Investigation of the mechanisms contributing to the compensatory increase in insulin secretion during dexamethasone-induced insulin resistance in rhesus macaques

Cummings, Bethany P.; Bremer, Andrew A.; Kieffer, Timothy J.; D’Alessio, David A.; Havel, Peter J.

doi:10.1530/joe-12-0459

Cited by 28 publications

(23 citation statements)

References 41 publications

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“…the stimulation of glucose-dependent insulin secretion. Furthermore, the increase in postprandial insulin secretion after dexamethasone administration were shown to be mediated, at least in part, by increases in meal-stimulated GIP secretion [30]. One of the most striking observations was the simultaneous shift towards higher concentrations of triglycerides in chylomicrons and VLDL together with decrease of LDL and HDL cholesterol in heterozygous animals in comparison with both SHR and the SHR- Dca −/−.…”

Section: Discussionmentioning

confidence: 99%

Heterozygous connexin 50 mutation affects metabolic syndrome attributes in spontaneously hypertensive rat

et al. 2016

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BackgroundSeveral members of connexin family of transmembrane proteins were previously implicated in distinct metabolic conditions. In this study we aimed to determine the effects of complete and heterozygous form of connexin50 gene (Gja8) mutation L7Q on metabolic profile and oxidative stress parameters in spontaneously hypertensive inbred rat strain (SHR).MethodsAdult, standard chow-fed male rats of SHR, heterozygous SHR-Dca+/− and SHR-Dca−/− coisogenic strains were used. At the age of 4 months, dexamethasone (2.6 μg/ml) was administered in the drinking water for three days. The lipidemic profile (cholesterol and triacylglycerol concentration in 20 lipoprotein fractions, chylomicron, VLDL, LDL and HDL particle sizes) together with 33 cytokines and hormones in serum and several oxidative stress parameters in plasma, liver, kidney and heart were assessed.ResultsSHR and SHR-Dca−/− rats had similar concentrations of triacylglycerols and cholesterol in all major lipoprotein fractions. The heterozygotes reached significantly highest levels of total (SHR-Dca+/−: 51.3 ± 7.2 vs. SHR: 34.5 ± 2.4 and SHR-Dca−/−: 34.4 ± 2.5 mg/dl, p = 0.026), chylomicron and VLDL triacylglycerols. The heterozygotes showed significantly lowest values of HDL cholesterol (40.9 ± 2.3 mg/dl) compared both to SHR (51.8 ± 2.2 mg/dl) and SHR-Dca−/− (48.6 ± 2.7 mg/dl). Total and LDL cholesterol in SHR-Dca+/− was lower compared to SHR. Glucose tolerance was improved and insulin concentrations were lowest in SHR-Dca−/− (1.11 ± 0.20 pg/ml) in comparison with both SHR (2.32 ± 0.49 pg/ml) and SHR-Dca+/− (3.04 ± 0.21 pg/ml). The heterozygous rats showed profile suggestive of increased oxidative stress as well as highest serum concentrations of several pro-inflammatory cytokines including interleukins 6, 12, 17, 18 and tumor necrosis factor alpha.ConclusionsOur results demonstrate that connexin50 mutation in heterozygous state affects significantly the lipid profile and the oxidative stress parameters in the spontaneously hypertensive rat strain.Electronic supplementary materialThe online version of this article (doi:10.1186/s12944-016-0376-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Heterozygous connexin 50 mutation affects metabolic syndrome attributes in spontaneously hypertensive rat

et al. 2016

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“…In this model, isolated pancreatic islets exhibited impaired inhibition of glucagon release at high glucose levels. Similarly, dexamethasone (0.25 mg/kg) administered for 7 days in rhesus macaques induced fasting hyperglucagonaemia (Cummings et al 2013), and prednisolone (0.2-0.3 mg daily) administered for 4 days increased basal and arginine-induced glucagon secretion in isolated mouse islets (Marco et al 1976). In contrast to the abovementioned results obtained for in vivo GC treatment, glucagon release was suppressed in isolated rat islet cells incubated for 18 h with dexamethasone at 10 K9 and 10 K10 M, but was without effect at higher steroid concentrations (Papachristou et al 1994).…”

