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Showing papers on "Insulin resistance published in 1994"


Journal ArticleDOI
G. Boden1, Xinhua Chen, J. Ruiz, J. V. White, Luciano Rossetti 
TL;DR: It is concluded that fatty acids caused a dose-dependent inhibition of insulin-stimulated glucose uptake (by decreasing glycogen synthesis and CHO oxidation) and that FFA and/or glycerol increased insulin-suppressed hepatic glucose output and thus caused insulin resistance at the peripheral and the hepatic level.
Abstract: Increased plasma FFA reduce insulin-stimulated glucose uptake. The mechanisms responsible for this inhibition, however, remain uncertain. It was the aim of this study to determine whether the FFA effect was dose dependent and to investigate its mechanism. We have examined in healthy volunteers (13 male/1 female) the effects of three steady state plasma FFA levels (approximately 50, approximately 550, approximately 750 microM) on rates of glucose uptake, glycolysis (both with 3-3H-glucose), glycogen synthesis (determined with two independent methods), carbohydrate (CHO) oxidation (by indirect calorimetry), hepatic glucose output, and nonoxidative glycolysis (glycolysis minus CHO oxidation) during euglycemic-hyperinsulinemic clamping. Increasing FFA concentration (from approximately 50 to approximately 750 microM) decreased glucose uptake in a dose-dependent fashion (from approximately 9 to approximately 4 mg/kg per min). The decrease was caused mainly (approximately 2/3) by a reduction in glycogen synthesis and to a lesser extent (approximately 1/3) by a reduction in CHO oxidation. We have identified two independent defects in glycogen synthesis. The first consisted of an impairment of muscle glycogen synthase activity. It required high FFA concentration (approximately 750 microM), was associated with an increase in glucose-6-phosphate, and developed after 4-6 h of fat infusion. The second defect, which preceded the glycogen synthase defect, was seen at medium (approximately 550 microM) FFA concentration, was associated with a decrease in muscle glucose-6-phosphate concentration, and was probably due to a reduction in glucose transport/phosphorylation. In addition, FFA and/or glycerol increased insulin-suppressed hepatic glucose output by approximately 50%. We concluded that fatty acids caused a dose-dependent inhibition of insulin-stimulated glucose uptake (by decreasing glycogen synthesis and CHO oxidation) and that FFA and/or glycerol increased insulin-suppressed hepatic glucose output and thus caused insulin resistance at the peripheral and the hepatic level.

1,342 citations


Journal ArticleDOI
01 Nov 1994-Diabetes
TL;DR: The results strongly suggest that TNF-α may play a crucial role in the systemic insulin resistance of NIDDM, and may allow for new treatments of disorders involving resistance to insulin.
Abstract: Recent data have suggested a key role for tumor necrosis factor (TNF)-alpha in the insulin resistance of obesity and non-insulin-dependent diabetes mellitus (NIDDM). TNF-alpha expression is elevated in the adipose tissue of multiple experimental models of obesity. Neutralization of TNF-alpha in one of these models improves insulin sensitivity by increasing the activity of the insulin receptor tyrosine kinase, specifically in muscle and fat tissues. On a cellular level, TNF-alpha is a potent inhibitor of the insulin-stimulated tyrosine phosphorylations on the beta-chain of the insulin receptor and insulin receptor substrate-1, suggesting a defect at or near the tyrosine kinase activity of the insulin receptor. Given the clear link between obesity, insulin resistance, and diabetes, these results strongly suggest that TNF-alpha may play a crucial role in the systemic insulin resistance of NIDDM. This may allow for new treatments of disorders involving resistance to insulin.

1,321 citations


Journal ArticleDOI
TL;DR: Results show that TNF-alpha directly interferes with the signaling of insulin through its receptor and consequently blocks biological actions of insulin.
Abstract: Insulin resistance is a common problem associated with infections and cancer and, most importantly, is the central component of non-insulin-dependent diabetes mellitus. We have recently shown that tumor necrosis factor (TNF) alpha is a key mediator of insulin resistance in animal models of non-insulin-dependent diabetes mellitus. Here, we investigate how TNF-alpha interferes with insulin action. Chronic exposure of adipocytes to low concentrations of TNF-alpha strongly inhibits insulin-stimulated glucose uptake. Concurrently, TNF-alpha treatment causes a moderate decrease in the insulin-stimulated autophosphorylation of the insulin receptor (IR) and a dramatic decrease in the phosphorylation of IR substrate 1, the major substrate of the IR in vivo. The IR isolated from TNF-alpha-treated cells is also defective in the ability to autophosphorylate and phosphorylate IR substrate 1 in vitro. These results show that TNF-alpha directly interferes with the signaling of insulin through its receptor and consequently blocks biological actions of insulin.

