Insulin Resistance In Human Disease Research Articles

Gerald “Jerry” M Reaven: the “father of insulin resistance”

Gerald “Jerry” M Reaven was a pioneer in insulin research, whose discoveries formed the basis of the concept of metabolic syndrome. He is credited with developing the first quantitative method...

Metabolic disorder of pregnancy (understanding pathophysiology of diabetes and preeclampsia)

The role of insulin resistance in human disease is implicated in the pathogenesis of some of the chief western chronic diseases: ischemic heart disease, type 2 diabetes mellitus, and essential hypertension. The occurrence of these diseases, alongside obesity, is termed the metabolic syndrome. Pregnancy is normally attended by progressive insulin resistance that begins near midpregnancy and progresses through the third trimester to levels that approximate the insulin resistance seen in individuals with type 2 diabetes. Insulin resistance and hyperinsulinemia may be the basic common ground for the metabolic syndrome of pregnancy - elevated blood pressure and diabetes mellitus. Moreover, the metabolic syndrome is also associated with endothelial dysfunction, oxidative stress, and attenuated inflammatory responses. In this review, we discuss the development of insulin resistance during pregnancy, hormones and newly discovered factors associated with insulin resistance and secretion, lipid metabolism, and the pathogenesis of hypertension during pregnancy.

Gerald M. Reaven, MD: Demonstration of the central role of insulin resistance in type 2 diabetes and cardiovascular disease.

Gerald M. Reaven, MD, could easily be epitomized as the “Father of Insulin Resistance.” (For those who do not know Dr. Reaven, he would humbly raise objection to being called Dr. Reaven rather than Jerry.) That said, Jerry is credited with developing the insulin suppression test, the first quantitative method to measure insulin-mediated glucose uptake in humans (1). Using this technique, he established the importance of insulin resistance in human disease, and importantly, in type 2 diabetes (2,3). In nondiabetic individuals, he demonstrated the role of insulin resistance/compensatory hyperinsulinemia in the development of 1 ) hypertriglyceridemia (4) and low HDL concentrations (5), 2 ) decreased urinary uric acid clearance and hyperuricemia (6), 3 ) decreased LDL particle diameter (7), 4 ) enhanced postprandial lipemia and remnant lipoprotein accumulation (8), 5 ) increased levels of plasminogen activator inhibitor-1 (9), 6 ) salt sensitivity (10), 7 ) essential hypertension (11), and 8 ) increased sympathetic nervous system activity (12). In addition to emphasizing the role of insulin resistance/compensatory hyperinsulinemia in increasing the likelihood of an individual developing one or more of the consequences listed above, he first pointed out the clustering of these abnormalities. It is clear now that this group of clinical abnormalities, initially designated Syndrome X, is an important factor leading to cardiovascular disease. Syndrome X was introduced to the medical community in his now famous Banting Lecture in 1988 (13) and only later became known as metabolic syndrome. Jerry was born in Gary, IN, on 28 July 1928, but spent most of his precollege years living in Cleveland, OH, thus accounting for his lifelong allegiance to the Cleveland Indians baseball team and a great deal of frustration on his part during their many less-than-stellar seasons. Jerry matriculated at the University of Chicago and graduated in 1949, also the year of his marriage to his …

The Expanding Pathogenic Role of Insulin Resistance in Human Disease.

The December 2011 issue of Diabetic Medicine celebrated the outstanding personal contributions of the renowned clinical scientist Prof. Sir Harold Himsworth in characterizing impaired insulin action in relation to phenotypes of diabetes. The commissioned articles in the special issue of the journal were assembled in recognition of the publication in 1936 of a landmark paper in which Himsworth summarized his innovative research, to which much of our current understanding of insulin resistance can be readily traced. The collection of invited articles that marked the 75th anniversary of the Lancet publication provided a state-of-the-art summary from internationally renowned investigators of what has become an increasingly diverse field reaching into myriad aspects of clinical medicine. This article is protected by copyright. All rights reserved.

