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Polycystic ovarian syndrome: signs and feedback effects of hyperandrogenism and insulin resistance.
Hernández-Jiménez, JL, Barrera, D, Espinoza-Simón, E, González, J, Ortíz-Hernández, R, Escobar, L, Echeverría, O, Torres-Ramírez, N
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2022;(1):2-9
Abstract
Polycystic ovary syndrome (PCOS) is a disease whose diagnosis is based on the detection of hyperandrogenism (HA) and ovulatory dysfunction. Women with PCOS frequently develop insulin resistance (IR), which generates a metabolic condition that involves a decrease in the action of insulin at the cellular level and is linked to compensatory hyperinsulinemia (HI). In PCOS, the ovary remains sensitive to the action of insulin. Additionally, it has been observed that the main effect of insulin in the ovary is the stimulation of androgen synthesis, resulting in HA, one of the fundamental characteristics of the PCOS. In this sense, the excess of androgens favors the development of IR, thus perpetuating the cycle of IR-HI-HA, and therefore PCOS. Moreover, mitochondrial dysfunction is present in PCOS patients and is a common feature in both IR and HA. This review places electron transfer as a key element in HA and IR development, with emphasis on the relationship between androgen biosynthesis and mitochondrial function. Indeed, metformin has been involved in repair mitochondrial dysfunction, decrease of oxidative stress, reduction of androgens levels and the enhancing of insulin sensitivity. Therefore, we propose that treatment with metformin could decrease HI and consequently HA, restoring, at least in part, the metabolic and hormonal disorders of PCOS.
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Genetic mutations of APOEε4 carriers in cardiovascular patients lead to the development of insulin resistance and risk of Alzheimer's disease.
Jabeen, K, Rehman, K, Akash, MSH
Journal of biochemical and molecular toxicology. 2022;(2):e22953
Abstract
Type 2 diabetes mellitus and Alzheimer's disease (AD), both are chronic and progressive diseases. Many cardiovascular and genetic risk factors are considered responsible for the development of AD and diabetes mellitus (DM). Genetic risk factor such as apolipoprotein E (APOE) plays a critical role in the progression of AD. Specifically, APOEε4 is genetically the strongest isoform associated with neuronal insulin deficiency, altered lipid homeostasis, and metabolism, decreased glucose uptake, impaired gray matter volume, and cerebrovascular functions. In this article, we have summarized the mechanisms of cardiovascular disturbances associated with AD and DM, impact of amyloid-β aggregation, and neurofibrillary tangles formation in AD. Moreover, cardiovascular risk factors leading to insulin resistance (IR) and amyloid-β aggregation are highlighted along with the effects of APOE risk alleles on cerebral, lipid, and cholesterol metabolism leading to CVD-mediated IR. Correspondingly, the contribution of IR, genetic and cardiovascular risk factors in amyloid-β aggregation, which may lead to the late onset of AD and DM, has been also discussed. In short, IR is related to significantly lower cerebral glucose metabolism, which sequentially forecasts poorer memory performance. Hence, there will be more chances for neural glucose intolerance and impairment of cognitive function in cardiac patients, particularly APOEε4 carriers having IR. Hence, this review provides a better understanding of the corresponding crosstalk among different pathways. This will help to investigate the rational application of preventive measures against IR and cognitive dysfunction, specifically in APOEε4 carriers' cardio-metabolic patients.
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Insight of the role of mitochondrial calcium homeostasis in hepatic insulin resistance.
Dong, Z, Yao, X
Mitochondrion. 2022;:128-138
Abstract
Due to the rapid rise in the prevalence of chronic metabolic disease, more and more clinicians and basic medical researchers focus their eyesight on insulin resistance (IR), an early and central event of metabolic diseases. The occurrence and development of IR are primarily caused by excessive energy intake and reduced energy consumption. Liver is the central organ that controls glucose homeostasis, playing a considerable role in systemic IR. Decreased capacity of oxidative metabolism and mitochondrial dysfunction are being blamed as the direct reason for the development of IR. Mitochondrial Ca2+ plays a fundamental role in maintaining proper mitochondrial function and redox stability. The maintaining of mitochondrial Ca2+ homeostasis requires the cooperation of ion channels in the inner and outer membrane of mitochondria, such as mitochondrial calcium uniporter complex (MCUC) and voltage-dependent anion channels (VDACs). In addition, the crosstalk between the endoplasmic reticulum (ER), lysosome and plasma membrane with mitochondria is also significant for mitochondrial calcium homeostasis, which is responsible for an efficient network of cellular Ca2+ signaling. Here, we review the recent progression in the research about the regulation factors for mitochondrial Ca2+ and how the dysregulation of mitochondrial Ca2+ homeostasis is involved in the pathogenesis of hepatic IR, providing a new perspective for further exploring the role of ion in the onset and development of IR.
