The effects of metabolic acidosis in vivo on insulin binding to isolated rat adipocytes

Whittaker, Jonathan; Cuthbert, C.; Hammond, Vanessa A.; Alberti, K. G. M. M.

doi:10.1016/0026-0495(82)90094-4

Cited by 42 publications

(26 citation statements)

References 17 publications

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“…Our experimental preparations are consistent with previous reports that indicated the decrease in insulin response at low pH, using the other cells (tiara et al 1981; Hidaka et al 1981). Several investigators have shown in the studies using the rat and human adipocytes that a reduced insulin action in acidic state was due to a decrease in insulin binding rate (Whittaker et al 1981(Whittaker et al , 1982Van Putten et al 1985 ;Ohtsuka et al 1990). Recently, it was proposed that a mechanism of receptor affinity regulation was based on the interaction of two functional components of the insulin receptor ; a binding component and an affinity regulator (Harmon et al 1980(Harmon et al , 1981(Harmon et al , 1983).…”

Section: Discussionsupporting

confidence: 92%

“…insulin resistance ; acidosis ; insulin receptor ; glucose uptake ; adipocyte It is well known that insulin resistance exists in diabetic patients during episodes of ketoacidosis (Walker et al 1963;Roth et al 1975;Ginsberg, H.N. 1977;Cuthbert and Alberti 1978;Whittaker et al 1981Whittaker et al , 1982Barrett et al 1982). Insulin resistance in metabolic ketoacidosis may be caused by several counterregulatory factors, of which low PH and ketone bodies are considered to be important factors (Ginsberg, H.N.…”

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confidence: 99%

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Effect of Acidosis on Insulin Binding and Glucose Uptake in Isolated Rat Adipocytes.

Inamori

Yamatani

Fukase

et al. 1993

Tohoku J. Exp. Med.

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A., TOMINAGA, M. and SASAKI, H. Effect of Acidosis on Insulin Binding and Glucose Uptake in Isolated Rat Adipocytes. Tohoku J. Exp. Med., 1993, 169 (3), 205-213 To assess the mechanism of insulin resistance in metabolic acidosis, we investigated insulin receptor binding and glucose uptake in isolated rat epididymal adipocytes at three pHs, acidic (pH 6.8), neutral (pH 7.4) and alkaline (pH 8.0) groups. After male Sprague-Dawley rats weighing 220-240 g were submitted under chloral hydrate anesthesia, epididymal fat pads were dissected and isolated. [12511-insulin binding rate was not different between alkaline and neutral groups, but that of acidic group was markedly decreased to approximately 30% of neutral group at maximum specific insulin binding rate. Scatchard analysis showed that numbers of insulin receptors were not different among three groups, but values of binding affinity in acidic group was significantly lower than those of the others. 2-[3H]deoxy-D-glucose uptake of alkaline and neutral groups were increased to reach steady state immediately, but that of acidic group increased slowly and reached at maximum which was lower than the other two groups. Furthermore, 2-deoxy-D-glucose uptake against amount of bound insulin was lower in acidic group than other two groups. From these results, it is suggested that insulin resistance in metabolic acidosis resulted from the combined defects in binding affinity and post-binding process in the insulin receptor. insulin resistance ; acidosis ; insulin receptor ; glucose uptake ; adipocyte

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

Effect of Acidosis on Insulin Binding and Glucose Uptake in Isolated Rat Adipocytes.

Inamori

Yamatani

Fukase

et al. 1993

Tohoku J. Exp. Med.

