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Ralph A. DeFronzo

Bio: Ralph A. DeFronzo is an academic researcher from University of Texas Health Science Center at San Antonio. The author has contributed to research in topics: Insulin & Insulin resistance. The author has an hindex of 160, co-authored 759 publications receiving 132993 citations. Previous affiliations of Ralph A. DeFronzo include National Research Council & American Diabetes Association.


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Journal ArticleDOI
TL;DR: It was deemed essential to develop an appropriate, uniform terminology and a functional, working classification of diabetes that reflects the current knowledge about the disease.
Abstract: the growth of knowledge regarding the etiology and pathogenesis of diabetes has led many individuals and groups in the diabetes community to express the need for a revision of the nomenclature, diagnostic criteria, and classification of diabetes. As a consequence, it was deemed essential to develop an appropriate, uniform terminology and a functional, working classification of diabetes that reflects the current knowledge about the disease. (1)

11,886 citations

Journal ArticleDOI
TL;DR: Methods for the quantification of beta-cell sensitivity to glucose (hyperglycemic clamp technique) and of tissue sensitivity to insulin (euglycemic insulin clamp technique] are described.
Abstract: Methods for the quantification of beta-cell sensitivity to glucose (hyperglycemic clamp technique) and of tissue sensitivity to insulin (euglycemic insulin clamp technique) are described. Hyperglycemic clamp technique. The plasma glucose concentration is acutely raised to 125 mg/dl above basal levels by a priming infusion of glucose. The desired hyperglycemic plateau is subsequently maintained by adjustment of a variable glucose infusion, based on the negative feedback principle. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of glucose metabolism. Under these conditions of constant hyperglycemia, the plasma insulin response is biphasic with an early burst of insulin release during the first 6 min followed by a gradually progressive increase in plasma insulin concentration. Euglycemic insulin clamp technique. The plasma insulin concentration is acutely raised and maintained at approximately 100 muU/ml by a prime-continuous infusion of insulin. The plasma glucose concentration is held constant at basal levels by a variable glucose infusion using the negative feedback principle. Under these steady-state conditions of euglycemia, the glucose infusion rate equals glucose uptake by all the tissues in the body and is therefore a measure of tissue sensitivity to exogenous insulin.

7,271 citations

Journal ArticleDOI
TL;DR: A novel estimate of insulin sensitivity that is simple to calculate and provides a reasonable approximation of whole-body insulin sensitivity from the oral glucose tolerance test (OGTT).
Abstract: OBJECTIVE: Several methods have been proposed to evaluate insulin sensitivity from the data obtained from the oral glucose tolerance test (OGTT). However, the validity of these indices has not been rigorously evaluated by comparing them with the direct measurement of insulin sensitivity obtained with the euglycemic insulin clamp technique. In this study, we compare various insulin sensitivity indices derived from the OGTT with whole-body insulin sensitivity measured by the euglycemic insulin clamp technique. RESEARCH DESIGN AND METHODS: In this study, 153 subjects (66 men and 87 women, aged 18-71 years, BMI 20-65 kg/m2) with varying degrees of glucose tolerance (62 subjects with normal glucose tolerance, 31 subjects with impaired glucose tolerance, and 60 subjects with type 2 diabetes) were studied. After a 10-h overnight fast, all subjects underwent, in random order, a 75-g OGTT and a euglycemic insulin clamp, which was performed with the infusion of [3-3H]glucose. The indices of insulin sensitivity derived from OGTT data and the euglycemic insulin clamp were compared by correlation analysis. RESULTS: The mean plasma glucose concentration divided by the mean plasma insulin concentration during the OGTT displayed no correlation with the rate of whole-body glucose disposal during the euglycemic insulin clamp (r = -0.02, NS). From the OGTT, we developed an index of whole-body insulin sensitivity (10,000/square root of [fasting glucose x fasting insulin] x [mean glucose x mean insulin during OGTT]), which is highly correlated (r = 0.73, P < 0.0001) with the rate of whole-body glucose disposal during the euglycemic insulin clamp. CONCLUSIONS: Previous methods used to derive an index of insulin sensitivity from the OGTT have relied on the ratio of plasma glucose to insulin concentration during the OGTT. Our results demonstrate the limitations of such an approach. We have derived a novel estimate of insulin sensitivity that is simple to calculate and provides a reasonable approximation of whole-body insulin sensitivity from the OGTT.