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The mother relationship between insulin resistance and non-alcoholic steatohepatitis: Glucosinolates hydrolysis products as a promising insulin resistance-modulator and fatty liver-preventer.
Mohammed, ED, Abdel-Naim, AB, Kangpeng, J, Jiang, R, Wei, J, Sun, B
Life sciences. 2021;:118615
Abstract
Non-alcoholic fatty liver disease (NFLD) is one of the present public health problems which have no specific and effective treatment. The speed of the disease progression depends on the patient's lifestyle. Due to life stresses and lack of time, a high number of people depend on fast food containing a high amount of fats which one of the main causes of insulin resistance (IR). IR is one of the metabolic disorders which strongly intersected with molecular NAFLD and leading to its progression into non-alcoholic steatohepatitis (NASH). In this review, we introduced the updated statistics of NAFLD and NASH progression all over the world shows its importance, etiologies, and pathogenesis. Also, IR and its role in NASH initiation and progression explored, and current treatments with its limitations have been explained. Glucosinolates (GLS) is a group of phytochemicals which known by its potent hydrolysis products with promising anti-cancer effect. In this review, we have collected the recent experimental studies of different GLS hydrolysis products against IR and chronic liver diseases supported by our lab finding. Finally, we recommend this group of phytochemicals as promising molecules to be studied experimentally and clinically against a wide range of chronic liver diseases with an acceptable safety margin.
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Amino Acid-Induced Impairment of Insulin Signaling and Involvement of G-Protein Coupling Receptor.
Zakaria, NF, Hamid, M, Khayat, ME
Nutrients. 2021;(7)
Abstract
Amino acids are needed for general bodily function and well-being. Despite their importance, augmentation in their serum concentration is closely related to metabolic disorder, insulin resistance (IR), or worse, diabetes mellitus. Essential amino acids such as the branched-chain amino acids (BCAAs) have been heavily studied as a plausible biomarker or even a cause of IR. Although there is a long list of benefits, in subjects with abnormal amino acids profiles, some amino acids are correlated with a higher risk of IR. Metabolic dysfunction, upregulation of the mammalian target of the rapamycin (mTOR) pathway, the gut microbiome, 3-hydroxyisobutyrate, inflammation, and the collusion of G-protein coupled receptors (GPCRs) are among the indicators and causes of metabolic disorders generating from amino acids that contribute to IR and the onset of type 2 diabetes mellitus (T2DM). This review summarizes the current understanding of the true involvement of amino acids with IR. Additionally, the involvement of GPCRs in IR will be further discussed in this review.
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6.
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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7.
Hypertension in Diabetes: An Update of Basic Mechanisms and Clinical Disease.
Jia, G, Sowers, JR
Hypertension (Dallas, Tex. : 1979). 2021;(5):1197-1205
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Abstract
Epidemiological studies have documented that insulin resistance and diabetes not only constitute metabolic abnormalities but also predispose to hypertension, vascular stiffness, and associated cardiovascular disease. Meanwhile, excessive arterial stiffness and impaired vasorelaxation, in turn, contribute to worsening insulin resistance and the development of diabetes. Molecular mechanisms promoting hypertension in diabetes include inappropriate activation of the renin-angiotensin-aldosterone system and sympathetic nervous system, mitochondria dysfunction, excessive oxidative stress, and systemic inflammation. This review highlights recent studies which have uncovered new underlying mechanisms for the increased propensity for the development of hypertension in association with diabetes. These include enhanced activation of epithelial sodium channels, alterations in extracellular vesicles and their microRNAs, abnormal gut microbiota, and increased renal sodium-glucose cotransporter activity, which collectively predispose to hypertension in association with diabetes. This review also covers socioeconomic factors and currently recommended blood pressure targets and related treatment strategies in diabetic patients with hypertension.
