The Emerging role of Branch Chain Amino Acids in the Prediction of Diabetes: A Brief Review

2020 ◽  
Vol 16 (6) ◽  
pp. 532-537 ◽  
Author(s):  
Shaik Sarfaraz Nawaz ◽  
Khalid Siddiqui
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Amino Acids ◽  
Causative Factor ◽  
Undiagnosed Diabetes ◽  
Future Research ◽  
Important Approach ◽  
Branch Chain Amino ◽  
Prediction Of Diabetes

Diabetes is a chronic condition; those with diabetes are at high risk of developing diabetes complications. One important approach to tackle the diabetes burden is to screen for undiagnosed diabetes and to identify factors that lead to the risk of developing diabetes in the future. The earlier identification of individuals at risk of developing diabetes is crucial for delaying or preventing the onset of type 2 diabetes. Numerous studies have demonstrated that circulating concentrations of branch chain amino acids (BCAAs) predict the risk for developing diabetes; thus, contributing to the recent resurgence of interest in these common analytes. The present review aimed to address the recent findings regarding BCAAs and their role in insulin resistance and diabetes. Recent studies demonstrate that BCAAs are strongly associated with a number of pathological mechanisms causing insulin resistance and type 2 diabetes. The research findings related to BCAA signaling pathways and metabolism broaden our understanding of this topic. However, it remains unclear how increased levels of BCAAs will assist in the prediction of future insulin resistance or type 2 diabetes. Future research needs to determine whether BCAAs are a causative factor for insulin resistance and type 2 diabetes, or just a biomarker of impaired insulin action.

scholarly journals Hyperinsulinemia and Its Pivotal Role in Aging, Obesity, Type 2 Diabetes, Cardiovascular Disease and Cancer

2021 ◽  
Vol 22 (15) ◽  
pp. 7797
Author(s):  
Joseph A. M. J. L. Janssen
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Insulin Secretion ◽  
Early Stage ◽  
Insulin Clearance ◽  
Future Research ◽  
Age Related ◽  
Hepatic Insulin Clearance

For many years, the dogma has been that insulin resistance precedes the development of hyperinsulinemia. However, recent data suggest a reverse order and place hyperinsulinemia mechanistically upstream of insulin resistance. Genetic background, consumption of the “modern” Western diet and over-nutrition may increase insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing hyperinsulinemia. Hyperinsulinemia disturbs the balance of the insulin–GH–IGF axis and shifts the insulin : GH ratio towards insulin and away from GH. This insulin–GH shift promotes energy storage and lipid synthesis and hinders lipid breakdown, resulting in obesity due to higher fat accumulation and lower energy expenditure. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, cancer and premature mortality. It has been further hypothesized that nutritionally driven insulin exposure controls the rate of mammalian aging. Interventions that normalize/reduce plasma insulin concentrations might play a key role in the prevention and treatment of age-related decline, obesity, type 2 diabetes, cardiovascular disease and cancer. Caloric restriction, increasing hepatic insulin clearance and maximizing insulin sensitivity are at present the three main strategies available for managing hyperinsulinemia. This may slow down age-related physiological decline and prevent age-related diseases. Drugs that reduce insulin (hyper) secretion, normalize pulsatile insulin secretion and/or increase hepatic insulin clearance may also have the potential to prevent or delay the progression of hyperinsulinemia-mediated diseases. Future research should focus on new strategies to minimize hyperinsulinemia at an early stage, aiming at successfully preventing and treating hyperinsulinemia-mediated diseases.

Strategies to enhance compliance to physical activity for patients with insulin resistance

2007 ◽  
Vol 32 (3) ◽  
pp. 549-556 ◽  
Author(s):  
Alison Kirk ◽  
Pierpaolo De Feo
Keyword(s):  
Physical Activity ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Wearable Sensors ◽  
Physical Activity Promotion ◽  
Physical Activity Behaviour ◽  
Future Research ◽  
Evidence Based ◽  
Activity Promotion

