Improved skeletal muscle oxidative enzyme activity and restoration of PGC-1α and PPARß/δ gene expression upon rosiglitazone treatment in obese patients with type 2 diabetes mellitus

Objective: To examine whether rosiglitazone alters gene expression of some key genes involved in mitochondrial biogenesis and oxidative capacity in skeletal muscle of type 2 diabetic patients, and whether this is associated with alterations in skeletal muscle oxidative capacity and lipid content.

Design: Skeletal muscle gene expression, mitochondrial protein content, oxidative capacity and lipid accumulation were measured in muscle biopsies obtained from diabetic patients, before and after 8 weeks of rosiglitazone treatment, and matched controls. Furthermore, whole-body insulin sensitivity and substrate utilization were assessed.

Subjects: Ten obese type 2 diabetic patients and 10 obese normoglycemic controls matched for age and BMI.

Methods: Gene expression and mitochondrial protein content of complexes I–V of the respiratory chain were measured by quantitative polymerase chain reaction and Western blotting, respectively. Histochemical staining was used to quantify lipid accumulation and complex II succinate dehydrogenase (SDH) activity. Insulin sensitivity and substrate utilization were measured during a hyperinsulinemic–euglycemic clamp with indirect calorimetry.

Results: Skeletal-muscle mRNA of PGC-1a and PPARb/d – but not of other genes involved in glucose, fat and oxidative metabolism – was significantly lower in diabetic patients (Po0.01). Rosiglitazone significantly increased PGC-1a (B2.2-fold, Po0.01) and PPARb/d (B2.6-fold, Po0.01), in parallel with an increase in insulin sensitivity, SDH activity and metabolic flexibility (Po0.01). Surprisingly, none of the measured mitochondrial proteins was reduced in type 2 diabetic patients, nor affected by rosiglitazone treatment. No alterations were seen in muscular fat accumulation upon treatment.

Conclusion: These results suggest that the insulin-sensitizing effect of rosiglitazone may involve an effect on muscular oxidative capacity, via PGC-1a and PPARb/d, independent of mitochondrial protein content and/or changes in intramyocellular lipid.

Aerobic exercise and resistance training for the management of type 2 diabetes mellitus

BACKGROUND
Implementation of a structured physical exercise program can improve glycemic control in patients with type 2 diabetes mellitus.

OBJECTIVE
To evaluate the efficacy of aerobic exercise and resistance training (either alone or in combination) in the management of type 2 diabetes mellitus.

DESIGN AND INTERVENTION
DARE (Diabetes Aerobic and Resistance Exercise) was a 26-week, single-center, parallel-group, randomized, controlled trial of patients with type 2 diabetes mellitus of >6 months' duration. Participants were aged 39-70 years with a baseline [HbA.sub.1c] level 6.6-9.9%. Exclusion criteria included current insulin therapy, regular exercise regime and blood pressure >160/95 mmHg. All participants underwent a 4-week run-in period that comprised 12 sessions of combined aerobic exercise and resistance training; participants who attended [greater than or equal to] 10 sessions were eligible to enter the study. Eligible participants were randomly allocated to one of four groups: aerobic exercise alone; resistance training alone; combined aerobic exercise and resistance training; and no intervention (control group). Exercise was performed three times weekly. The aerobic exercise group progressed from 15-20 min on a treadmill or bicycle ergometer per session at 60% of the maximum heart rate to 45 min per session at 75% of the maximum heart rate. The resistance training group performed 7 different exercises on weight machines per 45 min session, and progressed to 2-3 sets of each exercise at the maximum weight that could be lifted 7-9 times. The combined exercise group performed the full aerobic exercise program plus the full resistance training program. Participants in the control group reverted to their pre-study exercise levels.

OUTCOME MEASURES
The primary outcome measure was the change in [HbA.sub.1c] from baseline. Secondary outcome measures included changes in blood pressure, lipid profile, and body composition.

