[Antibodies directed against the insulin receptor and insulin-resistant diabetes].
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The suckling period in the rat is characterized by a continuously low plasma insulin concentration and a physiological insulin resistance, particularly in the adipose tissue. This insulin resistance disappears after weaning on the high-carbohydrate adult diet. We have studied the number, structure, and function of adipose tissue insulin receptors during the suckling-weaning transition. The insulin receptor number determined either on intact adipocytes or after partial purification was higher during suckling (15 days), whereas the affinity was similar when compared with weaned rats (30 days). The molecular weight of the alpha- and beta-subunits were identical in both groups and, when analyzed in nonreducing conditions, the alpha 2 beta 2-form was the unique detectable form of the receptor. Neither the basal and insulin-stimulated autophosphorylation of the insulin receptor beta-subunit nor the tyrosine kinase activity toward a synthetic substrate was decreased during the suckling period. Thus, in the adipose tissue of the suckling rat, a marked insulin resistance is concomitant with a normal insulin receptor number and function.
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Insulin, like leptin, is considered as a lipostatic signal acting at a central level. Aging and age-associated adiposity have been related to the development of leptin resistance in Wistar rats. In the present article, hypothalamic insulin response during aging has been studied in Wistar rats. Thus, the effects of intracerebroventricular infusion of insulin during a week on food intake and body weight as well as insulin signal transduction after acute intracerebroventricular insulin administration have been studied in 3-, 8-, and 24-month-old rats. To explore the possible role of age-associated adiposity, these experiments were also performed in 8- and 24-month-old rats after 3 months of food restriction to reduce visceral adiposity index to values below those of young animals. Intracerebroventricular administration of insulin during a week was more efficient at reducing food intake and body weight in 3-month-old rats than in 8- and 24-month-old rats. Hypothalamic insulin-stimulated insulin receptor, GSK3, AKT, and p70S6K phosphorylation decreased with aging. Insulin receptor and IRS-2 phosphoserine was increased in 24-month-old rats. Food restriction improved both insulin responsiveness and insulin signaling. These data suggest that Wistar rats develop hypothalamic insulin resistance with aging. This can be explained by alterations of the signal transduction pathway. The fact that food restriction improves central insulin response and signal transduction points to the age-associated adiposity as a key player in the development of central insulin resistance.
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Hybrid receptors (HRs), insulin receptor (IR)/insulin-like growth factor I receptor (IGF-I-R) heterodimers have been reported increased in skeletal muscle of obese and type 2 diabetic patients and to contribute to the patient insulin resistance. To investigate whether or not the increased expression of hybrid receptors is an early defect (probably genetic) of insulin resistance, we measured by specific enzyme-linked immunosorbent assays both IR, IGF-I-R, and HR content in skeletal muscle of healthy nonobese, nondiabetic subjects either insulin sensitive or insulin resistant, and also in patients with moderate obesity. IR content was significantly reduced in insulin-resistant subjects both nonobese and obese, compared with insulin-sensitive subjects (2.32± 0.26, 2.36 ± 0.18, and 3.45 ± 0.42 ng/mg protein, respectively, P = 0.002). In contrast, IGF-I-R content was similar in the three groups. Muscle HR content was not different in insulin-sensitive vs. insulin-resistant subjects (both nonobese and obese) (4.90 ± 0.46, 4.69 ± 0.29, and 4.91 ± 0.25 ng/mg protein, respectively, P = not significant). These studies indicate that, in insulin-resistant subjects without diabetes or severe obesity, muscle IR content but not IGF-I-R or HR content is reduced. They do not suggest, therefore, a primary (genetic) role of increased HR as a cause of IR decrease and insulin resistance.
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Type II diabetes originates from various genetic and environmental factors. Recent studies showed that an adverse uterine environment such as that caused by a gestational low-protein (LP) diet can cause insulin resistance in adult offspring. The mechanism of insulin resistance induced by gestational protein restriction is not clearly understood. Our aim was to investigate the role of insulin signaling molecules in gastrocnemius muscles of gestational LP diet–exposed male offspring to understand their role in LP-induced insulin resistance. Pregnant Wistar rats were fed a control (20% protein) or isocaloric LP (6%) diet from gestational day 4 until delivery and a normal diet after weaning. Only male offspring were used in this study. Glucose and insulin responses were assessed after a glucose tolerance test. mRNA and protein levels of molecules involved in insulin signaling were assessed at 4 months in gastrocnemius muscles. Muscles were incubated ex vivo with insulin to evaluate insulin-induced phosphorylation of insulin receptor (IR), Insulin receptor substrate-1, Akt, and AS160. LP diet-fed rats gained less weight than controls during pregnancy. Male pups from LP diet–fed mothers were smaller but exhibited catch-up growth. Plasma glucose and insulin levels were elevated in LP offspring when subjected to a glucose tolerance test; however, fasting levels were comparable. LP offspring showed increased expression of IR and AS160 in gastrocnemius muscles. Ex vivo treatment of muscles with insulin showed increased phosphorylation of IR (Tyr972) in controls, but LP rats showed higher basal phosphorylation. Phosphorylation of Insulin receptor substrate-1 (Tyr608, Tyr895, Ser307, and Ser318) and AS160 (Thr642) were defective in LP offspring. Further, glucose transporter type 4 translocation in LP offspring was also impaired. A gestational LP diet leads to insulin resistance in adult offspring by a mechanism involving inefficient insulin-induced IR, Insulin receptor substrate-1, and AS160 phosphorylation and impaired glucose transporter type 4 translocation.