1,185 citations


Journal ArticleDOI
10 Nov 1994-Nature
TL;DR: The data suggest that mice homozygous for targeted disruption of the IRS-1 gene were born alive but were retarded in embryonal and postnatal growth and the exis-tence of both IRS- 1-dependent and IRS-2-independent pathways for signal transduction of insulin and IGFs is suggested.
Abstract: INSULIN receptor substrate-1 (IRS-1) is the major substrate of insulin receptor and IGF-1 receptor tyrosine kinases; it has an apparent relative molecular mass of 160–190,000 (Mr, 160–190K) on SDS polyacrylamide gel1–3. Tyrosine-phosphorylated IRS-1 binds the 85K subunit of phosphatidylinositol 3-kinase4,5 which may be involved in the translocation of glucose transporters6,7 and the abundant src homology protein (ASH)/Grb28,9 which may be involved in activation of p2lras and MAP kinase cascade10. IRS-1 also has binding sites for Syp11 and Nck12 and other src homology 2 (SH2) signalling molecules10. To clarify the physiological roles of IRS-1 in vivo, we made mice with a targeted disruption of the IRS-1 gene locus. Mice homozygous for targeted disruption of the IRS-1 gene were born alive but were retarded in embryonal and postnatal growth. They also had resistance to the glucose-lowering effects of insulin, IGF-1 and IGF-2. These data suggest the exis-tence of both IRS-1-dependent and IRS-1-independent pathways for signal transduction of insulin and IGFs.

1,050 citations


Journal ArticleDOI
TL;DR: The ability of troglitazone to reduce insulin resistance and improves glucose tolerance in obese subjects with either impaired or normal glucose tolerance could be useful in preventing NIDDM.
Abstract: Background Troglitazone decreases insulin resistance and hyperglycemia in patients with non-insulin-dependent diabetes mellitus (NIDDM), but its effects on subjects without diabetes are not known. Methods We performed oral and intravenous glucose-tolerance tests, studies with the euglycemic-hyperinsulinemic clamp, meal-tolerance tests, and 24-hour blood-pressure measurements at base line and after the administration of troglitazone, 200 mg orally twice daily, or placebo for 12 weeks in 18 nondiabetic obese subjects, 9 of whom had impaired glucose tolerance. Results The mean (±SD) rates of glucose disposal increased from 4.7 ±1.7 to 6.0 ±1.7 mg per kilogram of body weight per minute (P = 0.004) and from 9.0 ±1.8 to 9.9 ±1.3 mg per kilogram per minute (P = 0.02) during insulin infusions of 40 and 300 mU per square meter of body-surface area per minute, respectively, in the troglitazone group. The insulin-sensitivity index, calculated from the results of intravenous glucose-tolerance tests, increased from 0....

954 citations


Journal ArticleDOI
TL;DR: It is demonstrated that TNF-alpha participates in obesity-related systemic insulin resistance by inhibiting the IR tyrosine kinase in the two tissues mainly responsible for insulin-stimulated glucose uptake: muscle and fat.
Abstract: Insulin resistance is an important metabolic abnormality often associated with infections, cancer, obesity, and especially non-insulin-dependent diabetes mellitus (NIDDM). We have previously demonstrated that tumor necrosis factor-alpha produced by adipose tissue is a key mediator of insulin resistance in animal models of obesity-diabetes. However, the mechanism by which TNF-alpha interferes with insulin action is not known. Since a defective insulin receptor (IR) tyrosine kinase activity has been observed in obesity and NIDDM, we measured the IR tyrosine kinase activity in the Zucker (fa/fa) rat model of obesity and insulin resistance after neutralizing TNF-alpha with a soluble TNF receptor (TNFR)-lgG fusion protein. This neutralization resulted in a marked increase in insulin-stimulated autophosphorylation of the IR, as well as phosphorylation of insulin receptor substrate 1 (IRS-1) in muscle and fat tissues of the fa/fa rats, restoring them to near control (lean) levels. In contrast, no significant changes were observed in insulin-stimulated tyrosine phosphorylations of IR and IRS-1 in liver. The physiological significance of the improvements in IR signaling was indicated by a concurrent reduction in plasma glucose, insulin, and free fatty acid levels. These results demonstrate that TNF-alpha participates in obesity-related systemic insulin resistance by inhibiting the IR tyrosine kinase in the two tissues mainly responsible for insulin-stimulated glucose uptake: muscle and fat.

829 citations


Journal ArticleDOI
TL;DR: Using polycystic ovary syndrome as a model of insulin resistance and hyperandrogenism, the effect of Metformin on lipoproteins, sex hormones, gonadotropins, and blood pressure in 26 women with PCOS was assessed.
Abstract: Using polycystic ovary syndrome (PCOS) as a model of insulin resistance and hyperandrogenism, our specific aim was to assess the effect of Metformin on lipoproteins, sex hormones, gonadotropins, and blood pressure in 26 women with PCOS who were studied at baseline, received Metformin 1.5 g/d for 8 weeks, and were then restudied. None of the women had normal menstrual cycles, 100% had multiple subcapsular follicules by pelvic ultrasound, 90% were hirsute, and 85% had high free testosterone. Comparing post-Metformin versus baseline levels, the Quetelet Index (QI) decreased 1.5% (P = .04) and the waist to hip ratio (WHR) decreased 2.8% (P = .003). After covariance adjusting for changes in the QI and WHR, on Metformin the area under the insulin curve (IA) during oral glucose tolerance testing decreased 35% (P = .04), and the insulin area to glucose area ratio decreased 31% (P = .03). On Metformin, covariance-adjusted systolic blood pressure (SBP) decreased (P = .04) and apo A-1 increased (P = .05). On Metformin, with improvement in insulin sensitivity, there were sharp reductions in covariance-adjusted luteinizing hormone ([LH] P = .0007), total testosterone ([T] P = .0004), free T (P = .0001), androstenedione (P = .002), dehydroepiandrosterone sulfate ([DHEAS] P = .006), and the free androgen index ([FAI] P = .0005), with increments in follicle-stimulating hormone ([FSH] P = .04) and sex hormone-binding globulin ([SHBG] P = .04).(ABSTRACT TRUNCATED AT 250 WORDS)

