讨既往最大体重与2型糖尿病(T2DM)发病的关系,推论其与当前体重及胰岛β细胞功能和胰岛素敏感性的关系。方法178例T2DM家系患病-非患病同胞,其中T2DM97例,正常糖耐量(NGT)81例,评价胰岛素抵抗及胰岛β细胞功能,logistic回归分析既往最大体质指数(BMI)与T2DM的发病关系。结果两组既往最大BMI分别为27·6±3·8kg/m2和25·6±3·0kg/m2,差异有统计学意义(P=0·000);既往最大BMI与T2DM的发生呈正相关(OR=1·193,P=0·000);既往最大BMI与当前BMI显著正相关(P=0·000),T2DM组和NGT组的相关系数分别为0·861和0·867。随既往最大BMI的增加,血压、空腹胰岛素、胰岛素抵抗指数升高,胰岛素敏感性下降。结论既往最大BMI越大,T2DM发病危险性越大,当前体重也越大;超重或肥胖个体由于胰岛素敏感性下降导致T2DM发病的危险性增加。     

Enhancement of B-cell secretion by blood glucose normalization in type 2 diabetes is associated with fasting C-peptide levels

OBJECTIVES: To investigate (i) the variability of beneficial effects achieved by short-term near-normalization of blood glucose in type 2 diabetes patients, and (ii) the relationship of beneficial effects to individual characteristics of diabetes. DESIGN: Arginine-induced insulin and glucagon release tested at two glucose levels before and after 3 days of intensive insulin treatment. SETTING: The Department of Endocrinology and Diabetology, Karolinska Hospital, Stockholm, Sweden. SUBJECTS: Type 2 diabetes patients with poor metabolic control sampled from an area-based population of diabetes patients. RESULTS: Levels of fasting blood glucose declined from 15.0 +/- 0.9 to 8.5 +/- 0.7 mmol L-1, C-peptide from 0.81 +/- 0.06 to 0.49 +/- 0.05 nmol L-1 and percent proinsulin (of total IRI) from 7.8 +/- 1.0 to 3.2 +/- 0.6%. At comparable glucose levels arginine-induced insulin secretion was enhanced 46.3 +/- 19.5% (range -36 to 220%). Enhancement correlated with extent of blood glucose normalization and also with fasting C-peptide levels and with overweight. Arginine-induced glucagon secretion was nonsignificantly depressed (17.2 +/- 7.4%, range -59 to 29%). Insulin sensitivity assessed by M:I ratio was increased by a median of 95%. CONCLUSIONS: In type 2 diabetes patients reversibility of the effects of poor metabolic control on B-cell function is variable. Variability is related to B-cell mass in individual patients with type 2 diabetes.     

Increased lipolysis by secretory phospholipase A(2) group V of lipoproteins in diabetic dyslipidaemia

Background. Lipolysis of lipoproteins by secretory phospholipase A₂ group V (sPLA₂‐V) promotes inflammation, lipoprotein aggregation and foam cell formation – all considered as atherogenic mechanisms. Objective. In this study, we compared the susceptibility to sPLA₂‐V lipolysis of VLDL and LDL from individuals with type 2 diabetes and the metabolic syndrome (T2D‐MetS) and from healthy controls. Design. VLDL and LDL were isolated from 38 T2D‐MetS subjects and 38 controls, treated pair‐wise. Extent of sPLA₂‐V lipolysis was measured as release of nonesterified free fatty acids (NEFA). In a subset of the subjects, lipoprotein composition was determined as a relationship between lipid and apolipoprotein components. Results. Mean paired increase in sPLA₂‐V lipolysis after 1 h for T2D‐MetS versus control was 2.0 μmol NEFA l^?1 for VLDL (P = 0.004) and 0.75 μmol NEFA l^?1 for LDL (P = 0.001). There were also substantial differences in lipoprotein composition between the groups. T2D‐MetS VLDL had higher triglyceride and cholesterol contents than control VLDL. T2D‐MetS LDL was smaller and contained more triglycerides and less cholesterol than control LDL. Both VLDL and LDL from T2D‐MetS subjects also contained more apolipoprotein CIII per particle. Conclusion. VLDL and LDL from T2D‐MetS individuals were more susceptible to sPLA₂‐V lipolysis than those from control individuals. This may result in elevated levels of NEFA and lysophosphatidylcholine, both in circulation and in LDL, possibly contributing to the elevated inflammatory state and increased risk of cardiovascular diseases seen in these individuals.