4,988 citations

Journal ArticleDOI
TL;DR: In summary, insulin resistance appears to be a syndrome that is associated with a clustering of metabolic disorders, including non-insulin-dependent diabetes mellitus, obesity, hypertension, lipid abnormalities, and atherosclerotic cardiovascular disease.
Abstract: Diabetes mellitus is commonly associated with systolic/diastolic hypertension, and a wealth of epidemiological data suggest that this association is independent of age and obesity. Much evidence indicates that the link between diabetes and essential hypertension is hyperinsulinemia. Thus, when hypertensive patients, whether obese or of normal body weight, are compared with age- and weight-matched normotensive control subjects, a heightened plasma insulin response to a glucose challenge is consistently found. A state of cellular resistance to insulin action subtends the observed hyperinsulinism. With the insulin/glucose-clamp technique, in combination with tracer glucose infusion and indirect calorimetry, it has been demonstrated that the insulin resistance of essential hypertension is located in peripheral tissues (muscle), is limited to nonoxidative pathways of glucose disposal (glycogen synthesis), and correlates directly with the severity of hypertension. The reasons for the association of insulin resistance and essential hypertension can be sought in at least four general types of mechanisms: Na+ retention, sympathetic nervous system overactivity, disturbed membrane ion transport, and proliferation of vascular smooth muscle cells. Physiological maneuvers, such as calorie restriction (in the overweight patient) and regular physical exercise, can improve tissue sensitivity to insulin; evidence indicates that these maneuvers can also lower blood pressure in both normotensive and hypertensive individuals. Insulin resistance and hyperinsulinemia are also associated with an atherogenic plasma lipid profile. Elevated plasma insulin concentrations enhance very-low-density lipoprotein (VLDL) synthesis, leading to hypertriglyceridemia. Progressive elimination of lipid and apolipoproteins from the VLDL particle leads to an increased formation of intermediate-density and low-density lipoproteins, both of which are atherogenic. Last, insulin, independent of its effects on blood pressure and plasma lipids, is known to be atherogenic. The hormone enhances cholesterol transport into arteriolar smooth muscle cells and increases endogenous lipid synthesis by these cells. Insulin also stimulates the proliferation of arteriolar smooth muscle cells, augments collagen synthesis in the vascular wall, increases the formation of and decreases the regression of lipid plaques, and stimulates the production of various growth factors. In summary, insulin resistance appears to be a syndrome that is associated with a clustering of metabolic disorders, including non-insulin-dependent diabetes mellitus, obesity, hypertension, lipid abnormalities, and atherosclerotic cardiovascular disease.

