Shining the light on sunshine: a systematic review of the influence of sun exposure on type 2 diabetes mellitus-related outcomes

Prospective observational studies uniformly link vitamin D deficiency with the incidence of type 2 diabetes mellitus (T2DM), yet trials supplementing participants at risk of T2DM with vitamin D to reduce progression to T2DM have yielded inconsistent results. Inconsistencies between supplementation trials may be due to insufficient dosing or small sample sizes. Observational studies may also have reported spurious associations due to uncontrolled confounding by lifestyle or genetic factors. Alternatively, observational and intervention studies may not be entirely comparable. Observational studies show an association between higher vitamin D status, which is predominantly derived from sun exposure, and decreased incidence of T2DM. Trials intervene with vitamin D supplementation, and therefore may be missing alternate causes of the effect of sun exposure, as seen in observational studies. We propose that sun exposure may be the driving force behind the associations seen in observational studies; sun exposure may have additional benefits beyond increasing serum 25-hydroxyvitamin D (25OHD) levels. We performed an electronic literature search to identify articles that examined associations between sun exposure and T2DM and/or glucose metabolism. A best evidence synthesis was then conducted using outcomes from analyses deemed to have high methodological quality. Ten eligible full-text articles were identified, yielding 19 T2DM-related outcomes. The best evidence analysis considered 11 outcomes which were grouped into six outcome types: T2DM, fasting glucose, glucose tolerance, fasting insulin, insulin secretion and insulin sensitivity. There was moderate evidence to support a role of recreational sun exposure in reducing odds of T2DM incidence. High-level evidence was lacking; evidence presented for other outcomes was of low or insufficient level. This review highlights significant gaps in research pertaining to sun exposure and T2DM-related outcomes. Further research is encouraged as we aim to identify novel preventative strategies for T2DM.

Age-related proteostasis and metabolic alterations in Caspase-2-deficient mice.

Ageing is a complex biological process for which underlying biochemical changes are still largely unknown. We performed comparative profiling of the cellular proteome and metabolome to understand the molecular basis of ageing in Caspase-2-deficient (Casp2(-/-)) mice that are a model of premature ageing in the absence of overt disease. Age-related changes were determined in the liver and serum of young (6-9 week) and aged (18-24 month) wild-type and Casp2(-/-) mice. We identified perturbed metabolic pathways, decreased levels of ribosomal and respiratory complex proteins and altered mitochondrial function that contribute to premature ageing in the Casp2(-/-) mice. We show that the metabolic profile changes in the young Casp2(-/-) mice resemble those found in aged wild-type mice. Intriguingly, aged Casp2(-/-) mice were found to have reduced blood glucose and improved glucose tolerance. These results demonstrate an important role for caspase-2 in regulating proteome and metabolome remodelling during ageing.

Evaluation of AUSDRISK as a screening tool for lifestyle modification programs: international implications for policy and cost-effectiveness

OBJECTIVE: To evaluate the current use of Australian Type 2 Diabetes Risk Assessment Tool (AUSDRISK) as a screening tool to identify individuals at high risk of developing type 2 diabetes for entry into lifestyle modification programs.

RESEARCH DESIGN AND METHODS: AUSDRISK scores were calculated from participants aged 40-74 years in the Greater Green Triangle Risk Factor Study, a cross-sectional population survey in 3 regions of Southwest Victoria, Australia, 2004-2006. Biomedical profiles of AUSDRISK risk categories were determined along with estimates of the Victorian population included at various cut-off scores. Sensitivity, specificity, positive predictive value (PPV), negative predictive value, and receiver operating characteristics were calculated for AUSDRISK in determining fasting plasma glucose (FPG) ≥6.1 mmol/L.

RESULTS: Increasing AUSDRISK scores were associated with an increase in weight, body mass index, FPG, and metabolic syndrome. Increasing the minimum cut-off score also increased the proportion of individuals who were obese and centrally obese, had impaired fasting glucose (IFG) and metabolic syndrome. An AUSDRISK score of ≥12 was estimated to include 39.5% of the Victorian population aged 40-74 (916 000), while a score of ≥20 would include only 5.2% of the same population (120 000). At AUSDRISK≥20, the PPV for detecting FPG≥6.1 mmol/L was 28.4%.