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A 14-yr-old woman presented with fasting hyperglycemia (269 mg/dl), fasting hyperinsulinemia (45 μU/ml), acanthosis nigricans, and insulin resistance. The patient's circulating insulin was normal by physical and biological criteria, and insulin receptor antibodies were not detected. Both the patient's in vivo dose-response curve for insulin-stimulated glucose uptake and the in vitro dose-response curve for insulin-stimulated glucose transport in isolated adipocytes were shifted to the right and showed marked decreases in the maximal insulin response. Basal hepatic glucose output was significantly increased, and the in vivo dose-response curve for insulin-mediated suppression of basal hepatic glucose output was shifted to the right. Insulin binding to the patient's erythrocytes, monocytes, and adipocytes was markedly decreased. To confirm that the severe reduction in cellular insulin receptors was a primary rather than an acquired defect, similar studies were conducted using cultured fibroblasts. No detectable binding of insulin to these cells was observed. Further studies showed that the patient's mother and two sisters were hyperinsulinemic and insulin resistant, and had comparable, although less severe, changes in insulin binding. The patient was also demonstrated to have an insulin secretory defect to both oral and iv glucose challenges. We thus conclude that this family demonstrates a genetic deficiency of insulin receptors, resulting in insulin resistance and, this patient, severe diabetes mellitus.
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Insulin resistance is associated with both obesity and hypertension. However, the cellular mechanisms of insulin resistance in genetic models of obese-hypertension have not been identified. The objective of the present study was to investigate the effects of genetic obesity on a background of inherited hypertension on initial components of the insulin signal transduction pathway and glucose transport in skeletal muscle and liver. Oral glucose tolerance testing in SHROB demonstrated a sustained postchallenge elevation in plasma glucose at 180 and 240 min compared with lean spontaneously hypertensive rat (SHR) littermates, which is suggestive of glucose intolerance. Fasting plasma insulin levels were elevated 18-fold in SHROB. The rate of insulin-stimulated 3- O-methylglucose transport was reduced 68% in isolated epitrochlearis muscles from the SHROB compared with SHR. Insulin-stimulated tyrosine phosphorylation of the insulin receptor β-subunit and insulin receptor substrate-1 (IRS-1) in intact skeletal muscle of SHROB was reduced by 36 and 23%, respectively, compared with SHR, due primarily to 32 and 60% decreases in insulin receptor and IRS-1 protein expression, respectively. The amounts of p85α regulatory subunit of phosphatidylinositol-3-kinase and GLUT-4 protein were reduced by 28 and 25% in SHROB muscle compared with SHR. In the liver of SHROB, the effect of insulin on tyrosine phosphorylation of IRS-1 was not changed, but insulin receptor phosphorylation was decreased by 41%, compared with SHR, due to a 30% reduction in insulin receptor levels. Our observations suggest that the leptin receptor mutation fa k imposed on a hypertensive background results in extreme hyperinsulinemia, glucose intolerance, and decreased expression of postreceptor insulin signaling proteins in skeletal muscle. Despite these changes, hypertension is not exacerbated in SHROB compared with SHR, suggesting these metabolic abnormalities may not contribute to hypertension in this model of Syndrome X.
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High dietary fat intake causes glucose intolerance and insulin resistance in man and in laboratory rats. We studied possible mechanisms of this insulin resistance in rat kidney, muscle and liver. In high-fat fed rats the body weight, plasma insulin concentration, plasma glucose levels, and serum triglyceride concentration were significantly higher than in the control rats. 125I-insulin binding to kidney basolateral membrane insulin receptors from high-fat fed rats was lower than in control rats. Basal as well as insulin-stimulated tyrosine kinase activity per insulin receptor was higher in the high-fat fed group, accompanied by increased autophosphorylation of the beta-subunit of the receptor and higher proportion of tyrosine-phosphorylated insulin receptors. In contrast, both in the skeletal muscle and the liver the insulin-stimulated tyrosine kinase activity per insulin receptor was significantly lower in high-fat fed animals, accompanied by diminished autophosphorylation of the beta-subunit of the receptor and lower proportion of tyrosine-phosphorylated receptors. Our results indicate tissue-specific alterations in transmembrane signaling induced by high-fat feeding in target tissues for insulin which in turn might contribute to the observed insulin resistance.
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