821 citations


Journal ArticleDOI
09 Apr 1994-BMJ
TL;DR: The relation of the prevalence of diabetes to birth weight in the Pima Indians is U shaped and is related to parental diabetes, and low birth weight is associated with non-insulin dependent diabetes.
Abstract: Objective : To determine the prevalence of diabetes in relation to birth weight in Pima Indians. Design : Follow up study of infants born during 1940-72 who had undergone a glucose tolerance test at ages 20-39 years. Setting : Gila River Indian community, Arizona. Subjects : 1179 American Indians. Main outcome measure: Prevalence of non-insulin dependent diabetes mellitus (plasma glucose concentration >=11.1 mmol/l two hours after ingestion of carbohydrate). Results : The prevalence was greatest in those with the lowest and highest birth weights. The age adjusted prevalences for birth weights =4500 g were 30%, 17%, and 32%, respectively. When age, sex, body mass index, maternal diabetes during pregnancy, and birth year were controlled for, subjects with birth weights =4500 g) was associated with maternal diabetes during pregnancy. Most diabetes, however, occurred in subjects with intermediate birth weights (2500-4500 g). Conclusions : The relation of the prevalence of diabetes to birth weight in the Pima Indians is U shaped and is related to parental diabetes. Low birth weight is associated with non-insulin dependent diabetes. Given the high mortality of low birthweight infants selective survival in infancy of those genetically predisposed to insulin resistance and diabetes provides an explanation for the observed relation between low birth weight and diabetes and the high prevalence of diabetes in many populations.

722 citations


Journal ArticleDOI
TL;DR: It is concluded that insulin resistance is associated with impaired development in fetal life and men and women who were thin at birth, as measured by a low ponderal index, were more insulin resistant.
Abstract: Type 2 (non-insulin-dependent) diabetes mellitus may originate through impaired development in fetal life. Both insulin deficiency and resistance to the action of insulin are thought to be important in its pathogenesis. Although there is evidence that impaired fetal development may result in insulin deficiency, it is not known whether insulin resistance could also be a consequence of reduced early growth. Insulin resistance was therefore measured in 81 normoglycaemic subjects, and 22 subjects with impaired glucose tolerance, who were born in Preston, UK, between 1935 and 1943. Their birth measurements had been recorded in detail. Insulin resistance was measured by the insulin tolerance test which uses the rate of fall in blood glucose concentrations after intravenous injection of insulin as an index of insulin resistance. Men and women who were thin at birth, as measured by a low ponderal index, were more insulin resistant. The association was statistically significant (p = 0.01) and independent of duration of gestation, adult body mass index and waist to hip ratio and of confounding variables including social class at birth or currently. Thinness at birth and in adult life has opposing effects such that resistance fell with increasing ponderal index at birth but rose with increasing adult body mass index. It is concluded that insulin resistance is associated with impaired development in fetal life.

686 citations


Journal ArticleDOI
TL;DR: It is concluded that the oral glucose tolerance test can be used to derive estimates of the relative roles of insulin secretion and insulin resistance in population studies of glucose tolerance.
Abstract: The extent to which the oral glucose tolerance test can be used to estimate insulin secretion and insulin resistance has been evaluated by comparing glucose and insulin concentrations during an oral glucose tolerance test with specific measurements of insulin secretion and insulin resistance in 85 normoglycaemic subjects and 23 subjects with impaired glucose tolerance (IGT). Insulin secretion was measured by the first phase insulin response to intravenous glucose and insulin resistance by the insulin tolerance test which measures the decline of plasma glucose after the injection of a bolus of insulin. The best measure of insulin secretion was the ratio of the 30 min increment in insulin concentration to the 30 min increment in glucose concentration following oral glucose loading. This correlated with the first phase insulin release following intravenous glucose (r=0.61, p 0.05). Insulin resistance could be estimated by the fasting insulin, proinsulin, or split proinsulin concentrations. However, fasting split proinsulin appeared to discriminate best between insulin resistance (r = −0.53, p 0.05). Relative insulin resistance estimated by homeostasis model assessment (HOMA) also correlated well with insulin resistance (r= −0.57, p 0.05). We conclude that the oral glucose tolerance test can be used to derive estimates of the relative roles of insulin secretion and insulin resistance in population studies of glucose tolerance.

