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Cited by 141Pituitary Gland Disorders and TreatmentsAdrenal Hormones and DisordersPancreatic function and diabetes

Glucose Metabolism Abnormalities in Cushing Syndrome: From Molecular Basis to Clinical Management

Open access
Scaroni, Carla, Zilio, Marialuisa, Foti, Michelangelo, Boscaro, Marco·2017·Endocrine Reviews
DOI 10.1210/er.2016-1105
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Abstract

An impaired glucose metabolism, which often leads to the onset of diabetes mellitus (DM), is a common complication of chronic exposure to exogenous and endogenous glucocorticoid (GC) excess and plays an important part in contributing to morbidity and mortality in patients with Cushing syndrome (CS). This article reviews the pathogenesis, epidemiology, diagnosis, and management of changes in glucose metabolism associated with hypercortisolism, addressing both the pathophysiological aspects and the clinical and therapeutic implications. Chronic hypercortisolism may have pleiotropic effects on all major peripheral tissues governing glucose homeostasis. Adding further complexity, both genomic and nongenomic mechanisms are directly induced by GCs in a context-specific and cell-/organ-dependent manner. In this paper, the discussion focuses on established and potential pathologic molecular mechanisms that are induced by chronically excessive circulating levels of GCs and affect glucose homeostasis in various tissues. The management of patients with CS and DM includes treating their hyperglycemia and correcting their GC excess. The effects on glycemic control of various medical therapies for CS are reviewed in this paper. The association between DM and subclinical CS and the role of screening for CS in diabetic patients are also discussed.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes molecular, epidemiological, diagnostic, and therapeutic evidence on glucose metabolism abnormalities in endogenous and exogenous Cushing syndrome, emphasizing that hypercortisolism causes insulin resistance and impaired insulin secretion. It concludes that controlling hypercortisolism is central to glycemic improvement, but evidence for optimal antidiabetic therapy in CS remains limited.

Key findings

  • In endogenous CS, 20%–45% of patients have DM and 10%–30% have defective glucose tolerance, with overall glucose metabolism impairment approaching 70%; fasting plasma glucose may be normal in 64% of endogenous CS patients with DM.
  • Exogenous GC use carries dose-dependent DM risk: nearly 9% of patients with rheumatoid arthritis developed DM within 2 years of starting GC treatment; odds ratios for starting an oral hypoglycemic agent or insulin were 1.77, 3.02, 5.82, and 10.34 for hydrocortisone-equivalent doses of 1–39, 40–79, 80–119, and ≥120 mg/d, respectively; a meta-analysis reported an odds ratio of 1.5 to 2.5 for newly diagnosed DM with exogenous GCs.
  • In subclinical CS/adrenal incidentalomas, DM or IGT was identified in 20%–25% of patients with AI and SCS, though prevalence varied with screening methods and diagnostic criteria.
  • Medical therapy effects varied: ketoconazole improved glycemic control in 56% of diabetic patients in a series of 200 CD patients; mifepristone reduced OGTT glucose AUC by at least 25% in 60% of patients with DM/IGT (median decrease 36%); cabergoline reduced DM prevalence from 25% to 10% and IGT from 37.5% to 20% after 24 months in responsive patients; pasireotide caused hyperglycemia in up to 73% and 6% discontinued treatment because of hyperglycemia-related adverse events or uncontrolled DM.

Methods

  • Design: narrative review of the pathogenesis, epidemiology, diagnosis, and management of changes in glucose metabolism associated with hypercortisolism, addressing pathophysiological and clinical/therapeutic implications.
  • Data: cited literature and summary tables on prevalence of DM/glucose intolerance in CS, adrenal incidentalomas, screening for CS in type 2 DM, and medication effects; no primary patient sample or systematic search strategy is described.
  • Analysis: qualitative synthesis of molecular mechanisms and clinical evidence; no meta-analysis or formal risk-of-bias assessment is described.