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“…Inhibition of the first step of insulin signaling, namely the phosphorylation of IR, by ischemia or low pH could result from inhibition of insulin binding to its receptor, as already reported for isolated adipocytes incubated at pH e 6.7 27 and/or from the inhibition of the IR tyrosine kinase activity itself. Removal of insulin from the medium by washout procedures is known to decrease insulin binding to its receptor.…”

Section: Inhibition Of the Ir Tyrosine Kinase Activitymentioning

confidence: 72%

No flow ischemia inhibits insulin signaling in the heart by decreasing intracellular pH

Beauloye¹,

Bertrand²,

Krause³

et al. 2001

Journal of Molecular and Cellular Cardiology

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Abstract-Glucose-insulin-potassium solutions exert beneficial effects on the ischemic heart by reducing infarct size and mortality and improving postischemic left ventricular function. Insulin could be the critical protective component of this mixture, although the insulin response of the ischemic and postischemic myocardium has not been systematically investigated. The aim of this work was to study the insulin response during ischemia by analyzing insulin signaling. This was evaluated by measuring changes in activity and/or phosphorylation state of insulin signaling elements in isolated perfused rat hearts submitted to no-flow ischemia. Intracellular pH (pH i ) was measured by NMR. No-flow ischemia antagonized insulin signaling including insulin receptor, insulin receptor substrate-1, phosphatidylinositol 3-kinase, protein kinase B, p70 ribosomal S6 kinase, and glycogen synthase kinase-3. These changes were concomitant with intracellular acidosis. Perfusing hearts with ouabain and amiloride in normoxic conditions decreased pH i and insulin signaling, whereas perfusing at pH 8.2 counteracted the drop in pH i and the inhibition of insulin signaling by ischemia. Incubation of cardiomyocytes in normoxic conditions, but at pH values below 6.75, mimicked the effect of ischemia and also inhibited insulin-stimulated glucose uptake. Finally, the in vitro insulin receptor tyrosine kinase activity was progressively inhibited at pH values below physiological pH i , being abolished at pH 6.0. Therefore, ischemic acidosis decreases kinase activity and tyrosine phosphorylation of the insulin receptor thereby preventing activation of the downstream components of the signaling pathway. We conclude that severe ischemia inhibits insulin signaling by decreasing pH i . (Circ Res. 2001;88:513-519.)

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“…Furthermore, metabolic acidosis decreases the binding of insulin to its receptors in rats, suggesting that metabolic acidosis may promote insulin resistance [23]. Finally, in experimental studies, acid/base alterations are associated with decreased insulin secretion [24].…”

Section: Biological Mechanismsmentioning

confidence: 99%

Dietary acid load and risk of type 2 diabetes: the E3N-EPIC cohort study

et al. 2013

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Aims/hypothesis The objective of this study was to evaluate the prospective relationship between dietary acid load, assessed with both the potential renal acid load (PRAL) and the net endogenous acid production (NEAP) scores, and type 2 diabetes risk. Methods A total of 66,485 women from the E3N-EPIC cohort were followed for incident diabetes over 14 years. PRAL and NEAP scores were derived from nutrient intakes. HRs for type 2 diabetes risk across quartiles of the baseline PRAL and NEAP scores were estimated with multivariate Cox regression models. Results During follow-up, 1,372 cases of incident type 2 diabetes were validated. In the overall population, the highest PRAL quartile, reflecting a greater acid-forming potential, was associated with a significant increase in type 2 diabetes risk, compared with the first quartile (HR 1.56, 95% CI 1.29, 1.90). The association was stronger among women with BMI <25 kg/m 2 (HR 1.96, 95% CI 1.43, 2.69) than in overweight women (HR 1.28, 95% CI 1.00, 1.64); statistically significant trends in risk across quartiles were observed in both groups ( p trend <0.0001 and p trend =0.03, respectively). The NEAP score provided similar findings. Conclusions/interpretationWe have demonstrated for the first time in a large prospective study that dietary acid load was positively associated with type 2 diabetes risk, independently of other known risk factors for diabetes. Our results need to be validated in other populations, and may lead to promotion of diets with a low acid load for the prevention of diabetes. Further research is required on the underlying mechanisms.

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The effects of metabolic acidosis in vivo on insulin binding to isolated rat adipocytes

Cited by 42 publications

References 17 publications

Effect of Acidosis on Insulin Binding and Glucose Uptake in Isolated Rat Adipocytes.

Effect of Acidosis on Insulin Binding and Glucose Uptake in Isolated Rat Adipocytes.

No flow ischemia inhibits insulin signaling in the heart by decreasing intracellular pH

Dietary acid load and risk of type 2 diabetes: the E3N-EPIC cohort study

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