Pathophysiology and pharmacological treatment of insulin. Implications for the insulinresistant state fatty acids and insulin resistance show more symposium on insulin resistance. Pathogenesis of insulin resistance and atherogenic. Association of obesity with insulin resistance and related cardiometabolic problems is well established. Symonds, in maternalfetal and neonatal endocrinology, 2020. Role of dietary proteins and amino acids in the pathogenesis. Results we screened 400 young, healthy, lean, sedentary subjects with an oral glucose tolerance test and assessed insulin sensitivity in. Insulin resistance plays a pivotal role in the development of nafldrelated dyslipidemia. The role of skeletal muscle insulin resistance in the. Insulin resistance is a core defect in type 2 diabetes, it is also associated with. Role of fatty acids in the pathogenesis of insulin resistance. Ir impacts the metabolism of triglycerides, highdensity lipoprotein cholesterol hdlc, lowdensity lipoprotein cholesterol ldlc, and very lowdensity lipoprotein cholesterol vldl.
Research design and methods we studied 23 obese adolescents with high hff hff 5. However, women who develop gdm tend also to be insulinresistant when not pregnant and become even more insulinresistant during pregnancy 18. Several mechanisms have been proposed, including increased nonesterified fatty acids. It is unquestioned that in conditions commonly associated with the term insulin resistance, such as obesity or type 2 diabetes, peripheral glucose dis posal, as. Shulman published january 4, 2016 citation information. Mar 18, 2017 how obesity is linked to insulin resistance, and how does it develop. Obesity, type 2 diabetes mellitus and hypertension are strongly associated with insulin resistance. Insulin resistance is a common feature of all these diseases, and much effort has been invested in delineating the pathogenesis of insulin resistance. However, women who develop gdm tend also to be insulin resistant when not pregnant and become even more insulin resistant during pregnancy 18. Disordered lipid metabolism and the pathogenesis of. Second, physiological elevations in plasma ffa concentrations inhibit insulin stimulated peripheral glucose uptake in a dosedependent manner in normal controls and in patients with niddm. Type 2 diabetes can be viewed as the consequence of a series. Insulin resistance in skeletal muscle manifests primarily as a reduction in insulin stimulated glycogen synthesis, which is in turn a consequence of reduced glucose transport.
Insulin resistance most likely is very influential upon development of impaired glucose tolerance and diabetes. Pathogenesis of lipid disorders in insulin resistance. Insulin resistance plays a major role in the pathogenesis of type 2 diabetes and the metabolic syndrome. Insulin resistance in adipose tissue impairs insulin mediated inhibition of lipolysis, leading to an increase in circulating ffas that further inhibit the antilipolytic effect of insulin. Thirtyone subjects who retained ngt over a similar period also gained weight, but their air increased with decreasing insulinstimulated glucose disposal. Hepatic insulin clearance is 67% lower in african americans than european americans. Feb 27, 2019 there are several mechanisms that have been suggested to play a role in the pathogenesis of pcos, including hormonal imbalance, insulin resistance, and genetic inheritance. Box 62000, nairobi 00200, kenya correspondence should be addressed to arnold n.
Cellular stresses and stress responses in the pathogenesis of insulin resistance arnold n. Role of subcutaneous adipose tissue in the pathogenesis of. Type 2 diabetes mellitus has become an epidemic, and virtually no physician is without patients who have the disease. Ivor cummins originally completed a chemical engineering degree in 1990 biochemical stream, bechem ceng miei, followed by over 25 years in. Discussing mechanism of insulin resistance, causes, diagnosis and. Cellular stresses and stress responses in the pathogenesis of. Jan 04, 2016 insulin resistance is a common feature of all these diseases, and much effort has been invested in delineating the pathogenesis of insulin resistance. Pathogenesis of insulin resistance in skeletal muscle. Disordered lipid metabolism and the pathogenesis of insulin. Pdf pathogenesis of insulin resistance in skeletal muscle. Improvement in insulin resistance with the use of insulin sensitizers, such as metformin and thiazoldinediones tzds have been seen to be associated with better ovulation and reduced testosterone levels in patients with pcos. Pathophysiology of insulin resistance sciencedirect.
