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Showing papers on "Insulin published in 1996"


Journal ArticleDOI
TL;DR: Obese/insulin-resistant subjects are characterized by endothelial dysfunction and endothelial resistance to insulin's effect on enhancement of endothelium-dependent vasodilation, which could contribute to the increased risk of atherosclerosis in obese insulin- resistant subjects.
Abstract: To test the hypothesis that obesity/insulin resistance impairs both endothelium-dependent vasodilation and insulin-mediated augmentation of endothelium-dependent vasodilation, we studied leg blood flow (LBF) responses to graded intrafemoral artery infusions of methacholine chloride (MCh) or sodium nitroprusside (SNP) during saline infusion and euglycemic hyperinsulinemia in lean insulin-sensitive controls (C), in obese insulin-resistant subjects (OB), and in subjects with non-insulin-dependent diabetes mellitus (NIDDM). MCh induced increments in LBF were approximately 40% and 55% lower in OB and NIDDM, respectively, as compared with C (P < 0.05). Euglycemic hyperinsulinemia augmented the LBF response to MCh by - 50% in C (P < 0.05 vs saline) but not in OB and NIDDM. SNP caused comparable increments in LBF in all groups. Regression analysis revealed a significant inverse correlation between the maximal LBF change in response to MCh and body fat content. Thus, obesity/insulin resistance is associated with (a) blunted endothelium-dependent, but normal endothelium-independent vasodilation and (b) failure of euglycemic hyperinsulinemia to augment endothelium-dependent vasodilation. Therefore, obese/insulin-resistant subjects are characterized by endothelial dysfunction and endothelial resistance to insulin's effect on enhancement of endothelium-dependent vasodilation. This endothelial dysfunction could contribute to the increased risk of atherosclerosis in obese insulin-resistant subjects.

1,704 citations


Journal ArticleDOI
05 Dec 1996-Nature
TL;DR: It is shown that subjects with the MODY3-form of NIDDM have mutations in the gene encoding hepatocyte nuclear factor-1α (HNF-1 α), which is encoded by the gene TCF1, which is a transcription factor that helps in the tissue-specific regulation of the expression of several liver genes.
Abstract: The disease non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is characterized by abnormally high blood glucose resulting from a relative deficiency of insulin. It affects about 2% of the world's population and treatment of diabetes and its complications are an increasing health-care burden. Genetic factors are important in the aetiology of NIDDM, and linkage studies are starting to localize some of the genes that influence the development of this disorder. Maturity-onset diabetes of the young (MODY), a single-gene disorder responsible for 2-5% of NIDDM, is characterized by autosomal dominant inheritance and an age of onset of 25 years or younger. MODY genes have been localized to chromosomes 7, 12 and 20 (refs 5, 7, 8) and clinical studies indicate that mutations in these genes are associated with abnormal patterns of glucose-stimulated insulin secretion. The gene on chromosome 7 (MODY2) encodes the glycolytic enzyme glucokinases which plays a key role in generating the metabolic signal for insulin secretion and in integrating hepatic glucose uptake. Here we show that subjects with the MODY3-form of NIDDM have mutations in the gene encoding hepatocyte nuclear factor-1alpha (HNF-1alpha, which is encoded by the gene TCF1). HNF-1alpha is a transcription factor that helps in the tissue-specific regulation of the expression of several liver genes and also functions as a weak transactivator of the rat insulin-I gene.

1,584 citations


Journal ArticleDOI
TL;DR: The insulin concentration in plasma has been estimated from the degree of hypoglycemia produced in hypophysectomized, adrenalectomization, alloxan-diabetic rats, and from the increased oxidation of glucose-1-C14 by the rat epididymal fat pad.
Abstract: For years investigators have sought an assay for insulin which would combine virtually absolute specificity with a high degree of sensitivity, sufficiently exquisite for measurement of the minute insulin concentrations usually present in the circulation. Methods in use recently depend on the ability of insulin to exert an effect on the metabolism of glucose in vivo or in excised muscle or adipose tissue. Thus, the insulin concentration in plasma has been estimated: a) from the degree of hypoglycemia produced in hypophysectomized, adrenalectomized, alloxan-diabetic rats (1); b) from the augmentation of glucose uptake by isolated rat hemidiaphragm (2); or c) from the increased oxidation of glucose-1-C14 by the rat epididymal fat pad (3). Since there have been reports indicating the presence, in plasma, of inhibitors of insulin action (4) and of noninsulin substances capable of inducing an insulin-like effect (5,6), these procedures, while yielding interesting information regarding the effects of various plasmas on glucose metabolism in tissues, are of doubtful specificity for the measurement of insulin per se (5).

1,477 citations


Journal ArticleDOI
TL;DR: It is hypothesized that the metabolic abnormalities linked to the hypertension by a pathophysiologic process that involves the sympathoadrenal system and exerts influence on blood pressure and complications in many patients.
Abstract: Abnormalities of glucose, insulin, and lipoprotein metabolism are common in patients with hypertension. These changes can also be discerned in normotensive first-degree relatives of hypertensive patients. They are not present in patients with secondary forms of hypertension, do not necessarily improve when blood pressure is lowered pharmacologically, and may even be made worse by some forms of antihypertensive treatment. These metabolic abnormalities may play a part in both the pathogenesis and the complications of hypertension in many patients. We hypothesize that the metabolic abnormalities are linked to the hypertension by a pathophysiologic process that involves the sympathoadrenal system and exerts . . .

