Receptor and postreceptor insulin resistance induced by in vivo hyperinsuiinemia

1983 ◽  
Vol 61 (8) ◽  
pp. 802-807 ◽  
Author(s):  
C. Martin ◽  
K. S. Desai ◽  
G. Steiner
Keyword(s):  
Insulin Resistance ◽  
Glucose Oxidation ◽  
Binding Capacity ◽  
Insulin Receptors ◽  
Insulin Binding ◽  
Insulin Concentration ◽  
Fat Cell ◽  
And Control

We examined the effects of inducing hyperinsuiinemia in vivo in rats on the insulin receptors of, and the glucose oxidation by their adipocytes. Hyperinsulinemia was induced over a 2-week period by injecting NPH insulin subcutaneously. This was given in doses that were gradually increased to a final dose of 6 units/day. Profound hypoglycemia was avoided by providing supplemental sucrose to both the insulin-treated and control rats. The insulin concentration was eight times greater in the insulin-treated rats. However, they were not grossly obese and their adipocytes were not enlarged. The adipocytes of the hyperinsulinemic rats had a 25% lower maximal insulin binding capacity and were resistant to the effects of insulin on glucose oxidation. We felt that the hyperinsuiinemia was sufficient so that, despite their somewhat lower insulin binding capacity, these adipocytes would not bind less insulin in vivo than would adipocytes from control rats. Hence, we postulated that, this massive hyperinsulinemia not only down regulated the insulin receptor, but also led to a postreceptor resistance. This notion was supported by two lines of in vitro data. First, even at maximally effective medium concentrations of insulin, the maximum rate of glucose oxidation by the adipocytes from hyperinsulinemic rats reached a plateau which was less than that reached by cells from controls. Second, when this in vitro glucose oxidation was related not merely to the medium insulin concentration, but to the amount of insulin bound to adipocytes, the response of the hyperinsulinemic rats' cells was always lower than control. These changes occurred in the absence of any difference in fat cell size. Thus, in vivo hyperinsulinemia led to insulin resistance in adipocytes. This was associated both with down regulation of the insulin receptors and with a postreceptor defect.

Failure of chronic experimental hyperinsulinism to alter insulin binding to hypothalamic receptors in the rat

1984 ◽  
Vol 107 (1) ◽  
pp. 86-90 ◽  
Author(s):  
Roman B. Melnyk ◽  
J. M. Martin
Keyword(s):  
Food Restriction ◽  
Insulin Treatment ◽  
Binding Capacity ◽  
Insulin Receptors ◽  
Insulin Binding ◽  
Insulin Concentration ◽  
Regulatory Mechanisms ◽  
Hypothalamic Region ◽  
Insulin Levels ◽  
Lateral Area

Abstract. We have previously shown that [125I]insulin binding to medial hypothalamic receptors is attenuated following 14 days of food restriction. Such rats are characterized by considerably reduced circulating insulin levels with unchanged hypothalamic insulin concentration. The present data demonstrate that, in contrast to the effects of starvation, [125I]insulin binding to hypothalamic receptors from rats made hyperinsulinaemic by daily injections of protamine zinc insulin (4–6 U/rat/day for 14 days) is unaffected by this manipulation, even though hypothalamic insulin concentration in insulininjected animals was significantly higher than in salineinjected controls. Insulin binding to partially purified membranes from the medial hypothalamic region was significantly greater than that from the lateral area, confirming a finding in our earlier study. Insulin treatment was associated with slight reductions in maximal insulin-binding capacity of medial hypothalamic receptors, a tendency which appeared to be compensated by reciprocal changes in receptor affinity for this hormone. The data indicate that hypothalamic insulin receptors are not regulated by peripheral or even central insulin levels per se; it appears, rather, that some other, as yet unidentified, correlate(s) of significantly altered food intake and/or body weight can modify hypothalamic insulin receptor function. Perhaps such modifications could, in turn, participate in the activation of regulatory mechanisms involved in correcting energy imbalance.

Insulin resistance in obesity, type II diabetes and stress

1983 ◽  
Vol 104 (4_Suppl) ◽  
pp. S67-S69
Author(s):  
Ulf Smith
Keyword(s):  
Insulin Resistance ◽  
Glucose Tolerance ◽  
Key Words ◽  
Glucose Transport ◽  
Type Ii Diabetes ◽  
Insulin Receptors ◽  
In Vitro Studies ◽  
Type Ii

ABSTRACT. Insulin resistance plays a major role for the reduced glucose tolerance in obesity, type II diabetes and stress. Both in vivo and in vitro studies strongly support the major importance of post-receptor perturbations as the cause of the insulin resistance in these conditions. One likely level for the post-receptor alterations is the reported reduction in glucose transport. Key words: Insulin resistance, diabetes, obesity, insulin receptors, glucose transport.