The evidence that physical activity is an effective therapeutic tool in the management of insulin resistance and type 2 diabetes is well documented. Limited research has addressed how best to promote and maintain physical activity in these individuals. This paper explores strategies to enhance compliance to physical activity for patients with insulin resistance. Several evidence-based guidelines and reviews recommend that physical activity interventions are based on a valid theoretical framework. However, there is no evidence-based consensus on the best theory or the combination of theories to use. Motivational tools such as pedometers, wearable sensors measuring energy expenditure, and point of choice prompts appear to be effective at stimulating short-term substantial increases in physical activity, but further strategies to maintain physical activity behaviour change are required. Physical activity consultation has demonstrated effective physical activity promotion over periods of up to 2 years in people with type 2 diabetes. Future research should identify the longer term effects of this intervention and the effectiveness of different methods of delivery. Overall, there needs to be a lot more focus on this area of research. Without this, the abundance of research investigating the effects of physical activity on people with insulin resistance and type 2 diabetes is essentially redundant.

scholarly journals Phenylalanine Impairs Insulin Signaling and Inhibits Glucose Uptake by Modifying IRβ

2021 ◽  
Author(s):  
Qian Zhou ◽  
Wan-Wan Sun ◽  
Jia-Cong Chen ◽  
Huilu Zhang ◽  
Jie Liu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Amino Acids ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Trna Synthetase ◽  
Blood Samples ◽  
Receptor Beta

Abstract Although elevated circulating amino acids are associated with the onset of type 2 diabetes (T2D), how amino acids act on cell insulin signaling and glucose uptake remains unclear. Herein, we report that phenylalanine modifies insulin receptor beta (IRβ) and inactivates insulin signaling and glucose uptake. Mice fed phenylalanine-rich chow or overexpressing human phenylalanyl-tRNA synthetase (hFARS) developed insulin resistance and symptoms of T2D. Mechanistically, FARS phenylalanylated lysine 1057/1079 of IRβ (F-K1057/1079) inactivated IRβ and prevented insulin from generating insulin signaling to promote glucose uptake by cells. SIRT1 reversed F-K1057/1079 and counteracted the insulin-inactivating effects of hFARS and phenylalanine. F-K1057/1079 and SIRT1 levels of white cells of T2D patients’ blood samples were positively and negatively correlated with T2D onset, respectively. Blocking F-K1057/1079 with phenylalaninol sensitized insulin signaling and relieved T2D symptoms in hFARS-transgenic and db/db mice. We revealed mechanisms of how phenylalanylation inactivates insulin signaling that may be employed to control T2D.

scholarly journals MECHANISMS IN ENDOCRINOLOGY: Skeletal muscle lipotoxicity in insulin resistance and type 2 diabetes: a causal mechanism or an innocent bystander?

2017 ◽  
Vol 176 (2) ◽  
pp. R67-R78 ◽  
Author(s):  
Charlotte Brøns ◽  
Louise Groth Grunnet
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Cellular Localization ◽  
Future Research ◽  
Causal Mechanism ◽  
Increased Risk ◽  
Adipose Tissue Expandability

Dysfunctional adipose tissue is associated with an increased risk of developing type 2 diabetes (T2D). One characteristic of a dysfunctional adipose tissue is the reduced expandability of the subcutaneous adipose tissue leading to ectopic storage of fat in organs and/or tissues involved in the pathogenesis of T2D that can cause lipotoxicity. Accumulation of lipids in the skeletal muscle is associated with insulin resistance, but the majority of previous studies do not prove any causality. Most studies agree that it is not the intramuscular lipids per se that causes insulin resistance, but rather lipid intermediates such as diacylglycerols, fatty acyl-CoAs and ceramides and that it is the localization, composition and turnover of these intermediates that play an important role in the development of insulin resistance and T2D. Adipose tissue is a more active tissue than previously thought, and future research should thus aim at examining the exact role of lipid composition, cellular localization and the dynamics of lipid turnover on the development of insulin resistance. In addition, ectopic storage of fat has differential impact on various organs in different phenotypes at risk of developing T2D; thus, understanding how adipogenesis is regulated, the interference with metabolic outcomes and what determines the capacity of adipose tissue expandability in distinct population groups is necessary. This study is a review of the current literature on the adipose tissue expandability hypothesis and how the following ectopic lipid accumulation as a consequence of a limited adipose tissue expandability may be associated with insulin resistance in muscle and liver.