RESULTS
A total of 251 participants were eligible for intervention. The median session attendance was 80% (aerobic exercise), 85% (resistance training) and 86% (combined exercise). When compared with the control group, the HbA1c levels were reduced by 0.50% in the aerobic exercise group (P = 0.007) and by 0.38% in the resistance training group (P = 0.038). The combined exercise group had an additional reduction of 0.46% when compared with the aerobic exercise group (P = 0.014) and of 0.59% when compared with the resistance training group (P = 0.001). Decreases in [HbA.sub.1c] levels were greatest for participants with a baseline [HbA.sub.1c] level = 7.5% (P <0.001). For participants with a baseline level [HbA.sub.1c] <7.5%, significant improvements in glycemic control were observed in the combined exercise group only (P = 0.002). Changes in blood pressure and lipid profiles did not differ between the groups. By contrast, participation in a structured exercise program improved body composition.

CONCLUSION
Although aerobic exercise or resistance training alone improved glycemic control, additional improvements were observed with the combined exercise regimen.

Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance. The Australian Diabetes, Obesity and Lifestyle Study (AusDiab)

Background--Diabetes mellitus increases the risk of cardiovascular disease (CVD) and all-cause mortality. The relationship between milder elevations of blood glucose and mortality is less clear. This study investigated whether impaired fasting glucose and impaired glucose tolerance, as well as diabetes mellitus, increase the risk of all-cause and CVD mortality.

Methods and Results--In 1999 to 2000, glucose tolerance status was determined in 10 428 participants of the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). After a median follow-up of 5.2 years, 298 deaths occurred (88 CVD deaths). Compared with those with normal glucose tolerance, the adjusted all-cause mortality hazard ratios (HRs) and 95% confidence intervals (CIs) for known diabetes mellitus and newly diagnosed diabetes mellitus were 2.3 (1.6 to 3.2) and 1.3 (0.9 to 2.0), respectively. The risk of death was also increased in those with impaired fasting glucose (HR 1.6, 95% CI 1.0 to 2.4) and impaired glucose tolerance (HR 1.5, 95% CI 1.1 to 2.0). Sixty-five percent of all those who died of CVD had known diabetes mellitus, newly diagnosed diabetes mellitus, impaired fasting glucose, or impaired glucose tolerance at baseline. Known diabetes mellitus (HR 2.6, 95% CI 1.4 to 4.7) and impaired fasting glucose (HR 2.5, 95% CI 1.2 to 5.1) were independent predictors for CVD mortality after adjustment for age, sex, and other traditional CVD risk factors, but impaired glucose tolerance was not (HR 1.2, 95% CI 0.7 to 2.2).

Conclusions--This study emphasizes the strong association between abnormal glucose metabolism and mortality, and it suggests that this condition contributes to a large number of CVD deaths in the general population. CVD prevention may be warranted in people with all categories of abnormal glucose metabolism.

The metabolic syndrome as a predictor of incident diabetes mellitus in Mauritius

Aims : To assess the utility of the metabolic syndrome (MetS) and a Diabetes Predicting Model as predictors of incident diabetes.

Methods : A longitudinal survey was conducted in Mauritius in 1987 (n = 4972; response 80%) and 1992 (n = 3685; follow-up 74.2%). Diabetes status was retrospectively determined using 1999 World Health Organization (WHO) criteria. MetS was determined according to four definitions and sensitivity, positive predictive value (PPV), specificity and the association with incident diabetes before and after adjustment for MetS components calculated.

Results : Of the 3198 at risk, 297 (9.2%) developed diabetes between 1987 and 1992. The WHO MetS definition had the highest prevalence (20.3%), sensitivity (42.1%) and PPV (26.8%) for prediction of incident diabetes, the strongest association with incident diabetes after adjustment for age and sex [odds ratio 4.6 (3.5–6.0)] and was the only definition to show a significant association after adjustment for its component parts (in men only). The low prevalence and sensitivity of the International Diabetes Federation (IDF) and ATPIII MetS definitions resulted from waist circumference cut-points that were high for this population, particularly in men, and both were not superior to a diabetes predicting model on receiver operating characteristic analysis.

Conclusions : Of the MetS definitions tested, the WHO definition best identifies those who go on to develop diabetes, but is not often used in clinical practice. If cut-points or measures of obesity appropriate for this population were used, the IDF and ATPIII MetS definitions could be recommended as useful tools for prediction of diabetes, given their relative simplicity.