CONCLUSIONS: AUSDRISK is powered to predict those with IFG and undiagnosed type 2 diabetes, but its effectiveness as the sole determinant for entry into a lifestyle modification program is questionable given the large proportion of the population screened-in using the current minimum cut-off of ≥12. AUSDRISK should be used in conjunction with oral glucose tolerance testing, fasting glucose, or glycated hemoglobin to identify those individuals at highest risk of progression to type 2 diabetes, who should be the primary targets for lifestyle modification.

Diabetes prevention and treatment strategies: are we doing enough?

OBJECTIVE: Effective interventions to prevent, delay, or remit diabetes are currently available. However, their impact on the prevalence of diabetes at the population level is unknown. This study aimed to estimate the impact of a range of diabetes interventions on the population prevalence of diabetes for Australian adults between 2010 and 2025. RESEARCH DESIGN AND METHODS: We used the Australian Diabetes Projection Model to estimate the impact of a population-wide strategy, high-risk prevention, surgical diabetes treatment, and a combination strategy on the future population prevalence of diabetes and to estimate the number of diabetes cases that could be potentially prevented in the year 2025. RESULTS: We estimate that a population-wide strategy would reduce the number of diabetes cases by 60,000-85,000 in 2025 from an estimated 2 million cases under the status quo scenario. A high-risk prevention strategy would result in 106,000 to 150,000 fewer cases of diabetes in 2025, and surgically induced weight loss would result in 3,000-6,000 fewer cases. No single intervention, or combination of interventions, reversed the increasing trend in diabetes prevalence over the next 15 years. CONCLUSIONS: To reverse upward trends in diabetes prevalence in future years, it is essential that current approaches to diabetes prevention and treatment are optimized and implemented and that alternative approaches to reduce the prevalence of diabetes at a population level are developed.

Lifetime risk and projected population prevalence of diabetes

AIMS/HYPOTHESIS: With incidence rates for diabetes increasing rapidly worldwide, estimates of the magnitude of the impact on population health are required. We aimed to estimate the lifetime risk of diabetes, the number of years lived free of, and the number of years lived with diabetes for the Australian adult population from the year 2000, and to project prevalence of diabetes to the year 2025. METHODS: Multi-state life-tables were constructed to simulate the progress of a cohort of 25-year-old Australians. National mortality rates were combined with incidence rates of diabetes and the RR of mortality in people with diabetes derived from the Australian Diabetes, Obesity and Lifestyle study (a national, population-based study of 11,247 adults aged >or=25 years). RESULTS: If the rates of mortality and diabetes incidence observed over the period 2000-2005 continue, 38.0% (95% uncertainty interval 36.6-38.9) of 25-year-olds would be expected to develop diabetes at some time throughout their life. On average, a 25-year-old Australian will live a further 56 years, 48 of these free of diabetes. On average, a 45-year-old person with diabetes can expect to live 6 years less than a person free of diabetes. The prevalence of diabetes is projected to rise from 7.6% in 2000 to 11.4% by 2025. CONCLUSIONS/INTERPRETATION: If we maintain current diabetes incidence rates, more than a third of individuals will develop diabetes within their lifetime and in Australia there will an additional 1 million cases of diabetes by the year 2025.

A modeling intervention in heart failure

BACKGROUND: Peak oxygen uptake (VO(2)) testing is commonly used to assess chronic heart failure (CHF) patients' exercise tolerance. The test requires maximal effort; however, many participants have low confidence (self-efficacy) to perform optimally. PURPOSE: This randomized controlled trial examined the effectiveness of a modeling intervention to increase Peak VO(2) (PVO(2)) and self-efficacy in people diagnosed with CHF. METHODS: Twenty participants with a diagnosis of CHF were randomized to either an intervention (modeling DVD) or a control group. Both groups completed a measure of self-efficacy prior to performing two PVO(2) tests, each separated by 7 days. After completing the first test (T1) the intervention group watched a 10-min coping model DVD. All participants returned 1 week later (T2) to complete identical study procedures. RESULTS: Analysis of covariance results showed that compared with the participants in the control group, those assigned to the modeling intervention had higher PVO(2) at T2, F (1, 19) = 4.38, p = 0.05, eta (2) = 0.21 and self-efficacy, F (1, 19) = 5.80, p < 0.05, eta (2) = 0.25. Only partial support was found for change in self-efficacy mediating treatment outcome (PVO(2)). CONCLUSIONS: Watching a modeling video is associated with increased PVO(2) and self-efficacy. These results have implications for testing patients in a clinical setting to maximize exercise tolerance test results.