Late-Life Depression Research: Lessons Learned From the Metabolic Syndrome

Late-Life Depression Research: Lessons Learned From the Metabolic Syndrome

Predicting glucose intolerance with normal fasting plasma glucose by the components of the metabolic syndrome

BACKGROUNDSurprisingly, it is estimated that about half of type 2 diabetics remain undetected. The possible causes may be partly attributable to people with normal fasting plasma glucose (FPG) but abnormal postprandial hyperglycemia. We attempted to develop an effective predictive model by using the metabolic syndrome (MeS) components as parameters to identify such persons.SUBJECTS AND METHODSAll participants received a standard 75-g oral glucose tolerance test, which showed that 106 had normal glucose tolerance, 61 had impaired glucose tolerance, and 6 had diabetes-on-isolated postchallenge hyperglycemia. We tested five models, which included various MeS components. Model 0: FPG; Model 1 (clinical history model): family history (FH), FPG, age and sex; Model 2 (MeS model): Model 1 plus triglycerides, high-density lipoprotein cholesterol, body mass index, systolic blood pressure and diastolic blood pressure; Model 3: Model 2 plus fasting plasma insulin (FPI); Model 4: Model 3 plus homeostasis model assessment of insulin resistance. A receiver-operating characteristic (ROC) curve was used to determine the predictive discrimination of these models.RESULTSThe area under the ROC curve of the Model 0 was significantly larger than the area under the diagonal reference line. All the other 4 models had a larger area under the ROC curve than Model 0. Considering the simplicity and lower cost of Model 2, it would be the best model to use. Nevertheless, Model 3 had the largest area under the ROC curve.CONCLUSIONWe demonstrated that Model 2 and 3 have a significantly better predictive discrimination to identify persons with normal FPG at high risk for glucose intolerance.

Metabolic Syndrome and Early Death

This editorial appraises an article in the current issue of Hypertension that examines the prospective relationships between features of the metabolic syndrome (MetS) and early death in a population-based cohort form Northern Italy.1 We also discuss, in light of that study’s findings, how relevant conventional definitions of the MetS are for identifying individuals at high risk of early death. The MetS describes a constellation of metabolic and cardiovascular disease risk factors. Although varying definitions of the MetS exist, all of the commonly used definitions include a measure of obesity, hyperglycemia, hypertension, and dyslipidemia.2–4 These definitions are based on “expert” opinion and not on evidence derived from prospective studies, which would be preferable. Thus, it remains uncertain whether the component features of the MetS or the thresholds at which each component is defined as present or absent are informative and optimal for predicting risk of disease or early death. It is also undetermined whether MetS represents a distinct pathophysiological entity. Notwithstanding these issues, the syndrome is extensively used in research studies, and many advocate its use in clinical practice5 to identify people at high risk of cardiovascular disease and early death. The idea that cardiovascular risk factors with a common etiology cluster in certain individuals at high risk of cardiovascular disease was first popularized by Reaven6 in the 1980s, although the origins of the MetS date back much earlier.7 Reaven’s6 emphasis was on elucidating the underlying pathophysiology of cardiovascular disease, for which he postulated that insulin resistance plays a pivotal role, and not on developing a diagnosis of MetS, which could be used in clinical practice. Superficially, at least, MetS relates strongly with cardiovascular morbidity and early death8; this is perhaps unsurprising, because so too do each of the component features of the …

Insulin Resistance, Type 2 Diabetes Mellitus, and Cardiovascular Disease

In his 1939 Goulstonian Lectures to the Royal College of Physicians in London, Harold Himsworth addressed the “Mechanisms of Diabetes.” In the course of these 3 presentations,1–3 he provided evidence that “diabetes mellitus is a disease in which the essential lesion is a diminished ability of the tissue to utilize glucose. The high blood sugar is a controlled and compensatory phenomenon, the object of which is to facilitate the utilization of glucose by the tissues.” In addition, he challenged the conventional wisdom that “all causes of human diabetes could be explained by deficiency of insulin” and went on to utter the heretical notion that “a state of diabetes might result from inefficient action of insulin as well as from a lack of insulin.” Thus, the notion of a causal role of insulin resistance in human disease was born almost 70 years ago. Article p 3066 Despite the fact that Himsworth was among the most distinguished clinical investigators of his time and in 1949 concluded in the Oliver-Shappey Lectures to the Royal College of Physicians4 “that it appears we should accustom ourselves to the idea that primary deficiency of insulin is only one, and then not the commonest cause of the diabetes syndrome,” the idea that resistance to insulin action could have adverse consequences had little resonance over the next several decades. However, this situation begin changing rapidly with the introduction of methods to quantify insulin-mediated glucose disposal,5,6 and it soon became clear7,8 that the majority of patients with type 2 diabetes mellitus were, in Himsworth’s terms, “insulin insensitive.” Subsequent prospective studies were published demonstrating that insulin resistance and/or compensatory hyperinsulinemia as a surrogate estimate of insulin resistance predicted the development of type 2 diabetes mellitus,9,10 providing the final evidence of the prescience of Himsworth’s mechanistic …

