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Environmental risk factors of type 2 diabetes-an exposome approach.
Beulens, JWJ, Pinho, MGM, Abreu, TC, den Braver, NR, Lam, TM, Huss, A, Vlaanderen, J, Sonnenschein, T, Siddiqui, NZ, Yuan, Z, et al
Diabetologia. 2022;(2):263-274
Abstract
Type 2 diabetes is one of the major chronic diseases accounting for a substantial proportion of disease burden in Western countries. The majority of the burden of type 2 diabetes is attributed to environmental risks and modifiable risk factors such as lifestyle. The environment we live in, and changes to it, can thus contribute substantially to the prevention of type 2 diabetes at a population level. The 'exposome' represents the (measurable) totality of environmental, i.e. nongenetic, drivers of health and disease. The external exposome comprises aspects of the built environment, the social environment, the physico-chemical environment and the lifestyle/food environment. The internal exposome comprises measurements at the epigenetic, transcript, proteome, microbiome or metabolome level to study either the exposures directly, the imprints these exposures leave in the biological system, the potential of the body to combat environmental insults and/or the biology itself. In this review, we describe the evidence for environmental risk factors of type 2 diabetes, focusing on both the general external exposome and imprints of this on the internal exposome. Studies provided established associations of air pollution, residential noise and area-level socioeconomic deprivation with an increased risk of type 2 diabetes, while neighbourhood walkability and green space are consistently associated with a reduced risk of type 2 diabetes. There is little or inconsistent evidence on the contribution of the food environment, other aspects of the social environment and outdoor temperature. These environmental factors are thought to affect type 2 diabetes risk mainly through mechanisms incorporating lifestyle factors such as physical activity or diet, the microbiome, inflammation or chronic stress. To further assess causality of these associations, future studies should focus on investigating the longitudinal effects of our environment (and changes to it) in relation to type 2 diabetes risk and whether these associations are explained by these proposed mechanisms.
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Mechanisms of action of SGLT2 inhibitors and their beneficial effects on the cardiorenal axis.
Gronda, E, Lopaschuk, GD, Arduini, A, Santoro, A, Benincasa, G, Palazzuoli, A, Gabrielli, D, Napoli, C
Canadian journal of physiology and pharmacology. 2022;(2):93-106
Abstract
Large clinical studies conducted with sodium-glucose co-transporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes and heart failure with reduced ejection fraction have demonstrated their ability to achieve both cardiac and kidney benefits. Although there is huge evidence on SGLT2i-mediated clinical benefits both in diabetic and non-diabetic patients, the pathophysiological mechanisms underlying their efficacy are still poorly understood. Some favorable mechanisms are likely due to the prompt glycosuric action which is associated with natriuretic effects leading to hemodynamic benefits as well as a reduction in glomerular hyperfiltration and renin-angiotensin-aldosterone system activation. In addition to the renal mechanisms, SGLT2i may play a relevant role in cardiorenal axis protection by improving the cardiomyocyte metabolism, by exerting anti-fibrotic and anti-inflammatory actions, and by increasing cardioprotective adipokine expression. New studies will be needed to better understand the specific molecular mechanisms that mediate the SGLT2i favorable effects in patients suffering diabetes. Our aim is to first discuss about the molecular mechanisms underlying the cardiovascular benefits of SGLT2i in each of the main organs involved in the cardiorenal axis. Furthermore, we update on the most recent clinical trials evaluating the beneficial effects of SGLT2i in treatment of both diabetic and non-diabetic patients suffering heart failure.
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Lower carbohydrate diets for adults with type 2 diabetes.
Singh, M, Hung, ES, Cullum, A, Allen, RE, Aggett, PJ, Dyson, P, Forouhi, NG, Greenwood, DC, Pryke, R, Taylor, R, et al
Diabetic medicine : a journal of the British Diabetic Association. 2022;(3):e14674
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Chiglitazar: First Approval.