Cross-fostering reduces obesity induced by early exposure to monosodium glutamate in male rats

Maternal obesity programmes a range of metabolic disturbances for the offspring later in life. Moreover, environmental changes during the suckling period can influence offspring development. Because both periods significantly affect long-term metabolism, we aimed to study whether cross-fostering during the lactation period was sufficient to rescue a programmed obese phenotype in offspring induced by maternal obesity following monosodium L-glutamate (MSG) treatment. Obesity was induced in female Wistar rats by administering subcutaneous MSG (4 mg/g body weight) for the first 5 days of postnatal life. Control and obese female rats were mated in adulthood. The resultant pups were divided into control second generation (F2) (CTLF2), MSG-treated second generation (F2) (MSGF2), which suckled from their CTL and MSG biological dams, respectively, or CTLF2-CR, control offspring suckled by MSG dams and MSGF2-CR, MSG offspring suckled by CTL dams. At 120 days of age, fat tissue accumulation, lipid profile, hypothalamic leptin signalling, glucose tolerance, glucose-induced, and adrenergic inhibition of insulin secretion in isolated pancreatic islets were analysed. Maternal MSG-induced obesity led to an obese phenotype in male offspring, characterized by hyperinsulinaemia, hyperglycaemia, hyperleptinaemia, dyslipidaemia, and impaired leptin signalling, suggesting central leptin resistance, glucose intolerance, impaired glucose-stimulated, and adrenergic inhibition of insulin secretion. Cross-fostering normalized body weight, food intake, leptin signalling, lipid profiles, and insulinaemia, but not glucose homeostasis or insulin secretion from isolated pancreatic islets. Our findings suggest that alterations during the lactation period can mitigate the development of obesity and prevent the programming of adult diseases.

Mothers after gestational diabetes in Australia (MAGDA) : a randomised controlled trial of a postnatal diabetes prevention program

BACKGROUND: Gestational diabetes mellitus (GDM) is an increasingly prevalent risk factor for type 2 diabetes. We evaluated the effectiveness of a group-based lifestyle modification program in mothers with prior GDM within their first postnatal year. METHODS AND FINDINGS: In this study, 573 women were randomised to either the intervention (n = 284) or usual care (n = 289). At baseline, 10% had impaired glucose tolerance and 2% impaired fasting glucose. The diabetes prevention intervention comprised one individual session, five group sessions, and two telephone sessions. Primary outcomes were changes in diabetes risk factors (weight, waist circumference, and fasting blood glucose), and secondary outcomes included achievement of lifestyle modification goals and changes in depression score and cardiovascular disease risk factors. The mean changes (intention-to-treat [ITT] analysis) over 12 mo were as follows: -0.23 kg body weight in intervention group (95% CI -0.89, 0.43) compared with +0.72 kg in usual care group (95% CI 0.09, 1.35) (change difference -0.95 kg, 95% CI -1.87, -0.04; group by treatment interaction p = 0.04); -2.24 cm waist measurement in intervention group (95% CI -3.01, -1.42) compared with -1.74 cm in usual care group (95% CI -2.52, -0.96) (change difference -0.50 cm, 95% CI -1.63, 0.63; group by treatment interaction p = 0.389); and +0.18 mmol/l fasting blood glucose in intervention group (95% CI 0.11, 0.24) compared with +0.22 mmol/l in usual care group (95% CI 0.16, 0.29) (change difference -0.05 mmol/l, 95% CI -0.14, 0.05; group by treatment interaction p = 0.331). Only 10% of women attended all sessions, 53% attended one individual and at least one group session, and 34% attended no sessions. Loss to follow-up was 27% and 21% for the intervention and control groups, respectively, primarily due to subsequent pregnancies. Study limitations include low exposure to the full intervention and glucose metabolism profiles being near normal at baseline. CONCLUSIONS: Although a 1-kg weight difference has the potential to be significant for reducing diabetes risk, the level of engagement during the first postnatal year was low. Further research is needed to improve engagement, including participant involvement in study design; it is potentially more effective to implement annual diabetes screening until women develop prediabetes before offering an intervention. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000338066.