624 citations


Journal ArticleDOI
TL;DR: A previous clinical observation that hepatitis C virus infection and diabetes mellitus appeared to be associated was formally tested by a retrospective review of 100 consecutive adult patients with cirrhosis undergoing assessment for liver transplantation.

Journal ArticleDOI
TL;DR: The purpose of this study was to evaluate the long-term efficacy of acarbose in improving the metabolic control of patients with noninsulin-dependent diabetes mellitus that was not well controlled by diet alone, diet or metformin, diet and sulfonylurea, or diet and insulin.
Abstract: Objective: To evaluate the long-term efficacy of acarbose, an α-glucosidase inhibitor, in improving glycemic control in patients with non–insulin-dependent diabetes mellitus. Design: A 1-year, mult...

Journal ArticleDOI
TL;DR: It is suggested that visceral fat accumulations may play an important role in the occurrence of CAD regardless of obesity.

Journal ArticleDOI
01 Sep 1994-Diabetes
TL;DR: The insulin-modified frequently sampled intravenous glucose tolerance test (FSIGTT) with minimal model analysis provides estimates of insulin sensitivity that correlate significantly with those from the glucose clamp, however, in NIDDM.
Abstract: An insulin-modified frequently sampled intravenous glucose tolerance test (FSIGTT) with minimal model analysis was compared with the glucose clamp in 11 subjects with normal glucose tolerance (NGT), 20 with impaired glucose tolerance (IGT), and 24 with non-insulin-dependent diabetes mellitus (NIDDM). The insulin sensitivity index (SI) was calculated from FSIGTT using 22- and 12-sample protocols (SI(22) and SI(12), respectively). Insulin sensitivity from the clamp was expressed as SI(clamp) and SIP(clamp). Minimal model parameters were similar when calculated with SI(22) and SI(12). SI could not be distinguished from 0 in approximately 50% of diabetic patients with either protocol. SI(22) correlated significantly with SI(clamp) in the whole group (r = 0.62), and in the NGT (r = 0.53), IGT (r = 0.48), and NIDDM (r = 0.41) groups (P < 0.05 for each). SI(12) correlated significantly with SI(clamp) in the whole group (r = 0.55, P < 0.001) and in the NGT (r = 0.53, P = 0.046) and IGT (r = 0.58, P = 0.008) but not NIDDM (r = 0.30, P = 0.085) groups. When SI(22), SI(clamp), and SIP(clamp) were expressed in the same units, SI(22) was 66 +/- 5% (mean +/- SE) and 50 +/- 8% lower than SI(clamp) and SIP(clamp), respectively. Thus, minimal model analysis of the insulin-modified FSIGTT provides estimates of insulin sensitivity that correlate significantly with those from the glucose clamp. The correlation was weaker, however, in NIDDM. The insulin-modified FSIGTT can be used as a simple test for assessment of insulin sensitivity in population studies involving nondiabetic subjects. Additional studies are needed before using this test routinely in patients with NIDDM.

Journal ArticleDOI
TL;DR: Results indicate that gene expression for the TNF systems can be regulated by an insulin-sensitizing drug and reduction of body weight, and support a role for this cytokine in the insulin-resistant diabetic state.
Abstract: As obesity is a major risk factor for noninsulin-dependent diabetes mellitus, adipose tissue may generate a mediator that influences the activity of insulin on various target tissues. Recent evidence suggests that a cytokine, tumor necrosis factor-alpha (TNF alpha), may serve this role. This study investigates whether the expression of TNF alpha and its receptors is modulated during drug treatment to reduce insulin resistance. The effects of moderate weight loss by dietary restriction were also examined. We show here that a marked induction of TNF alpha mRNA occurs in adipose tissues from a mouse model of obesity-linked diabetes (KKAy) compared to that in nondiabetic mice (C57). Likewise, RNA transcripts encoding TNF R2 receptors (p75) were significantly increased in fat tissues of the obese diabetic animals. In muscle from these diabetic animals, RNA transcripts encoding both TNF R1 (p55) and R2 were significantly elevated, although R2 transcript abundance was less elevated than in fat. We also observed that the overexpression of mRNA for TNF alpha and both of its receptors could be at least partly normalized by treatment of the diabetic animals with the insulin-sensitizing agent pioglitazone. Treating of the obese diabetic animals by food restriction reduced the expression of mRNA for TNF R2 in muscle, but not fat. These results clearly indicate that gene expression for the TNF systems can be regulated by an insulin-sensitizing drug and reduction of body weight. Such findings support a role for this cytokine in the insulin-resistant diabetic state and show its modulation by therapies that reverse the disorder.