The Relation Between Glucose Tolerance and Insulin Binding to Circulating Monocytes in Obese Children

PEDIATRICS ◽  
1982 ◽  
Vol 70 (4) ◽  
pp. 633-637
Author(s):  
Kaichi Kida ◽  
Noriyoshi Watanabe ◽  
Yoshiki Fujisawa ◽  
Yoshinori Goto ◽  
Hiroshi Matsuda
Keyword(s):  
Glucose Tolerance ◽  
Insulin Receptors ◽  
Insulin Binding ◽  
Tolerance Test ◽  
Quantitative Relation ◽  
Immunoreactive Insulin ◽  
Oral Glucose ◽  
Obese Children

The quantitative relation between insulin binding to circulating monocytes in vitro and glucose tolerance in obese children in vivo is reported. Sixty-one obese children and 11 healthy control children participated in this study. The oral glucose tolerance test (OGTT) was performed by giving them glucose (1.75 gm/kg of body weight), orally in the morning, and the binding of 125I-labeled insulin to circulating monocytes in vitro was measured prior to OGTT. The glucose tolerance expressed by ΣBS (milligrams/100 ml), the sum of the plasma glucose (blood sugar [BS]) values at OGTT, was significantly correlated with the degree of overweight (r = .316, P < .01) and more highly with ΣIRI (microunits per milliliter), the sum of immunoreactive insulin (IRI) values at OGTT (r = .512, P < .001). Insulin binding to monocytes in vitro (picograms/106 cells) was inversely correlated with the degree of overweight (r = -. 687, P < .001). Furthermore, ΣBS was inversely correlated significantly with insulin binding to monocytes in vitro (r = -.435, P < .002). These data suggest that the decrease of insulin receptors might be one cause for the impairment of the glucose tolerance associated with obesity in children.

scholarly journals Intervention of Gastrodin in Type 2 Diabetes Mellitus and Its Mechanism

2021 ◽  
Vol 12 ◽  
Author(s):  
Yu Bai ◽  
Ke Mo ◽  
Guirong Wang ◽  
Wanling Chen ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Receptors ◽  
Control Group ◽  
Sensitivity Index

As a severe metabolic disease, type 2 diabetes mellitus (T2DM) has become a serious threat to human health in recent years. Gastrodin, as a primary chemical constituent in Gastrodia elata Blume, has antidiabetic effects. However, the possible mechanisms are unclear. The aim of the present study was to investigate the effects and possible mechanisms of gastrodin on the treatment of T2DM. In vivo, after treatment with gastrodin for 6 weeks, fasting blood glucose levels, blood lipid metabolism, and insulin sensitivity index values were remarkably reduced compared with those of the diabetic control group. The values of aspartate aminotransferase and alanine aminotransferase also showed that gastrodin alleviates liver toxicity caused by diabetes. Moreover, gastrodin relieved pathological damage to the pancreas in T2DM rats. In vitro, gastrodin alleviated insulin resistance by increasing glucose consumption, glucose uptake, and glycogen content in dexamethasone-induced HepG2 cells. The Western blotting results showed that gastrodin upregulated the expression of insulin receptors and ubiquitin-specific protease 4 (USP4) and increased the phosphorylation of GATA binding protein 1 (GATA1) and protein kinase B (AKT) in vivo and in vitro. Furthermore, gastrodin decreased the ubiquitin level of the insulin receptor via UPS4 and increased the binding of GATA1 to the USP4 promoter. Additionally, administration of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway inhibitors MK-2206 and LY294002 abolished the beneficial effects of gastrodin. Our results indicate that gastrodin promotes the phosphorylation of GATA1 via the PI3K/AKT pathway, enhances the transcriptional activity of GATA1, and then increases the expression level of USP4, thereby reducing the ubiquitination and degradation of insulin receptors and ultimately improving insulin resistance. Our study provides scientific evidence for the beneficial actions and underlying mechanism of gastrodin in the treatment of T2DM.