Deeks, ED
Drugs. 2022;(1):87-92
Abstract
Chiglitazar (Bilessglu®) is an orally administered, non-thiazolidinedione small-molecule agonist of α, δ and γ peroxisome proliferator-activated receptors (PPARs) being developed by Chipscreen Biosciences for the treatment of type 2 diabetes (T2D) and non-alcoholic steatohepatitis. In October 2021, chiglitazar was approved in China for use as an adjunct to diet and exercise to improve glycaemic control in adult patients with T2D. The drug is also in phase 2 clinical development in China for the treatment of non-alcoholic steatohepatitis. This article summarizes the milestones in the development of chiglitazar leading to this first approval for the treatment of T2D.
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Mediterranean Diet and Type 2 Diabetes Mellitus: A Perpetual Inspiration for the Scientific World. A Review.
Milenkovic, T, Bozhinovska, N, Macut, D, Bjekic-Macut, J, Rahelic, D, Velija Asimi, Z, Burekovic, A
Nutrients. 2021;(4)
Abstract
For the past 80 years, the effect of the Mediterranean diet on overall health has been a constant topic of interest among medical and scientific researchers. Parallel with the persistent global rise of cases of type 2 diabetes, many studies conducted in the past 20 years have shown the benefits of the Mediterranean lifestyle for people with, or at risk of developing, type 2 diabetes mellitus. However, despite the large body of evidence, concerns exist amongst scientists regarding the reliability of the data related to this topic. This review offers a glimpse of the onset of the Mediterranean diet and follows its significant impact on the prevention and treatment of type 2 diabetes. There is a constant rise in type 2 diabetes cases on the Balkan Peninsula and North Macedonia in particular. Having in mind that North Macedonia, as well as most of the countries on the Balkans have low to middle income, there is a need for a certain affordable dietary pattern to ameliorate the rise in diabetes incidence, as well as improve the glycemic control. We did a review based on the available literature regarding Mediterranean diet and people with or at risk of developing type 2 diabetes mellitus, its effects on glycemic control, lipid profile and metabolic outcome.
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6.
Secondary analyses of global datasets: do obesity and physical activity explain variation in diabetes risk across populations?
Alkaf, B, Blakemore, AI, Järvelin, MR, Lessan, N
International journal of obesity (2005). 2021;(5):944-956
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Abstract
Type 2 diabetes rates vary significantly across geographic regions. These differences are sometimes assumed to be entirely driven by differential distribution of environmental triggers, including obesity and insufficient physical activity (IPA). In this review, we discuss data which conflicts with this supposition. We carried out a secondary analysis of publicly available data to unravel the relative contribution of obesity and IPA towards diabetes risk across different populations. We used sex-specific, age-standardized estimates from Non-Communicable Disease Risk Factor Collaboration (NCD-RisC) on diabetes (1980-2014) and obesity (1975-2016) rates, in 200 countries, and from WHO on IPA rates in 168 countries in the year 2016. NCD-RisC and WHO organized countries into nine super-regions. All analyses were region- and sex-specific. Although obesity has been increasing since 1975 in every part of the world, this was not reflected in a proportional increase in diabetes rates in several regions, including Central and Eastern Europe, and High-income western countries region. Similarly, the association of physical inactivity with diabetes is not homogeneous across regions. Countries from different regions across the world could have very similar rates of diabetes, despite falling on opposite ends of IPA rate spectrum. The combined effect of obesity and IPA on diabetes risk was analyzed at the worldwide and country level. The overall findings highlighted the larger impact of obesity on disease risk; low IPA rates do not seem to be protective of diabetes, when obesity rates are high. Despite that, some countries deviate from this overall observation. Sex differences were observed across all our analyses. Overall, data presented in this review indicate that different populations, while experiencing similar environmental shifts, are apparently differentially subject to diabetes risk. Sex-related differences observed suggest that males and females are either subject to different risk factor exposures or have different responses to them.
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Glucose-Lowering Drugs to Reduce Cardiovascular Risk in Type 2 Diabetes.
Kalyani, RR
The New England journal of medicine. 2021;(13):1248-1260
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Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes.