Limitations

  • Stated: there is a lack of studies specifically investigating antidiabetic therapy in endogenous CS and few studies in exogenous GC-induced hyperglycemia; evidence on optimal antidiabetic treatment is scarce, and recommendations are based largely on current best practice.
  • Stated: there is no general consensus on diagnostic criteria for SCS, and prevalence estimates vary with screening methods and criteria.
  • Evident: as a narrative review, it does not report a systematic search, meta-analysis, or primary data; many cited therapeutic studies are retrospective, small, or uncontrolled.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1210/er.2016-1105

Cites

363 of 363 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 145 cited sources checked · 0 supported · 0 flagged

  • Premisenone given

    Glucocorticoids may indirectly affect peripheral insulin sensitivity and glucose homeostasis through changes in protein and lipid metabolism and through impaired interorgan communication by organ-derived circulating factors.

    “There may also be indirect effects of GCs on peripheral insulin sensitivity and glucose homeostasis through GC-dependent changes in protein and lipid metabolism, as well as GC-mediated impairments in interorgan communication conducted by organderived circulating factors.”
    Quote in the paperNot a substantial claim
  • Premisenone given

    Chronic hypercortisolism can affect all major peripheral tissues that control glucose homeostasis.

    “Chronic hypercortisolism may have pleiotropic effects on all major peripheral tissues governing glucose homeostasis.”
    Quote in the paperNot a substantial claim
  • Premisereasoning

    In the liver, the excessive hepatic glucose output that contributes to hyperglycemia is attributed largely to transcriptional upregulation of key gluconeogenic enzymes.

    “In the liver, the aberrant HGO that contributes to hyperglycemia is attributed largely to the transcriptional upregulation of key gluconeogenic enzymes.”
    Quote in the paperSubstantial claim
  • Premisereasoning

    Glucocorticoids strongly alter hepatic insulin action, leading to increased gluconeogenesis and hepatic glucose output through direct and indirect effects.

    “In particular, GCs profoundly alter the hepatic action of insulin, resulting in exacerbated gluconeogenesis and hepatic glucose output (HGO) through both direct and indirect effects on the mechanisms controlling these processes.”
    Quote in the paperSubstantial claim
  • Premisenone given

    Glucocorticoids induce a selective hepatic insulin resistance that blocks insulin's suppression of hepatic glucose output while preserving insulin's lipogenic effect.

    “A second important effect of GCs in the liver is to induce a selective IR that impedes the inhibitory effect of insulin on HGO while preserving the lipogenic effect of the hormone.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 12
  • May combine two claims. 35

  • Classified as probably not a substantial claim.

    Findingnone given

    The lack of studies on the effects of different antidiabetic agents in Cushing syndrome patients with altered glucose homeostasis has complicated the development of guidelines on an optimal antidiabetic strategy for such patients.

    “In conclusion, the lack of studies on the effects of different antidiabetic agents in CS patients with altered glucose homeostasis has complicated development of guidelines on an optimal antidiabetic strategy for such patients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Impaired glucose metabolism is a frequent complication of chronic endogenous or exogenous glucocorticoid excess and contributes to illness and death in Cushing syndrome.

    “An impaired glucose metabolism, which often leads to the onset of diabetes mellitus (DM), is a common complication of chronic exposure to exogenous and endogenous glucocorticoid (GC) excess and plays an important part in contributing to morbidity and mortality in patients with Cushing syndrome (CS).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Only about 20% of Cushing syndrome patients developed hepatic steatosis, suggesting that lipotoxicity from aberrant hepatic lipid storage is not a predominant mechanism of insulin resistance in this disease.

    “Surprisingly, only % of patients with CS developed hepatic steatosis (, ), suggesting that lipotoxicity associated with aberrant lipid storage in hepatocytes is not a predominant pathologic mechanism of IR in this disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Glucocorticoid excess can impair glucose metabolism through complex mechanisms and is linked to impaired fasting glucose, impaired glucose tolerance, and overt diabetes.