Section: Acute Effects Of Gcs On A-cell Function and Glucagon Releasementioning

confidence: 99%

Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes

Rafacho¹,

Ortsäter²,

Nadal³

et al. 2014

Journal of Endocrinology

184

114

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Glucocorticoids (GCs) are broadly prescribed for numerous pathological conditions because of their anti-inflammatory, antiallergic and immunosuppressive effects, among other actions. Nevertheless, GCs can produce undesired diabetogenic side effects through interactions with the regulation of glucose homeostasis. Under conditions of excess and/or long-term treatment, GCs can induce peripheral insulin resistance (IR) by impairing insulin signalling, which results in reduced glucose disposal and augmented endogenous glucose production. In addition, GCs can promote abdominal obesity, elevate plasma fatty acids and triglycerides, and suppress osteocalcin synthesis in bone tissue. In response to GC-induced peripheral IR and in an attempt to maintain normoglycaemia, pancreatic b-cells undergo several morphofunctional adaptations that result in hyperinsulinaemia. Failure of b-cells to compensate for this situation favours glucose homeostasis disruption, which can result in hyperglycaemia, particularly in susceptible individuals. GC treatment does not only alter pancreatic b-cell function but also affect them by their actions that can lead to hyperglucagonaemia, further contributing to glucose homeostasis imbalance and hyperglycaemia. In addition, the release of other islet hormones, such as somatostatin, amylin and ghrelin, is also affected by GC administration. These undesired GC actions merit further consideration for the design of improved GC therapies without diabetogenic effects. In summary, in this review, we consider the implication of GC treatment on peripheral IR, islet function and glucose homeostasis.

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“…This suggests food intake and body weight reductions due to DEX may not be directly related to its pressor effect through the sympathoadrenal system. Studies in the literature point to a complex interplay between GCs and other hormonal factors that regulate feeding behavior and subsequent body weight changes (Jahng et al, 2008;Cummings et al, 2013). For instance, DEX was shown to increase insulin secretion via improvement of b cell function (Cummings et al, 2013), in addition to affecting leptin release and its hypothalamic actions (Jahng et al, 2008), enhancing energy expenditure and anorexia.…”

Section: Discussionmentioning

confidence: 99%

“…Studies in the literature point to a complex interplay between GCs and other hormonal factors that regulate feeding behavior and subsequent body weight changes (Jahng et al, 2008;Cummings et al, 2013). For instance, DEX was shown to increase insulin secretion via improvement of b cell function (Cummings et al, 2013), in addition to affecting leptin release and its hypothalamic actions (Jahng et al, 2008), enhancing energy expenditure and anorexia. In contrast, GC therapy in humans is often associated with weight gain, in addition to increase in blood pressure (Whitworth et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

A Novel Model of Dexamethasone-Induced Hypertension: Use in Investigating the Role of Tyrosine Hydroxylase

Soto‐Piña

Franklin

Rani

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Our objective was to study hypertension induced by chronic administration of synthetic glucocorticoid, dexamethasone (DEX), under nonstressful conditions and examine the role of catecholamine biosynthesis. To achieve this, we did the following: 1) used radiotelemetry to record mean arterial pressure (MAP) and heart rate (HR) in freely moving rats, and 2) administered different doses of DEX in drinking water. To evaluate the involvement of tyrosine hydroxylase (TH), the rate-limiting step in catecholamine biosynthesis, we treated rats with the TH inhibitor, a-methyl-paratyrosine (a-MPT), for 3 days prior to administration of DEX and assessed TH mRNA and protein expression by quantitative realtime polymerase chain reaction and Western blot in the adrenal medulla. We observed a dose-dependent elevation in blood pressure with a DEX dose of 0.3 mg/kg administered for 10 days, significantly increasing MAP by 115.0 6 1.1 mm Hg, while concomitantly reducing HR. Although this DEX treatment also significantly decreased body weight, pair-fed animals that showed similar decreases in body weight due to lowered food intake were not hypertensive, suggesting that body weight changes may not account for DEX-induced hypertension. Chronic DEX treatment significantly increased the TH mRNA and protein levels in the adrenal medulla, and a-MPT administration not only reduced DEX pressor effects, but also inhibited TH (serine 40 ) phosphorylation. Our study thus validates a novel model to study hypertension induced by chronic intake of DEX in freely moving rats not subject to the confounding factors of previous models and establishes its dependence on concomitant activation of peripheral catecholamine biosynthesis.

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Investigation of the mechanisms contributing to the compensatory increase in insulin secretion during dexamethasone-induced insulin resistance in rhesus macaques

Cited by 28 publications

References 41 publications

Heterozygous connexin 50 mutation affects metabolic syndrome attributes in spontaneously hypertensive rat

Heterozygous connexin 50 mutation affects metabolic syndrome attributes in spontaneously hypertensive rat

Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes

A Novel Model of Dexamethasone-Induced Hypertension: Use in Investigating the Role of Tyrosine Hydroxylase

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