scholarly journals The impact of persistent milk consumption in the pathogenesis of type 2 diabetes mellitus

2019 ◽  
Vol 9 (10) ◽  
pp. 629
Author(s):  
Bodo Melnik
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Amino Acids ◽  
Type 2 Diabetes Mellitus ◽  
Branched Chain Amino Acids ◽  
Milk Consumption ◽  
Increased Risk ◽  
Branched Chain

Background: Milk and sugar are excessively consumed in a Western diet. There is increasing epidemiological evidence that the intake of unfermented pasteurized cow´s milk is associated with an increased risk of type 2 diabetes mellitus (T2D). It is the intention of this review to provide translational biochemical evidence for milk´s diabetogenic mode of action. Milk proteins provide the highest amounts of branched-chain amino acids (BCAAs) and thus contribute to total BCAA intake, which enhances BCAA plasma levels associated with increased risk of T2D. The consumption of pasteurized milk raises plasma levels of miRNA-29b, which is a diabetogenic miRNA promoting insulin resistance (IR). miRNA29b inhibits the activity of branched-chain-keta acid dehydrogenase, the rate limiting enzyme of BCAA catabolism, which is impaired in patients with IR and T2D. Milk consumption stimulates mTORC1 activity and increases insulin synthesis. -cell mTORC1 is overactivated in T2D patients resulting in impaired autophagy which enhances endoplasmic reticulum (ER) stress associated with a greater risk of early -cell apoptosis, the pathogenic hallmark of T2D. Chronic insulinotropic action of milk-derived BCAAs, IR-promoting mTORC1 overactivity, and miRNA-29b signaling combined with excessive glucose-mediated insulin secretion overburden -cell insulin homeostasis. Epidemiological and translational evidence identifies continued milk intake as a promoter of T2D, the most common metabolic disease of Western civilization. Keywords: Branched-chain amino acids, branched-chain-keto acid dehydrogenase, diabetes mellitus type 2, insulin resistance, milk, miRNA-29b, mechanistic target of rapamycin complex 1.

PM20D1 Is a Circulating Biomarker Closely Associated with Obesity, Insulin resistance and Metabolic Syndrome

2021 ◽  
Author(s):  
Ranyao Yang ◽  
Yue Hu ◽  
Chi Ho Lee ◽  
Yan Liu ◽  
Candela Diaz-Canestro ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Amino Acids ◽  
Metabolic Complications ◽  
The Metabolic Syndrome ◽  
Clinical Biomarkers ◽  
The Impact ◽  
Circulating Levels

Objective: Peptidase M20 domain containing 1 (PM20D1), a secreted enzyme catalysing condensation of fatty acids and amino acids into the bioactive lipids N-acyl amino acids (NAAA), induces uncoupling protein 1 (UCP1)-independent adaptive thermogenesis in brown/beige adipocytes in mice. This study aimed to explore the associations of the circulating levels of PM20D1 and major NAAA with obesity-related metabolic complications in humans. Design and Methods: Serum concentrations of PM20D1 and NAAA (C18:1-Leu and C18:1-Phe) in 256 Chinese subjects, including 78 lean and 178 overweight/obese individuals with or without diabetes, were measured with immunoassays and liquid chromatography-mass spectrometry respectively. The impact of sulfonylurea and rosiglitazone on their circulating levels was examined in 62 patients with type 2 diabetes. Results: Serum PM20D1 level was significantly elevated in overweight/obese individuals, and was closely associated with circulating levels of C18:1-Leu and C18:1-Phe. Furthermore, serum PM20D1, C18:1-Leu and C18:1-Phe concentrations correlated positively with several parameters of adiposity as well as fasting and 2-h postprandial glucose, HbA1c, fasting insulin, and HOMA-IR independent of BMI and age. Moreover, a significant elevation in PM20D1, C18:1-Leu and C18:1-Phe concentrations corresponding with increases in the number of components of the metabolic syndrome (MetS) was observed. Treatment with sulfonylurea significantly decreased circulating PM20D1, C18:1-Leu and C18:1-Phe in patients with type 2 diabetes. Conclusions: Increased serum levels of PM20D1 and its catalytic products NAAA are closely associated with obesity-related glucose dysregulation, insulin resistance and MetS, and can be potentially used as clinical biomarkers for diagnosing and monitoring these disorders.

