Neurohumoral stimulation in type-2-diabetes as an emerging disease concept

Neurohumoral stimulation comprising both autonomic-nervous-system dysfunction and activation of hormonal systems including the renin-angiotensin-aldosterone system (RAAS) was found to be associated with Type-2-diabetes (T2D). Therapeutic strategies such as RAAS interference proved to be beneficial in both T2D treatment and prevention. In addition to an activated RAAS, hyperleptinemia in obesity, hyperinsulinemia in conditions of peripheral insulin resistance and overall oxidative stress in T2D represent known activators of the sympathetic component of the autonomic nervous system. Here, we hypothesize that sympathetic activation may cause peripheral insulin resistance defined as partial blocking of insulin effects on glucose uptake. Resulting hyperinsulinemia or hyperglycemia-related oxidative stress may further aggravate sympatho-excitation. This notion leads to a secondary hypothesis: sympathetic activation worsens from obesity towards insulin resistance, and further towards T2D. In this review, existing evidence relating to neurohumoral stimulation in T2D and consequences thereof, such as oxidative stress and inflammation, are discussed. The aim of this review is to provide a rationale for therapies, which are able to intercept neuroendocrine pathways in T2D and precursor states such as obesity

Understanding the barriers and improving care in type 2 diabetes: Brazilian perspective in time to do more in diabetes

This is the final version of the article. Available from the publisher via the DOI in this record.BACKGROUND: Type 2 diabetes mellitus (T2DM) is a complex disease, particularly in a continental country like Brazil. We attempted to understand and evaluate the perceptions and routines of Brazilians with T2DM and physicians, compared with other countries. METHODS: We compared the results from a 20-min online survey in Brazil with simultaneously collated data from India, Japan, Spain, UK and USA. RESULTS: In total, 652 adults with T2DM and 337 treating physicians were enrolled, of whom 100 patients and 55 physicians were from Brazil. The numbers of primary care physicians from the five countries were 221 versus 43 in Brazil, diabetes specialists were 61 versus 12. There was disconnect between the opinions of physicians and people with diabetes globally. Further, there were differences between clinical practices in Brazil versus the rest of the world, in many areas Brazilians were performing better. CONCLUSIONS: Communication between patients and physicians should be clearer. There is an urgent need to identify the deficits in education, in order to address the clinical inertia within the diabetes management team. There is a necessity to understand the specific requirements of the Brazilian population in order to contextualise international guidelines and implement local changes in practice.The online survey was supported by Novarti

Comorbidities as an Indication for Metabolic Surgery

Metabolic diseases, comprising type 2 diabetes mellitus (T2DM), dyslipidemia, and non-alcoholic steatohepatitis (NASH), are rapidly increasing worldwide. Conservative medical therapy, including the newly available drugs, has only limited effects and does neither influence survival or the development of micro- or macrovascular complications, nor the progression of NASH to liver cirrhosis, nor the development of hepatocellular carcinomas in the NASH liver. In contrast, metabolic surgery is very effective independent of the preoperative body mass index (BMI) in reducing overall and cardiovascular mortality in patients with T2DM. Furthermore, metabolic surgery significantly reduces the development of microand macrovascular complications while being the most effective therapy in order to achieve remission of T2DM and to reach the targeted glycemic control. Importantly, even existing diabetic complications such as nephropathy as well as the features of NASH can be reversed by metabolic surgery. Here, we propose indications for metabolic surgery due to T2DM and NASH based on a simple but objective, disease-specific staging system. We outline the use of the Edmonton Obesity Staging System (EOSS) as a clinical staging system independent of the BMI that will identify patients who will benefit the most from metabolic surgery

Olfactory receptor 984: a new target for obesity in rats and humans?

Aims: Obesity is a complex multifactorial and heterogeneous condition with an important genetic component matched with behavioral and environmental factors. Feeding behavior and body weight are controlled through complex interactions between the central nervous system (CNS) and peripheral organs. The aim of the present study was to identify and functionally characterize candidate gene/s involved in the development of resistance to diet-induced obesity (DIO) in rats. Methods: RNA Chip-Technology and genotype analysis was done in 10 visceral adipose tissue samples of DR (n=5) and DIO (n=5) rats. The most promising candidate gene, OR6C3 (orthologous with the rat Olr984 and mouse Olfr788) was measured by quantitative real-time PCR in adipocytes and stromal vascular fraction (SVF) from paired samples of human visceral and subcutaneous adipose tissue (AT) (n=225). Moreover, Olfr788 expression in 3T3-L1 adipocytes was measured after treatment with various hormones and cytokines. Results: Gene expression analyses showed Olr984 differently regulated in DIO-resistant rats. In the subcutaneous AT of human samples we found a down-regulation of OR6C3 compared to the visceral AT of the same population, independent of gender, glucose tolerance or type 2 diabetes. OR6C3 is more expressed in SVF than in adipocytes. Interestingly, treatment of 3T3-L1 cells with insulin decreased Olfr788 expression mRNA compared to untreated controls. Conclusions: Olr984 is a novel candidate gene related to diet-induced obesity in rats. Moreover, variation in human mRNA expression in AT is related to obesity parameters and glucose homeostasis, which might be attributed to the regulatory role of insulin on the Olr984

