Hypothalamic arousal, insulin resistance and Type 2 diabetes mellitus

Björntorp, Per; Holm, Göran; Rosmond, Roland

doi:10.1046/j.1464-5491.1999.00067.x

Cited by 279 publications

(217 citation statements)

References 78 publications

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“…The net effect of such resetting of the HPA axis might be a flatter, lower 24-h cortisol profile. Such a profile is in keeping with the original findings of Bjorntorp et al [45], who measured 24-h salivary cortisol concentrations, and described an association between features of the metabolic syndrome and a flat rigid cortisol day curve, with poor feedback control. Thus, we suggest that our study now emphasises the need to undertake cortisol turnover studies to understand fully the relationship between cortisol metabolism and insulin resistance.…”

Section: Discussionsupporting

confidence: 89%

Cortisol clearance and associations with insulin sensitivity, body fat and fatty liver in middle-aged men

et al. 2007

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Aims/hypothesis The regulation of cortisol metabolism in vivo is not well understood. We evaluated the relationship between cortisol metabolism and insulin sensitivity, adjusting for total and regional fat content and for non-alcoholic fatty liver disease. Materials and methods Twenty-nine middle-aged healthy men with a wide range of BMI were recruited. We measured fat content by dual-energy X-ray absorptiometry and magnetic resonance imaging (MRI), liver fat by ultrasound and MRI, the hypothalamic-pituitary-adrenal axis by adrenal response to ACTH 1-24 , unconjugated urinary cortisol excretion, corticosteroid-binding globulin, and cortisol clearance by MS. We assessed insulin sensitivity by hyperinsulinaemic-euglycaemic clamp and by OGTT. Results Cortisol clearance was strongly inversely correlated with insulin sensitivity (M value) (r=−0.61, p=0.002). Cortisol clearance was increased in people with fatty liver compared with those without (mean±SD: 243±10 vs 158± 36 ml/min; p = 0.014). Multiple regression modelling showed that the relationship between cortisol clearance and insulin sensitivity was independent of body fat. The relationship between fatty liver and insulin sensitivity was significantly influenced by body fat and cortisol clearance. Conclusions/interpretation Cortisol clearance is strongly associated with insulin sensitivity, independently of the amount of body fat. The relationship between fatty liver and insulin sensitivity is mediated in part by both fatness and cortisol clearance.

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Section: Discussionsupporting

confidence: 89%

Cortisol clearance and associations with insulin sensitivity, body fat and fatty liver in middle-aged men

et al. 2007

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“…This finding is in keeping with the original description by Bjorntorp [9] of a flat, rigid day curve for plasma cortisol, with poor feedback control in insulinresistant individuals with abdominal obesity, increased leptin levels, hyperglycaemia, dyslipidaemia and hypertension. Moreover, there is increased skeletal muscle glucocorticoid receptor expression with obesity and features of the metabolic syndrome [10,11].…”

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confidence: 91%

Insulin resistance and cortisol metabolism. Reply to Kerstens MN, Dullaart RPF [letter]