1,462 citations


Journal ArticleDOI
01 Dec 1996-Diabetes
TL;DR: Clinical studies in patients with type II diabetes, as well as other syndromes characterized by insulin resistance, have demonstrated that thiazolidinediones may represent a safe and effective new treatment.
Abstract: Insulin resistance, characterized by reduced responsiveness to normal circulating concentrations of insulin, is a common feature of almost all patients with type II diabetes. The presumed central roles of both peripheral and hepatic insulin resistance suggest that the enhancement of insulin action might be an effective pharmacological approach to diabetes. Thiazolidinediones are a new class of orally active drugs that are designed to enhance the actions of insulin. These agents reduce insulin resistance by increasing insulin-dependent glucose disposal and reducing hepatic glucose output. Clinical studies in patients with type II diabetes, as well as other syndromes characterized by insulin resistance, have demonstrated that thiazolidinediones may represent a safe and effective new treatment. Although the precise mechanism of action of these drugs remains unknown, transcriptional changes are observed in tissue culture cells that produce enhanced insulin action. This regulation of gene expression appears to be mediated by the interactions of thiazolidinediones with a family of nuclear receptors known as the peroxisome proliferator-activated receptors (PPARs). The further elucidation of the molecular actions of these drugs may reveal much about the underlying mechanisms of insulin resistance.

1,056 citations


Journal ArticleDOI
22 Nov 1996-Science
TL;DR: Results indicate that aP2 is central to the pathway that links obesity to insulin resistance, possibly by linking fatty acid metabolism to expression of TNF-α.
Abstract: Fatty acid binding proteins (FABPs) are small cytoplasmic proteins that are expressed in a highly tissue-specific manner and bind to fatty acids such as oleic and retinoic acid. Mice with a null mutation in aP2 , the gene encoding the adipocyte FABP, were developmentally and metabolically normal. The aP2 -deficient mice developed dietary obesity but, unlike control mice, they did not develop insulin resistance or diabetes. Also unlike their obese wild-type counterparts, obese aP2 −/− animals failed to express in adipose tissue tumor necrosis factor-α (TNF-α), a molecule implicated in obesity-related insulin resistance. These results indicate that aP2 is central to the pathway that links obesity to insulin resistance, possibly by linking fatty acid metabolism to expression of TNF-α.

914 citations


Journal ArticleDOI
TL;DR: It is demonstrated that GLP1 plays a central role in the regulation of glycemia; however, disruption of GLP 1/GLP1R signaling in the central nervous system is not associated with perturbation of feeding behavior or obesity in vivo.
Abstract: Glucagon-like peptide 1 (GLP1) is postulated to regulate blood glucose and satiety, but the biological importance of GLP1 as an incretin and neuropeptide remains controversal. The regulation of nutrient-induced insulin secretion is dependent on the secretion of incretins, gut-derived peptides that potentiate insulin secretion from the pancreatic islets. To ascertain the relative physiological importance of GLP1 as a regulator of feeding behavior and insulin secretion, we have generated mice with a targeted disruption of the GLP1 receptor gene (GLP1R). These GLP1R-/- mice are viable, develop normally but exhibit increased levels of blood glucose following oral glucose challenge in association with diminished levels of circulating insulin. It is surprising that they also exhibit abnormal levels of blood glucose following intraperitoneal glucose challenge. Intracerebroventricular administration of GLP1 inhibited feeding in wild-type mice but not in GLP1R-/- mice; however, no evidence for abnormal body weight or feeding behavior was observed in GLP1R-/- mice. These observations demonstrate that GLP1 plays a central role in the regulation of glycemia; however, disruption of GLP1/GLP1R signaling in the central nervous system is not associated with perturbation of feeding behavior or obesity in vivo.

813 citations


Journal ArticleDOI
TL;DR: The rapid decrease in serum leptin levels during fasting indicated that leptin release was regulated by factors other than changes in body fat mass, and suggested that insulin and/or glucose may play a role in the regulation of leptin release.
Abstract: We have studied the effect of fasting on serum leptin levels in normal volunteers. Five normal-weight (BMI 28, 2 males/3 females) were fasted (0 Kcal) for 52 h. Mean plasma glucose decreased from 88 +/- 3 to 63 +/- 5 mg/dl, serum insulin from 16 +/- 1 to 10 +/- 1 microU/ml, plasma beta-hydroxybutyrate increased from 0.2 +/- 0.1 to 1.8 +/- 0.4 mumol/ml. Serum leptin levels were higher in the obese than in the normal-weight volunteers (31 +/- 12 vs 11 +/- 3 ng/ml, p < 0.01). In the obese, serum leptin decreased from 31 +/- 10 to 12 +/- 5 ng/ml aft552 h (-72%, p < 0.001); in the normal-weight it decreased from 11 +/- 3 to 4 +/- 0.5 ng/ml (-64%, p < 0.001). Serum leptin correlated positively with serum insulin (r = 0.51, p < 0.001) and with plasma glucose (r = 0.61, p < 0.001). To determine effects of fasting induced decreases in plasma glucose and insulin on serum leptin, four normal subjects (3 males/1 female) were fasted for 72 h while their plasma glucose was clamped at basal levels with a variable rate glucose infusion. In these volunteers, serum leptin and insulin concentrations remained unchanged. In summary, the rapid decrease in serum leptin levels during fasting indicated that leptin release was regulated by factors other than changes in body fat mass. The lack of leptin changes during fasting, when basal insulin and glucose levels were maintained at basal levels, suggested that insulin and/or glucose may play a role in the regulation of leptin release.

