- Email: [email protected]
Insulin-Mediated Diseases: Adrenal Mass and Polycystic Ovary Syndrome
recent study demonstrated that GPR43 signaling in murine pancreatic islets can enhance insulin secretion and protect against the development of insulin resistance under obesogenic conditions [8]. Given that insulin resistance is both a hallmark of chronic obesity and a major contributor to diabetes, GPR43 agonists may be promising targets for drug development for metabolic disorders. However, the exact mechanisms behind the metabolic functions of GPR43 need to be unraveled. GPR43 couples to either the pertussis toxin-sensitive Gi/o or -insensitive Gq subunits. Indeed, a recent study investigating glucose-stimulated insulin secretion (GSIS) in murine islets revealed that different GPR43 agonists could either increase or inhibit GSIS [12], with Gq/11 increasing GSIS whereas Gi/o decreased GSIS. This dichotomy exists in mice, but whether it holds for human GPR43 is unclear. Both G protein subunits are simultaneously activated by human GPR43 signaling [2], suggesting potential regulation of insulin release by SCFAs both in rodents and in humans. GPR43 signaling is likely to be even more complex because this receptor (in common with most metabolitesensing GPCRs) also signals through barrestin. It is also possible that GPR43 signaling in islets or adipose tissue leads to inflammasome activation, as is the case in gut epithelium and macrophages.
explain the link between metabolism and inflammation? GPR43 may enhance FOXP3 expression and function in Tregs, which may alter macrophage infiltration in white adipose tissue and associated inflammatory responses in obesity. Furthermore, Tregs have been shown to reduce insulin resistance. Maintenance of epithelial integrity by GPR43 may also prevent insulin resistance through reduced translocation of bacterial lipopolysaccharide that would otherwise induce inflammation in adipose tissue. An interesting consideration is – why has the metabolite sensor GPR43 evolved to function in both the metabolic and immune systems? Dietary fiber is a typical foodstuff, and GPR43 may therefore simply be a sensor for nutrition in general. The presence or absence of adequate nutrition may feed back to metabolic processes as well as immune responses. Another possibility is that GPR43 has simply been ‘adopted’ by the immune system to regulate proper immune responses in the gut (where SCFA concentrations are high). Interestingly, the gut microbiome may play its part through its ability (or not) to produce the relevant metabolites. Regardless, GPR43 and related metabolite sensors such as GPR41 and GPR109A offer an exciting new opportunity to understand and treat metabolic diseases and inflammation. 1
Concluding Remarks GPR43 plays an important role in inflammation and metabolism. The practical benefits of dietary fiber and SCFAs have been appreciated for decades, and it is now clear that at least part of this benefit is mediated by GPR43. Indeed, GPR43 small-molecule agonists may find utility in human metabolic syndrome or inflammatory diseases. Given the possibility of variable signaling to different GPR43 agonists, care may be required to bias signaling of G protein subunits for desired effects on human metabolism or inflammation. However, many questions remain. Will the mouse studies translate to humans? How might GPR43 biology
512
Department of Immunology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Wellington Road,
Clayton, Victoria 3800, Australia 2 Pfizer Inc., 610 Main Street, Cambridge, MA 02139, USA 3 Charles Perkins Centre, The University of Sydney, NSW 2006, Australia 4 School of Medical Sciences, The University of Sydney, NSW 2006, Australia *Correspondence: charles.mackay@pfizer.com (C.R. Mackay), [email protected] (L. Macia) http://dx.doi.org/10.1016/j.tem.2015.07.009 References 1. Macia, L. et al. (2012) Microbial influences on epithelial integrity and immune function as a basis for inflammatory diseases. Immunol. Rev. 245, 164–176 2. Brown, A.J. et al. (2003) The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J. Biol. Chem. 278, 11312–11319 3. Maslowski, K.M. et al. (2009) Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282–1286
Trends in Endocrinology & Metabolism, October 2015, Vol. 26, No. 10