Protecting skeletal muscle with protein and amino acid during periods of disuse

Habitual sedentary behavior increases risk of chronic disease, hospitalization and poor quality of life. Short-term bed rest or disuse accelerates the loss of muscle mass, function, and glucose tolerance. Optimizing nutritional practices and protein intake may reduce the consequences of disuse by preserving metabolic homeostasis and muscle mass and function. Most modes of physical inactivity have the potential to negatively impact the health of older adults more than their younger counterparts. Mechanistically, mammalian target of rapamycin complex 1 (mTORC1) signaling and muscle protein synthesis are negatively affected by disuse. This contributes to reduced muscle quality and is accompanied by impaired glucose regulation. Simply encouraging increased protein and/or energy consumption is a well-intentioned, but often impractical strategy to protect muscle health. Emerging evidence suggests that leucine supplemented meals may partially and temporarily protect skeletal muscle during disuse by preserving anabolism and mitigating reductions in mass, function and metabolic homeostasis.

Substrate utilization during exercise performed with and without glucose ingestion in female and male endurance trained athletes

Compared to males, females oxidize proportionately more fat and less carbohydrate during endurance exercise performed in the fasted state. This study was designed to test the hypothesis that there may also be gender differences in exogenous carbohydrate (CHOexo) oxidation during exercise. Healthy, young males (n = 7) and females (n = 7) each completed 2 exercise trials (90 min cycle ergometry at 60% VO[sub2peak]), 1 week apart. Females were eumenorrheic and were tested in the midfollicular phase of their menstrual cycle. Subjects drank intermittently either 8% CHOexo (1 g glucose ⋅ kg ⋅ h[sup-1]) enriched with U-13C glucose or an artificially sweetened placebo during the trial. Whole-body substrate oxidation was determined from PER, urinary urea excretion, and the ratio of 13C:12C in expired gas during the final 60 min of exercise. During the placebo trial, fat oxidation was higher in females than in males (0.42 ± 0.07 vs. 0.32 ± 0.09 g ⋅ min[sup-1] . kg LBM[sup-1] x 10[sup-2]) at 30 min of exercise (p < .05). When averaged over the final 60 min of exercise, the relative proportions of fat, total carbohydrate, and protein were similar between groups. During CHOexo ingestion, both the ratio of 13C: 12C in expired gas (p < .05) and the proportion of energy derived from CHOexo relative to LBM (p < .05) were higher in females compared to males at 75- and 90-min exercise. When averaged over the final 60 min of exercise, the percentage of CHOexo to the total energy contribution tended to be higher in females (14.3 + 1.2%) than in males (11.2 ± 1.2%; p = .09). The reduction in endogenous CHO oxidation with CHOexo intake was also greater in females (12.9 ± 3.1%) than in males (5.1 ± 2.0%; p = .05). Compared to males, females may oxidize a greater relative proportion of CHOexo during endurance exercise which, in turn, may spare more endogenous fuel. Based on these observations, ingested carbohydrate may be a particularly beneficial source of fuel during endurance exercise for females.

Should capillary blood glucose measurements be used in population surveys?