Does high dietary protein intake contribute to the increased risk of developing prediabetes and type 2 diabetes?

2021 ◽  
Vol 46 (1) ◽  
pp. 1-9
Author(s):  
Oana Ancu ◽  
Monika Mickute ◽  
Nicola D. Guess ◽  
Nicholas M. Hurren ◽  
Nicholas A. Burd ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Amino Acids ◽  
Amino Acid ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Protein Intake ◽  
High Protein Diets ◽  
Protein Diets

Insulin resistance is a complex metabolic disorder implicated in the development of many chronic diseases. While it is generally accepted that body mass loss should be the primary approach for the management of insulin resistance-related disorders in overweight and obese individuals, there is no consensus among researchers regarding optimal protein intake during dietary restriction. Recently, it has been suggested that increased plasma branched-chain amino acids concentrations are associated with the development of insulin resistance and type 2 diabetes. The exact mechanism by which excessive amino acid availability may contribute to insulin resistance has not been fully investigated. However, it has been hypothesised that mammalian target of rapamycin (mTOR) complex 1 hyperactivation in the presence of amino acid overload contributes to reduced insulin-stimulated glucose uptake because of insulin receptor substrate (IRS) degradation and reduced Akt-AS160 activity. In addition, the long-term effects of high-protein diets on insulin sensitivity during both weight-stable and weight-loss conditions require more research. This review focusses on the effects of high-protein diets on insulin sensitivity and discusses the potential mechanisms by which dietary amino acids can affect insulin signalling. Novelty: Excess amino acids may over-activate mTOR, resulting in desensitisation of IRS-1 and reduced insulin-mediated glucose uptake.

scholarly journals Distinctive Metabolomics Patterns Associated With Insulin Resistance and Type 2 Diabetes Mellitus

2020 ◽  
Vol 7 ◽  
Author(s):  
Xinyun Gu ◽  
Mohammed Al Dubayee ◽  
Awad Alshahrani ◽  
Afshan Masood ◽  
Hicham Benabdelkamel ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Amino Acids ◽  
Type 2 Diabetes Mellitus ◽  
High Performance ◽  
Isotope Labeling ◽  
Normal Weight ◽  
Increased Risk

Obesity is associated with an increased risk of insulin resistance (IR) and type 2 diabetes mellitus (T2DM) which is a multi-factorial disease associated with a dysregulated metabolism and can be prevented in pre-diabetic individuals with impaired glucose tolerance. A metabolomic approach emphasizing metabolic pathways is critical to our understanding of this heterogeneous disease. This study aimed to characterize the serum metabolomic fingerprint and multi-metabolite signatures associated with IR and T2DM. Here, we have used untargeted high-performance chemical isotope labeling (CIL) liquid chromatography-mass spectrometry (LC-MS) to identify candidate biomarkers of IR and T2DM in sera from 30 adults of normal weight, 26 obese adults, and 16 adults newly diagnosed with T2DM. Among the 3633 peak pairs detected, 62% were either identified or matched. A group of 78 metabolites were up-regulated and 111 metabolites were down-regulated comparing obese to lean group while 459 metabolites were up-regulated and 166 metabolites were down-regulated comparing T2DM to obese groups. Several metabolites were identified as IR potential biomarkers, including amino acids (Asn, Gln, and His), methionine (Met) sulfoxide, 2-methyl-3-hydroxy-5-formylpyridine-4-carboxylate, serotonin, L-2-amino-3-oxobutanoic acid, and 4,6-dihydroxyquinoline. T2DM was associated with dysregulation of 42 metabolites, including amino acids, amino acids metabolites, and dipeptides. In conclusion, these pilot data have identified IR and T2DM metabolomics panels as potential novel biomarkers of IR and identified metabolites associated with T2DM, with possible diagnostic and therapeutic applications. Further studies to confirm these associations in prospective cohorts are warranted.

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