4. Smith, P.M. et al. (2013) The microbial metabolites, shortchain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 5. Macia, L. et al. (2015) Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat. Commun. 6, 6734 6. Tang, Y. et al. (2011) G-protein-coupled receptor for shortchain fatty acids suppresses colon cancer. Int. J. Cancer 128, 847–856 7. Vieira, A.T. et al. (2015) A role for gut microbiota and the metabolite-sensing receptor GPR43 in a murine model of gout. Arthritis Rheumatol. 67, 1646–1656 8. McNelis, J.C. et al. (2015) GPR43 potentiates beta cell function in obesity. Diabetes 64, 3203–3217 9. Psichas, A. et al. (2015) The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. Int. J. Obes. 39, 424–429 10. Bjursell, M. et al. (2011) Improved glucose control and reduced body fat mass in free fatty acid receptor 2-deficient mice fed a high-fat diet. Am. J. Physiol. Endocrinol. Metab. 300, E211–E220 11. Kimura, I. et al. (2013) The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat. Commun. 4, 1829 12. Priyadarshini, M. et al. (2015) An acetate-specific GPCR, FFAR2, regulates insulin secretion. Mol. Endocrinol. 29, 1055–1066
Forum
Insulin-Mediated Diseases: Adrenal Mass and Polycystic Ovary Syndrome Giovanna Muscogiuri,1,* Annamaria Colao,1 and Francesco Orio2,3 Adrenal incidentalomas (AIs) and polycystic ovary syndrome (PCOS) have often been associated with compensatory hyperinsulinemia and insulin resistance (IR). The link between these diseases and IR may be changes in hormone secretions that provoke IR and in turn promote the growth of adrenal gland masses and/or ovarian cysts through compensatory hyperinsulinemia. AI Incidentaloma Management Adrenal masses occasionally detected during radiological examinations, the
so-called AIs, have become fairly common owing to the widespread use of imaging techniques [1]. AI management is still controversial, mostly because the associated morbidity is unknown. Patients with AI do not show physical signs of adrenal hormonal excess that would have led to its clinical suspicion and detection. However, although AI is considered to be hormonally inactive, it has been associated with hypertension, dyslipidemia, glucose intolerance, and obesity that are all parameters closely linked to IR [2].
Insulin resistance Subclinical cortisol secretion
Hyperandrogenemia
H a Hyperinsulinemia Insulin Adrenal masses
PCOS
AIs and IR Despite AIs being silent, their presence has been associated with higher prevalence of IR [2]. Thus, a tight association between AI and IR-related disease begs the question: is IR involved in the pathogenesis of AI, or vice versa? Healthy overweight (not obese) non-diabetic subjects are expected to display an insulin sensitivity of 7 mg kg 1 min 1 by hyperinsulinemic–euglycemic clamp (HEC) [3]. However, non-diabetic overweight subjects with AI displayed reduced insulin sensitivity compared to healthy overweight controls [4]. Making the distinction between peripheral (muscle) and central (hepatic) IR, patients with AIs may appear have normal hepatic insulin sensitivity in the fasting condition but display muscle IR after glucose load [4]. This metabolic phenotype resembles that of patients with type 2 diabetes (T2D) where the primary deficiency in insulin action resides in the skeletal muscle. An undetectable cortisol secretion seems to be responsible for the IR associated to AI [5]. An interesting correlation between the degree of IR and free urinary cortisol, adrenocorticotropic hormone (ACTH), and serum cortisol levels after dexamethasone suppression has been found: patients with AI displayed slightly higher ACTH and cortisol levels after dexamethasone (1 mg) administration than did control subjects; although this difference did not reach statistical significance (possibly
Insulin/IGF-1 receptors
Figure 1. Hypothetical Link Between Adrenal Mass and PCOS (Polycystic Ovary Syndrome). Adrenal mass and PCOS may have a common link represented by insulin resistance (IR). IR might be caused by the secretion of hormones, particularly cortisol in the case of adrenal masses and androgens in the case of PCOS. The compensatory hyperinsulinemia driven by cortisol and androgens leading to IR might promote the growth of both adrenal masses and ovarian cysts through binding of insulin to insulin and/or insulin-like growth factor 1 (IGF-1) receptors.