Journal ArticleDOI
TL;DR: It is concluded that sex hormone administration, i.e. testosterone treatment in females and ethinyl estradiol treatment in males, can induce insulin resistance in healthy subjects.
Abstract: Hyperinsulinemia is a common finding in hyperandrogenic women, during pregnancy, and in women using oral contraceptives. To test whether sex hormone treatment can induce insulin resistance in healthy subjects, we studied the effects of administration of testosterone to 13 female to male and of ethinyl estradiol to 18 male to female transsexuals. Utilization and production of glucose and levels of sex steroids were measured during a three-step hyperinsulinemic-euglycemic clamp before and after 4 months of hormone administration. Females were treated with im injections of testosterone esters (250 mg/2 weeks); males were treated with ethinyl estradiol alone (0.1 mg/day, orally) or a combination of ethinyl estradiol and cyproterone acetate (100 mg/day, orally). Similar insulin levels were achieved at each of the three steps of the clamp studies before and during hormone administration. During step 1 of each clamp, with insulin levels in the physiological range, glucose utilization decreased from 3.5 +/- 1.2 to 2.6 +/- 0.9 mmol/kg lean body mass (LBM).h in women treated with testosterone esters (P < 0.001) and from 3.2 +/- 0.7 to 2.5 +/- 0.5 mmol/kg lean body mass.h in men treated with ethinyl estradiol (P < 0.001). The effects of sex steroids during steps 2 and 3 of the clamp at higher (supraphysiological) insulin levels were less clear. Endogenous glucose production (measured by isotope dilution with tritiated glucose) was not affected by hormone administration, indicating that the observed changes in glucose requirement were determined by a diminished peripheral glucose uptake. We conclude that sex hormone administration, i.e. testosterone treatment in females and ethinyl estradiol treatment in males, can induce insulin resistance in healthy subjects.

Journal ArticleDOI
TL;DR: One hundred veterans with paralysis due to spinal cord injury, equally divided between those with paraplegia and quadriplegia, and 50 able-bodied veteran controls underwent a 75-g oral glucose tolerance test, suggesting an accentuated state of insulin resistance in those with SCI.
Abstract: One hundred veterans with paralysis due to spinal cord injury (SCI), equally divided between those with paraplegia and quadriplegia, and 50 able-bodied veteran controls underwent a 75-g oral glucose tolerance test (OGTT). In subjects with SCI, 22% were diabetic by criteria established by the World Health Organization (WHO), whereas only 6% of the control group were diabetic. Eighty-two percent of the controls had normal (NL) oral glucose tolerance, compared with 38% of those with quadriplegia and 50% of those with paraplegia. Subjects with diabetes mellitus (DM) were older in both the SCI and control groups, but those with SCI developed carbohydrate disorders at younger ages than did the control group. SCI subjects had significantly higher mean glucose and insulin values at several points during the OGTT when compared with controls, suggesting an accentuated state of insulin resistance in those with SCI. Mean fasting plasma glucose (FPG) values for both SCI and control groups were significantly higher in subjects with DM compared with those with NL glucose tolerance. When the FPG value was compared between SCI or control subjects with abnormalities in glucose tolerance, the subgroups with SCI and NL or impaired glucose tolerance (IGT) had significantly lower FPG levels than the respective control subgroups, suggestive of decreased hepatic glucose output in SCI.(ABSTRACT TRUNCATED AT 250 WORDS)

Journal ArticleDOI
TL;DR: Resistance to the action of insulin on glucose metabolism in skeletal muscle has been proposed as the inherited basis for this syndrome and since insulin resistance is observed several decades before the onset of hyperglycemia an early detection can open the prospect of intervention in order to prevent the disease process.
Abstract: Non-insulin-dependent diabetes mellitus (NIDDM)' is phenotypically heterogenous and may therefore not be explained by one simple pathophysiological mechanism. Despite the heterogenous nature of the disease, the major form as discussed in this review is linked to overweight, arterial hypertension, dyslipidemia, and macroangiopathy (coronary heart disease), all conditions which become more common with aging (1). This form of NIDDMseems to be growing worldwide in the footsteps of Westernized life style. Around 3%in the Western world suffers from the disease, but in subjects 60 yr and older, the prevalence is as high as 10-20% (2). In certain ethnic populations as the Pima Indians and the Nauruans the prevalence approaches 40% (2). Therefore, NIDDM imposes an enormous burden on the health care system all over the world. In general, the goals of treatment are achieved in only a small subset of patients, but nevertheless progression of macroangiopathy is a more severe problem than worsening of glycemia. The overall mortality rate in patients with NIDDMis two to three times higher than in control subjects, primarily due to excess mortality of coronary heart disease (2). Of note, 40% of patients already suffer from clinical macroangiopathy at diagnosis, indicating that these complications may not be secondary to the diabetic state itself, but rather a part of the NIDDM syndrome, also referred to as Syndrome X or \"The Insulin Resistance Syndrome\" (1). Resistance to the action of insulin on glucose metabolism in skeletal muscle has been proposed as the inherited basis for this syndrome and since insulin resistance is observed several decades before the onset of hyperglycemia an early detection can open the prospect of intervention in order to prevent the disease process (4-7). The present review discusses the metabolic and genetic background of NIDDMtogether with the current knowledge of the sequence of events leading to NIDDM. Based on that a new