788 citations


Journal ArticleDOI
TL;DR: The nocturnal rise in leptin observed in the present study resembles those reported for prolactin, thyroid-stimulating hormone, and free fatty acids and is speculated to have an effect in suppressing appetite during the night while sleeping.
Abstract: We studied 24-h profiles of circulating leptin levels using a sensitive and specific RIA in lean controls and obese subjects with or without non-insulin-dependent diabetes mellitus (NIDDM) during normal routine activity. Serum leptin levels were significantly higher in obese (41.7 +/- 9.0 ng/ml; n = 11) and obese NIDDM (30.8 +/- 6.7; n = 9) subjects compared with those in lean controls (12.0 +/- 4.4, n = 6). In all the three groups, serum leptin levels were highest between midnight and early morning hours and lowest around noon to midafternoon. The nocturnal rise in leptin levels was significant when data were analyzed by ANOVA (lean: F = 3.17, P 0.05) were observed between circulating levels of leptin and either insulin or glucose levels in any of the 20 subjects studied for 24-h profiles. The nocturnal rise in leptin observed in the present study resembles those reported for prolactin, thyroid-stimulating hormone, and free fatty acids. We speculate that the nocturnal rise in leptin could have an effect in suppressing appetite during the night while sleeping.

773 citations


Journal ArticleDOI
TL;DR: TNF is expressed in human muscle, and is expressed at a higher level in the muscle tissue and in the cultured muscle cells from insulin resistant and diabetic subjects, which suggest another mechanism by which TNF may play an important role in human insulin resistance.
Abstract: TNFalpha is orverexpressed in the adipose tissue of obese rodents and humans, and is associated with insulin resistance. To more closely link TNF expression with whole body insulin action, we examined the expression of TNF by muscle, which is responsible for the majority of glucose uptake in vivo. Using RT-PCR, TNF was detected in human heart, in skeletal muscle from humans and rats, and in cultured human myocytes. Using competitive RT-PCR, TNF was quantitated in the muscle biopsy specimens from 15 subjects whose insulin sensitivity had been characterized using the glucose clamp. technique. TNF expression in the insulin resistant subjects and the diabetic patients was fourfold higher than in the insulin sensitive subjects, and there was a significant inverse linear relationship between maximal glucose disposal rate and muscle TNF (r = -0.60, P < 0.02). In nine subjects, muscle cells from vastus lateralis muscle biopsies were placed into tissue culture for 4 wk, and induced to differentiate into myotubes. TNF was secreted into the medium from these cells, and cells from diabetic patients expressed threefold more TNF than cells from nondiabetic subjects. Thus, TNF is expressed in human muscle, and is expressed at a higher level in the muscle tissue and in the cultured muscle cells from insulin resistant and diabetic subjects. These data suggest another mechanism by which TNF may play an important role in human insulin resistance.

758 citations


Journal ArticleDOI
TL;DR: The data suggest that NO is a novel effector of insulin signaling pathways that are also involved with glucose metabolism, and that PI 3-kinase activity is required for insulin-stimulated glucose transport.
Abstract: Hypertension is associated with insulin-resistant states such as diabetes and obesity. Nitric oxide (NO) contributes to regulation of blood pressure. To gain insight into potential mechanisms linking hypertension with insulin resistance we directly measured and characterized NO production from human umbilical vein endothelial cells (HUVEC) in response to insulin using an amperometric NO-selective electrode. Insulin stimulation of HUVEC resulted in rapid, dose-dependent production of NO with a maximal response of approximately 100 nM NO (200,000 cells in 2 ml media; ED50 approximately 500 nM insulin). Although HUVEC have many more IGF-1 receptors than insulin receptors (approximately 400,000, and approximately 40,000 per cell respectively), a maximally stimulating dose of IGF-1 generated a smaller response than insulin (40 nM NO; ED50 approximately 100 nM IGF-1). Stimulation of HUVEC with PDGF did not result in measurable NO production. The effects of insulin and IGF-1 were completely blocked by inhibitors of either tyrosine kinase (genestein) or nitric oxide synthase (L-NAME). Wortmannin (an inhibitor of phosphatidylinositol 3-kinase [PI 3-kinase]) inhibited insulin-stimulated production of NO by approximately 50%. Since PI 3-kinase activity is required for insulin-stimulated glucose transport, our data suggest that NO is a novel effector of insulin signaling pathways that are also involved with glucose metabolism.

Journal ArticleDOI
17 Feb 1996-BMJ
TL;DR: It is confirmed that reduced fetal growth is associated with increased risk of diabetes and suggest a specific association with thinness at birth and this relation seems to be mediated through insulin resistance rather than through impaired β cell function and to depend on an interaction with obesity in adult life.
Abstract: Objective: To establish whether the relation between size at birth and non-insulin dependent diabetes is mediated through impaired β cell function or insulin resistance. Design: Cohort study. Setting: Uppsala, Sweden. Subjects: 1333 men whose birth records were traced from a cohort of 2322 men born during 1920-4 and resident in Uppsala in 1970. Main outcome measures: Intravenous glucose tolerance test at age 50 years and non-insulin dependent diabetes at age 60 years. Results: There was a weak inverse correlation (r=-0.07, P=0.03) between ponderal index at birth and 60 minute insulin concentrations in the intravenous glucose tolerance test at age 50 years. This association was stronger (r=-0.19, P=0.001) in the highest third of the distribution of body mass index than in the other two thirds (P=0.01 for the interaction between ponderal index and body mass index). Prevalence of diabetes at age 60 years was 8% in men whose birth weight was less than 3250 g compared with 5% in men with birth weight 3250 g or more (P=0.08; 95% confidence interval for difference −0.3% to 6.8%). There was a stronger association between diabetes and ponderal index: prevalence of diabetes was 12% in the lowest fifth of ponderal index compared with 4% in the other four fifths (P=0.001; 3.0% to 12.6%). Conclusion: These results confirm that reduced fetal growth is associated with increased risk of diabetes and suggest a specific association with thinness at birth. This relation seems to be mediated through insulin resistance rather than through impaired β cell function and to depend on an interaction with obesity in adult life.