Sociodemographic correlates of the increasing trend in prevalence of gestational diabetes mellitus in a large population of women between 1995 and 2005

OBJECTIVE—Gestational diabetes mellitus (GDM) is an increasingly prevalent risk factor for the development of type 2 diabetes in the mother and is  responsible for morbidity in the child. To better identify women at risk of developing GDM we examined sociodemographic correlates and changes in the prevalence of GDM among all births between 1995 and 2005 in Australia's largest state.
RESEARCH DESIGN AND METHODS—A computerized database of all births (n = 956,738) between 1995 and 2005 in New South Wales, Australia, was used in a multivariate logistic regression that examined the association between sociodemographic characteristics and the occurrence of GDM.
RESULTS—Between 1995 and 2005, the prevalence of GDM increased by 45%, from 3.0 to 4.4%. Women born in South Asia had the highest adjusted odds ratio (OR) of any region (4.33 [95% CI 4.12–4.55]) relative to women born in Australia. Women living in the three lowest socioeconomic quartiles had higher adjusted ORs for GDM relative to women in the highest quartile (1.54 [1.50–1.59], 1.74 [1.69–1.8], and 1.65 [1.60–1.70] for decreasing socioeconomic status quartiles). Increasing age was strongly associated with GDM, with women aged >40 years having an adjusted OR of 6.13 (95% CI 5.79–6.49) relative to women in their early 20s. Parity was associated with a small reduced risk. There was no association between smoking and GDM.
CONCLUSIONS—Maternal age, socioeconomic position, and ethnicity are important correlates of GDM. Future culturally specific interventions should target prevention of GDM in these high-risk groups.

Vitamin C and the risk of gestational diabetes mellitus: a case-control study

OBJECTIVE: To examine whether low maternal dietary intake of vitamin C and low maternal plasma ascorbic acid (AA) concentrations are associated with an increased risk of gestational diabetes mellitus (GDM).
METHODS: Cases were 67 women with GDM meeting National Diabetes Data Group criteria. Controls were 260 women without such a diagnosis. Maternal dietary vitamin C consumption during the periconceptional period and during pregnancy was assessed using a 121-item, semiquantitative food frequency questionnaire. Maternal plasma AA concentrations were determined using automated enzymatic procedures on specimens collected during the intrapartum period.
RESULTS: Mean maternal daily consumption of vitamin C and plasma AA concentrations were 10% and 31% lower, respectively, among GDM cases as compared with controls (130.7 +/- 10.2 vs. 145 +/- 4.9 mg/d, P = .190; 36 +/- 2.0 vs. 53 +/- 1.0 micromol/L, P <.001). After controlling for maternal age, race, prepregnancy adiposity, family history of type 2 diabetes, energy intake and income, women reporting low daily vitamin C intake (< 70 mg/d), as compared with the other women, experienced a 3.7-fold increased risk of GDM (odds ratio [OR] = 3.7, 95% confidence interval [CI] 1.7-8.2). There was a linear relation in risk of GDM with decreasing concentrations of plasma AA (P for linear trend <.001). After adjusting for confounders, women in the lowest quartile (< 42.6 micromol/L), as compared with women in the highest quartile (> 63.3 micromol/L), experienced > 12-fold increased risk of GDM (OR = 12.8, 95% CI 3.5-46.2). CONCLUSION: Low maternal dietary vitamin C intake and low plasma AA concentrations are associated with an increased risk of GDM. Large, prospective, cohort studies are needed to further evaluate the potential beneficial role of vitamin C and other antioxidants in the prevention of impaired glucose tolerance in pregnancy.

Maternal plasma ascorbic acid (vitamin C) and risk of gestational diabetes mellitus

Background : Antioxidants, particularly vitamin C (ascorbic acid), have the capacity to influence glucose tolerance. Modification of diet could reduce the likelihood of developing gestational diabetes mellitus.