owing to the low sensitivity of the test to detect subtle cortisol hypersecretion), it suggested that there may be subtle disturbances in cortisol steroid secretion [5]. Androulakis et al. [6] found that the increased cardiovascular risk in patients with AI could be explained by excessive cortisol secretion [there was a higher AUC (area under the curve) for cortisol after ACTH stimulation and urinary free cortisol in patients with AI compared to controls], although there was no statistically significant difference [6]. Using salivary cortisol as a tool to assess endogenous cortisol excess, patients with AI subjected to ACTH or dexamethasone challenge displayed higher morning and late-night salivary cortisol compared to controls [7]. Thus, patients with AI may have a cortisol hyper-response to stimulus test (ACTH), or to inhibition test (dexamethasone), although they may preserve a physiological rhythm of cortisol secretion. Patients with AI undergoing surgery for tumor size or growth experienced an improvement in blood pressure and fasting glucose, even
in the absence of any (causative) hormonal change [2]. The undetectable cortisol secretion may be responsible for the IR that encourages visceral adipose tissue deposition. Patients with AI had higher total (particularly abdominal) fat [8] that tightly correlated with IR [5]. The degree of IR may be directly correlated to adrenal mass size [5]. In fact, although AIs were associated to undetectable cortisol secretion, the latter seems to be directly related to the size of adrenal mass; thus, increased cortisol secretion, although subclinical, could be responsible for IR, and the compensatory hyperinsulinemia might play a role in the growth of adrenal masses [5]. Hyperinsulinemia increases the expression of insulin-like growth factor 1 receptors (IGF-1R) and binding of insulin to IGF-1R in the adrenal cortex. Hyperinsulinemia also upregulates human hepatic growth hormone (GH) receptors, and increases receptor-mediated GH signaling in the liver, the main stimulus for IGF-1 release. Insulin also
Trends in Endocrinology & Metabolism, October 2015, Vol. 26, No. 10
513
downregulates IGF-binding proteins (IGFBPs), in particular IGF-BP1 and IGF-BP2, thereby increasing the extravascular availability of bioactive IGF-1 and its tumorpromoting properties [4] (Figure 1). These alterations may explain the increased prevalence of tumors that are often reported in obese and diabetic subjects.
hyperandrogenism exhibit a higher risk of developing hepatic steatosis, a hallmark of IR [12]. PCOS patients with hyperandrogenism undergoing anti-androgen treatment experienced partial reversal of peripheral IR, regardless of which antiandrogen was used [13] (Figure 1).
Concluding Remarks PCOS A mirror to the condition of AI may be observed in PCOS. Ovaries express IGF-1Rs and at the same time secrete IGF-1. Insulin can bind to IGF-1R and activate downstream signaling pathways. Thus, hyperinsulinemia may be related to PCOS through two mechanisms. First, high insulin concentrations may promote the growth and thus the polycystic morphology of ovaries, as has been demonstrated by the tight relationship between ovarian volume and IR in PCOS [9]. Second, high insulin can mimic IGF-1 actions by binding to IGF-1Rs and/or to insulin receptors in human ovarian tissue, thus leading to insulin-mediated hyperandrogenism. Clinical evidence has suggested that hyperandrogenism is a key contributing factor to IR. Recently, a study performed in 275 premenopausal PCOS patients identified the testosterone to dihydrotestosterone ratio as a new biomarker for IR in PCOS [10]. The persistence of hyperandrogenism in postmenopausal PCOS patients may be responsible for the metabolic abnormalities and increased cardiovascular risk reported in post-menopausal PCOS [11]. In addition, PCOS patients with
514
The pathogenesis of AIs and PCOS may share a common link that is represented by IR and even more by compensatory hyperinsulinemia. Insulin could bind to both insulin and IGF-1 receptors on adrenal gland and ovaries, thus promoting the growth of AI as well as of ovarian cysts. In turn, adrenal glands and ovaries may secrete cortisol and androgens, respectively, that could encourage the onset of IR and thus compensatory hyperinsulinemia. Because both AIs and PCOS are associated with a high prevalence of IR, the assessment of IR should be encouraged during endocrinological evaluations of patients with AI and/or PCOS. Further investigations should assess whether the treatment of IR might be beneficial for the treatment of these diseases and whether it could have an effect on the morphology of these glands. 1 Department of Clinical Medicine and Surgery, University ‘Federico II’, Naples, Italy 2 Department of Sports Science and Wellness, ‘Parthenope’ University Naples, Naples, Italy 3 Endocrinology and Diabetology, Fertility Techniques Structure, University Hospital'S. Giovanni di Dio e Ruggi d’Aragona’, Largo Città d’Ippocrate, Salerno, Italy