Journal ArticleDOI
01 May 1996-Diabetes
TL;DR: In summary, insulin does not stimulate leptin production acutely; however, a long-term effect of insulin on leptin production could be demonstrated both in vivo and in vitro, suggesting that insulin regulates OB gene expression and leptin production indirectly, probably through its trophic effect on adipocytes.
Abstract: This study was undertaken to investigate the changes in obesity (OB) gene expression and production of leptin in response to insulin in vitro and in vivo under euglycemic and hyperglycemic conditions in humans. Three protocols were used: 1) euglycemic clamp with insulin infusion rates at 40, 120, 300, and 1,200 mU / m / min carried out for up to 5 h performed in 16 normal lean individuals, 30 obese individuals, and 31 patients with NIDDM; 2) 64-to 72-h hyperglycemic (glucose 12.6 mmol/l) clamp performed on 5 lean individuals; 3) long-term (96-h) primary culture of isolated abdominal adipocytes in the presence and absence of 100 nmol/l insulin. Short-term hyperinsulinemia in the range of 80 to > 10,000 microU/ml had no effect on circulating levels of leptin. During the prolonged hyperglycemic clamp, a rise in leptin was observed during the last 24 h of the study (P < 0.001). In the presence of insulin in vitro, OB gene expression increased at 72 h (P < 0.01), followed by an increase in leptin released to the medium (P < 0.001). In summary, insulin does not stimulate leptin production acutely; however, a long-term effect of insulin on leptin production could be demonstrated both in vivo and in vitro. These data suggest that insulin regulates OB gene expression and leptin production indirectly, probably through its trophic effect on adipocytes.

Journal ArticleDOI
15 Nov 1996-Science
TL;DR: In vitro studies raise the possibility that leptin modulates insulin activities in obese individuals by causing attenuation of several insulin-induced activities and increasing the activity of IRS-1-associated phosphatidylinositol 3-kinase.
Abstract: Leptin mediates its effects on food intake through the hypothalamic form of its receptor OB-R. Variants of OB-R are found in other tissues, but their function is unknown. Here, an OB-R variant was found in human hepatic cells. Exposure of these cells to leptin, at concentrations comparable with those present in obese individuals, caused attenuation of several insulin-induced activities, including tyrosine phosphorylation of the insulin receptor substrate-1 (IRS-1), association of the adapter molecule growth factor receptor-bound protein 2 with IRS-1, and down-regulation of gluconeogenesis. In contrast, leptin increased the activity of IRS-1-associated phosphatidylinositol 3-kinase. These in vitro studies raise the possibility that leptin modulates insulin activities in obese individuals.

Journal ArticleDOI
TL;DR: This large epidemiological study evaluated insulin sensitivity by the frequently sampled intravenous glucose tolerance test with analysis by the minimal model of Bergman and measured intimal-medial thickness of the carotid artery as an index of atherosclerosis by use of noninvasive B-mode ultrasonography.
Abstract: Background Reduced insulin sensitivity has been proposed as an important risk factor in the development of atherosclerosis. However, insulin sensitivity is related to many other cardiovascular risk factors, including plasma insulin levels, and it is unclear whether an independent role of insulin sensitivity exists. Large epidemiological studies that measure insulin sensitivity directly have not been conducted. Methods and Results The Insulin Resistance Atherosclerosis Study (IRAS) evaluated insulin sensitivity (SI) by the frequently sampled intravenous glucose tolerance test with analysis by the minimal model of Bergman. IRAS measured intimal-medial thickness (IMT) of the carotid artery as an index of atherosclerosis by use of noninvasive B-mode ultrasonography. These measures, as well as factors that may potentially confound or mediate the relationship between insulin sensitivity and atherosclerosis, were available in relation to 398 black, 457 Hispanic, and 542 non-Hispanic white IRAS participants. Ther...

Journal ArticleDOI
TL;DR: Exercise increases insulin sensitivity in both normal subjects and the insulin-resistant offspring of diabetic parents because of a twofold increase in insulin-stimulated glycogen synthesis in muscle, due to an increase in Diabetes mellitus-related glucose transport-phosphorylation.
Abstract: Background Insulin resistance in the offspring of parents with non-insulin-dependent diabetes mellitus (NIDDM) is the best predictor of development of the disease and probably plays an important part in its pathogenesis. We studied the mechanism and degree to which exercise training improves insulin sensitivity in these subjects. Methods Ten adult children of parents with NIDDM and eight normal subjects were studied before starting an aerobic exercise-training program, after one session of exercise, and after six weeks of exercise. Insulin sensitivity was measured by the hyperglycemic–hyperinsulinemic clamp technique combined with indirect calorimetry, and the rate of glycogen synthesis in muscle and the intramuscular glucose-6-phosphate concentration were measured by carbon-13 and phosphorus-31 nuclear magnetic resonance spectroscopy, respectively. Results During the base-line study, the mean (±SE) rate of muscle glycogen synthesis was 63±9 percent lower in the offspring of diabetic parents than in the n...