2007

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Abbreviations HOMA-IR homeostasis model assessment of insulin resistanceTo the Editor: We thank M. N. Kerstens and R. P. F. Dullaart for their interest in our paper [1]. Our results show that there was an inverse relationship between cortisol clearance from the plasma and whole-body insulin sensitivity as measured by the hyperinsulinaemic-euglycaemic clamp in middle-aged men (mean age 53.0 years, mean. Importantly, we show that this relationship was independent of potential confounding factors such as body fat and fatty liver. These findings were contrary to our expectations and we agree that it is now crucial to undertake careful kinetic studies to study cortisol production (and excretion) in more detail to determine specifically whether cortisol production is increased. We agree that by measuring urinary free cortisol we have only assessed a small fraction of all urinary cortisol metabolites. It is possible that there is increased renal loss of cortisol with insulin resistance that we have not detected. We appreciate that we have not assessed salt resistance in our subjects, but there is no consensus as to whether salt loading worsens, improves, or has no effect on insulin sensitivity [3][4][5][6]. Kerstens et al. [7] studied cortisol metabolism, insulin sensitivity (according to homeostasis model assessment of insulin resistance [HOMA-IR]) and renal haemodynamics in 19 salt-resistant and nine salt-sensitive normotensive subjects after a low-and high-salt diet. Although in their letter [1] Kerstens and Dullaart pass comment on their observation of a significant positive relationship between percentage change in HOMA-IR and percentage change in plasma cortisol during salt loading [7] (at variance with our findings), it should be noted that in the same study [7] they also describe a significant inverse relationship between percentage change in HOMA-IR and percentage change in the sum of urinary metabolites (in keeping with our findings). Moreover, the authors studied young men and women (mean age 24 years) who were lean (mean BMI 22 kg/m 2 ). In contrast, we studied middle-aged men only and our volunteers were predominantly obese. The relationships between cortisol metabolism and insulin sensitivity may differ in insulin-resistant, obese individuals Diabetologia

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“…Cortisol is a stress hormone, which stimulates glucose production, increases lipolysis and circulating free fatty acids, decreases insulin secretion from beta cells and decreases sensitivity to insulin [24][25][26][27]. It is postulated that a chronically high cortisol level, which is a feature of about 50% of depressed patients, results in obesity, insulin resistance and type 2 diabetes [24,28,29]. Some studies found evidence for this hypothesis [27,28].…”

Section: Discussionmentioning

confidence: 99%

“…It is postulated that a chronically high cortisol level, which is a feature of about 50% of depressed patients, results in obesity, insulin resistance and type 2 diabetes [24,28,29]. Some studies found evidence for this hypothesis [27,28]. Epinephrine generates responses in glucose and fat metabolism similar to those of cortisol [26], also possibly resulting in insulin resistance and type 2 diabetes.…”

Section: Discussionmentioning

confidence: 99%

Depression as a risk factor for the onset of type 2 diabetes mellitus. A meta-analysis

et al. 2006

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Aims/hypothesis: Evidence strongly suggests that depression and type 2 diabetes are associated, but the direction of the association is still unclear. Depression may occur as a consequence of having diabetes, but may also be a risk factor for the onset of type 2 diabetes. This study examined the latter association by reviewing the literature and conducting a meta-analysis of longitudinal studies on this topic. Methods: Medline and PsycInfo were searched for articles published up to January 2005. All studies that examined the relationship between depression and the onset of type 2 diabetes were included. Pooled relative risks were calculated using fixed and random effects models. To explore sources of heterogeneity between studies, subgroup analyses and meta-regression analyses were performed. Results: Nine studies met our inclusion criteria for this meta-analysis. The pooled relative risk was 1.26 (1.13-1.39) using the fixed effects model and 1.37(1.14-1.63) using the random effects model. Heterogeneity between studies could not be explained by (1) whether studies controlled for undetected diabetes at baseline; (2) the method of diabetes assessment at followup; (3) the baseline overall risk of diabetes in the study population; and (4) follow-up duration. Conclusions/ interpretation: Depressed adults have a 37% increased risk of developing type 2 diabetes mellitus. The pathophysiological mechanisms underlying this relationship are still unclear and warrant further research. A randomised controlled study is needed to test whether effective prevention or treatment of depression can reduce the incidence of type 2 diabetes and its health consequences.

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Hypothalamic arousal, insulin resistance and Type 2 diabetes mellitus

Cited by 279 publications

References 78 publications

Cortisol clearance and associations with insulin sensitivity, body fat and fatty liver in middle-aged men

Cortisol clearance and associations with insulin sensitivity, body fat and fatty liver in middle-aged men

Insulin resistance and cortisol metabolism. Reply to Kerstens MN, Dullaart RPF [letter]

Depression as a risk factor for the onset of type 2 diabetes mellitus. A meta-analysis

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