*Correspondence: [email protected] (G. Muscogiuri). http://dx.doi.org/10.1016/j.tem.2015.07.010
Trends in Endocrinology & Metabolism, October 2015, Vol. 26, No. 10
References 1. Chidiac, R.M. and Aron, D.C. (1997) Incidentalomas. A disease of modern technology. Endocrinol. Metab. Clin. North Am. 26, 233–253 2. Terzolo, M. et al. (2002) Adrenal incidentaloma: a new cause of the metabolic syndrome? J. Clin. Endocrinol. Metab. 87, 998–1003 3. Anderwald, C. et al. (2007) The Clamp-Like Index: a novel and highly sensitive insulin sensitivity index to calculate hyperinsulinemic clamp glucose infusion rates from oral glucose tolerance tests in nondiabetic subjects. Diabetes Care 30, 2374–2380 4. Anderwald, C.H. et al. (2013) Adequately adapted insulin secretion and decreased hepatic insulin extraction cause elevated insulin concentrations in insulin resistant nondiabetic adrenal incidentaloma patients. PLoS ONE 8, e77326 5. Muscogiuri, G. et al. (2011) The size of adrenal incidentalomas correlates with insulin resistance. Is there a cause– effect relationship? Clin. Endocrinol. 74, 300–305 6. Androulakis, I.I. et al. (2014) Patients with apparently nonfunctioning adrenal incidentalomas may be at increased cardiovascular risk due to excessive cortisol secretion. J. Clin. Endocrinol. Metab. 99, 2754–2762 7. Ceccato, F. et al. (2013) Performance of salivary cortisol in the diagnosis of Cushing's syndrome, adrenal incidentaloma, and adrenal insufficiency. Eur. J. Endocrinol. 169, 31–36 8. Garrapa, G.G. et al. (2001) Body composition and metabolic features in women with adrenal incidentaloma or Cushing's syndrome. J. Clin. Endocrinol. Metab. 86, 5301–5306 9. Carmina, E. et al. (2005) Ovarian size and blood flow in women with polycystic ovary syndrome and their correlations with endocrine parameters. Fertil. Steril. 84, 413–419 10. Münzker, J. et al. (2015) Testosterone to dihydrotestosterone ratio as a new biomarker for an adverse metabolic phenotype in the polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 100, 653–660 11. Puurunen, J. et al. (2011) Unfavorable hormonal, metabolic, and inflammatory alterations persist after menopause in women with PCOS. J. Clin. Endocrinol. Metab. 96, 1827–1834 12. Jones, H. et al. (2012) Polycystic ovary syndrome with hyperandrogenism is characterized by an increased risk of hepatic steatosis compared to nonhyperandrogenic PCOS phenotypes and healthy controls, independent of obesity and insulin resistance. J. Clin. Endocrinol. Metab. 97, 3709–3716 13. Moghetti, P. et al. (1996) The insulin resistance in women with hyperandrogenism is partially reversed by antiandrogen treatment: evidence that androgens impair insulin action in women. J. Clin. Endocrinol. Metab. 81, 952–960
explain the link between metabolism and inflammation? GPR43 may enhance FOXP3 expression and function in Tregs, which may alter macrophage infiltration in white adipose tissue and associated inflammatory responses in obesity. Furthermore, Tregs have been shown to reduce insulin resistance. Maintenance of epithelial integrity by GPR43 may also prevent insulin resistance through reduced translocation of bacterial lipopolysaccharide that would otherwise induce inflammation in adipose tissue. An interesting consideration is – why has the metabolite sensor GPR43 evolved to function in both the metabolic and immune systems? Dietary fiber is a typical foodstuff, and GPR43 may therefore simply be a sensor for nutrition in general. The presence or absence of adequate nutrition may feed back to metabolic processes as well as immune responses. Another possibility is that GPR43 has simply been ‘adopted’ by the immune system to regulate proper immune responses in the gut (where SCFA concentrations are high). Interestingly, the gut microbiome may play its part through its ability (or not) to produce the relevant metabolites. Regardless, GPR43 and related metabolite sensors such as GPR41 and GPR109A offer an exciting new opportunity to understand and treat metabolic diseases and inflammation. 1
Concluding Remarks GPR43 plays an important role in inflammation and metabolism. The practical benefits of dietary fiber and SCFAs have been appreciated for decades, and it is now clear that at least part of this benefit is mediated by GPR43. Indeed, GPR43 small-molecule agonists may find utility in human metabolic syndrome or inflammatory diseases. Given the possibility of variable signaling to different GPR43 agonists, care may be required to bias signaling of G protein subunits for desired effects on human metabolism or inflammation. However, many questions remain. Will the mouse studies translate to humans? How might GPR43 biology
512
Department of Immunology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Wellington Road,