Journal ArticleDOI
01 May 1996-Diabetes
TL;DR: Abdominal fat had a significantly stronger relationship with insulin sensitivity than peripheral nonabdominalfat, and higher levels were associated with increased fasting nonesterified fatty acids, lipid oxidation, and hepatic glucose output, which may be a major determinant of insulin resistance in women.
Abstract: Insulin resistance appears to be central to obesity, NIDDM, hyperlipidemia, and cardiovascular disease. While obese women with abdominal (android) fat distribution are more insulin resistant than those with peripheral (gynecoid) obesity, in nonobese women, the relationship between abdominal fat and insulin resistance is unknown. By measuring regional adiposity with dual-energy X-ray absorptiometry and insulin sensitivity by euglycemic-hyperinsulinemic clamp in 22 healthy women, with a mean +/- SE body BMI of 26.7 +/- 0.9 kg/m2 and differing risk factors for NIDDM, we found a strong negative relationship between central abdominal (intra-abdominal plus abdominal subcutaneous) fat and whole-body insulin sensitivity (r = -0.89, P < 0.0001) and nonoxidative glucose disposal (r = -0.77, P < 0.001), independent of total adiposity, family history of NIDDM, and past gestational diabetes. There was a large variation in insulin sensitivity, with a similar variation in central fat, even in those whose BMI was <25 kg/m2. Abdominal fat had a significantly stronger relationship with insulin sensitivity than peripheral nonabdominal fat (r2 = 0.79 vs. 0.44), and higher levels were associated with increased fasting nonesterified fatty acids, lipid oxidation, and hepatic glucose output. Because 79% of the variance in insulin sensitivity in this heterogeneous population was accounted for by central fat, abdominal adiposity appears to be a strong marker and may be a major determinant of insulin resistance in women.

Journal ArticleDOI
TL;DR: These studies are reviewed and how insulin resistance and genetically programmed pancreatic beta-cell dysfunction may interact in susceptible persons to cause diabetes are suggested.
Abstract: Non-insulin-dependent diabetes mellitus (NIDDM), the commonest form of diabetes, affects approximately 5 percent of the population of the United States. Although the pathophysiology of this condition has not been fully characterized and the nature of the primary defect is controversial, the results of recent studies provide insights into its basic causes. Here, we review these studies and suggest how insulin resistance and genetically programmed pancreatic beta-cell dysfunction may interact in susceptible persons to cause diabetes. Insulin Resistance Insulin resistance is a diminished ability of insulin to exert its biologic action across a broad range of concentrations. Unless persons with insulin . . .

Journal ArticleDOI
TL;DR: troglitazone improves total body insulin action in PCOS, resulting in lower circulating insulin levels; 2) insulin resistance, probably via hyperinsulinemia, results in a general augmentation of steroidogenesis and LH release in PCos; and 3) insulin-sensitizing agents, such as trog litazone, may provide a novel therapy for PCOS.
Abstract: We performed this study to investigate the hypothesis that insulin resistance plays a role in the pathogenesis of reproductive abnormalities in women with the polycystic ovary syndrome (PCOS). Twenty-five women with PCOS were enrolled in a double-blind randomized 3-month trial of two doses of the insulin-sensitizing agent, troglitazone, 21 of whom completed the study: 200 mg, n = 10; 400 mg, n = 11. Baseline hormonal parameters and glucose tolerance were compared with 12 age- and weight-matched ovulatory control women. There were no significant changes in body mass index during the study. Fasting (P < 0.01) and 2-h post-75-g glucose load insulin levels (P < 0.05), as well as integrated insulin responses to the glucose load, decreased (P < 0.05), and insulin sensitivity assessed by a frequently sampled iv glucose tolerance test increased significantly (P < 0.001) during troglitazone treatment. This was accompanied by significant decreases in the levels of nonsex hormone-binding globulin-bound testosterone (P < 0.01), dehydroepiandrosterone sulfate (P < 0.001), estradiol (P < 0.01), and estrone (P < 0.001). Stepwise regression analysis indicated that decreases in nonsex hormone-binding globulin testosterone levels were significantly correlated with decreases in integrated insulin responses to the glucose load (r2 0.44, P < 0.01). The only significant changes at the 200-mg troglitazone dose were an increase in insulin sensitivity (P < 0.05) and decreases in dehydro-epiandrosterone sulfate (P < 0.01) and estrone (P < 0.05) levels. At the 400-mg dose, in addition to the changes noted in the entire troglitazone treatment group, increases in the disposition index (the product of insulin sensitivity and secretion) achieved significance, as did decreases in androstenedione (P < 0.01) and LH (P < 0.05) levels and increases in sex hormone-binding globulin levels (P < 0.01). Two PCOS women had ovulatory menses. We conclude that 1) troglitazone improves total body insulin action in PCOS, resulting in lower circulating insulin levels; 2) insulin resistance, probably via hyperinsulinemia, results in a general augmentation of steroidogenesis and LH release in PCOS; and 3) insulin-sensitizing agents, such as troglitazone, may provide a novel therapy for PCOS.