    “GC excess may impair glucose metabolism through many complex pathophysiological mechanisms and is associated with varying degrees of glucose intolerance, including impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and overt diabetes mellitus (DM).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Glucocorticoids directly induce both genomic and nongenomic mechanisms in a context-specific and cell- or organ-dependent way.

    “Adding further complexity, both genomic and nongenomic mechanisms are directly induced by GCs in a contextspecific and cell-/organ-dependent manner.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Abdominal obesity is closely associated with metabolic syndrome and Cushing syndrome.

    “Abdominal obesity is closely associated with metabolic syndrome and CS.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    The precise mechanisms behind glucocorticoid-induced muscle outcomes are still unclear, but they appear to involve pleiotropic effects that impair insulin signaling and glucose uptake.

    “The precise mechanisms underlying these pathologic GC-induced outcomes in muscle are still not entirely clear, but they too appear to stem from pleiotropic effects that contribute to impairment of insulin signaling and glucose uptake.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    Aldosterone-induced glucose intolerance may involve effects on insulin signaling, hepatic gluconeogenesis, sodium-glucose transport, and fibrosis-induced dysfunction in insulin-producing or insulin-sensitive tissues.

    “Several other mechanisms of aldosterone-induced glucose intolerance have been suggested, including effects on insulin signaling, stimulation of hepatic gluconeogenesis, effects on sodium-glucose transport, and fibrosis-induced dysfunction in insulin-producing or insulin-sensitive tissues.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Nongenomic mineralocorticoid receptor actions may increase collagen synthesis and fibrosis in the heart and in insulin-sensitive tissues such as pancreas, liver, fat, and muscle.

    “It has been suggested that nongenomic actions of MRs might result in increased collagen synthesis and fibrosis, not only in the heart but also in other insulin-sensitive tissues such as the pancreas, liver, fat, and”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Patients with primary aldosteronism had low adiponectin levels and weaker insulin sensitivity.

    “Similarly, patients with PA had low adiponectin levels with an associated weaker insulin sensitivity ().”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [178] Cooper, 2007, Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance, Am J Physiol Heart Circ Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Among patients with endogenous Cushing syndrome, 20% to 45% have diabetes and 10% to 30% have defective glucose tolerance, so overall prevalence of glucose metabolism impairment can approach 70%.

    “From % to % of patients with endogenous CS have DM, and % to % have defective glucose tolerance, so the overall prevalence of glucose metabolism impairments can come close to %, as shown in Table  (, , -).”
    Quote in the paperNot a substantial claim0 of 10 sources checked
    • cites [107] Giordano, 2014, Is diabetes in Cushing’s syndrome only a consequence of hypercortisolism?, Eur J Endocrinol source

      Not checked in the free run.

    • cites [143] Ferron, 2014, Regulation of energy metabolism by the skeleton: osteocalcin and beyond, Arch Biochem Biophys source

      Not checked in the free run.

    • cites [181] Friedman, 1996, Carbohydrate and lipid metabolism in endogenous hypercortisolism: shared features with metabolic syndrome X and NIDDM, Endocr J source

      Not checked in the free run.

    • cites [182] Biering, 2000, Prevalence of diabetes in acromegaly and Cushing syndrome [in German], Acta Med Austriaca source

      Not checked in the free run.

    • cites [183] Faggiano, 2003, Cardiovascular risk factors and common carotid artery caliber and stiffness in patients with Cushing’s disease during active disease and 1 year after disease remission, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [184] Pecori Giraldi, 2003, Study Group on the Hypothalamo-Pituitary-Adrenal Axis of the Italian Society of Endocrinology. Gender-related differences in the presentation and course of Cushing’s disease, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [185] Mancini, 2004, High cardiovascular risk in patients with Cushing’s syndrome according to 1999 WHO/ISH guidelines, Clin Endocrinol (Oxf) source

      Not checked in the free run.