Effect of insulin on glucose uptake by the maternal hindlimb and uterus, and by the fetus in conscious pregnant sheep

1984 ◽  
Vol 100 (1) ◽  
pp. 119-124 ◽  
Author(s):  
W. W. Hay ◽  
J. W. Sparks ◽  
M. Gilbert ◽  
F. C. Battaglia ◽  
G. Meschia
Keyword(s):  
Glucose Uptake ◽  
Specific Binding ◽  
Insulin Receptors ◽  
Fold Increase ◽  
Late Gestation ◽  
Insulin Concentration ◽  
In Vivo Studies ◽  
Pregnant Sheep

ABSTRACT Previous studies have demonstrated the presence of insulin receptors on the maternal surface of the placenta in several species and the specific binding of insulin to the placenta in sheep. However, both in-vitro and in-vivo studies have produced conflicting evidence concerning the effect of insulin on placental glucose uptake. To clarify this problem, we measured maternal hindlimb, uterine and fetal glucose and oxygen extractions and glucose/oxygen quotients in chronically catheterized, non-stressed, late-gestation pregnant sheep over 1 h at a constant concentration of arterial plasma glucose, and again during the next 2 h at the same glucose level but at a higher insulin concentration using glucose 'clamp' methodology. Insulin produced a 4·9-fold increase in glucose extraction and a 3·5-fold increase in glucose/oxygen quotient across the hindlimb; in contrast, insulin did not significantly affect uterine or fetal glucose extraction or glucose/oxygen quotient. We conclude that in contrast to other tissues of the pregnant ewe, placental glucose uptake and transfer are insensitive to variations in maternal insulin concentration. J. Endocr. (1984) 100, 119–124

Metformin ameliorates extreme insulin resistance in a patient with anti-insulin receptor antibodies: description of insulin receptor and postreceptor effects in vivo and in vitro

1992 ◽  
Vol 126 (2) ◽  
pp. 117-123 ◽  
Author(s):  
Salvatore Di Paolo
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Glucose Transport ◽  
Insulin Binding ◽  
Severe Insulin Resistance ◽  
Binding Data ◽  
Extreme Insulin Resistance ◽  
Receptor Antibodies

The effect of metformin on insulin binding and insulin action in the presence of anti-insulin receptor antibodies was investigated in a case of type B extreme insulin resistance. Oral administration of metformin (1 500 mg/d) for 10 days significantly decreased plasma blood glucose and insulin levels and enhanced the hypoglycemic response to exogenous insulin. In vitro preincubation of normal erythrocytes with insulin receptor antibody from the patient plus 4× 10−5 mol/l metformin markedly enhanced insulin binding to receptors, compared to cells incubated with antibody alone. This effect was apparent after 2 h, was maximal after 4 h and did not change up to 24 h. Closely similar results were found when human adipocytes were studied. Analysis of binding data confirmed the increase in both receptor number and affinity. One hour exposure of control adipocytes to metformin enhanced basal lipogenesis by more than 30%. Acute exposure of fat cells to the patient's receptor antibodies resulted in a stimulation of glucose transport and a state of severe insulin resistance. The addition of metformin to antibody in preincubation buffer strongly enhanced basal glucose incorporation into lipids, but did not prevent insulin unresponsiveness. It is suggested that metformin increases, possibly through a change in the spatial conformation of insulin receptor within the plasma membrane, the availability of preexisting receptors to insulin binding and/or decreases the availability of specific epitopes to antibody anchoring. Further, in the model of insulin resistance described here, metformin enhanced the basal rate of glucose transport through a direct insulin-mimicking activity and/or a potentiation of the sensitivity of glucose transport to the antibody.

scholarly journals Angiotensin II Enhances Insulin Sensitivity in Vitro and in Vivo

Endocrinology ◽  
2005 ◽  
Vol 146 (5) ◽  
pp. 2246-2254 ◽  
Author(s):  
Chi-Chang Juan ◽  
Yueh Chien ◽  
Liang-Yi Wu ◽  
Wei-Ming Yang ◽  
Chih-Ling Chang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Angiotensin Ii ◽  
Glucose Uptake ◽  
Intracellular Signaling ◽  
Binding Capacity ◽  
Critical Role ◽  
At1 Antagonist

Abstract The renin-angiotensin system plays a critical role in the pathogenesis of obesity, obesity-associated hypertension, and insulin resistance. However, the biological actions of angiotensin II (AII) on insulin sensitivity remain controversial. Because angiotensinogen and AII receptors are expressed on adipose tissue, we investigated the effect of AII on the insulin sensitivity of isolated rat adipocytes. The results of a receptor binding assay showed the maximal AII binding capacity of adipocytes to be 8.3 ± 0.9 fmol/7 × 106 cells and the dissociation constant to be 2.72 ± 0.11 nm. Substantial expression of both type 1 and 2 AII (AT1 and AT2) receptors was detected by RT-PCR. AII had no effect on basal glucose uptake, but significantly potentiated insulin-stimulated glucose uptake; this effect was abolished by the AT1 antagonist, losartan. In addition, AII did not alter the insulin binding capacity of adipocytes, but increased insulin-stimulated tyrosine phosphorylation of the insulin receptor β-subunit, Akt phosphorylation, and translocation of glucose transporter 4 to the plasma membrane. AII potentiated insulin-stimulated glucose uptake through the AT1 receptor and by alteration of the intracellular signaling of insulin. Intraperitoneal injection of Sprague Dawley rats with AII increased insulin sensitivity in vivo. In conclusion, we have shown that AII enhances insulin sensitivity both in vitro and in vivo, suggesting that dysregula-tion of the insulin-sensitizing effect of AII may be involved in the development of insulin resistance.