Insulin and Blood Pressure

Hypertension has long been known to be more prevalent among obese subjects or in patients with diabetes, ie, in states of insulin resistance.1 After the demonstration that essential hypertension is an insulin-resistant state in its own right,2 it was logical to include hypertension in the insulin resistance syndrome,3 later transmuted into the metabolic syndrome.4 A large number of studies, both epidemiological and physiological, have explored this association and, more in general, the interrelationships between blood pressure and insulin action. Summarizing the available evidence—and critically analyzing its merits and pitfalls—is beyond the scope of this brief commentary. It may be nevertheless useful to recall a few general points. First, the association between insulin resistance and hypertension extends into the normal state as an association between insulin action on glucose metabolism and blood pressure levels5; this clearly speaks for the existence of multiple cross-talk between the 2 homeostatic systems. Second, longitudinal studies have confirmed that insulin resistance (as measured by its surrogate, fasting hyperinsulinemia) may precede the development of frank hypertension.6 The reverse temporal sequence, ie, hypertension antedating insulin resistance, has not been documented. Third, associations, even if fairly consistent, do …

The metabolic syndrome: a practical guide to origins and treatment: Part II.

The metabolic syndrome (MetS), a cluster of metabolic abnormalities with insulin resistance as a major characteristic, has gone by several names over the past two decades. The diagnostic criteria proposed by the Adult Treatment Program III (ATP III) of the National Cholesterol Education Program (NCEP) have led to greater awareness of the components and treatment strategies.1 Five diagnostic traits are listed in the ATP III version of the MetS (Table; referred to as the “metabolic syndrome”), and the presence of any 3 of these factors is considered sufficient for diagnosis. This practical review will consider each in turn, providing advice for cardiologists, internists, and other health care providers who are diagnosing and treating persons with the syndrome in an effort to prevent a variety of clinical outcomes. View this table: Diagnostic Criteria for the Metabolic Syndrome The major adverse consequence of the MetS is cardiovascular disease (CVD). Several of the metabolic abnormalities associated with the syndrome, in fact, are CVD risk factors. One of these abnormalities, insulin resistance, also predisposes to the development of type 2 diabetes mellitus (T2DM). In age-adjusted estimates from the National Health and Nutrition Examination Survey III in 1998 to 1994, approximately 24% of adult Americans had ≥3 of the 5 MetS criteria. Key determinants of greater prevalence were age and ethnicity. Prevalence rates were highest in Mexican Americans and were successively lower in white, African American and other racial groups.2 These published estimates included persons with diabetes mellitus who had met the 1998 fasting glucose criteria (≥126 mg/dL [8.0 mmol/L]) of the American Diabetes Association.3 This article will focus on the features of the MetS in persons without diabetes mellitus, although most persons with T2DM also have the MetS. Moreover, the therapeutic approaches to metabolic risk factors described here also can be applied to …

Metabolic Syndrome

Case Presentation: E.C. is a 53-year-old postmenopausal female, referred for treatment of hypertension, with a family history of type 2 diabetes, hypertension, and coronary heart disease (CHD). Until learning that her blood pressure was “too high” during a routine physical examination, she felt well, and her postmenopausal symptoms had responded to hormone replacement therapy. She was not overweight (her body mass index [BMI] was 23.7 kg/m2), and the only abnormality on physical examination was a blood pressure of 145/95 RAR. Laboratory results revealed a normal blood count and urinalysis, with the following fasting plasma concentrations of relevant metabolic variables (in mg/dL): glucose 102, triglycerides (TG) 238, low-density lipoprotein cholesterol (LDL-C) 147, and high-density lipoprotein cholesterol (HDL-C) 52. E.C. is hypertensive and hypertriglyceridemic and at increased risk for CHD. Less obvious is that these metabolic abnormalities are highly likely to be the manifestations of a more fundamental defect—resistance to insulin-mediated glucose disposal and compensatory hyperinsulinemia, changes that greatly increase CHD risk.1,2⇓ The importance of insulin resistance as a CHD risk factor was first explicated in 1998, and the cluster of abnormalities likely to appear as manifestations of the defect in insulin action designated as syndrome X.1 Support for this notion has grown almost as fast as the names used to describe the phenomenon. The Adult Treatment Panel III (ATP III) has recently3 recognized the importance as CHD risk factors of a “constellation of lipid and nonlipid risk factors of metabolic origin,” designated this cluster of abnormalities as “the metabolic syndrome,” and indicated that “this syndrome is closely linked to insulin resistance.” Table 1 lists the criteria the ATP III stipulated be used to diagnose the metabolic syndrome, and a recent report4 has applied these criteria to the database of the Third National Health and Nutrition …

Early menarche and adult height: Reprise of the hare and the tortoise?