    • cites [186] Giordano, 2011, Metabolic and cardiovascular outcomes in patients with Cushing’s syndrome of different aetiologies during active disease and 1 year after remission, Clin Endocrinol (Oxf) source

      Not checked in the free run.

    • cites [187] Valassi, 2011, The European Registry on Cushing’s syndrome: 2-year experience. Baseline demographic and clinical characteristics, Eur J Endocrinol source

      Not checked in the free run.

    • cites [188] Dekkers, 2013, Multisystem morbidity and mortality in Cushing’s syndrome: a cohort study, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mineralocorticoid receptors on adipocytes promote inflammatory adipokine expression, leading to lower insulin receptor expression and impaired insulin-induced glucose uptake.

    “MRs on adipocytes promoted the expression of inflammatory adipokines (-), giving rise to lower insulin receptor expression and impaired insulin-induced glucose uptake ().”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [173] Ehrhart-Bornstein, 2004, Fat cells may be the obesity-hypertension link: human adipogenic factors stimulate aldosterone secretion from adrenocortical cells, Endocr Res source

      Not checked in the free run.

    • cites [174] Rondinone, 1993, Aldosterone stimulated differentiation of mouse 3T3-L1 cells into adipocytes, Endocrinology source

      Not checked in the free run.

    • cites [175] Caprio, 2007, Pivotal role of the mineralocorticoid receptor in corticosteroid-induced adipogenesis, FASEB J source

      Not checked in the free run.

    • cites [176] Guo, 2008, Mineralocorticoid receptor blockade reverses obesity-related changes in expression of adiponectin, peroxisome proliferator-activated receptor-gamma, and proinflammatory adipokines, Circulation source

      Not checked in the free run.

    • cites [177] Lamounier-Zepter, 2006, Fat tissue metabolism and adrenal steroid secretion, Curr Hypertens Rep source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Mineralocorticoids may indirectly limit pancreatic insulin secretion through hypokalemia; potassium depletion in primary aldosteronism could impair insulin secretion.

    “Mineralocorticoids might also indirectly limit insulin secretion by the pancreas as a result of hypokalemia; in other words, impaired insulin secretion could be caused by potassium depletion in individuals with PA.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    These fibrotic mechanisms can damage tissue and potentially alter insulin release and sensitivity.

    “These mechanisms can lead to tissue damage, potentially resulting in altered insulin release and sensitivity ().”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [170] Giacchetti, 2005, The renin-angiotensin-aldosterone system, glucose metabolism and diabetes, Trends Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Corticosteroid-binding globulin binds cortisol with high capacity and affinity, reducing free glucocorticoid levels to about 10%, while aldosterone circulates mainly in free form.

    “Corticosteroid-binding globulin binds cortisol with a high capacity and affinity, reducing free GC levels to ~%, whereas aldosterone circulates mainly in its free form ().”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [163] Funder, 1973, The roles of plasma binding and receptor specificity in the mineralocorticoid action of aldosterone, Endocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In primary aldosteronism, resection of aldosterone-producing tumors and pharmacological treatment both reduced blood insulin and glucose levels, suggesting improved insulin sensitivity.

    “In patients with primary aldosteronism (PA), resection of aldosteroneproducing tumors and pharmacological treatment both reduced blood insulin and glucose levels, suggesting an improvement in insulin sensitivity (, ).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [167] Giacchetti, 2007, Aldosterone as a key mediator of the cardiometabolic syndrome in primary aldosteronism: an observational study, J Hypertens source

      Not checked in the free run.

    • cites [168] Catena, 2006, Insulin sensitivity in patients with primary aldosteronism: a follow-up study, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fasting plasma glucose may not suffice to assess glucose homeostasis in Cushing syndrome because 64% of patients with endogenous Cushing syndrome and diabetes have normal fasting glucose levels.