Journal ArticleDOI
TL;DR: It is possible that muscle fiber composition abnormalities in insulin-resistant conditions are secondary to hyperinsulinemia, but it is also possible that the low capillary density, hypothetically, may contribute to insulin resistance.
Abstract: OBJECTIVE To determine whether muscle fiber composition and capillary density differed between diabetic and nondiabetic subjects. RESEARCH DESIGN AND METHODS Muscle fiber composition and capillary density were determined in biopsies from women and men with non-insulindependent diabetes mellitus (NIDDM) and compared with those of control subjects matched for gender, age, obesity, and the waist-to-hip ratio, which are all factors known to influence muscle morphology. RESULTS Patients with NIDDM, as well as control subjects with abdominal obesity and insulin resistance, showed the same abnormalities in muscle morphology, namely, a low percentage of type I fibers, elevated type II (particularly type IIB) fibers, and a low capillary density. These changes correlated closely with insulin concentrations in both diabetic and nondiabetic groups. CONCLUSIONS Recent information suggests that insulin may regulate myosin synthesis in muscle in the direction of the changes observed. Therefore, it is possible that muscle fiber composition abnormalities in insulin-resistant conditions are secondary to hyperinsulinemia. However, the low capillary density, hypothetically, may contribute to insulin resistance.

Journal ArticleDOI
01 Feb 1994-Diabetes
TL;DR: Higher WHR and lower testosterone were strongly associated with a decrease in total and nonoxidative whole-body glucose disposal in men, and this relationship was significantly associated with fasting insulin and glucose oxidation.
Abstract: Although many studies have suggested that increased androgenicity is associated with insulin resistance and hyperinsulinemia in both pre- and postmenopausal women, relatively few data are available on this relationship in men. We examined the association of body mass index (BMI), waist-to-hip ratio (WHR), sex hormone-binding globulin (SHBG), total and free testosterone, dehydroepiandrosterone sulfate (DHEA-SO4), and estradiol with insulin concentrations and whole-body glucose disposal in 87 men from a population-based study in Kuopio, Finland. BMI was significantly correlated with fasting insulin (r = 0.46), total whole-body glucose disposal (r = -0.30), glucose oxidation (r = -0.21), and nonoxidative glucose disposal (r = -0.25). WHR also was significantly associated with fasting insulin (r = 0.61), total whole-body glucose disposal (r = -0.54), glucose oxidation (r = -0.23), and nonoxidative whole-body glucose disposal (r = -0.50). SHBG and total and free testosterone were significantly associated with insulin concentrations and total and nonoxidative glucose disposal but not with glucose oxidation. DHEA-SO4 and estradiol were not associated with insulin, glucose concentrations, or whole-body glucose disposal in univariate analysis. In multivariate analysis, total whole-body glucose disposal was associated negatively with WHR and positively associated with total testosterone and SHBG; nonoxidative whole-body glucose disposal was associated negatively with WHR and positively associated with total and free testosterone. Glucose oxidation was significantly associated only with WHR. In conclusion, higher WHR and lower testosterone were strongly associated with a decrease in total and nonoxidative whole-body glucose disposal in men.

Journal ArticleDOI
TL;DR: Chronic, physiologic hyperinsulinaemia, whether created by exogenous insulin infusion or by stimulation of endogenous insulin secretion, leads to the development of insulin resistance, which is characterized by a specific defect in the non-oxidative (glycogen synthetic) pathway.
Abstract: Two study protocols to examine the effects of chronic (72-96 h) physiologic euglycaemic hyperinsulinaemia (+ 72 pmol/l) and chronic hyperglycaemic (+ 1.4 mmol/l) hyperinsulinaemia (+ 78 pmol/l) on insulin sensitivity and insulin secretion were performed in 15 healthy young subjects. Subjects received a three-step euglycaemic insulin (insulin infusion rates = 1.5, 3, and 6 nmol.kg-1.min-1) clamp and a hyperglycaemia (6.9 mmol/l) clamp before and after chronic insulin or glucose infusion. Following 4 days of sustained euglycaemic hyperinsulinaemia whole body glucose disposal decreased by 20-40%. During each insulin clamp step, the defect in insulin action was accounted for by impaired non-oxidative glucose disposal (p < 0.01). Chronic euglycaemic hyperinsulinaemia did not alter insulin-mediated suppression of hepatic glucose production. Following insulin infusion the ability of hyperglycaemia to stimulate insulin secretion was significantly diminished. Following 72 h of chronic glucose infusion (combined hyperglycaemic hyperinsulinaemia), there was no change in whole body glucose disposal. However, glucose oxidation during each insulin clamp step was significantly increased and there was a reciprocal decline in non-oxidative glucose disposal by 25-39% (p < 0.01); suppression of hepatic glucose production by insulin was unaltered by chronic hyperglycaemic hyperinsulinaemia. Chronic glucose infusion increased the plasma insulin response to acute hyperglycaemia more than twofold. These results demonstrate that chronic, physiologic hyperinsulinaemia, whether created by exogenous insulin infusion or by stimulation of endogenous insulin secretion, leads to the development of insulin resistance, which is characterized by a specific defect in the non-oxidative (glycogen synthetic) pathway. These findings indicate that hyperinsulinaemia should be considered, not only as a compensatory response to insulin resistance, but also as a self-perpetuating cause of the defect in insulin action.

