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European Association for the Study of Diabetes (EASD) conference 2012: Tackling type 2 diabetes

European Association for the Study of Diabetes (EASD) conference 2012: Tackling type 2 diabetes
  • Endocrinology and metabolism
  • Diabetes

Resource type

Article

Tags

Type 2 diabetes mellitus
T2DM
dyslipidemia
Metabolic syndrome
Visceral obesity
Glucocorticoid receptors
Glucose metabolism
11-beta HSD receptors

Professor Al Madani reports on the highlights of the 2012 meeting of the European Association for the Study of Diabetes (EASD), Berlin, Germany, 1−5 October. 

Of great interest for delegates at this year’s meeting of the EASD was a presentation focusing on one particular pathophysiologic aspect of type 2 Diabetes Mellitus (T2DM) which may represent an important breakthrough in understanding this disease and may impact on its future therapeutic strategies.

T2DM and dyslipidemia are both associated with metabolic syndrome, which is related to insulin insensitivity in certain tissues such as adipose tissue, muscle and liver.

Many theories have been advanced to explain how T2DM relates to visceral obesity; one of these theories is based on distinct regional differences in adipocyte biology. This theory states that visceral adipose tissue has different characteristics to subcutaneous fat; one of these is its responsiveness to glucocorticoids (GCs). The visceral adipose tissue expresses higher numbers of GC receptors and appears to have a higher rate of conversion of inactive GC precursors to active GCs than the subcutaneous one. This conversion is mediated by the enzyme 11βhydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts cortisone to cortisol.

GCs and glucose metabolism

GCs are known antagonists of insulin action. They directly inhibit insulin release from the pancreatic islet cells; furthermore, they impair insulin dependent glucose uptake, increase lipolysis, and promote proteolysis which results in increased hepatic gluconeogenesis.  This opposing effect of steroids and insulin is clinically evident in patients with Cushing’s syndrome, whose insulin dose-response curve is shifted to the right, denoting insulin resistance. This is reflected in the fact that 20% of Cushing’s patients have impaired glucose tolerance or diabetes mellitus. Moreover, treatment with steroids causes insulin resistance and exacerbates hyperglycemia in diabetic patients.

Studies with 11β-HSD inhibitors

The bioflavonoids, bile acids, and some of the steroid hormones, including the progesterone metabolites, are some of the natural compounds that inhibit 11β-HSD1.  Liquorice derivatives as well as carbenoxolone are also among the most widely reported 11β-HSD1 inhibitors. However, all these compounds are non-specific and inhibit both type 1 and 2 HSD enzymes. Studies with carbenoxolone showed that it is not only able to access subcutaneous adipose tissue, but also that it is able to limit local cortisol availability and limit GC-induced lipolysis. Non-selective HSD inhibitors are not long-term therapies as they induce hypertension and hypokalemia due to induction of mineralocorticoid excess. Moreover, most T2DM patients are obese and often have hypertrophy of the visceral adipose tissue that highly expresses 11β-HSD1. Therefore, inhibition or down-regulation of 11β-HSD1 could improve glycemia.

In studies of diet-induced obese mice, triazole administered for 11 days resulted in reductions in fasting glucose, insulin, glucagon, triglycerides, and free fatty acids, as well as improved glucose tolerance. 11β-HSD1 inhibition also slowed atherosclerotic plaque progression in mice with a targeted deletion of apolipoprotein E. More recent studies have supported these findings.

Concerns about the safety of selective 11β-HSD1 inhibitors have been raised, particularly with regard to their potential effect on the hypothalamic-pituitary-adrenal axis, since inhibition of central nervous system 11β-HSD1 could disrupt negative HPA feedback regulation. This could result in excess GC production by the adrenal glands. To avoid interference with hypothalamic 11β-HSD1, inhibitors should not be able to cross the blood-brain barrier.

Overall, data from rodent studies are encouraging, but human data are limited.

References:

1. Montague CT, O’Rahilly S The perils of portliness: causes and consequences of visceral adiposity. Diabetes 2000; 49:883–888. 

2. Tomlinson JW, Sherlock M, Hughes B et al. Inhibition of 11{beta}-HSD1 activity in vivo limits glucocorticoid exposure to human adipose tissue and decreases lipolysis. The Journal of Clinical Endocrinology and Metabolism 2007; 92: 857–864.

3. Hermanowski-Vosatka A, Balkovec JM, Cheng K et al. 11beta-HSD1 inhibition ameliorates metabolic 
syndrome and prevents progression of atherosclerosis in mice. The Journal of Experimental Medicine 
2005; 202: 517–527.

4. Harris HJ, Kotelevtsev Y, Mullins JJ, Seckl JR, Holmes MC Intracellular regeneration of glucocorticoids by 11beta-hydroxysteroid dehydrogenase (11beta-HSD)-1 plays a key role in regulation of the hypothalamic-pituitary-adrenal axis: analysis of 11beta-HSD-1-deficient mice. Endocrinology 2001; 142:114–120.

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