Dexamethasone-induced impairment in skeletal muscle glucose transport is not reversed by inhibition of free fatty acid oxidation

Venkatesan, Natarajan; Lim, John; Bouch, C.; Marciano, Denise K.; Davidson, Mayer B.

doi:10.1016/s0026-0495(96)90205-x

Cited by 35 publications

(38 citation statements)

References 42 publications

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“…Apparently, this discrepancy was due to differences neither in insulin secretory response nor in lipid disregulation, since circulating insulin and FFA levels increased similarly in both hyper-and normoglycaemic animals of this age-group. It is worth noticing that our results confirm that the antilipolytic effect of insulin is blunted by DEX treatment (Venkatesan et al 1996). The present study clearly indicates that the variable effects of glucocorticoid treatment on blood glucose concentrations are not only genetically determined as suggested by Ogawa et al (1992), but also dependent on acquired factors such as age, overweight or both.…”

Section: Figuresupporting

confidence: 79%

“…Taking into account the hypothetical involvement of abundant lipid availability in the pathogenesis of hyperglycaemia in insulin resistant states such as obesity (Unger 1995), it is possible that the elevation of blood glucose in older rats could be mediated, at least in part, by the DEX-induced rise in circulating FFA levels, which interferes with glucose uptake and utilization particularly in muscles (Venkatesan et al 1987, Groop et al 1991, Roden et al 1996. However, besides the reported failure of inhibitors of FFA oxidation in improving muscle glucose uptake (Venkatesan et al 1996), it should be stressed that in our study the putative unfavourable effect of elevated plasma FFA levels occurred only in rats which were likely to be already insulin resistant because of advanced age and/or overweight. Indeed, it is of interest that DEX-treated 26-month-old rats became hyperglycaemic despite a modest increase in FFA circulating levels and that in 18-month-old animals post-treatment glucose levels were positively correlated with the initial body weight, but not with plasma FFA concentrations.…”

Section: Figurementioning

confidence: 99%

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Insufficient adaptive capability of pancreatic endocrine function in dexamethasone-treated ageing rats

Novelli¹,

Tata²,

Bombara³

et al. 1999

Journal of Endocrinology

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This study was aimed at exploring the capability of the pancreatic endocrine adaptive mechanisms of ageing Sprague-Dawley rats to counteract the metabolic challenge induced by the prolonged administration of dexamethasone (DEX) (0·13 mg/kg per day for 13 days). DEX treatment induced peripheral insulin resistance in 3-, 18-and 26-month-old rats, as indicated by the significant and persistent rise of plasma insulin levels in each age group (plasma insulin in 3-, 18-and 26-monthold rats from basal values of 4·3 0·8, 4·7 0·5 and 5·6 1·0 ng/ml (means ...) respectively, rose to 11·9 1·7, 29·1 5·5 and 27·9 2·7 ng/ml respectively, after 9 days of administration). However, plasma glucose concentrations remained unchanged during the treatment in young rats, whereas they increased up to frankly diabetic levels in most 18-month-old and in all 26-monthold animals after a few days of DEX administration. Plasma free fatty acid concentrations increased 2-fold in 3-and 26-month-old rats and 4-fold in 18-month-old rats and could possibly be involved in the glucocorticoid-induced enhancement in insulin resistance, although they showed no significant correlation with glycaemic values.Incubation of pancreatic islets obtained from treated rats showed that DEX administration increased the insulin responsiveness of islets from not only younger but also older donors. However, in the islets of ageing rats, which already showed an age-dependent impairment of the sensitivity to glucose and other secretagogues, this enhancing effect was clearly attenuated with respect to the younger counterpart. Furthermore, DEX treatment depressed significantly the priming effect of glucose in islets isolated from all the three age groups.In conclusion, our results show that ageing rats are unable to counteract effectively a prolonged hyperglycaemic challenge as such induced by DEX administration. This homeostatic defect can be ascribed to the age-dependent failure of the endocrine pancreas to provide enough insulin to overcome the aggravation of an antecedent state of increased peripheral insulin resistance.