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Mechanisms Involved in the Relationship between Vitamin D and Insulin Resistance: Impact on Clinical Practice.
Contreras-Bolívar, V, García-Fontana, B, García-Fontana, C, Muñoz-Torres, M
Nutrients. 2021;(10)
Abstract
Recent evidence has revealed anti-inflammatory properties of vitamin D as well as extra-skeletal activity. In this context, vitamin D seems to be involved in infections, autoimmune diseases, cardiometabolic diseases, and cancer development. In recent years, the relationship between vitamin D and insulin resistance has been a topic of growing interest. Low 25-hydroxyvitamin D (25(OH)D) levels appear to be associated with most of the insulin resistance disorders described to date. In fact, vitamin D deficiency may be one of the factors accelerating the development of insulin resistance. Vitamin D deficiency is a common problem in the population and may be associated with the pathogenesis of diseases related to insulin resistance, such as obesity, diabetes, metabolic syndrome (MS) and polycystic ovary syndrome (PCOS). An important question is the identification of 25(OH)D levels capable of generating an effect on insulin resistance, glucose metabolism and to decrease the risk of developing insulin resistance related disorders. The benefits of 25(OH)D supplementation/repletion on bone health are well known, and although there is a biological plausibility linking the status of vitamin D and insulin resistance supported by basic and clinical research findings, well-designed randomized clinical trials as well as basic research are necessary to know the molecular pathways involved in this association.
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Epidemiology of diabetes among South Asians in the United States: lessons from the MASALA study.
Gujral, UP, Kanaya, AM
Annals of the New York Academy of Sciences. 2021;(1):24-39
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Abstract
South Asian individuals in the United States are at an increased risk of type 2 diabetes (T2DM); however, the mechanisms behind this are not well understood. The Mediators of Atherosclerosis in South Asians Living in America (MASALA) study is the only longitudinal cohort of South Asians in the United States and provides key insights as to the epidemiology of T2DM in South Asians. Evidence from the MASALA study suggests that South Asians experience a disproportionately high burden of prevalent and incident T2DM compared with members of other race/ethnic groups. Higher insulin resistance in South Asians, even with low body mass index (BMI), more impairment in insulin secretion, and greater deposition of ectopic fat likely play a role in T2DM etiology. Furthermore, South Asian migrants to the United States experience a range of factors related to acculturation, social networks, and religious beliefs, which may impact physical activity and dietary practices. Interventions to prevent T2DM in South Asians should include a focus on cultural factors related to health and should consider the complete mechanistic pathway and the relative contributions of insulin resistance, β cell dysfunction, and ectopic fat deposition on T2DM development in South Asians, particularly in those with lower BMI.
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Impact of SGLT2 Inhibitors on Heart Failure: From Pathophysiology to Clinical Effects.
Palmiero, G, Cesaro, A, Vetrano, E, Pafundi, PC, Galiero, R, Caturano, A, Moscarella, E, Gragnano, F, Salvatore, T, Rinaldi, L, et al
International journal of molecular sciences. 2021;(11)
Abstract
Heart failure (HF) affects up to over 20% of patients with type 2 diabetes (T2DM), even more in the elderly. Although, in T2DM, both hyperglycemia and the proinflammatory status induced by insulin resistance are crucial in cardiac function impairment, SGLT2i cardioprotective mechanisms against HF are several. In particular, these beneficial effects seem attributable to the significant reduction of intracellular sodium levels, well-known to exert a cardioprotective role in the prevention of oxidative stress and consequent cardiomyocyte death. From a molecular perspective, patients' exposure to gliflozins' treatment mimics nutrient and oxygen deprivation, with consequent autophagy stimulation. This allows to maintain the cellular homeostasis through different degradative pathways. Thus, since their introduction in the clinical practice, the hypotheses on SGLT2i mechanisms of action have changed: from simple glycosuric drugs, with consequent glucose lowering, erythropoiesis enhancing and ketogenesis stimulating, to intracellular sodium-lowering molecules. This provides their consequent cardioprotective effect, which justifies its significant reduction in CV events, especially in populations at higher risk. Finally, the updated clinical evidence of SGLT2i benefits on HF was summarized. Thus, this review aimed to analyze the cardioprotective mechanisms of sodium glucose transporter 2 inhibitors (SGLT2i) in patients with HF, as well as their clinical impact on cardiovascular events.