Journal ArticleDOI
TL;DR: To address the question of whether both metabolic and growth-promoting actions of insulin are mediated by the insulin receptor, mice lacking insulin receptors by targeted mutagenesis in embryo-derived stem (ES) cells are generated.
Abstract: Insulin action is viewed as a set of branching pathways, with some actions serving to regulate energy metabolism and others to regulate cellular growth and development1. Thus far, available genetic evidence has supported this view. In humans, complete lack of insulin receptors due to mutations of the insulin receptor gene results in severe growth retardation and mild diabetes2,3. In mice, targeted inactivation of insulin receptor sub-strate-1, an important substrate of the insulin receptor kinase, leads to inhibition of growth and mild resistance to the metabolic actions of insulin4,5. To address the question of whether both metabolic and growth-promoting actions of insulin are mediated by the insulin receptor, we have generated mice lacking insulin receptors by targeted mutagenesis in embryo-derived stem (ES) cells. Unlike human patients lacking insulin receptors6–9, mice homozygous for a null allele of the insulin receptor gene are born at term with apparently normal intrauterine growth and development. Within hours of birth, however, homozygous null mice develop severe hyperglycaemia and hyperketonaemia, and die as the result of diabetic ketoacidosis in 48–72 hours. These data are consistent with a model in which the insulin receptor functions primarily to mediate the metabolic actions of insulin.

Journal ArticleDOI
TL;DR: It is concluded that the HOMA provides a useful model to assess ²-cell function in epidemiological studies and that it is important to take into account the degree of IR in assessing insulin secretion.
Abstract: OBJECTIVE Both insulin resistance (IR) and decreased insulin secretion have been shown to predict the development of NIDDM. However, methods to assess insulin sensitivity and secretion are complicated and expensive to apply in epidemiological studies. The homeostasis model assessment (HOMA) has been suggested as a method to assess IR and secretion from the fasting glucose and insulin concentrations. RESEARCH DESIGN AND METHODS We applied the HOMA model in the 3.5-year follow-up of the Mexico City Diabetes Study. RESULTS Out of 1,449 subjects, 97 developed diabetes. When modeled separately insulin resistance but not insulin secretion predicted NIDDM. However, when both variables were entered into the same regression model, both increased IR and decreased β-cell function significantly predicted NIDDM. CONCLUSIONS We conclude that the HOMA provides a useful model to assess ²-cell function in epidemiological studies and that it is important to take into account the degree of IR in assessing insulin secretion.

Journal ArticleDOI
TL;DR: The identification of cis-acting elements and associated trans-acting factors through which insulin either increases or decreases the transcription of specific genes is reviewed in detail and emphasis is placed on the gaps that remain between the upstream signaling molecules and the downstream trans-acts factors whose binding/transactivation potential is ultimately regulated.
Abstract: While insulin has long been known to modulate intracellular metabolism by altering the activity or intracellular location of various enzymes, it is only in the past 10 years that the regulation of gene expression by insulin has been recognized as a major action of this hormone. This review principally focuses on the regulation of gene transcription by insulin, although recent progress in the understanding of insulin-regulated mRNA stability and translation is also summarized. The identification of cis-acting elements and associated trans-acting factors through which insulin either increases or decreases the transcription of specific genes is reviewed in detail. Recent advances in the understanding of the mechanisms of insulin signaling are discussed in the context of insulin-regulated gene transcription, and emphasis is placed on the gaps that remain between the upstream signaling molecules and the downstream trans-acting factors whose binding/transactivation potential is ultimately regulated. Finally, potential gene expression defects that may contribute to the pathophysiology of non-insulin-dependent diabetes mellitus and hypertriglyceridemia are considered.

Journal ArticleDOI
TL;DR: Together with the stimulation of insulin and the inhibition of glucagon secretion, this effect probably contributes to the blood glucose-lowering action of GLP-1-(7-36) amide in type 2-diabetic patients when studied after meal ingestion.
Abstract: The aim of the study was to investigate whether inhibition of gastric emptying of meals plays a role in the mechanism of the blood glucose-lowering action of glucagon-like peptide-1-(7-36) amide [GLP-1-(7-36) amide] in type 2 diabetes. Eight poorly controlled type 2 diabetic patients (age, 58 +/- 6 yr; body mass index, 30.0 +/- 5.2 kg/m2; hemoglobin A1c, 10.5 +/- 1.2%) were studied in the fasting state (plasma glucose, 11.1 +/- 1.1 mmol/L). A liquid meal of 400 mL containing 8% amino acids and 50 g sucrose (327 Kcal) was administered at time zero by a nasogastric tube. Gastric volume was determined by a dye dilution technique using phenol red. In randomized order, GLP-1-(7-36) amide (1.2 pmol/kg.min; Saxon Biochemicals) or placebo (0.9% NaCl with 1% human serum albumin) was infused between -30 and 240 min. In the control experiment, gastric emptying was completed within 120 min, and plasma glucose, insulin, C-peptide, GLP-1-(7-36) amide, and glucagon concentrations transiently increased. With exogenous GLP-1-(7-36) amide (plasma level, approximately 70 pmol/L), gastric volume remained constant over the period it was measured (120 min; P < 0.0001 vs. placebo), and plasma glucose fell to normal fasting values (5.4 +/- 0.7 mmol/L) within 3-4 h, whereas insulin was stimulated in most, but not all, patients, and glucagon remained at the basal level or was slightly suppressed. In conclusion, GLP-1-(7-36) amide inhibits gastric emptying in type 2 diabetic patients. Together with the stimulation of insulin and the inhibition of glucagon secretion, this effect probably contributes to the blood glucose-lowering action of GLP-1-(7-36) amide in type 2-diabetic patients when studied after meal ingestion. At the degree observed, inhibition of gastric emptying, however, must be overcome by tachyphylaxis, reduction in dose, or pharmacological interventions so as not to interfere with the therapeutic use of GLP-1-(7-36) amide in type 2 diabetic patients.