Journal ArticleDOI
TL;DR: This animal model shows that primary alterations in the rate of liver glucose production may induce insulin resistance and NIDDM.
Abstract: An increase in hepatic gluconeogenesis is believed to be an important factor responsible for the fasting hyperglycemia detected in patients with non-insulin-dependent diabetes mellitus (NIDDM). Phosphoenolpyruvate carboxykinase (GTP) (PEPCK; EC 4.1.1.32) is a regulatory enzyme of gluconeogenesis. To study the role of the expression of PEPCK gene in the development of NIDDM, we have produced lines of transgenic mice expressing a PEPCK minigene under control of its own promoter. Transgenic mice were hyperglycemic and had higher serum insulin concentrations. In addition, alterations in liver glycogen content and muscle glucose transporter GLUT-4 gene expression were detected. The overexpression of the PEPCK gene led to an increase in glucose production from pyruvate in hepatocytes in primary culture. When intraperitoneal glucose tolerance tests were performed, blood glucose levels were higher than those detected in normal mice. This animal model shows that primary alterations in the rate of liver glucose production may induce insulin resistance and NIDDM.

Journal ArticleDOI
TL;DR: It is concluded that insulin resistance in obese subjects is associated with increased fasting MSNA and a specific impairment of sympathetic neural responsiveness to physiological hyperinsulinemia in skeletal muscle tissue.
Abstract: The sympathetic nervous system is an important regulatory mechanism of both metabolic and cardiovascular function, and altered sympathetic activity may play a role in the etiology and/or complications of obesity. In lean subjects, insulin evokes sympathetic activation and vasodilation in skeletal muscle. In obese subjects such vasodilation is impaired and, in turn, may contribute to insulin resistance. To examine the relationship between sympathetic and vasodilatory responses in skeletal muscle to hyperinsulinemia, we simultaneously measured muscle sympathetic nerve activity (MSNA) and calf blood flow at basal and during a 2-h hyperinsulinemic (6 pmol/kg per min) euglycemic clamp in eight lean and eight obese subjects. The major findings of this study are twofold: obese subjects had a 2.2 times higher fasting rate of MSNA, and euglycemic hyperinsulinemia, which more than doubled MSNA and increased calf blood flow by roughly 30% in lean subjects, had only a minor vasodilatory and sympathoexcitatory effect in obese subjects. In contrast, two non-insulin-sympathetic stimuli evoked comparably large increases in MSNA in lean and obese subjects. We conclude that insulin resistance in obese subjects is associated with increased fasting MSNA and a specific impairment of sympathetic neural responsiveness to physiological hyperinsulinemia in skeletal muscle tissue.

Journal ArticleDOI
Jan Holte1, T Bergh1, Christian Berne1, Lars Berglund1, Hans Lithell1 
TL;DR: It is concluded that the early insulin response to glucose was increased in women with PCOS, not accounted for by insulin resistance, closely associated to the increased androgenicity, and present also at low-normal BMI.
Abstract: Insulin secretion in response to iv glucose and insulin sensitivity (euglycemic hyperinsulinemic clamp) were evaluated in 49 women with polycystic ovary syndrome (PCOS) [body mass index (BMI), 17.6-37.2 kg/m2] and 42 control subjects (BMI, 18.8-38.1 kg/m2). Seven women with PCOS exhibited glucose intolerance with subnormal insulin secretion. Compared with control subjects, women with PCOS and normal glucose tolerance had an increased (36-56%) insulin increment, not explained by insulin resistance, and over the whole range of BMI. In contrast, insulin sensitivity was similar in women with PCOS and control subjects at BMI 21 kg/m2, but showed a more pronounced decline with increasing BMI in women with PCOS, who had 35% and 70% lower insulin sensitivities at BMI 28 and 35 kg/m2, respectively. After adjusting for truncal-abdominal sc fat distribution, which was more pronounced in the women with PCOS, the two groups had similar insulin sensitivity over the entire range of BMI (P = 0.9), whereas the difference in insulin increment was insignificant after adjusting for the free androgen index (testosterone x 100/sex hormone binding globulin; P = 0.16). Hemoglobin A1C levels were lower in women with PCOS than in the control subjects. It is concluded that the early insulin response to glucose was increased in women with PCOS, not accounted for by insulin resistance, closely associated to the increased androgenicity, and present also at low-normal BMI. In contrast, insulin resistance was seen only at higher BMI levels and was largely determined by the increased truncal-abdominal fat mass in PCOS.

Journal ArticleDOI
TL;DR: The data indicate that hyperuricemia is indeed an inherent component of the metabolic syndrome and could also be used as a simple marker of insulin resistance.
Abstract: The associates of gout-obesity, hypertriglyceridemia, glucose intolerance, and hypertension, strikingly resemble those of insulin resistance. In the present study we determined whether hyperuricemia is associated with insulin resistance and, if so, whether this association can be explained by other components of the syndrome. For this purpose we quantitated insulin sensitivity (euglycemic clamp) in 37 nondiabetic subjects (aged 30-68 yr) exhibiting varying degrees of the metabolic syndrome (body mass index, 21.5-35.7 kg/m2; serum triglycerides, 0.4-22.0 mmol/L; high density lipoprotein cholesterol 0.38-1.86 mmol/L; blood pressure, 190-100/116-60 mm Hg). In simple linear regression analysis, the serum uric acid concentration (range, 182-568 mumol/L) was inversely correlated with insulin sensitivity (rate of glucose utilization; r = -0.61; P < 0.001) and positively with serum triglycerides (r = 0.68; P < 0.001), but not with body mass index, age, or the plasma glucose concentration. In multiple linear regre...