Availability of central α4β2* nicotinic acetylcholine receptors in human obesity

Purpose: Obesity is thought to arise, in part, from deficits in the inhibitory control over appetitive behavior. Such motivational processes are regulated by neuromodulators, specifically acetylcholine (ACh), via α4β2* nicotinic ACh receptors (nAChR). These nAChR are highly enriched in the thalamus and contribute to the thalamic gating of cortico-striatal signaling, but also act on the mesoaccumbal reward system. The changes in α4β2* nAChR availability, however, have not been demonstrated in human obesity thus far. The aim of our study was, thus, to investigate whether there is altered brain α4β2* nAChR availability in individuals with obesity compared to normal-weight healthy controls. Methods: We studied 15 non-smoking individuals with obesity (body mass index, BMI: 37.8 ± 3.1 kg/m2; age: 39 ± 14 years, 9 females) and 16 normal-weight controls (non-smokers, BMI: 21.9 ± 1.7 kg/m2; age: 28 ± 7 years, 13 females) by using PET and the α4β2* nAChR selective (−)-[18F]flubatine, which was applied within a bolus-infusion protocol (294 ± 16 MBq). Volume-of-interest (VOI) analysis was performed in order to calculate the regional total distribution volume (VT). Results: No overall significant difference in VT between the individuals with obesity and the normal-weight volunteers was found, while the VT in the nucleus basalis of Meynert tended to be lower in the individuals with obesity (10.1 ± 2.1 versus 11.9 ± 2.2; p = 0.10), and the VT in the thalamus showed a tendency towards higher values in the individuals with obesity (26.5 ± 2.5 versus 25.9 ± 4.2; p = 0.09). Conclusion: While these first data do not show greater brain α4β2* nAChR availability in human obesity overall, the findings of potentially aberrant α4β2* nAChR availability in the key brain regions that regulate feeding behavior merit further exploration

Renal Function Following Three Distinct Weight Loss Dietary Strategies During 2 Years of a Randomized Controlled Trial

OBJECTIVE This study addressed the long-term effect of various diets, particularly low-carbohydrate high-protein, on renal function on participants with or without type 2 diabetes. RESEARCH DESIGN AND METHODS In the 2-year Dietary Intervention Randomized Controlled Trial (DIRECT), 318 participants (age, 51 years; 86% men; BMI, 31 kg/m2; mean estimated glomerular filtration rate [eGFR], 70.5 mL/min/1.73 m2; mean urine microalbumin-to-creatinine ratio, 12:12) with serum creatinine 0.05) across diet groups. The increased eGFR was at least as prominent in participants with (+6.7%) or without (+4.5%) type 2 diabetes or those with lower baseline renal function of eGFR <60 mL/min/1.73 m2 (+7.1%) versus eGFR ≥60 mL/min/1.73 m2 (+3.7%). In a multivariable model adjusted for age, sex, diet group, type 2 diabetes, use of ACE inhibitors, 2-year weight loss, and change in protein intake (confounders and univariate predictors), only a decrease in fasting insulin (β = −0.211; P = 0.004) and systolic blood pressure (β = −0.25; P < 0.001) were independently associated with increased eGFR. The urine microalbumin-to-creatinine ratio improved similarly across the diets, particularly among participants with baseline sex-adjusted microalbuminuria, with a mean change of −24.8 (P < 0.05). CONCLUSIONS A low-carbohydrate diet is as safe as Mediterranean or low-fat diets in preserving/improving renal function among moderately obese participants with or without type 2 diabetes, with baseline serum creatinine <176 μmol/L. Potential improvement is likely to be mediated by weight loss–induced improvements in insulin sensitivity and blood pressure

Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial

18openInternationalBothObjective To examine the effectiveness of green-Mediterranean (MED) diet, further restricted in red/processed meat, and enriched with green plants and polyphenols on non-alcoholic fatty liver disease (NAFLD), reflected by intrahepatic fat (IHF) loss. Design For the DIRECT-PLUS 18-month randomized clinical trial, we assigned 294 participants with abdominal obesity/dyslipidaemia into healthy dietary guidelines (HDG), MED and green-MED weight-loss diet groups, all accompanied by physical activity. Both isocaloric MED groups consumed 28 g/day walnuts (+440 mg/day polyphenols provided). The green-MED group further consumed green tea (3–4 cups/day) and Mankai (a Wolffia globosa aquatic plant strain; 100 g/day frozen cubes) green shake (+1240 mg/day total polyphenols provided). IHF% 18-month changes were quantified continuously by proton magnetic resonance spectroscopy (MRS). Results Participants (age=51 years; 88% men; body mass index=31.3 kg/m2; median IHF%=6.6%; mean=10.2%; 62% with NAFLD) had 89.8% 18-month retention-rate, and 78% had eligible follow-up MRS. Overall, NAFLD prevalence declined to: 54.8% (HDG), 47.9% (MED) and 31.5% (green-MED), p=0.012 between groups. Despite similar moderate weight-loss in both MED groups, green-MED group achieved almost double IHF% loss (−38.9% proportionally), as compared with MED (−19.6% proportionally; p=0.035 weight loss adjusted) and HDG (−12.2% proportionally; p<0.001). After 18 months, both MED groups had significantly higher total plasma polyphenol levels versus HDG, with higher detection of Naringenin and 2-5-dihydroxybenzoic-acid in green-MED. Greater IHF% loss was independently associated with increased Mankai and walnuts intake, decreased red/processed meat consumption, improved serum folate and adipokines/lipids biomarkers, changes in microbiome composition (beta-diversity) and specific bacteria (p<0.05 for all). Conclusion The new suggested strategy of green-Mediterranean diet, amplified with green plant-based proteins/polyphenols as Mankai, green tea, and walnuts, and restricted in red/processed meat can double IHF loss than other healthy nutritional strategies and reduce NAFLD in half.openYaskolka Meir, Anat; Rinott, Ehud; Tsaban, Gal; Zelicha, Hila; Kaplan, Alon; Rosen, Philip; Shelef, Ilan; Youngster, Ilan; Shalev, Aryeh; Blüher, Matthias; Ceglarek, Uta; Stumvoll, Michael; Tuohy, Kieran; Diotallevi, Camilla; Vrhovsek, Urska; Hu, Frank; Stampfer, Meir; Shai, IrisYaskolka Meir, A.; Rinott, E.; Tsaban, G.; Zelicha, H.; Kaplan, A.; Rosen, P.; Shelef, I.; Youngster, I.; Shalev, A.; Blüher, M.; Ceglarek, U.; Stumvoll, M.; Tuohy, K.; Diotallevi, C.; Vrhovsek, U.; Hu, F.; Stampfer, M.; Shai, I

Many obesity-associated SNPs strongly associate with DNA methylation changes at proximal promoters and enhancers

Background: The mechanisms by which genetic variants, such as single nucleotide polymorphisms (SNPs), identified in genome-wide association studies act to influence body mass remain unknown for most of these SNPs, which continue to puzzle the scientific community. Recent evidence points to the epigenetic and chromatin states of the genome as having important roles. Methods: We genotyped 355 healthy young individuals for 52 known obesity-associated SNPs and obtained DNA methylation levels in their blood using the Illumina 450 K BeadChip. Associations between alleles and methylation at proximal cytosine residues were tested using a linear model adjusted for age, sex, weight category, and a proxy for blood cell type counts. For replication in other tissues, we used two open-access datasets (skin fibroblasts, n = 62; four brain regions, n = 121-133) and an additional dataset in subcutaneous and visceral fat (n = 149). Results: We found that alleles at 28 of these obesity-associated SNPs associate with methylation levels at 107 proximal CpG sites. Out of 107 CpG sites, 38 are located in gene promoters, including genes strongly implicated in obesity (MIR148A, BDNF, PTPMT1, NR1H3, MGAT1, SCGB3A1, HOXC12, PMAIP1, PSIP1, RPS10-NUDT3, RPS10, SKOR1, MAP2K5, SIX5, AGRN, IMMP1L, ELP4, ITIH4, SEMA3G, POMC, ADCY3, SSPN, LGR4, TUFM, MIR4721, SULT1A1, SULT1A2, APOBR, CLN3, SPNS1, SH2B1, ATXN2L, and IL27). Interestingly, the associated SNPs are in known eQTLs for some of these genes. We also found that the 107 CpGs are enriched in enhancers in peripheral blood mononuclear cells. Finally, our results indicate that some of these associations are not blood-specific as we successfully replicated four associations in skin fibroblasts. Conclusions: Our results strongly suggest that many obesity-associated SNPs are associated with proximal gene regulation, which was reflected by association of obesity risk allele genotypes with differential DNA methylation. This study highlights the importance of DNA methylation and other chromatin marks as a way to understand the molecular basis of genetic variants associated with human diseases and traits