Objective
To determine the accuracy and appropriateness of capillary blood glucose testing in population surveys.
Materials and methods
Capillary blood glucose using the Rochec ACCU-CHEK instrument and Advantage 11 Test Strips was compared to a laboratory instrument. Three independent cross-sectional risk factor surveys (n=1432) and baseline individuals from the Greater Green Triangle Diabetes Prevention Project (n=341) provided both fasting plasma and capillary blood glucose measurements. Accuracy of capillary glucoses was assessed using the ISO 15197 standard. The median age of the participants was 71years, ranging from 25 to 84years. There were 799 males and 974 females.
Results
Capillary glucose method had poorer precision at lower concentrations (CV: 9.50%, mean=3.09mmol/L, CV: 4.90%, mean=16.78mmol/L, n=233 replicates). Individual discrepancies were seen across the measuring range (2.8–19.9mmol/L, n=1773). In total, 94.5% of results fell within the minimum acceptable accuracy standards. This was slightly short of the 95% of results required to meet the ISO 15197 standard. The prevalence of diabetes in the study population using glucose 7.0mmol/L was 2.4% (95%CI 1.8–3.3%) according to fasting plasma glucose and 2.8% (2.1–3.8%) according to fasting capillary glucose. The lower WHO-defined cut-off of 6.1mmol/L for capillary blood glucose testing gave a prevalence of 10.7% (9.0–12.5%).
Conclusions
This study of matched capillary and plasma glucose results concludes that while it is appropriate to use fasting capillary glucose levels to determine the prevalence of diabetes in populations, it should not be used to reliably diagnose diabetes in individuals.

Repair and tolerance of DNA damage in higher plants

DNA repair mechanisms constitute an essential cellular response to DNA damage arising either from metabolic processes or from environmental sources such as ultraviolet radiation. Repair of these lesions may be via direct reversal, or by processes such as nucleotide excision repair (NER), a coordinated pathway in which lesions and the surrounding nucleotides are excised and replaced via DNA resynthesis. The importance of repair is illustrated by human disease states such as xeroderma pigmentosum and Cockayne's syndrome which result from defects in the NER system arising from mutations in XP- genes or XP- and CS- genes respectively Little detail is known of DNA damage repair processes in plants, despite the economic and ecological importance of these organisms. This study aimed to expand our knowledge of the process of NER in plants, largely via a polymerase chain reaction (PCR)-based approach involving amplification, cloning and characterisation of plant genomic DNA and cDNA. Homologues of the NER components XPF/RAD1 and XPD/RAD3 were isolated as both genomic and complete cDNA sequences from the model dicotyledonous plant Arabidopsis thaliana. The sequence of the 3'-untranslated region of atXPD was also determined. Comparison of genomic and cDNA sequences allowed a detailed analysis of gene structures, including details of intron/exon processing. Variable transcript processing to produce three distinct transcripts was found in the case of atXPF. In an attempt to validate the proposed homologous function of these cDNAs, assays to test complementation of resistance to ultraviolet radiation in the relevant yeast mutants were performed. Despite extensive amino acid sequence conservation, neither plant cDNA was able to restore UV-resistance. As the yeast RAD3 gene product is also involved in vivo in transcription, and so is required for viability, the atXPD cDNA was tested in a complementation assay for this function in an appropriate yeast mutant. The plant cDNA was found to substantially increase the viability of the yeast mutant. The structural and functional significance of these results is discussed comparatively with reference to yeast, human and other known homologues. Other putative NER homologues were identified in A. thaliana database sequences, including those of ERCC1/RAD10 and XPG/ERCC5/RAD2, and are now the subjects of ongoing investigations. This study also describes preliminary investigations of putative REVS and RAD30 translesion synthesis genes from A. thaliana.

Intravenous AICAR administration reduces hepatic glucose output and inhibits whole body lipolysis in type 2 diabetic patients

Aims/hypothesis: The 5′-AMP-activated protein kinase (AMPK) pathway is intact in type 2 diabetic patients and is seen as a target for diabetes treatment. In this study, we aimed to assess the impact of the AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR) on both glucose and fatty acid metabolism in vivo in type 2 diabetic patients.