01 Jan 1994
TL;DR: In this article, the authors reviewed the evidence supporting the balanced view that both insulin resistance and insulin deficiency contribute to the pathogen in non-insulin-dependent diabetes mellitus (NIDDM).
Abstract: Extensive investigations of the pathophysiology of non-insulin-dependent diabetes mellitus (NIDDM) have identified two defects in endocrine function: insulin resistance and insulin deficiency. Despite general agreement that both defects are present in most patients with established NIDDM, many authorities have debated the question of which defect is the primary cause of NIDDM. Many interesting physiological studies have been conducted in an effort to address the following questions: Which defect can be detected earliest in the course of the disease? Which defect is more important in the pathogenesis of NIDDM? These clinical investigations have provided valuable insights into the pathophysiology of NIDDM. However, like many productive scientific investigations, they have raised as many questions as they have answered. Fortunately, after years of spirited debate, methods are becoming available that are likely to resolve the controversy. Genetic factors contribute importantly to the predisposition to develop NIDDM. Nevertheless, abundant evidence suggests that environmental factors (e.g., nutrition, physical exercise, etc.) may also modulate the expression of the diabetic phenotype. (Such interactions between genetics and the environment are commonly observed in many genetic diseases. For example, patients with mild forms of glucose&-phosphate dehydrogenase deficiency are usually asymptomatic unless they are exposed to environmental stresses [e.g., administration of certain drugs, infections, etc.].) Inasmuch as NIDDM is a genetic disease, the identity of the cause of the disease is encrypted in the sequence of nucleotides in the patients' DNA. To learn the secret of the disease, we need to decipher the code. With the development of powerl:ul methods of molecular genetic analysis, the time is rapidly approaching when identification of the primary genetic defects that render an individual susceptible to NIDDM will be possible. In this perspective, we review the evidence supporting the balanced view that both insulin resistance and insulin deficiency contribute to the pathogen

Journal ArticleDOI
TL;DR: It is demonstrated that strength training increases insulin action and lowers plasma insulin levels in middle-aged and older men.
Abstract: The insulin resistance associated with aging may be due, in part, to reduced levels of physical activity in the elderly. We hypothesized that strength training increases insulin action in older ind...

Journal ArticleDOI
TL;DR: Women with NIDDM have high levels of free testosterone and low levels of SHBG, and it is suggested that these androgen abnormalities might be causally related to insulin resistance in NID DM.
Abstract: OBJECTIVE To evaluate androgen concentrations in relation to insulin resistance in men and women with and without NIDDM. Recent studies have indicated the potential importance of the regulation of insulin sensitivity by androgens in both women and men. Low sex hormone binding globulin (SHBG) concentration is an independent risk factor for the development of non-insulin-dependent diabetes mellitus (NIDDM) in women and is strongly associated statistically with signs of insulin resistance. RESEARCH DESIGN AND METHODS We compared measurements of anthropometric variables and SHBG, steroid hormone, and insulin concentrations of women and men who have NIDDM with those of control subjects. RESULTS Women with NIDDM had somewhat higher plasma insulin concentrations, lower SHBG, and higher free testosterone values than did control subjects with similar body mass index (BMI). Women with NIDDM had marginally higher waist-to-hip ratios (WHR). Plasma insulin concentrations correlated positively with BMI, WHR, and free testosterone and negatively with SHBG. In multivariate analyses, insulin concentrations remained positively associated with BMI and free testosterone. Men with NIDDM had higher fasting plasma insulin concentrations than did the nondiabetic control subjects. Testosterone and SHBG were lower in the diabetic men than in both control groups. The derived value of free testosterone was not different between groups. Univariate correlation analyses revealed tight statistical couplings between plasma insulin on the one hand and SHBG and testosterone concentrations (negative) on the other. In multivariate analyses, only the insulin-testosterone association remained. CONCLUSIONS Women with NIDDM have high levels of free testosterone and low levels of SHBG. Insulin resistance is closely correlated with these signs of hyperandrogenicity as well as with obesity. Men with NIDDM also have low levels of SHBG and, in contrast to women, low testosterone values. Insulin values correlate negatively with these hormonal factors. Based on the results of experimental work and intervention studies, we suggest that these androgen abnormalities might be causally related to insulin resistance in NIDDM.

Journal ArticleDOI
01 Jun 1994-Diabetes
TL;DR: The evidence supporting the balanced view that both insulin resistance and insulin deficiency contribute to the pathogen is reviewed.

Journal ArticleDOI
TL;DR: In conclusion, diabetes mellitus in insulinresistant cirrhotic patients develops as the result of progressive impairment in insulin secretion together with the development of hepatic insulin resistance leading to fasting hyperglycemia and a diabetic glucose tolerance profile.