Clayton, Victoria 3800, Australia 2 Pfizer Inc., 610 Main Street, Cambridge, MA 02139, USA 3 Charles Perkins Centre, The University of Sydney, NSW 2006, Australia 4 School of Medical Sciences, The University of Sydney, NSW 2006, Australia *Correspondence: charles.mackay@pfizer.com (C.R. Mackay), [email protected] (L. Macia) http://dx.doi.org/10.1016/j.tem.2015.07.009 References 1. Macia, L. et al. (2012) Microbial influences on epithelial integrity and immune function as a basis for inflammatory diseases. Immunol. Rev. 245, 164–176 2. Brown, A.J. et al. (2003) The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J. Biol. Chem. 278, 11312–11319 3. Maslowski, K.M. et al. (2009) Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282–1286
Trends in Endocrinology & Metabolism, October 2015, Vol. 26, No. 10
4. Smith, P.M. et al. (2013) The microbial metabolites, shortchain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 5. Macia, L. et al. (2015) Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat. Commun. 6, 6734 6. Tang, Y. et al. (2011) G-protein-coupled receptor for shortchain fatty acids suppresses colon cancer. Int. J. Cancer 128, 847–856 7. Vieira, A.T. et al. (2015) A role for gut microbiota and the metabolite-sensing receptor GPR43 in a murine model of gout. Arthritis Rheumatol. 67, 1646–1656 8. McNelis, J.C. et al. (2015) GPR43 potentiates beta cell function in obesity. Diabetes 64, 3203–3217 9. Psichas, A. et al. (2015) The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. Int. J. Obes. 39, 424–429 10. Bjursell, M. et al. (2011) Improved glucose control and reduced body fat mass in free fatty acid receptor 2-deficient mice fed a high-fat diet. Am. J. Physiol. Endocrinol. Metab. 300, E211–E220 11. Kimura, I. et al. (2013) The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat. Commun. 4, 1829 12. Priyadarshini, M. et al. (2015) An acetate-specific GPCR, FFAR2, regulates insulin secretion. Mol. Endocrinol. 29, 1055–1066
Forum
Insulin-Mediated Diseases: Adrenal Mass and Polycystic Ovary Syndrome Giovanna Muscogiuri,1,* Annamaria Colao,1 and Francesco Orio2,3 Adrenal incidentalomas (AIs) and polycystic ovary syndrome (PCOS) have often been associated with compensatory hyperinsulinemia and insulin resistance (IR). The link between these diseases and IR may be changes in hormone secretions that provoke IR and in turn promote the growth of adrenal gland masses and/or ovarian cysts through compensatory hyperinsulinemia. AI Incidentaloma Management Adrenal masses occasionally detected during radiological examinations, the
so-called AIs, have become fairly common owing to the widespread use of imaging techniques [1]. AI management is still controversial, mostly because the associated morbidity is unknown. Patients with AI do not show physical signs of adrenal hormonal excess that would have led to its clinical suspicion and detection. However, although AI is considered to be hormonally inactive, it has been associated with hypertension, dyslipidemia, glucose intolerance, and obesity that are all parameters closely linked to IR [2].
Insulin resistance Subclinical cortisol secretion
Hyperandrogenemia
H a Hyperinsulinemia Insulin Adrenal masses
PCOS
AIs and IR Despite AIs being silent, their presence has been associated with higher prevalence of IR [2]. Thus, a tight association between AI and IR-related disease begs the question: is IR involved in the pathogenesis of AI, or vice versa? Healthy overweight (not obese) non-diabetic subjects are expected to display an insulin sensitivity of 7 mg kg 1 min 1 by hyperinsulinemic–euglycemic clamp (HEC) [3]. However, non-diabetic overweight subjects with AI displayed reduced insulin sensitivity compared to healthy overweight controls [4]. Making the distinction between peripheral (muscle) and central (hepatic) IR, patients with AIs may appear have normal hepatic insulin sensitivity in the fasting condition but display muscle IR after glucose load [4]. This metabolic phenotype resembles that of patients with type 2 diabetes (T2D) where the primary deficiency in insulin action resides in the skeletal muscle. An undetectable cortisol secretion seems to be responsible for the IR associated to AI [5]. An interesting correlation between the degree of IR and free urinary cortisol, adrenocorticotropic hormone (ACTH), and serum cortisol levels after dexamethasone suppression has been found: patients with AI displayed slightly higher ACTH and cortisol levels after dexamethasone (1 mg) administration than did control subjects; although this difference did not reach statistical significance (possibly
Insulin/IGF-1 receptors
Figure 1. Hypothetical Link Between Adrenal Mass and PCOS (Polycystic Ovary Syndrome). Adrenal mass and PCOS may have a common link represented by insulin resistance (IR). IR might be caused by the secretion of hormones, particularly cortisol in the case of adrenal masses and androgens in the case of PCOS. The compensatory hyperinsulinemia driven by cortisol and androgens leading to IR might promote the growth of both adrenal masses and ovarian cysts through binding of insulin to insulin and/or insulin-like growth factor 1 (IGF-1) receptors.
