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1.
Understanding Metabolic Memory: A Tale of Two Studies.
Miller, RG, Orchard, TJ
Diabetes. 2020;(3):291-299
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Abstract
The results of the Diabetes Control and Complications Trial (DCCT) have given rise to much encouragement in the battle to stave off the complications of type 1 diabetes, showing dramatic declines in the development of severe retinopathy, nephropathy, and neuropathy in those treated intensively compared with conventional therapy. Particularly encouraging has been the continuing difference between the two groups despite both having similar HbA1c (∼8%) since the end of DCCT, when 96% of participants entered the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. This continuing relative benefit has been termed "metabolic memory," which implies altered metabolic regulation. Based on evidence from both the Epidemiology of Diabetes Complications (EDC) prospective cohort study of childhood-onset type 1 diabetes and DCCT/EDIC, we show that the metabolic memory effect can be largely explained by lower cumulative glycemic exposure in the intensive therapy group, and, on average, the development of complications increases with greater glycemic exposure, irrespective of whether this results from a high exposure for a short time or a lower exposure for a longer time. Thus, there is no need for a concept like "metabolic memory" to explain these observations. Potential mechanisms explaining the cumulative glycemic effect are also briefly discussed.
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Insulin resistance in bariatric surgery.
Stenberg, E, Thorell, A
Current opinion in clinical nutrition and metabolic care. 2020;(4):255-261
Abstract
PURPOSE OF REVIEW To give an updated review on the underlying mechanisms and clinical effects of improved glucose control after bariatric surgery. RECENT FINDINGS The basic principles of the mechanism for the metabolic effects of bariatric surgery can be categorized into calorie restriction, deviation of nutrients, and reduced amounts of adipose tissue. Recent findings suggest the importance of early changes following deviation of nutrients to more distal parts of the small bowel resulting in altered release of gastrointestinal hormones, altered gut microbiota, and weight-reduction. In the long-term, loss of adipose tissue results in reduced inflammation and improved insulin sensitivity. From a clinical perspective these changes are associated with remission of diabetes in patients with morbid obesity and type 2 diabetes, prevention of diabetes in patients with insulin resistance without overt type 2 diabetes and prevention of both microvascular and macrovascular complications for all patients with morbid obesity. SUMMARY At present, bariatric surgery remains the most effective treatment option to improve glucose control and long-term complications associated with hyperglycemia in patients with obesity.Although the mechanisms behind these metabolic effects remain only partially understood, further knowledge on these complex mechanisms may help identifying durable treatment options for morbid obesity and important metabolic comorbidities.
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A State-of-the-Science Review of Arsenic's Effects on Glucose Homeostasis in Experimental Models.
Castriota, F, Rieswijk, L, Dahlberg, S, La Merrill, MA, Steinmaus, C, Smith, MT, Wang, JC
Environmental health perspectives. 2020;(1):16001
Abstract
BACKGROUND The prevalence of type 2 diabetes (T2D) has more than doubled since 1980. Poor nutrition, sedentary lifestyle, and obesity are among the primary risk factors. While an estimated 70% of cases are attributed to excess adiposity, there is an increased interest in understanding the contribution of environmental agents to diabetes causation and severity. Arsenic is one of these environmental chemicals, with multiple epidemiology studies supporting its association with T2D. Despite extensive research, the molecular mechanism by which arsenic exerts its diabetogenic effects remains unclear. OBJECTIVES We conducted a literature search focused on arsenite exposure in vivo and in vitro, using relevant end points to elucidate potential mechanisms of oral arsenic exposure and diabetes development. METHODS We explored experimental results for potential mechanisms and elucidated the distinct effects that occur at high vs. low exposure. We also performed network analyses relying on publicly available data, which supported our key findings. RESULTS While several mechanisms may be involved, our findings support that arsenite has effects on whole-body glucose homeostasis, insulin-stimulated glucose uptake, glucose-stimulated insulin secretion, hepatic glucose metabolism, and both adipose and pancreatic β-cell dysfunction. DISCUSSION This review applies state-of-the-science approaches to identify the current knowledge gaps in our understanding of arsenite on diabetes development. https://doi.org/10.1289/EHP4517.
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Dietary polyphenols modulate starch digestion and glycaemic level: a review.