Milardi, D, Gazit, E, Radford, SE, Xu, Y, Gallardo, RU, Caflisch, A, Westermark, GT, Westermark, P, Rosa, C, Ramamoorthy, A
Chemical reviews. 2021;(3):1845-1893
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Abstract
The possible link between hIAPP accumulation and β-cell death in diabetic patients has inspired numerous studies focusing on amyloid structures and aggregation pathways of this hormone. Recent studies have reported on the importance of early oligomeric intermediates, the many roles of their interactions with lipid membrane, pH, insulin, and zinc on the mechanism of aggregation of hIAPP. The challenges posed by the transient nature of amyloid oligomers, their structural heterogeneity, and the complex nature of their interaction with lipid membranes have resulted in the development of a wide range of biophysical and chemical approaches to characterize the aggregation process. While the cellular processes and factors activating hIAPP-mediated cytotoxicity are still not clear, it has recently been suggested that its impaired turnover and cellular processing by proteasome and autophagy may contribute significantly toward toxic hIAPP accumulation and, eventually, β-cell death. Therefore, studies focusing on the restoration of hIAPP proteostasis may represent a promising arena for the design of effective therapies. In this review we discuss the current knowledge of the structures and pathology associated with hIAPP self-assembly and point out the opportunities for therapy that a detailed biochemical, biophysical, and cellular understanding of its aggregation may unveil.
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Defining the underlying defect in insulin action in type 2 diabetes.
Batista, TM, Haider, N, Kahn, CR
Diabetologia. 2021;(5):994-1006
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Abstract
Insulin resistance is one of the earliest defects in the pathogenesis of type 2 diabetes. Over the past 50 years, elucidation of the insulin signalling network has provided important mechanistic insights into the abnormalities of glucose, lipid and protein metabolism that underlie insulin resistance. In classical target tissues (liver, muscle and adipose tissue), insulin binding to its receptor initiates a broad signalling cascade mediated by changes in phosphorylation, gene expression and vesicular trafficking that result in increased nutrient utilisation and storage, and suppression of catabolic processes. Insulin receptors are also expressed in non-classical targets, such as the brain and endothelial cells, where it helps regulate appetite, energy expenditure, reproductive hormones, mood/behaviour and vascular function. Recent progress in cell biology and unbiased molecular profiling by mass spectrometry and DNA/RNA-sequencing has provided a unique opportunity to dissect the determinants of insulin resistance in type 2 diabetes and the metabolic syndrome; best studied are extrinsic factors, such as circulating lipids, amino acids and other metabolites and exosomal microRNAs. More challenging has been defining the cell-intrinsic factors programmed by genetics and epigenetics that underlie insulin resistance. In this regard, studies using human induced pluripotent stem cells and tissues point to cell-autonomous alterations in signalling super-networks, involving changes in phosphorylation and gene expression both inside and outside the canonical insulin signalling pathway. Understanding how these multi-layered molecular networks modulate insulin action and metabolism in different tissues will open new avenues for therapy and prevention of type 2 diabetes and its associated pathologies.
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Nutrition in Patients with Type 2 Diabetes: Present Knowledge and Remaining Challenges.
Petroni, ML, Brodosi, L, Marchignoli, F, Sasdelli, AS, Caraceni, P, Marchesini, G, Ravaioli, F
Nutrients. 2021;(8)
Abstract
Unhealthy behaviours, including diet and physical activity, coupled with genetic predisposition, drive type 2 diabetes (T2D) occurrence and severity; the present review aims to summarise the most recent nutritional approaches in T2D, outlining unmet needs. Guidelines consistently suggest reducing energy intake to counteract the obesity epidemic, frequently resulting in sarcopenic obesity, a condition associated with poorer metabolic control and cardiovascular disease. Various dietary approaches have been proposed with largely similar results, with a preference for the Mediterranean diet and the best practice being the diet that patients feel confident of maintaining in the long term based on individual preferences. Patient adherence is indeed the pivotal factor for weight loss and long-term maintenance, requiring intensive lifestyle intervention. The consumption of nutritional supplements continues to increase even if international societies do not support their systematic use. Inositols and vitamin D supplementation, as well as micronutrients (zinc, chromium, magnesium) and pre/probiotics, result in modest improvement in insulin sensitivity, but their use is not systematically suggested. To reach the desired goals, patients should be actively involved in the collaborative development of a personalised meal plan associated with habitual physical activity, aiming at normal body weight and metabolic control.