Early menarche and adult height: Reprise of the hare and the tortoise?

Response

PCOS is a common endocrine disorder that often goes undiagnosed. Exactly how and why the syndrome develops is not quite clear; however, the cause is believed to be genetic ( (1) Reaven G.M Role of insulin resistance in human disease. Diabetes. 1988; 37: 1595-1607 Google Scholar ). The major biochemical abnormality present in the majority of women with PCOS is hyperinsulinemia. Hyperinsulinemia leads to ovarian and adrenal overproduction of male hormones, causing any or all of the following symptoms: erratic menstrual periods, infertility, acne, hirsutism, and alopecia. Hyperinsulinemia can also cause abnormal lipid metabolism (elevated low-density lipoprotein and triglyceride levels and decreased high-density lipoprotein levels [HDL]) and abnormal clotting factors, thus increasing the risk of heart disease ( (1) Reaven G.M Role of insulin resistance in human disease. Diabetes. 1988; 37: 1595-1607 Google Scholar ). In addition, women with PCOS have increased risk of hypertension and type 2 diabetes mellitus ( (2) Kidson W. Polycystic ovary syndrome: a new direction in treatment. BMJ [serial online] 1998;169:537-540. Available at: http://www.mja.com.au/public/issues/nov16/kidson/kidson/html AccessedDate: June 1, 2000 Google Scholar ).

Insulin resistance, iron, and the liver

In a report in 1997, 1 Moirand R Mortaji AM Loréal O Paillard F Brissot P Deugnier Y A new syndrome of liver iron overload with normal transferrin saturation. Lancet. 1997; 349: 95-97 Summary Full Text Full Text PDF PubMed Scopus (310) Google Scholar a French group led by Yves Deugnier described a new clinical-pathological syndrome of primary hepatic iron overload (HIO), in which the transferrin saturation was normal, the frequency of the HLA A3 genotype (which is linked to genetic haemochromatosis) was normal, and serum and liver iron concentrations were raised disproportionately to the increase in serum ferritin concentration. Among the 65 patients with this syndrome, 72% had a body-mass index (BMI) greater than 25 kg/m 2 Reaven GM Pathophysiology of insulin resistance in human disease. Physiol Rev. 1995; 75: 473-486 Crossref PubMed Scopus (1040) Google Scholar , 65% were dyslipidaemic, and 43% had abnormal glucose tolerance-ie, there was a high frequency of some of the features of the insulin-resistance syndrome (IRS). 2 Reaven GM Pathophysiology of insulin resistance in human disease. Physiol Rev. 1995; 75: 473-486 Crossref PubMed Scopus (1040) Google Scholar In a subsequent study of 161 patients, 3 Mendler MH Turlin B Moirand R et al. Insulin resistance-associated hepatic iron overload. Gastroenterology. 1999; 117: 1155-1163 Summary Full Text Full Text PDF PubMed Scopus (435) Google Scholar the same group of investigators broadened the scope of unexplained HIO by including patients with increased transferrin saturation or non-alcoholic steato-hepatitis (NASH-ie, steatosis accompanied by lobular inflammation, sinusoidal fibrosis, and hepatocyte degeneration/necrosis). No patients were homozygous for Cys282Tyr but a higher than expected proportion of individuals were compound heterozygotes for the two main point mutations (Cys282Tyr and His63Asp.) of HFE (the gene associated with genetic haemochromatosis), a finding that is expected in a cohort selected on the basis of iron overload. Also, with this extended definition, the patients with the syndrome of unexplained HIO, mostly middle-aged men, had a high rate of IRS (94%), by the investigators' definition.