Insulin resistance ir is recognized to play an important role in the pathogenesis of dyslipidemia. Insulin resistance in skeletal muscle manifests itself primarily as a reduction in insulin stimulated glycogen synthesis, which is in turn a consequence of reduced glucose transport. Sep 21, 2019 normal pregnancy and gdm are states of profound insulin resistance and the mediating factors are similar, if not identical. New concepts in pathogenesis and management of polycystic. These include age, ethnicity, weight, body fat primarily abdominal, medications, and physical activity. Dysregulation of fatty acid metabolism plays a pivotal role in the pathogenesis of insulin resistance in skeletal muscle. Iddm, is caused by lack of insulin secretion by beta cells of the pancreas. Accumulation of ectopic lipid metabolites, activation of the unfolded protein response upr pathway, and innate immune pathways have all been implicated in the pathogenesis of insulin resistance. Resistance to the actions of insulin in skeletal muscle is a major pathogenic factor in type 2 or type 1 diabetes mellitus 2,3. Insulin increases glucose uptake in muscle and liver, and inhibits lipolysis and hepatic gluconeogenesis. Insulin resistance an overview sciencedirect topics. Insulin resistance in skeletal muscle is manifested by decreased insulin stimulated glucose uptake and results from impaired insulin signaling and multiple. Thus, lean healthy offspring of diabetic parents have a significant decrease in insulinstimulated total body and muscle glucose disposal which is of a similar magnitude to that observed in their diabetic parents 3032.
Insulin resistance or its sequelae may be the common etiology of maladies associated with metabolic syndrome eg, hypertension, type 2 diabetes, atherosclerosis, heart attack, stroke, and kidney. Pathophysiology and pathogenesis of gdm insulin resistance. Insulin resistance in skeletal muscle is manifested long before the hyperglycemia becomes evident. The pathogenesis of type 1a diabetes is quite different from that of type 2 diabetes mellitus, in which both decreased insulin release not on an autoimmune. In general, several intrinsic and extrinsic cellular mechanisms have been identified, which display a causeeffect relationship molecular mechanisms of insulin resistance.
Understanding the pathogenesis of type 2 diabetes is complicated by several factors. Furthermore, insulin resistance in these subjects was independent of changes in the plasma concentrations of tnf, il6, highmolecularweight adiponectin, resistin, retinol binding protein4, or intraabdominal obesity, suggesting that these factors do not play a primary role in causing insulin resistance in the early stages of the metabolic. Insulin resistance is found to be the common denominator of the pathogenesis of the cardiovascular and metabolic complications of obesity. Childhood obesity is associated with reduced insulin sensitivity, which persists into adulthood causing type 2 diabetes mellitus. Lastly, the health consequences related to pcos are discussed, with a focus on insulin resistance. Role of fatty acids in the pathogenesis of insulin. Mechanisms of insulin resistance in humans and possible links. Insulin resistance in skeletal muscle manifests primarily as a reduction in insulinstimulated glycogen synthesis, which is in turn a consequence of reduced glucose transport. Thus, insulin resistance caused in part by mitochondrial dysfunction may contribute to a common pathophysiologic etiology for many chronic diseases. Insulin resistance refers to reduced insulin action in metabolic and vascular target tissues, hence higher than normal concentration of insulin is required to maintain normoglycemia and other actions of insulin, hence it may be considered as a euglycemic prediabetic state. Although high intake of dietary proteins has positive effects on energy homeostasis by inducing satiety and possibly increasing energy expenditure, it has detrimental effects on glucose homeostasis by promoting insulin resistance and increasing gluconeogenesis. However, growing body of the literature has suggested that adipose tissue. Many of the conflicting studies can be explained by differing diagnostic criteria for pcos and by the inclusion of.
Pdf this is a paper describing the pathophysiology of insulin resistance. Polycystic ovary syndrome pathogenesis medical news. Insulin resistance has also been arbitrarily defined as the requirement of 200 or more units of insulin per day to attain glycemic control and to prevent ketosis. Traditionally, adipose tissue in visceral fat depot has been considered a major culprit in development of insulin resistance. Lower hepatic insulin clearance will result in peripheral hyperinsulinemia. Onyango department of food science and technology, jomo kenyatta university of agriculture and technology, p.
Objective we evaluated the role of fatty liver in the alteration of insulin sensitivity and. Dec 28, 2019 initial studies involving patients with generalized lipodystrophy and lipodystrophic mouse models showed significant hepatic insulin resistance and recovery of insulin action post leptin therapy and fat transplantation respectively. Insulin resistance is characterized by chronic peripheral insulin elevations, and it is accompanied by reduced brain insulin levels and insulin activity. Pdf on dec 30, 2018, emil kopeevich mukhamedzhanov and others published insulin resistance pathogenesis of prevention and treatment find, read and cite all the research you need on researchgate. Implications for the insulin resistant state fatty acids and insulin resistance show more symposium on insulin resistance. Type 2 diabetes, also called noninsulin dependent diabetes mellitus niddm, is caused by decreased sensitivity of target tissues to insulin. First, plasma ffa levels are elevated in most obese subjects. Normal pregnancy and gdm are states of profound insulin resistance and the mediating factors are similar, if not identical. Insulin resistance and alzheimers disease pathogenesis. Oct 17, 2018 insulin resistance ir is recognized to play an important role in the pathogenesis of dyslipidemia. Insulin modulates cognition and other aspects of normal brain function.
