Marta Silvestre

The AMPK-SIRT signaling network regulates glucose tolerance under calorie restriction conditions

AIMS SIRT1 and AMP-activated protein kinase (AMPK) share common activators, actions and target molecules. Previous studies have suggested that a putative SIRT1-AMPK regulatory network could act as the prime initial sensor for calorie restriction-induced adaptations in skeletal muscle-the major site of insulin-stimulated glucose disposal. Our study aimed to investigate whether a feedback loop exists between AMPK and SIRT1 in skeletal muscle and how this may be involved glucose tolerance. MAIN METHODS To investigate this, we used skeletal muscle-specific AMPKα1/2 knockout mice (AMPKα1/2(-/-)) fed ad libitum (AL) or a 30% calorie restricted (CR) diet and L6 rat myoblasts incubated with SIRT1 inhibitor (EX527). KEY FINDINGS CR-AMPKα1/2(-/-) displayed impaired glucose tolerance (*p<0.05), in association with down-regulated SIRT1 and PGC-1α expression (<300% vs. CR-WT, (±±)p<0.01). Moreover, AMPK activity was decreased following SIRT1 inhibition in L6 cells (~0.5-fold vs. control, *p<0.05). SIGNIFICANCE This study demonstrates that skeletal muscle-specific AMPK deficiency impairs the beneficial effects of CR on glucose tolerance and that these effects may be dependent on reduced SIRT1 levels.

Integrity of the human faecal microbiota following long-term sample storage

In studies of the human microbiome, faecal samples are frequently used as a non-invasive proxy for the study of the intestinal microbiota. To obtain reliable insights, the need for bacterial DNA of high quality and integrity following appropriate faecal sample collection and preservation steps is paramount. In a study of dietary mineral balance in the context of type 2 diabetes (T2D), faecal samples were collected from healthy and T2D individuals throughout a 13-day residential trial. These samples were freeze-dried, then stored mostly at -20°C from the trial date in 2000/2001 until the current research in 2014. Given the relative antiquity of these samples (~14 years), we sought to evaluate DNA quality and comparability to freshly collected human faecal samples. Following the extraction of bacterial DNA, gel electrophoresis indicated that our DNA extracts were more sheared than extracts made from freshly collected faecal samples, but still of sufficiently high molecular weight to support amplicon-based studies. Likewise, spectrophotometric assessment of extracts revealed that they were of high quality and quantity. A subset of bacterial 16S rRNA gene amplicons were sequenced using Illumina MiSeq and compared against publicly available sequence data representing a similar cohort analysed by the American Gut Project (AGP). Notably, our bacterial community profiles were highly consistent with those from the AGP data. Our results suggest that when faecal specimens are stored appropriately, the microbial profiles are preserved and robust to extended storage periods.

PREVIEW: Prevention of Diabetes through Lifestyle Intervention and Population Studies in Europe and around the World. Design, Methods, and Baseline Participant Description of an Adult Cohort Enrolled into a Three-Year Randomised Clinical Trial

Type-2 diabetes (T2D) is one of the fastest growing chronic diseases worldwide. The PREVIEW project has been initiated to find the most effective lifestyle (diet and physical activity) for the prevention of T2D, in overweight and obese participants with increased risk for T2D. The study is a three-year multi-centre, 2 × 2 factorial, randomised controlled trial. The impact of a high-protein, low-glycaemic index (GI) vs. moderate protein, moderate-GI diet in combination with moderate or high-intensity physical activity on the incidence of T2D and the related clinical end-points are investigated. The intervention started with a two-month weight reduction using a low-calorie diet, followed by a randomised 34-month weight maintenance phase comprising four treatment arms. Eight intervention centres are participating (Denmark, Finland, United Kingdom, The Netherlands, Spain, Bulgaria, Australia, and New Zealand). Data from blood specimens, urine, faeces, questionnaires, diaries, body composition assessments, and accelerometers are collected at months 0, 2, 6, 12, 18, 24, and 36. In total, 2326 adults were recruited. The mean age was 51.6 (SD 11.6) years, 67% were women. PREVIEW is, to date, the largest multinational trial to address the prevention of T2D in pre-diabetic adults through diet and exercise intervention. Participants will complete the final intervention in March, 2018.

