Hyperactivity of the hypothalamic-pituitary-adrenal axis in patients with type 2 diabetes and relations with insulin resistance and chronic complications

Prpić-Križevac, Ivana; Canecki-Varžić, Silvija; Bilić-Ćurčić, Ines

doi:10.1007/s00508-012-0191-4

Cited by 33 publications

(31 citation statements)

References 33 publications

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“…Similar meta-analysis concerning 24-h urinary free cortisol (eight studies, [27, 34, 40, 43, 44, 46, 48, 50]) demonstrated a similar lack of overall effect (Fig 3). ES = 2.87 95% CI (-3.63, 9.37), p = 0.387.…”

Section: Resultssupporting

confidence: 54%

“…Two of them found some association between obesity and morning blood cortisol or urinary free cortisol [44, 46]. One study reported morning blood cortisol data of male participants without analyzing potential correlation [45], and the remaining ten clinical observations pooled data of male and female volunteers [27, 29–32, 36, 40, 42, 43, 48]. These statistics suggest that an association between peripheral cortisol output and BMI would be more probably found in studies focusing on women.…”

Section: Discussionmentioning

confidence: 99%

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In Obesity, HPA Axis Activity Does Not Increase with BMI, but Declines with Aging: A Meta-Analysis of Clinical Studies

et al. 2016

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BackgroundObesity is one of the major public health challenges worldwide. It involves numerous endocrine disorders as etiological factors or as complications. Previous studies strongly suggested the involvement of the hypothalamic-pituitary-adrenal (HPA) axis activity in obesity, however, to date, no consistent trend in obesity-associated alterations of the HPA axis has been identified. Aging has been demonstrated to aggravate obesity and to induce abnormalities of the HPA axis. Thus, the question arises whether obesity is correlated with peripheral indicators of HPA function in adult populations.ObjectivesWe aimed to meta-analyze literature data on peripheral cortisol levels as indicators of HPA activity in obesity during aging, in order to identify possible explanations for previous contradictory findings and to suggest new approaches for future clinical studies.Data Sources3,596 records were identified through searching of PubMed, Embase and Cochrane Library Database. Altogether 26 articles were suitable for analyses.Study Eligibility CriteriaEmpirical research papers were eligible provided that they reported data of healthy adult individuals, included body mass index (BMI) and measured at least one relevant peripheral cortisol parameter (i.e., either morning blood cortisol or 24-h urinary free cortisol).Statistical MethodsWe used random effect models in each of the meta-analyses calculating with the DerSimonian and Laird weighting methods. I-squared indicator and Q test were performed to assess heterogeneity. Meta-regression was applied to explore the effect of BMI and age on morning blood and urinary free cortisol levels. To assess publication bias Egger’s test was used.ResultsObesity did not show any correlation with the studied peripheral cortisol values. On the other hand, peripheral cortisol levels declined with aging within the obese, but not in the non-obese groups.ConclusionsOur analysis demonstrated that obesity or healthy aging does not lead to enhanced HPA axis activity, peripheral cortisol levels rather decline with aging.

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Section: Resultssupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

In Obesity, HPA Axis Activity Does Not Increase with BMI, but Declines with Aging: A Meta-Analysis of Clinical Studies

et al. 2016

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“…DM2 patients have elevated basal ACTH levels (Vermes et al 1985, Chiodini et al 2006) and high cortisol levels, both basal and after Dex suppression (Hudson et al 1984, Prpić-Križevac et al 2012. In this regard, the activity of the HPA axis is enhanced in diabetic patients with asymptomatic autonomic imbalance due to prevalent parasympathetic failure.…”

Section: Hpa In Diabetesmentioning

confidence: 99%

Stressing diabetes? The hidden links between insulinotropic peptides and the HPA axis