The syndromes of insulin resistance actually make up a broad clinical spectrum, which includes obesity, glucose intolerance, diabetes, and the metabolic syndrome, as well as an extreme insulinresistant state. Clearance is also lower in african american children 7 years of age. Apr 26, 2010 insulin resistance in skeletal muscle is manifested long before the hyperglycemia becomes evident. Shulman departments of internal medicine and cellular and molecular physiology, howard hughes medical institute, yale university school of medicine, new haven, connecticut i. Insulin promotes ffa uptake into the adipocyte by stimulating the. Please use one of the following formats to cite this article in your essay, paper or report.
Mechanisms of insulin resistance in humans and possible. Central role of fatty liver in the pathogenesis of insulin. Initial studies involving patients with generalized lipodystrophy and lipodystrophic mouse models showed significant hepatic insulin resistance and recovery of insulin action post leptin therapy and fat transplantation respectively. Insulin resistance is a state in which a given concentration of insulin produces a lessthanexpected biological effect. Thirtyone subjects who retained ngt over a similar period also gained weight, but their air increased with decreasing insulin stimulated glucose disposal. Pathogenesis of type 2 diabetes mellitus t2dm and development of insulin resistance are characterized by multi. There is wide variance among individuals in the fraction of insulin cleared by the liver 20% to 80%. Thus, defects in insulin secretion and insulin action occur early in the pathogenesis of diabetes. Shulman 1,3,4 1 department of medicine, yale university school of medicine, new haven, connecticut, usa.
Insulin resistance in the pathogenesis of dyslipidemia. Dietary proteins and amino acids are important modulators of glucose metabolism and insulin sensitivity. Insulin resistance often is the primary metabolic abnormality leading to the development of type 2 diabetes. Understanding insulin resistance, in turn, requires knowledge of normal insulin action.
Tissuespecific insulin resistance in mice with mutations in the insulin receptor, irs1, and irs2. However, these pathways are also closely linked to changes in fatty acid uptake. Solid lines indicate flux of metabolic substrates, and dashed lines indicate stimulatory or inhibitory effects of insulin. Pdf insulin resistance pathogenesis of prevention and. Nafld is considered to be the hepatic manifestation of metabolic syndrome and is strongly associated with obesity, insulin resistance and dyslipidemia. Acute effects of insulin in the control of vldl production in humans. Insulin resistance is a complex metabolic disorder that defies explanation by a single etiological pathway. Whereas insulin insensitivity is an early phenomenon partly related to obesity, pancreas. Mechanisms of insulin action and insulin resistance. Insulin resistance and the polycystic ovary syndrome. Nonalcoholic fatty liver disease nafld is the most common cause of chronic liver disease in the developed world, with a global prevalence of around 25%. Molecular mechanism of insulin resistance in obesity and type 2. Type 2 diabetes, also called non insulin dependent diabetes mellitus niddm, is caused by decreased sensitivity of target tissues to insulin.
Cellular stresses and stress responses in the pathogenesis. Insulin resistance is a core defect in type 2 diabetes, it is also associated with obesity and the metabolic syndrome. Disordered lipid metabolism and the pathogenesis of insulin resistance david b. Burden of obesity has increased significantly in the united states over last few decades. Furthermore, each of the clinical features can arise through genetic or environmental. Insulin resistance in skeletal muscle is manifested by decreased insulinstimulated glucose uptake and results from impaired insulin signaling and multiple postreceptor intracellular defects including impaired glucose transport, glucose phosphorylation, and reduced glucose oxidation and glycogen synthesis.
The reduced sensitivity to insulin is often called insulin resistance and its causes are shown in table 1. The reduced sensitivity to insulin is often called insulin resistance and. Insulin resistance in skeletal muscle also can develop independent of. There are a number of markers of insulin resistance and its treatment includes lifestyle changes and drug therapy for components of the syndrome. Notably, sirt3, a member of sirtuins located in mitochondria, can regulate the function of mitochondrial proteins via reversible posttranslational modification in response to metabolic stress. Insulin resistance in skeletal muscle manifests itself primarily as a reduction in insulinstimulated glycogen synthesis due to reduced glucose transport. Pdf pathophysiology of insulin resistance researchgate. Insulin resistance is a key mediator of obesityrelated cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Insulin resistance in skeletal muscle manifests itself primarily as a reduction in insulinstimulated glycogen synthesis, which is in turn a consequence of reduced glucose transport. Insulin resistance is regularly found in patients with type 2 diabetes. Patients present with a combination of varying degrees of insulin resistance and relative insulin deficiency, and it is likely that both contribute to type 2 diabetes. Understanding the pathogenesis and treatment of insulin. Insulin resistance is a key element in the pathogenesis of the metabolic syndrome and type 2 diabetes mellitus t2dm, both of which have reached epidemic proportions worldwide.
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