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Section: Figuresupporting

confidence: 79%

Section: Figurementioning

confidence: 99%

Insufficient adaptive capability of pancreatic endocrine function in dexamethasone-treated ageing rats

Novelli¹,

Tata²,

Bombara³

et al. 1999

Journal of Endocrinology

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“…Until this type of data are presented we have to conclude that the combined administration of GH and MP does not generally decrease peripheral insulin-stimulated glucose disposal. Such a conclusion is further supported by the fact that neither GH (Cartee & Bohn 1995, Napoli et al 1996 nor dexamethasone (Haber & Weinstein 1992, Venkatesan et al 1996, Dimitriadis et al 1997 change the abundance of the glucose transporter molecule GLUT-4 in muscle cell membranes.…”

Section: Carbohydrate Metabolismmentioning

confidence: 97%

“…Animals treated with GH and MP showed no difference in [ 3 H]deoxyglucose uptake in fat or muscle but the potential of insulin to depress circulating glucose levels was significantly decreased. Although some support for these results could be found in the literature (Marfaing et al 1991) they are surprising because there is a large body of evidence published which suggests that the elevated circulating glucose and insulin levels following treatment with GH or glucocorticoids is a consequence of peripheral insulin resistance (Pagano et al 1983, Jorgensen et al 1994, Fowelin et al 1995, Hettiarachchi et al 1996, Venkatesan et al 1996. The reason for these conflicting results is at present not clear but the dose of insulin used might be of importance.…”

Section: Carbohydrate Metabolismmentioning

confidence: 99%

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The role of growth hormone and glucocorticoid in glucose handling in vivo

Johansen

Deckert²,

Mandrup-Poulsen³

et al. 1999

Journal of Endocrinology

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Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years

Randle

1998

Diabetes Metab. Rev.

763

531

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Competition for respiration between substrates in animal tissues has been known for at least 80 Years. The most important interaction, quantitatively is between glucose and fatty acids. The starting point in 1963 for the so called Glucose Fatty Acid Cycle was the realisation that the metabolic relationship between glucose and fatty acids is reciprocal and not dependent. Glucose provision promotes glucose oxidation and glucose and lipid storage, and inhibits fatty acid oxidation. Provision of free fatty acids promotes fatty acid oxidation and storage, inhibits glucose oxidation and may promote glucose storage if glycogen reserves are incomplete. This review is concerned predominantly with evidence in man in vivo. In the authors opinion the evidence for inhibitory effects of fatty acids on whole body glucose utilization ad oxidation (predominantly muscles) is decisive and enzyme mechanisms mediating these effects are well established. There is also much evidence that fatty acid oxidation inhibits glucose oxidation and stimulates glucose formation in liver and again enzyme mechanism are known. A permissive role for fatty acids in the insulin secretory response of islet β‐cells has now been firmly established and can be visualised as a mechanism to protect continuing provision of respiratory substrate. Longer term exposure of islet β‐cells to fatty acids impairs the insulin secretory response to glucose and mechanisms are known. There is compelling evidence that fatty acid oxidation may impair glucose oxidation in uncontrolled Type 1 and Type 2 diabetes, but no convincing evidence that fatty acids have a role in diminished glucose storage (glycogen deposition) in Type 2 diabetes. The inhibition of glucose storage which may follow prolonged elevation of plasma FFA in man and experimental animals is associated with glycogen repletion whereas the inhibition of glucose storage in Type 2 diabetes is associated with glycogen depletion. The precise role of fatty acids in disturbed carbohydrate metabolism in Type 2 diabetes is an area where future progress is confidently predicted. Copyright © 1998 John Wiley & Sons, Ltd.

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Dexamethasone-induced impairment in skeletal muscle glucose transport is not reversed by inhibition of free fatty acid oxidation

Cited by 35 publications

References 42 publications

Insufficient adaptive capability of pancreatic endocrine function in dexamethasone-treated ageing rats

Insufficient adaptive capability of pancreatic endocrine function in dexamethasone-treated ageing rats

The role of growth hormone and glucocorticoid in glucose handling in vivo

Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years

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