Insulin binding and action in adipocytes of pregnant rats: evidence that insulin resistance is caused by post-receptor binding defects

1984 ◽  
Vol 102 (2) ◽  
pp. 209-214 ◽  
Author(s):  
M. Th. Sutter-Dub ◽  
A. Sfaxi ◽  
F. Latrille ◽  
F. Sodoyez-Goffaux ◽  
J. C. Sodoyez
Keyword(s):  
Insulin Resistance ◽  
Biological Effect ◽  
Response Curve ◽  
Glucose Oxidation ◽  
Insulin Receptors ◽  
Insulin Binding ◽  
Receptor Interaction ◽  
Fat Cells ◽  
Pregnant Rats ◽  
Duration Of Pregnancy

ABSTRACT Insulin resistance was investigated in the adipose cell of rats which were at days 16 and 20 of pregnancy. Data are presented to relate insulin binding and biological effect, which was evaluated by the ability of insulin to stimulate [1-14C]glucose oxidation. Adipocytes from pregnant rats bound more insulin than fat cells from control (non-pregnant) animals and the number of insulin receptors per adipocyte increased during pregnancy. Basal glucose oxidation rate was decreased at 16 and 20 days of pregnancy: however, the dose–response curve for insulin-stimulated glucose oxidation was significantly depressed only after 20 days of pregnancy. The concentration at which insulin increased glucose oxidation by 50% increased with the duration of pregnancy. We conclude that during pregnancy in the rat the adipocyte response to insulin was decreased, despite an increase in insulin binding. This result suggests that a major determinant of insulin resistance in rat adipocytes during pregnancy is present after the initial insulin–receptor interaction. Consequently, a post-receptor defect may be largely responsible for the insulin resistance. J. Endocr. (1984) 102, 209–214

Expression of insulin receptors and of 60-kDa receptor substrate in rat mature and immature enterocytes

1997 ◽  
Vol 273 (1) ◽  
pp. G217-G226 ◽  
Author(s):  
J. P. Buts ◽  
N. De Keyser ◽  
S. Marandi ◽  
A. S. Maernoudt ◽  
E. M. Sokal ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Radioligand Binding ◽  
Binding Capacity ◽  
Insulin Receptors ◽  
Insulin Binding ◽  
Scatchard Analysis ◽  
Binding Assays ◽  
Age Related ◽  
High Affinity Receptor

The mechanism(s) by which rat immature enterocytes exhibit increased responsiveness to insulin before weaning is unknown. Therefore, we have analyzed the distribution, ontogeny, and molecular properties of insulin receptors (IR) and of related substrates in immature and mature enterocytes. IR were studied by radioligand binding assays, cross-linking labeling, immunohistochemistry, and in vitro phosphorylated substrates by immunoprecipitation. Regardless of age, 125I-insulin binding to IR was five times higher in crypt cells than in villus cells and two times higher in the ileum than in the jejunum. Binding capacity to villus cells from sucklings (day 14) exceeded three times that of older animals (day 30 and day 60). Scatchard analysis of equilibrium binding data confirmed an age-related decrease in low- and high-affinity receptor classes without change in affinity constants. In concordance, both alpha- and beta-IR subunits were more abundant in immature than in mature membranes. In vitro, insulin elicited the phosphorylation of three membrane proteins (96, 60 and 42 kDa), whose signals were virtually inhibited by preincubating membranes with antireceptor monoclonal antibodies. By immunoprecipitation, the 60-kDa signal was rapidly detected as a tyrosine-phosphorylated protein, expressed in mature and immature membranes, and identified as a receptor substrate phosphorylated in vitro by the IR tyrosine kinase. In conclusion, 1) increased responsiveness of rat immature enterocytes to insulin could be related to high membrane concentrations of IR and 2) normal rat enterocytes express a 60-kDa phosphotyrosine protein identified as a direct substrate of the IR tyrosine kinase.

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