Prevention of Type 2 Diabetes through Lifestyle Modification: Is There a Role for Higher-Protein Diets?

Type 2 diabetes (T2D) incidence is increasing worldwide, driven by a rapidly changing environment and lifestyle and increasing rates of overweight and obesity. Prevention of diabetes is key and is most likely achieved through prevention of weight gain and/or successful long-term weight loss maintenance. Weight loss is readily achievable but there is considerable challenge in maintaining that weight loss over the long term. Lower-fat carbohydrate-based diets are widely used for T2D prevention. This is supported primarily by 3 successful long-term interventions, the US Diabetes Prevention Program, the Finnish Diabetes Prevention Study, and the Chinese Da Qing Study, but evidence is building in support of novel higher-protein (>20% of energy) diets for successful weight loss maintenance and prevention of T2D. Higher-protein diets have the advantage of having relatively low energy density, aiding longer-term appetite suppression, and preserving lean body mass, all central to successful weight loss and prevention of weight regain. Here, we review the carbohydrate-based intervention trials and present mechanistic evidence in support of increased dietary protein for weight loss maintenance and a possible novel role in prevention of dysglycemia and T2D.

The role of glucagon in weight loss‐mediated metabolic improvement: a systematic review and meta‐analysis

Aims

Higher Protein Intake Is Not Associated with Decreased Kidney Function in Pre-Diabetic Older Adults Following a One-Year Intervention—A Preview Sub-Study

Concerns about detrimental renal effects of a high-protein intake have been raised due to an induced glomerular hyperfiltration, since this may accelerate the progression of kidney disease. The aim of this sub-study was to assess the effect of a higher intake of protein on kidney function in pre-diabetic men and women, aged 55 years and older. Analyses were based on baseline and one-year data in a sub-group of 310 participants included in the PREVIEW project (PREVention of diabetes through lifestyle Intervention and population studies in Europe and around the World). Protein intake was estimated from four-day dietary records and 24-hour urinary urea excretion. We used linear regression to assess the association between protein intake after one year of intervention and kidney function markers: creatinine clearance, estimated glomerular filtration rate (eGFR), urinary albumin/creatinine ratio (ACR), urinary urea/creatinine ratio (UCR), serum creatinine, and serum urea before and after adjustments for potential confounders. A higher protein intake was associated with a significant increase in UCR (p = 0.03) and serum urea (p = 0.05) after one year. There were no associations between increased protein intake and creatinine clearance, eGFR, ACR, or serum creatinine. We found no indication of impaired kidney function after one year with a higher protein intake in pre-diabetic older adults.

Evaluating FINDRISC as a screening tool for type 2 diabetes among overweight adults in the PREVIEW:NZ cohort

AIMS This study aimed to evaluate the efficacy of a high (≥12) Finnish diabetes risk (FINDRISC) score in identifying undiagnosed prediabetes and type 2 diabetes (T2D) in an New Zealand population of overweight and obese individuals, across a variety of ethnic groups. METHODS We estimated the efficacy of elevated FINDRISC scores in predicting prediabetes and T2D in 424 overweight adults with no prior diagnosis recruited for the PREVention of diabetes through lifestyle Interventions in Europe and Worldwide (PREVIEW) study. All participants who completed the FINDRISC questionnaire during a pre-screening phase with a score of ≥12 were then screened using a 2h oral glucose tolerance test (2h-OGTT) to identify undiagnosed dysglycaemia. RESULTS Of the 424 participants, 65% (n=280) were pre-diabetic and 7% (n=32) had undiagnosed T2D. A higher FINDRISC score was significantly associated with prediabetes and T2D (P=0.02). There was a significant association between ethnicity and glycaemic status (normal vs prediabetes/T2D, P=0.02). Increasing the FINDRISC cut-off to ≥15 resulted in a non-significant increase in the proportion of participants correctly classified with dysglycaemia. ROC-AUC=0.6 with sensitivity=0.6026 (95% CI: 0.5459-0.6573) and specificity=0.5536 (95% CI: 0.4567-0.6476). Isolated impaired fasting glucose (IFG) was more efficient in predicting dysglycaemia than isolated impaired glucose tolerance (IGT). CONCLUSIONS The FINDRISC questionnaire is a useful and efficacious screening tool to identify unknown prediabetes and T2D in overweight New Zealanders, particularly in Maori individuals.