Methods : In a prospective cohort study of pregnant women, we studied the association of maternal plasma ascorbic acid concentrations, measured at an average of 13 weeks' gestation, with subsequent risk of gestational diabetes. Maternal plasma ascorbic acid concentrations were determined using automated enzymatic procedures. Dietary vitamin C intake during the periconceptional period and early pregnancy was ascertained using a semiquantitative food frequency questionnaire. We fitted generalized linear models to derive estimates of relative risks and 95% confidence intervals (CIs).

Results : Approximately 4% (n = 33) of 755 women who completed pregnancy developed gestational diabetes mellitus. Plasma ascorbic acid concentrations were inversely associated with the risk of gestational diabetes (P for trend = 0.023). After adjusting for maternal age, race, prepregnancy adiposity, parity, family history of type 2 diabetes, and household income, women with plasma ascorbic acid <55.9 micromol/L (lowest quartile) experienced a 3.1-fold increased risk of gestational diabetes (95% CI = 1.0 - 9.7) compared with women whose concentrations were > or = 74.6 micromol/L (upper quartile). Women who consumed <70 mg vitamin C daily experienced a 1.8-fold increased risk of gestational diabetes compared with women who consumed higher amounts (95% CI = 0.8 - 4.4).

Conclusions : If confirmed, our results raise the possibility that current efforts to encourage populations to consume diets rich in antioxidants, including vitamin C, could reduce the occurrence of gestational diabetes mellitus.

Sucrose as an added sweetener in diabetes mellitus

For many years the Diabetes Associations of several countries have recommended the dietary elimination of added sucrose. However, contrary to popular belief, there is no evidence that modest use of added sucrose is detrimental to diabetic control. In this study of 17 non-insulin dependent diabetics, the medium-term metabolic effects of the daily supplementation of a subject's usual diet with either 28 g of sucrose or with saccharin and starch of equivalent sweetener and energy value, were compared over six-week periods. Neither dietary period had any significant effect on fasting concentrations of blood glucose, plasma insulin, GIP or serum triglyceride. The metabolic responses to two different test meals, consisting of a standard breakfast supplemented with either sucrose or saccharin plus starch, did not differ significantly either between test meals or between dietary periods. Similarly neither dietary period had any significant effect on urinary excretion of glucose. Na+ or K+. There was no significant difference in mean blood pressure between dietary periods.

The results of this medium-term study indicate that there are no metabolic contraindications to including a moderate amount of sucrose (up to 28 g e 7 teaspoons) in the diets of patients with non-insulin dependent diabetes mellitus.

Patient-reported outcomes in trials of incretin-based therapies in patients with type 2 diabetes mellitus

Incretin-based therapies have a glucose-dependent mode of action that results in excellent glucose-lowering efficacy with very low risk of hypoglycaemia, and weight neutrality [dipeptidyl peptidase-4 (DPP-4) inhibitors] or weight loss [glucagon-like peptide-1 (GLP-1) receptor agonists], in people with type 2 diabetes mellitus (T2DM). Patient-reported outcomes (PROs) complement physician evaluations of efficacy and tolerability and offer insights into the subjective experience of using modern diabetes treatments. We conducted a systematic search of clinical trials of the GLP-1 receptor agonists liraglutide, exenatide and long-acting exenatide, one of which included the oral DPP-4 inhibitor sitagliptin as a comparator. No other PRO data for DPP-4 inhibitors were identified. This review summarizes PRO data from eight clinical trials, the majority of which used the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and/or Impact of Weight on Quality of Life-Lite (IWQOL-Lite) to evaluate patient experience. People with T2DM were highly satisfied with modern incretin-based therapies compared with traditional therapies. Treatment satisfaction (including perceptions of convenience and flexibility) was high and generally higher with GLP-1 agonists in association with their greater glucose-lowering efficacy and tendency to facilitate weight loss. Weight-related quality of life (QoL) also improved in people using incretin therapies. The glycaemic improvements achieved with GLP-1 receptor agonists, coupled with the low incidence of hypoglycaemia and ability to cause weight loss, seemed to offset potential concern about injections. It is plausible that superior patient-reported benefits found in clinical trials may translate into improved, clinically meaningful, long-term outcomes through increased treatment acceptability. Long-term, prospective data are needed to ascertain whether this is the case in practice.