Methods: Stable isotope methodology and blood and muscle biopsy sampling were applied to assess blood glucose and fatty acid kinetics following continuous i.v. infusion of AICAR (0.75 mg kg−1 min−1) and/or NaCl (0.9%) in ten male type 2 diabetic patients (age 64 ± 2 years; BMI 28 ± 1 kg/m2).
Results Plasma glucose rate of appearance (R a) was reduced following AICAR administration, while plasma glucose rate of disappearance (R d) was similar in the AICAR and control test. Consequently, blood glucose disposal (R d expressed as a percentage of R a) was increased following AICAR infusion (p < 0.001). Accordingly, a greater decline in plasma glucose concentration was observed following AICAR infusion (p < 0.001). Plasma NEFA R a and R d were both significantly reduced in response to AICAR infusion, and were accompanied by a significant decline in plasma NEFA concentration. Although AMPK phosphorylation in skeletal muscle was not increased, we observed a significant increase in acetyl-CoA carboxylase phosphorylation (p < 0.001).

Conclusions/interpretation: The i.v. administration of AICAR reduces hepatic glucose output, thereby lowering blood glucose concentrations in vivo in type 2 diabetic patients. Furthermore, AICAR administration stimulates hepatic fatty acid oxidation and/or inhibits whole body lipolysis, thereby reducing plasma NEFA concentration.

Breaking up prolonged sitting reduces postprandial glucose and insulin responses

OBJECTIVE--Observational studies show breaking up prolonged sitting has beneficial associations with cardiometabolic risk markers, but intervention studies are required to investigate causality. We examined the acute effects on postprandial glucose and insulin levels of uninterrupted sitting compared with sitting interrupted by brief bouts of light- or moderate-intensity walking.

RESEARCH DESIGN AND METHODS--Overweight/obese adults (n = 19), aged 45-65 years, were recruited for a randomized three-period, three-treatment acute crossover trial: I) uninterrupted sitting; 2) seated with 2-min bouts of light-intensity walking every 20 rain; and 3) seated with 2-min bouts of moderate-intensity walking every 20 min. A standardized test drink was provided after an initial 2-h period of uninterrupted sitting. The positive incremental area under curves (iAUC) for glucose and insulin (mean [95% CI]) for the 5 h after the test drink (75 g glucose, 50 g fat) were calculated for the respective treatments.

RESULTS--The glucose iAUC (mmol/L) x h after both activity-break conditions was reduced (light: 5.2 [4.1-6.6]; moderate: 4.9 [3.8-6.1]; both P < 0.01) compared with uninterrupted sitting (6.9 [5.5-8.7]). Insulin iAUC (pmol/L) x h was also reduced with both activity-break conditions (light: 633.6 [552.4-727.1]; moderate: 637.6 [555.5-731.9], P < 0.0001) compared with uninterrupted sitting (828.6 [722.0-950.9]).

CONCLUSIONS--Interrupting sitting time with short bouts of light- or moderate-intensity walking lowers postprandial glucose and insulin levels in overweight/obese adults. This may improve glucose metabolism and potentially be an important public health and clinical intervention strategy for reducing cardiovascular risk.

Poor tolerance of motor cortex rTMS in chronic migraine

Background:
Two small studies had evaluated the efficacy of rTMS in migraine. One tested high frequency rTMS over the dorsolateral prefrontal cortex while the other evaluated 1 Hz rTMS over the vertex.
Aim:
To test the feasibility of 10 Hz rTMS of motor cortex as an adjunctive therapy in patients with chronic migraine.
Materials and Methods:
We randomized (2:1 ratio) chronic migraine patients on medical preventive treatment to receive either rTMS or sham therapy for 10 sessions. rTMS (80% resting motor threshold, 10Hz, 20 trains, 5 secs/train, inter-train interval 1 min, total 1000 stimuli/session) was applied over the right motor cortex.
Result:
Nine patients were randomized. Six received rTMS
and three had sham therapy. Three patients in the rTMS arm withdrew from the study due to increased headache frequency and discomfort from the treatment. The remaining six cases (3 rTMS, 3 sham) completed the study. The study was prematurely stopped due to the significant worsening of headache from rTMS. No significant differences in outcome measures were found between real and sham rTMS.
Conclusion:
Although the study was terminated prematurely, the high dropout rate (50%) due to worsening headaches suggested that rTMS over the motor cortex is poorly tolerated in chronic migraine.