Journal ArticleDOI
21 Jun 1996-Science
TL;DR: By binding to SUR NBF2 and antagonizing ATP inhibition of KATP channels, intracellular MgADP may regulate insulin secretion.
Abstract: Adenosine triphosphate (ATP)-sensitive potassium (K ATP ) channels couple the cellular metabolic state to electrical activity and are a critical link between blood glucose concentration and pancreatic insulin secretion. A mutation in the second nucleotide-binding fold (NBF2) of the sulfonylurea receptor (SUR) of an individual diagnosed with persistent hyperinsulinemic hypoglycemia of infancy generated K ATP channels that could be opened by diazoxide but not in response to metabolic inhibition. The hamster SUR, containing the analogous mutation, had normal ATP sensitivity, but unlike wild-type channels, inhibition by ATP was not antagonized by adenosine diphosphate (ADP). Additional mutations in NBF2 resulted in the same phenotype, whereas an equivalent mutation in NBF1 showed normal sensitivity to MgADP. Thus, by binding to SUR NBF2 and antagonizing ATP inhibition of K ATP channels, intracellular MgADP may regulate insulin secretion.

Journal ArticleDOI
01 Jun 1996-Diabetes
TL;DR: The association between SI and upper body adiposity (waist-to-hip ratio) was similar in each ethnic group, suggesting that greater insulin resistance may be in large part responsible for the higher prevalence of NIDDM in these minority groups.
Abstract: The etiology of NIDDM is still controversial, with both insulin resistance and decreased insulin secretion postulated as potential important factors. African-Americans and Hispanics have a two- to threefold excess risk of developing NIDDM compared with non-Hispanic whites. Yet little is known concerning the prevalence of insulin resistance and secretion defects in minorities, especially in African-Americans in population-based studies. Fasting and 2-h post-glucose load glucose and insulin levels, insulin-mediated glucose disposal (insulin sensitivity index) (S(I)), glucose effectiveness (S(G)), and first-phase insulin response (acute insulin response [AIR]) were determined in nondiabetic African-Americans (n= 288), Hispanics (n= 363), and non-Hispanic whites (n= 435) as part of the Insulin Resistance Atherosclerosis Study. Subjects received a standard 2-h oral glucose tolerance test on the first day and an insulin-modified frequently sampled intravenous glucose tolerance test on the second day. African-Americans and Hispanics were more obese than non-Hispanic whites. Both African-Americans and Hispanics had higher fasting and 2-h insulin concentrations and AIR but lower S(I) than non-Hispanic whites. No ethnic difference was observed in S(G). After further adjustments for obesity, body fat distribution, and behavioral factors, African-Americans continued to have higher fasting and 2-h insulin levels and AIR, but lower S(I) than non-Hispanic whites. In contrast, after adjustment for these covariates, no significant ethnic differences in S(I) or fasting insulin levels were observed between Hispanics and non-Hispanic whites. Hispanics continued to have higher 2-h insulin levels and AIRs than those in non-Hispanic whites. In this report, the association between S(I) and upper body adiposity (waist-to-hip, ratio) was similar in each ethnic group. Both nondiabetic African-Americans and Hispanics have increased insulin resistance and higher AIR than nondiabetic non-Hispanic whites, suggesting that greater insulin resistance may be in large part responsible for the higher prevalence of NIDDM in these minority groups. However, in Hispanics. the greater insulin resistance may be due to greater adiposity and other behavioral factors.

Journal ArticleDOI
01 Jul 1996-Diabetes
TL;DR: It is demonstrated that insulin resistance is associated with elevated plasma leptin levels independent of body fat mass, however, plasma insulin itself does not acutely regulate leptin production.
Abstract: Alterations in the production of or the sensitivity to leptin, the protein encoded by the ob gene, cause obesity and diabetes in rodents. We evaluated the isolated relationship between leptin and insulin sensitivity in lean and obese humans. Three groups of subjects who were carefully matched for either insulin sensitivity (determined by the modified intravenous glucose tolerance test and minimal model analysis) or adiposity (determined by hydrodensitometry) were studied: 1) lean insulin-sensitive men (percentage body fat, 15 +/- 1%); 2) lean insulin-resistant men (percentage body fat, 16 +/- 1%), matched on percentage body fat and fat mass with the lean insulin-sensitive group; and 3) obese insulin-resistant men (percentage body fat, 31 +/- 3), matched on insulin sensitivity with the lean insulin-resistant group. Basal plasma leptin concentrations were significantly lower in the lean insulin-sensitive than in the lean insulin-resistant men (1.90 +/- 0.4 vs. 4.35 +/- 1.21 ng/ml, P < 0.05) despite identical body composition. Plasma leptin in the obese men (9.27 +/- 1.4 ng/ml) was significantly higher than values in the two lean groups (P < 0.01). Marked alterations in plasma glucose and insulin concentrations induced by glucose and tolbutamide injection did not cause any change in plasma leptin levels. These results demonstrate that insulin resistance is associated with elevated plasma leptin levels independent of body fat mass. However, plasma insulin itself does not acutely regulate leptin production.