Diz-Chaves

Gil‐Lozano

Toba

et al. 2016

Journal of Endocrinology

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Diabetes mellitus exerts metabolic stress on cells and it provokes a chronic increase in the long-term activity of the hypothalamus-pituitary-adrenocortical (HPA) axis, perhaps thereby contributing to insulin resistance. GLP-1 receptor (GLP-1R) agonists are pleiotropic hormones that not only affect glycaemic and metabolic control, but they also produce many other effects including activation of the HPA axis. In fact, several of the most relevant effects of GLP-1 might involve, at least in part, the modulation of the HPA axis. Thus, the anorectic activity of GLP-1 could be mediated by increasing CRF at the hypothalamic level, while its lipolytic effects could imply a local increase in glucocorticoids and glucocorticoid receptor (GC-R) expression in adipose tissue. Indeed, the potent activation of the HPA axis by GLP-1R agonists occurs within the range of therapeutic doses and with a short latency. Interestingly, the interactions of GLP-1 with the HPA axis may underlie most of the effects of GLP-1 on food intake control, glycaemic metabolism, adipose tissue biology and the responses to stress. Moreover, such activity has been observed in animal models (mice and rats), as well as in normal humans and in type I or type II diabetic patients. Accordingly, better understanding of how GLP-1R agonists modulate the activity of the HPA axis in diabetic subjects, especially obese individuals, will be crucial to design new and more efficient therapies for these patients.

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“…To date, the pharmacologic mechanism potentially related to the metabolic changes remains unknown. Because hyperactivity of the glucocorticoid system is associated with obesity and insulin resistance (Prpi c-Kri zevac et al, 2012), it is a compelling target for intervention. In preclinical studies, estra-4,9-dien-3-one, 11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)-(11b,17b)-(9CI), a GR antagonist (GRA) and progesterone receptor antagonist (PRA) medication (Ulmann et al, 1990), reduced the weight gain seen in young obese fa/fa Zucker rats (Langley and York, 1990) and decreased the elevated insulin levels and weight gain observed in olanzapine-treated rats (Beebe et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

LLY-2707, A Novel Nonsteroidal Glucocorticoid Antagonist That Reduces Atypical Antipsychotic–Associated Weight Gain in Rats

Sindelar¹,

Carson²,

Morin³

et al. 2013

J Pharmacol Exp Ther

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Weight gain and diabetes have been reported during treatment with atypical antipsychotic drugs (AAPDs). Patients treated with the glucocorticoid receptor antagonist (GRA) and the progesterone receptor antagonist (PRA) mifepristone [estra-4,9-dien-3-one, 11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)-(11b,17b)-(9CI)] experienced significant reduction in the weight gain observed when patients were treated with olanzapine or risperidone. To understand the pharmacology responsible for this finding, we discovered LLY-2707, a novel and selective GRA, and evaluated its utility in preclinical models of AAPD-associated weight gain and diabetes. In vitro, LLY-2707 was a highly selective and potent GRA. GR occupancy in vivo was assessed using ex vivo binding where LLY-2707 inhibited [ Central activity of the GRAs was confirmed by their ability to suppress amphetamine-induced increases in locomotor activity. The increases in the body weight of female rats treated with olanzapine (2 mg/kg PO) over 14 days were reduced in a dosedependent manner by coadministration of LLY-2707. Similar decreases, although less robust, in body weight were seen with mifepristone and CORT-108297. In addition, sGRAs prevented the glucose excursion after intragastric olanzapine infusions consistent with a direct effect on the hyperglycemia observed during treatment with AAPDs. At doses effectively preventing weight gain, LLY-2707 did not substantially interfere with the dopamine D2 receptor occupancy by olanzapine. Therefore, GRA coadministration may provide a novel treatment modality to prevent the weight gain and diabetes observed during treatment with AAPDs.

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Hyperactivity of the hypothalamic-pituitary-adrenal axis in patients with type 2 diabetes and relations with insulin resistance and chronic complications

Cited by 33 publications

References 33 publications

In Obesity, HPA Axis Activity Does Not Increase with BMI, but Declines with Aging: A Meta-Analysis of Clinical Studies

In Obesity, HPA Axis Activity Does Not Increase with BMI, but Declines with Aging: A Meta-Analysis of Clinical Studies

Stressing diabetes? The hidden links between insulinotropic peptides and the HPA axis

LLY-2707, A Novel Nonsteroidal Glucocorticoid Antagonist That Reduces Atypical Antipsychotic–Associated Weight Gain in Rats

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