4,582 citations

Journal ArticleDOI
TL;DR: The International Expert Committee was convened to reexamine the classification and diagnostic criteria of diabetes, which were based on the 1979 publication of the National Diabetes Data Group and subsequent WHO study group and adopted several changes to the diagnostic criteria for diabetes and for lesser degrees of impaired glucose regulation (IFG/IGT).
Abstract: In 1997, an International Expert Committee was convened to reexamine the classification and diagnostic criteria of diabetes, which were based on the 1979 publication of the National Diabetes Data Group (1) and subsequent WHO study group (2). As a result of its deliberations, the Committee recommended several changes to the diagnostic criteria for diabetes and for lesser degrees of impaired glucose regulation (IFG/IGT) (3). The following were the major changes or issues addressed. 1) The use of a fasting plasma glucose (FPG) test for the diagnosis of diabetes was recommended, and the cut point separating diabetes from nondiabetes was lowered from FPG 140 mg/dl (7.8 mmol/l) to 126 mg/dl (7.0 mmol/l). (All glycemic values represent venous plasma.) This change was based on data that showed an increase in prevalence and incidence of diabetic retinopathy beginning at approximately a FPG of 126 mg/dl, as well as on the desire to reduce the discrepancy that existed in the number of cases detected by the FPG cut point of 140 mg/dl and the 2-h value in the OGTT (2-h plasma glucose [2-h PG]) of 200 mg/dl (11.1 mmol/l). 2) Normal FPG was defined as 110 mg/dl (6.1 mmol/l). 3) The use of HbA1c (A1C) as a diagnostic test for diabetes was not recommended. The primary reason for this decision was a lack of standardized methodology resulting in varying nondiabetic reference ranges among laboratories. 4) Although the OGTT (which consists of an FPG and 2-h PG value) was recognized as a valid way to diagnose diabetes, the use of the test for diagnostic purposes in clinical practice was discouraged for several reasons (e.g., inconvenience, less reproducibility, greater cost). The diagnostic category of impaired glucose tolerance (IGT) was retained to describe people whose FPG was 126 mg/dl but whose 2-h PG after a 75-g oral glucose challenge was 140–199 mg/dl. 5) The range of FPG levels between “normal” and that diagnostic for diabetes was named “impaired fasting glucose” (IFG). IFG identified people whose FPG ranged from 110 mg/dl (6.1 mmol/l) to 125 mg/dl (6.9 mmol/l). This construct was established so that there would be a fasting category analogous to IGT. The WHO consultation (4) also adopted most of the above conclusions. The two significant differences were that, whenever feasible, individuals with IFG should receive an OGTT to exclude the presence of diabetes, and the adoption of different criteria for the diagnosis of gestational diabetes. Since the 1997 Expert Committee report, many new data related to the diagnosis of diabetes have been published. First, many analyses of both old and new epidemiological data have examined the equivalence of the FPG and the 2-h PG to predict diabetes, and questions have been raised about the preference of the FPG test over the 2-h PG to diagnose diabetes (5– 7). Second, the IGT category has now been associated with cardiovascular disease (CVD) risk factors (8–10) and CVD events (10,11), whereas IFG is much less strongly associated with CVD events and CVD mortality (10,11). Third, the National Glycosylated Hemoglobin Standardization Program (NGSP) has now ensured that most laboratories in the U.S. perform the assays using standardized controls and report glycated hemoglobin results in a manner traceable to the assay used in the Diabetes Control and Complications Trial (DCCT) (12). These development s have improved as say performance and now allow caregivers and patients to compare reported results obtained among laboratories. Additional studies have suggested that the A1C may assist in diagnosing diabetes (13–17). Finally, data from major clinical trials that tested whether the progression from IGT to diabetes could be delayed or prevented by a treatment intervention have produced concordant results: intensive lifestyle modification (nutritional and exercise interventions) (18,19), metformin (19,20), and acarbose (20,21) were effective to variable degrees. In addition, a thiazolidinedione drug (troglitazone) reduced the incidence of diabetes in high-risk women with prior gestational diabetes (22). An inherent difficulty in the diagnosis of diabetes is the present lack of an identified unique qualitative biological marker that separates all people with diabetes from all nondiabetic individuals. The closest such characteristic for practical purposes is diabetic retinopathy, but this suffers from the obvious defect that in most diabetic patients, retinopathy usually becomes evident years after the recognized onset of diabetes. The lack of a suitable, unique marker of diabetes has led to reliance on the metabolic abnormality historically associated with the disease, i.e., hyperglycemia (as measured by the FPG or 2-h PG) as the most useful diagnostic test. The selection of diagnostic cut points for these tests rests on two ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

3,687 citations


Cited by
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TL;DR: The Gene Set Enrichment Analysis (GSEA) method as discussed by the authors focuses on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation.
Abstract: Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.

34,830 citations

Journal ArticleDOI
TL;DR: The correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.
Abstract: The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.

29,217 citations

Journal ArticleDOI
TL;DR: In this paper, the authors compared a lifestyle intervention with metformin to prevent or delay the development of Type 2 diabetes in nondiabetic individuals. And they found that the lifestyle intervention was significantly more effective than the medication.
Abstract: Background Type 2 diabetes affects approximately 8 percent of adults in the United States. Some risk factors — elevated plasma glucose concentrations in the fasting state and after an oral glucose load, overweight, and a sedentary lifestyle — are potentially reversible. We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes. Methods We randomly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo, metformin (850 mg twice daily), or a lifestyle modification program with the goals of at least a 7 percent weight loss and at least 150 minutes of physical activity per week. The mean age of the participants was 51 years, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 34.0; 68 percent were women, and 45 percent were members of minority groups. Results The average follow-up was 2.8 years. The incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and lifestyle groups, respectively. The lifestyle intervention reduced the incidence by 58 percent (95 percent confidence interval, 48 to 66 percent) and metformin by 31 percent (95 percent confidence interval, 17 to 43 percent), as compared with placebo; the lifestyle intervention was significantly more effective than metformin. To prevent one case of diabetes during a period of three years, 6.9 persons would have to participate in the lifestyle-intervention program, and 13.9 would have to receive metformin. Conclusions Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than metformin.

17,333 citations

Journal Article
TL;DR: In this article, the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial were compared.

17,108 citations

Journal ArticleDOI
TL;DR: The chronic hyperglycemia of diabetes is associated with long-term damage, dys-function, and failure of differentorgans, especially the eyes, kidneys, nerves, heart, and blood vessels.

13,077 citations