0.S.10 Role of insulin resistance in human disease - Syndrome X revisited

0.S.10 Role of insulin resistance in human disease - Syndrome X revisited

Banting lecture 1988: Role of insulin resistance in human disease

Banting lecture 1988: Role of insulin resistance in human disease

Role of insulin resistance in human disease

Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in ∼25% of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the β-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration.Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulinstimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration and blood pressure has been noted. Hypertension can also be produced in normal rats when they are fed a fructose-enriched diet, an intervention that also leads to the development of insulin resistance and hyperinsulinemia. The development of hypertension in normal rats by an experimental manipulation known to induce insulin resistance and hyperinsulinemia provides further support for the view that the relationship between the three variables may be a causal one. However, even if insulin resistance and hyperinsulinemia are not involved in the etiology of hypertension, it is likely that the increased risk of coronary artery disease (CAD) in patients with hypertension and the fact that this risk if not reduced with antihypertensive treatment are due to the clustering of risk factors for CAD, in addition to high blood pressure, associated with insulin resistance. These include hyperinsulinemia, IGT, increased plasma triglyceride concentration, and decreased high-density lipoprotein cholesterol concentration, all of which are associated with increased risk for CAD. It is likely that the same risk factors play a significant role in the genesis of CAD in the population as a whole. Based on these considerations the possibility is raised that resistance to insulin-stimulated glucose uptake and hyperinsulinemia are involved in the etiology and clinical course of three major related diseases— NIDDM, hypertension, and CAD.

Insulin Resistance, Its Consequences, and Coronary Heart Disease

Approximately 25 years ago, our research group1 2 used quantitative methods to show that resistance to insulin-mediated glucose disposal was present in patients with either impaired glucose tolerance or NIDDM. These initial observations have been confirmed on multiple occasions since then, and there is now a large body of evidence that shows that this defect is present in the vast majority of glucose-intolerant individuals.3 4 5 6 7 8 In addition, several reports9 10 11 demonstrated that first-degree relatives of patients with NIDDM are also relatively insulin resistant compared with well-matched volunteers without a family history of NIDDM. Finally, prospective studies12 13 14 15 16 have identified insulin resistance and/or compensatory hyperinsulinemia as the initial defect in the development of NIDDM. Thus, the central role of insulin resistance in the pathogenesis and clinical course of patients with NIDDM has been well established. Of greater relevance to the IRAS study of “Insulin Sensitivity and Atherosclerosis” published in this issue of Circulation 17 is recent awareness that the ability of insulin to mediate glucose disposal can differ by as much as 10-fold in subjects with normal glucose tolerance.18 19 Because the degree of insulin resistance in a substantial portion of these persons approaches that seen in patients with impaired glucose tolerance or NIDDM, it is assumed that they are able to secrete enough insulin to overcome the insulin resistance and maintain normal glucose tolerance. Unfortunately, the philanthropic response on the part of the pancreatic β-cell is not without cost, and in 1988,20 it was emphasized that these individuals were at increased risk to have higher plasma TG and lower HDL cholesterol concentrations and higher blood pressure. More importantly, it was suggested that the cluster of abnormalities associated with insulin resistance, designated as Syndrome X, significantly increased …

Pathophysiology of insulin resistance in human disease

The ability of insulin to stimulate glucose uptake varies widely from person to person, and these differences, as well as how the individual attempts to compensate for them, are of fundamental importance in the development and clinical course of what are often designated as diseases of Western civilization. Evidence is presented that non-insulin-dependent diabetes mellitus (NIDDM) results from a failure on the part of pancreatic beta-cells to compensate adequately for the defect in insulin action in insulin-resistant individuals. In addition, a coherent formulation of the physiological changes that lead from the defect in cellular insulin action to the loss in glucose homeostasis is presented. However, the ability to maintain the degree of compensatory hyperinsulinemia necessary to prevent loss of glucose tolerance in insulin-resistant individuals does not represent an unqualified homeostatic victory. In contrast, evidence is presented supporting the view that the combination of insulin resistance and compensatory hyperinsulinemia predisposes to the development of a cluster of abnormalities, including some degree of glucose intolerance, an increase in plasma triglyceride and a decrease in high-density lipoprotein cholesterol concentrations, high blood pressure, hyperuricemia, smaller denser low-density lipoprotein particles, and higher circulating levels of plaminogen activator inhibitor 1. The cluster of changes associated with insulin resistance has been said to comprise syndrome X, and all of the manifestations of syndrome X have been shown to increase risk of coronary heart disease. Thus it is concluded that insulin resistance and its associated abnormalities are of utmost importance in the pathogenesis of NIDDM, hypertension, and coronary heart disease.

Insulin Resistance in Human Disease edited by K. B. Huh, S. H. Shinn, T. Kaneko

<b>Insulin Resistance in Human Disease</b> edited by K. B. Huh, S. H. Shinn, T. Kaneko