Journal ArticleDOI
01 Oct 1996-Diabetes
TL;DR: Results clearly indicate that both insulin and cortisol are potent and possibly physiological regulators of leptin expression in human adipose tissue.
Abstract: The aim of this study was to investigate the regulation of leptin expression and production in cultured human adipocytes using the model of in vitro differentiated human adipocytes. Freshly isolated human preadipocytes did not exhibit significant leptin mRNA and protein levels as assessed by reverse transcriptase (RT)-polymerase chain reaction (PCR) and radioimmunoassay (RIA). However, during differentiation induced by a defined adipogenic serum-free medium, cellular leptin mRNA and leptin protein released into the medium increased considerably in accordance with the cellular lipid accumulation. In fully differentiated human fat cells, insulin provoked a dose-dependent rise in leptin protein. Cortisol at a near physiological concentration of 10−8 mol/l was found to potentiate this insulin effect by almost threefold. Removal of insulin and cortisol, respectively, was followed by a rapid decrease in leptin expression, which was reversible after readdition of the hormones. These results clearly indicate that both insulin and cortisol are potent and possibly physiological regulators of leptin expression in human adipose tissue.

Journal ArticleDOI
01 Sep 1996-Diabetes
TL;DR: The first few days of islet transplantation, even under the most advantageous circumstances of excellent metabolic control, are characterized by dynamic changes, with substantial islet cell dysfunction and death followed by tissue remodeling and then stable engraftment.
Abstract: To learn more about islet vulnerability in the immediate posttransplant period, 400 syngeneic islets were transplanted under the kidney capsule of B6AF1 mice. Three groups of recipients were used: normal mice (normal), streptozotocin (STZ)-diabetic (diabetic), and STZ-diabetic kept hypo- or normoglycemic with insulin pellets (diabetic-normalized). Normoglycemia was achieved in all three groups 14 days after transplantation; however, in the diabetic and diabetic-normalized groups, blood glucose levels throughout the posttransplantation period were respectively higher and lower than in the normal group. Grafts were harvested 1, 3, 7, and 14 days after transplantation and analyzed for morphology, beta-cell death, beta-cell mass, insulin content, and insulin mRNA expression. In all groups, substantial damage in islet grafts was found on days 1 and 3 with apoptotic nuclei and necrotic cores; on day 3, beta-cell death was significantly higher in the diabetic group than in the other groups. Tissue remodelling occurred in all groups with stable graft appearance on day 14; the actual beta-cell mass of the grafts was lowest in the diabetic group. Graft insulin content decreased in all groups on day 1 and fell even further on days 3 and 7. Insulin mRNA levels of grafts retrieved from both the diabetic and diabetic-normalized group were lower than those from the normal group already by day 1 and remained lower on day 14. In conclusion, the first few days of islet transplantation, even under the most advantageous circumstances of excellent metabolic control, are characterized by dynamic changes, with substantial islet cell dysfunction and death followed by tissue remodelling and then stable engraftment.

Journal Article
TL;DR: In this article, dietary protein has long been thought to play a role in the progression of chronic renal disease, but clinical trials to date have not consistently shown that dietary protein restrictio...
Abstract: Background: Dietary protein has long been thought to play a role in the progression of chronic renal disease, but clinical trials to date have not consistently shown that dietary protein restrictio...

Journal ArticleDOI
01 Mar 1996-Diabetes
TL;DR: If the hypothesis is correct that common signaling abnormalities in the metabolism of malonyl-CoA and LC- CoA contribute to altered insulin release and sensitivity, it offers a novel explanation for the presence of variable combinations of these defects in individuals with differing genetic backgrounds.
Abstract: Widely held theories of the pathogenesis of obesity-associated NIDDM have implicated apparently incompatible events as seminal: 1) insulin resistance in muscle, 2) abnormal secretion of insulin, and 3) increases in intra-abdominal fat Altered circulating or tissue lipids are characteristic features of obesity and NIDDM The etiology of these defects is not known In this perspective, we propose that the same metabolic events, elevated malonyl-CoA and long-chain acyl-CoA (LC-CoA), in various tissues mediate, in part, the pleiotropic alterations characteristic of obesity and NIDDM We review the evidence in support of the emerging concept that malonyl-CoA and LC-CoA act as metabolic coupling factors in beta-cell signal transduction, linking fuel metabolism to insulin secretion We suggest that acetyl-CoA carboxylase, which synthesizes malonyl-CoA, a "signal of plenty," and carnitine palmitoyl transferase 1, which is regulated by it, may perform as fuel sensors in the beta-cell, integrating the concentrations of all circulating fuel stimuli in the beta-cell as well as in muscle, liver, and adipose tissue The target effectors of LC-CoA may include protein kinase C sub-types, complex lipid formation, genes encoding metabolic enzymes or transduction factors, and protein acylation We support the concept that only under conditions in which both glucose and lipids are plentiful will the metabolic abnormality, which may be termed glucolipoxia, become apparent If our hypothesis is correct that common signaling abnormalities in the metabolism of malonyl-CoA and LC-CoA contribute to altered insulin release and sensitivity, it offers a novel explanation for the presence of variable combinations of these defects in individuals with differing genetic backgrounds and for the fact that it has been difficult to determine whether one or the other is the primary event