owing to the low sensitivity of the test to detect subtle cortisol hypersecretion), it suggested that there may be subtle disturbances in cortisol steroid secretion [5]. Androulakis et al. [6] found that the increased cardiovascular risk in patients with AI could be explained by excessive cortisol secretion [there was a higher AUC (area under the curve) for cortisol after ACTH stimulation and urinary free cortisol in patients with AI compared to controls], although there was no statistically significant difference [6]. Using salivary cortisol as a tool to assess endogenous cortisol excess, patients with AI subjected to ACTH or dexamethasone challenge displayed higher morning and late-night salivary cortisol compared to controls [7]. Thus, patients with AI may have a cortisol hyper-response to stimulus test (ACTH), or to inhibition test (dexamethasone), although they may preserve a physiological rhythm of cortisol secretion. Patients with AI undergoing surgery for tumor size or growth experienced an improvement in blood pressure and fasting glucose, even
in the absence of any (causative) hormonal change [2]. The undetectable cortisol secretion may be responsible for the IR that encourages visceral adipose tissue deposition. Patients with AI had higher total (particularly abdominal) fat [8] that tightly correlated with IR [5]. The degree of IR may be directly correlated to adrenal mass size [5]. In fact, although AIs were associated to undetectable cortisol secretion, the latter seems to be directly related to the size of adrenal mass; thus, increased cortisol secretion, although subclinical, could be responsible for IR, and the compensatory hyperinsulinemia might play a role in the growth of adrenal masses [5]. Hyperinsulinemia increases the expression of insulin-like growth factor 1 receptors (IGF-1R) and binding of insulin to IGF-1R in the adrenal cortex. Hyperinsulinemia also upregulates human hepatic growth hormone (GH) receptors, and increases receptor-mediated GH signaling in the liver, the main stimulus for IGF-1 release. Insulin also
Trends in Endocrinology & Metabolism, October 2015, Vol. 26, No. 10
513
downregulates IGF-binding proteins (IGFBPs), in particular IGF-BP1 and IGF-BP2, thereby increasing the extravascular availability of bioactive IGF-1 and its tumorpromoting properties [4] (Figure 1). These alterations may explain the increased prevalence of tumors that are often reported in obese and diabetic subjects.
hyperandrogenism exhibit a higher risk of developing hepatic steatosis, a hallmark of IR [12]. PCOS patients with hyperandrogenism undergoing anti-androgen treatment experienced partial reversal of peripheral IR, regardless of which antiandrogen was used [13] (Figure 1).