Sun, L, Miao, M
Critical reviews in food science and nutrition. 2020;(4):541-555
Abstract
Polyphenols, as one group of secondary metabolite, are widely distributed in plants and have been reported to show various bioactivities in recent year. Starch digestion not only is related with food industrial applications such as brewing but also plays an important role in postprandial blood glucose level, and therefore insulin resistance. Many studies have shown that dietary phenolic extracts and pure polyphenols can retard starch digestion in vitro, and the retarding effect depends on the phenolic composition and molecular structure. Besides, dietary polyphenols have also been reported to alleviate elevation of blood glucose level after meal, indicating the inhibition of starch digestion in vivo. This review aims to analyze how dietary polyphenols affect starch digestion both in vitro and in vivo. We can conclude that the retarded starch digestion in vitro by polyphenols results from inhibition of key digestive enzymes, including α-amylase and α-glucosidase, as well as from interactions between polyphenols and starch. The alleviation of postprandial hyperglycemia by polyphenols might be caused by both the inhibited starch digestion in vivo and the influenced glucose transport. Therefore, phenolic extracts or pure polyphenols may be alternatives for preventing and treating type II diabetes disease.
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Glycemic Variability and CNS Inflammation: Reviewing the Connection.
Watt, C, Sanchez-Rangel, E, Hwang, JJ
Nutrients. 2020;(12)
Abstract
Glucose is the primary energy source for the brain, and exposure to both high and low levels of glucose has been associated with numerous adverse central nervous system (CNS) outcomes. While a large body of work has highlighted the impact of hyperglycemia on peripheral and central measures of oxidative stress, cognitive deficits, and vascular complications in Type 1 and Type 2 diabetes, there is growing evidence that glycemic variability significantly drives increased oxidative stress, leading to neuroinflammation and cognitive dysfunction. In this review, the latest data on the impact of glycemic variability on brain function and neuroinflammation will be presented. Because high levels of oxidative stress have been linked to dysfunction of the blood-brain barrier (BBB), special emphasis will be placed on studies investigating the impact of glycemic variability on endothelial and vascular inflammation. The latest clinical and preclinical/in vitro data will be reviewed, and clinical/therapeutic implications will be discussed.
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Current status of insulin degludec in type 1 and type 2 diabetes based on randomized and observational trials.
Preumont, V, Buysschaert, M
Diabetes & metabolism. 2020;(2):83-88
Abstract
Insulin degludec is a new ultra-long-action basal insulin. Using treat-to-target protocols, controlled trials have shown comparable HbA1c reductions with insulin degludec and comparators in both type 1 and type 2 diabetes. Most studies identify, however, better control of fasting plasma glucose with insulin degludec vs. either insulin glargine U100 or detemir, and all have consistently demonstrated clinically relevant decreases in (nocturnal) hypoglycaemic episodes. These characteristics have provided added therapeutic value for insulin degludec in clinical practice. Thus, the aim of this review is to discuss, within the context of randomized and observational studies, the clinical effects of insulin degludec use in type 1 and type 2 diabetes.
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Mechanisms of the Regulation and Dysregulation of Glucagon Secretion.
Onyango, AN
Oxidative medicine and cellular longevity. 2020;:3089139
Abstract
Glucagon, a hormone secreted by pancreatic alpha cells, contributes to the maintenance of normal blood glucose concentration by inducing hepatic glucose production in response to declining blood glucose. However, glucagon hypersecretion contributes to the pathogenesis of type 2 diabetes. Moreover, diabetes is associated with relative glucagon undersecretion at low blood glucose and oversecretion at normal and high blood glucose. The mechanisms of such alpha cell dysfunctions are not well understood. This article reviews the genesis of alpha cell dysfunctions during the pathogenesis of type 2 diabetes and after the onset of type 1 and type 2 diabetes. It unravels a signaling pathway that contributes to glucose- or hydrogen peroxide-induced glucagon secretion, whose overstimulation contributes to glucagon dysregulation, partly through oxidative stress and reduced ATP synthesis. The signaling pathway involves phosphatidylinositol-3-kinase, protein kinase B, protein kinase C delta, non-receptor tyrosine kinase Src, and phospholipase C gamma-1. This knowledge will be useful in the design of new antidiabetic agents or regimens.
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8.