Metabolic outcomes after an 8 weeks low-calorie-diet in overweight, pre-diabetic individuals: the role of gender in the PREVIEW study

Basel · Freiburg · Paris · London · New York · Chennai · New Delhi · Bangkok · Beijing · Shanghai · Tokyo · Kuala Lumpur · Singapore · Sydney European Obesity Summit (EOS) – Joint Congress of EASO and IFSO-EC Gothenburg, Sweden, June 1 – 4, 2016Background and Aims: Bariatric surgery has emerged as an effective method to reduce morbid obesity. Nutritional counseling is essential in order to achieve maximal treatment success and to avoid long term complications. Increased dietary protein intake or its amino acid composition could have beneficial influence on various postoperative results. The aim of this systematic review is to examine the level of evidence of the relationship between dietary protein intake or supplementation with amino acids and postoperative outcomes after gastric bypass surgery. Material and Methods: We conducted a systematic literature search in four electronic databases (Cochrane Central Register of Controlled Trials, EMBASE, Pub Med and Scopus). Results: Out of 6043 hits, nineteen studies were included, seven randomized and twelve non-randomized studies with varying study designs, interventions and outcomes. For most postoperative outcomes, studies did not provide solid evidence of any beneficial effect. Only an increased dietary protein intake was associated with improved weight loss after gastric bypass surgery, but the level of evidence is low (Grade C). Conclusion: The study of the influence of protein and its amino acid composition represents an important developing domain of knowledge and needs further attention considering the high popularity of bariatric surgery. For future study purposes, we recommend a clear description of the exact quantity and composition of the proteins and amino acids in the diet or supplement.

PREVIEW study—influence of a behavior modification intervention (PREMIT) in over 2300 people with pre-diabetes: intention, self-efficacy and outcome expectancies during the early phase of a lifestyle intervention

Purpose Onset of type 2 diabetes (T2D) is often gradual and preceded by impaired glucose homeostasis. Lifestyle interventions including weight loss and physical activity may reduce the risk of developing T2D, but adherence to a lifestyle change is challenging. As part of an international T2D prevention trial (PREVIEW), a behavior change intervention supported participants in achieving a healthier diet and physically active lifestyle. Here, our aim was to explore the influence of this behavioral program (PREMIT) on social-cognitive variables during an 8-week weight loss phase. Methods PREVIEW consisted of an initial weight loss, Phase I, followed by a weight- maintenance, Phase II, for those achieving the 8-week weight loss target of ≥ 8% from initial bodyweight. Overweight and obese (BMI ≥25 kg/m2) individuals aged 25 to 70 years with confirmed pre-diabetes were enrolled. Uni- and multivariate statistical methods were deployed to explore differences in intentions, self-efficacy, and outcome expectancies between those who achieved the target weight loss (“achievers”) and those who did not (“non-achievers”). Results At the beginning of Phase I, no significant differences in intentions, self-efficacy and outcome expectancies between “achievers” (1,857) and “non-achievers” (163) were found. “Non-achievers” tended to be younger, live with child/ren, and attended the PREMIT sessions less frequently. At the end of Phase I, “achievers” reported higher intentions (healthy eating χ2(1)=2.57; P <0.008, exercising χ2(1)=0.66; P <0.008), self-efficacy (F(2; 1970)=10.27, P <0.005), and were more positive about the expected outcomes (F(4; 1968)=11.22, P <0.005). Conclusion Although statistically significant, effect sizes observed between the two groups were small. Behavior change, however, is multi-determined. Over a period of time, even small differences may make a cumulative effect. Being successful in behavior change requires that the “new” behavior is implemented time after time until it becomes a habit. Therefore, having even slightly higher self-efficacy, positive outcome expectancies and intentions may over time result in considerably improved chances to achieve long-term lifestyle changes.

Men and women respond differently to rapid weight loss: Metabolic outcomes of a multi-centre intervention study after a low-energy diet in 2500 overweight, individuals with pre-diabetes (PREVIEW)

The PREVIEW lifestyle intervention study (ClinicalTrials.gov Identifier: NCT01777893) is, to date, the largest, multinational study concerning prevention of type‐2 diabetes. We hypothesized that the initial, fixed low‐energy diet (LED) would induce different metabolic outcomes in men vs women.