Concluding Remarks PCOS A mirror to the condition of AI may be observed in PCOS. Ovaries express IGF-1Rs and at the same time secrete IGF-1. Insulin can bind to IGF-1R and activate downstream signaling pathways. Thus, hyperinsulinemia may be related to PCOS through two mechanisms. First, high insulin concentrations may promote the growth and thus the polycystic morphology of ovaries, as has been demonstrated by the tight relationship between ovarian volume and IR in PCOS [9]. Second, high insulin can mimic IGF-1 actions by binding to IGF-1Rs and/or to insulin receptors in human ovarian tissue, thus leading to insulin-mediated hyperandrogenism. Clinical evidence has suggested that hyperandrogenism is a key contributing factor to IR. Recently, a study performed in 275 premenopausal PCOS patients identified the testosterone to dihydrotestosterone ratio as a new biomarker for IR in PCOS [10]. The persistence of hyperandrogenism in postmenopausal PCOS patients may be responsible for the metabolic abnormalities and increased cardiovascular risk reported in post-menopausal PCOS [11]. In addition, PCOS patients with
514
The pathogenesis of AIs and PCOS may share a common link that is represented by IR and even more by compensatory hyperinsulinemia. Insulin could bind to both insulin and IGF-1 receptors on adrenal gland and ovaries, thus promoting the growth of AI as well as of ovarian cysts. In turn, adrenal glands and ovaries may secrete cortisol and androgens, respectively, that could encourage the onset of IR and thus compensatory hyperinsulinemia. Because both AIs and PCOS are associated with a high prevalence of IR, the assessment of IR should be encouraged during endocrinological evaluations of patients with AI and/or PCOS. Further investigations should assess whether the treatment of IR might be beneficial for the treatment of these diseases and whether it could have an effect on the morphology of these glands. 1 Department of Clinical Medicine and Surgery, University ‘Federico II’, Naples, Italy 2 Department of Sports Science and Wellness, ‘Parthenope’ University Naples, Naples, Italy 3 Endocrinology and Diabetology, Fertility Techniques Structure, University Hospital'S. Giovanni di Dio e Ruggi d’Aragona’, Largo Città d’Ippocrate, Salerno, Italy
*Correspondence: [email protected] (G. Muscogiuri). http://dx.doi.org/10.1016/j.tem.2015.07.010
Trends in Endocrinology & Metabolism, October 2015, Vol. 26, No. 10
References 1. Chidiac, R.M. and Aron, D.C. (1997) Incidentalomas. A disease of modern technology. Endocrinol. Metab. Clin. North Am. 26, 233–253 2. Terzolo, M. et al. (2002) Adrenal incidentaloma: a new cause of the metabolic syndrome? J. Clin. Endocrinol. Metab. 87, 998–1003 3. Anderwald, C. et al. (2007) The Clamp-Like Index: a novel and highly sensitive insulin sensitivity index to calculate hyperinsulinemic clamp glucose infusion rates from oral glucose tolerance tests in nondiabetic subjects. Diabetes Care 30, 2374–2380 4. Anderwald, C.H. et al. (2013) Adequately adapted insulin secretion and decreased hepatic insulin extraction cause elevated insulin concentrations in insulin resistant nondiabetic adrenal incidentaloma patients. PLoS ONE 8, e77326 5. Muscogiuri, G. et al. (2011) The size of adrenal incidentalomas correlates with insulin resistance. Is there a cause– effect relationship? Clin. Endocrinol. 74, 300–305 6. Androulakis, I.I. et al. (2014) Patients with apparently nonfunctioning adrenal incidentalomas may be at increased cardiovascular risk due to excessive cortisol secretion. J. Clin. Endocrinol. Metab. 99, 2754–2762 7. Ceccato, F. et al. (2013) Performance of salivary cortisol in the diagnosis of Cushing's syndrome, adrenal incidentaloma, and adrenal insufficiency. Eur. J. Endocrinol. 169, 31–36 8. Garrapa, G.G. et al. (2001) Body composition and metabolic features in women with adrenal incidentaloma or Cushing's syndrome. J. Clin. Endocrinol. Metab. 86, 5301–5306 9. Carmina, E. et al. (2005) Ovarian size and blood flow in women with polycystic ovary syndrome and their correlations with endocrine parameters. Fertil. Steril. 84, 413–419 10. Münzker, J. et al. (2015) Testosterone to dihydrotestosterone ratio as a new biomarker for an adverse metabolic phenotype in the polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 100, 653–660 11. Puurunen, J. et al. (2011) Unfavorable hormonal, metabolic, and inflammatory alterations persist after menopause in women with PCOS. J. Clin. Endocrinol. Metab. 96, 1827–1834 12. Jones, H. et al. (2012) Polycystic ovary syndrome with hyperandrogenism is characterized by an increased risk of hepatic steatosis compared to nonhyperandrogenic PCOS phenotypes and healthy controls, independent of obesity and insulin resistance. J. Clin. Endocrinol. Metab. 97, 3709–3716 13. Moghetti, P. et al. (1996) The insulin resistance in women with hyperandrogenism is partially reversed by antiandrogen treatment: evidence that androgens impair insulin action in women. J. Clin. Endocrinol. Metab. 81, 952–960