Benefits and Adverse Effects of Histidine Supplementation.
Thalacker-Mercer, AE, Gheller, ME
The Journal of nutrition. 2020;(Suppl 1):2588S-2592S
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Abstract
Histidine is a nutritionally essential amino acid with many recognized benefits to human health, while circulating concentrations of histidine decline in pathologic conditions [e.g., chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD)]. The purpose of this review is to examine the existing literature regarding the benefits of histidine intake, the adverse effects of excess histidine, and the upper tolerance level for histidine. Supplementation with doses of 4.0-4.5 g histidine/d and increased dietary histidine intake are associated with decreased BMI, adiposity, markers of glucose homeostasis (e.g., HOMA-IR, fasting blood glucose, 2-h postprandial blood glucose), proinflammatory cytokines, and oxidative stress. It is unclear from the limited number of studies in humans whether the improvements in glucoregulatory markers, inflammation, and oxidative stress are due to reduced BMI and adiposity, increased carnosine (a metabolic product of histidine with antioxidant effects), or both. Histidine intake also improves cognitive function (e.g., reduces appetite, anxiety, and stress responses and improves sleep) potentially through the metabolism of histidine to histamine; however, this relation is ambiguous in humans. At high intakes of histidine (>24 g/d), studies report adverse effects of histidine such as decreased serum zinc and cognitive impairment. There is limited research on the effects of histidine intake at doses between 4.5 and 24 g/d, and thus, a tolerable upper level has not been established. Determining tolerance to histidine supplementation has been limited by small sample sizes and, more important, a lack of a clear biomarker for histidine supplementation. The U-shaped curve of circulating zinc concentrations with histidine supplementation could be exploited as a relevant biomarker for supplemental histidine tolerance. Histidine is an important amino acid and may be necessary as a supplement in some populations; however, gaps in knowledge, which this review highlights, need to be addressed scientifically.
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A position statement on screening and management of prediabetes in adults in primary care in Australia.
Bell, K, Shaw, JE, Maple-Brown, L, Ferris, W, Gray, S, Murfet, G, Flavel, R, Maynard, B, Ryrie, H, Pritchard, B, et al
Diabetes research and clinical practice. 2020;:108188
Abstract
Prediabetes has a high prevalence, with early detection essential to facilitate optimal management to prevent the development of conditions such as type 2 diabetes and cardiovascular disease. Prediabetes can include impaired fasting glucose, impaired glucose tolerance and elevated HbA1c. This position statement outlines the approaches to screening and management of prediabetes in primary care. There is good evidence to implement intensive, structured lifestyle interventions for individuals with impaired glucose tolerance. The evidence for those with impaired fasting glucose or elevated HbA1c is less clear, but individuals should still be provided with generalised healthy lifestyle strategies. A multidisciplinary approach is recommended to implement healthy lifestyle changes through education, nutrition and physical activity. Individuals should aim to lose weight (5-10% of body mass) using realistic and sustainable dietary approaches supported by an accredited practising dietitian, where possible. Physical activity and exercise should be used to facilitate weight maintenance and reduce blood glucose. Moderate-vigorous intensity aerobic exercise and resistance training should be prescribed by an accredited exercise physiologist, where possible. When indicated, pharmacotherapy, metabolic surgery and psychosocial care should be considered, in order to enhance the outcomes associated with lifestyle change. Individuals with prediabetes should generally be evaluated annually for their diabetes status.
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Dapagliflozin and cardiovascular outcomes in patients with Type 2 diabetes.
Al-Bazz, DY, Wilding, JP
Future cardiology. 2020;(2):77-88
Abstract
The relationship between cardiovascular disease, heart failure (HF) and Type-2 diabetes (T2DM) is widely recognized. Cardiovascular (CV) outcome trials are required for all new glucose-lowering agents to confirm safety with respect to CV risk. CV outcome trials with SGLT2i inhibitors have shown CV benefit, with reductions in major CV events and HF. This review focuses on the DECLARE-TIMI 58 trial with dapagliflozin in T2DM, which showed noninferiority for major adverse cardiovascular events and reduction in hospitalization for HF and associated CV mortality in a broad range of patients with T2DM. The DAPA-HF trial of dapagliflozin in people with HF with reduced ejection fraction with and without T2DM confirms benefits for those with HF.