    “Fasting plasma glucose (FPG) level may not suffice to assess glucose homeostasis in CS because more than one in two patients (%) with endogenous CS and DM have normal FGP levels () and because an oral glucose tolerance test (OGTT) is not always performed in patients with apparently normal fasting glycemia ().”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [185] Mancini, 2004, High cardiovascular risk in patients with Cushing’s syndrome according to 1999 WHO/ISH guidelines, Clin Endocrinol (Oxf) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    No sex-related differences have been described in the prevalence of this Cushing syndrome complication.

    “No sex-related differences have been described in the prevalence of this CS complication (, ).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [184] Pecori Giraldi, 2003, Study Group on the Hypothalamo-Pituitary-Adrenal Axis of the Italian Society of Endocrinology. Gender-related differences in the presentation and course of Cushing’s disease, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [189] Zilio, 2014, Diagnosis and complications of Cushing’s disease: gender-related differences, Clin Endocrinol (Oxf) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The risk of diabetes was greater in subjects with abdominal adiposity or genetic predisposition and in those taking higher doses of glucocorticoids for longer periods.

    “The risk of DM was greater in subjects with abdominal adiposity or a genetic predisposition to DM and in those taking higher doses of GCs and for longer periods (, -).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [194] Gurwitz, 1994, Glucocorticoids and the risk for initiation of hypoglycemic therapy, Arch Intern Med source

      Not checked in the free run.

    • cites [196] Henriksen, 1997, Risk and mechanism of dexamethasone-induced deterioration of glucose tolerance in non-diabetic first-degree relatives of NIDDM patients, Diabetologia source

      Not checked in the free run.

    • cites [197] Darmon, 2006, Insulin resistance induced by hydrocortisone is increased in patients with abdominal obesity, Am J Physiol Endocrinol Metab source

      Not checked in the free run.

    • cites [198] Donihi, 2006, Prevalence and predictors of corticosteroid-related hyperglycemia in hospitalized patients, Endocr Pract source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    There is no general consensus on diagnostic criteria for subclinical Cushing syndrome, so criteria vary among investigators and studies.

    “There is no general consensus, however, on the diagnostic criteria for identifying cases of SCS, which consequently vary considerably among different investigators and studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    By definition, adrenal incidentaloma patients have no clinical signs of abnormal cortisol secretion, but 15% to 30% may have subclinical Cushing syndrome.

    “By definition, AI patients have no clinical signs of abnormal cortisol secretion; however, % to % of them may have SCS.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The severity of hypercortisolism correlates with the presence of insulin resistance and diabetes, as shown by an association with higher urinary free cortisol levels, though not all studies found this.

    “Generally speaking, the severity of hypercortisolism correlates with the presence of IR and DM, as evidenced by an association with higher urinary free cortisol (UFC) levels (, ), though this was not identified in all studies (, ).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [181] Friedman, 1996, Carbohydrate and lipid metabolism in endogenous hypercortisolism: shared features with metabolic syndrome X and NIDDM, Endocr J source

      Not checked in the free run.

    • cites [185] Mancini, 2004, High cardiovascular risk in patients with Cushing’s syndrome according to 1999 WHO/ISH guidelines, Clin Endocrinol (Oxf) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The 1-mg dexamethasone overnight suppression test is recommended for screening adrenal incidentaloma patients for subclinical Cushing syndrome, with a threshold of 138 nmol/L; 50 nmol/L virtually excludes subclinical Cushing syndrome, and 50-138 nmol/L is an area of uncertainty.

    “The -mg dexamethasone overnight suppression test is recommended for screening patients with AI for SCS, setting the threshold at  nmol/L; a value of  nmol/L virtually excludes SCS, whereas values between  and  nmol/L occupy an area of uncertainty ().”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [207] Terzolo, 2002, Adrenal incidentaloma: a new cause of the metabolic syndrome?, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The prevalence of impaired glucose tolerance or diabetes has been higher in patients with subclinical Cushing syndrome than in nonfunctioning adenoma or controls, but other studies did not confirm this.

    “Focusing on glucose metabolism, the prevalence of IGT or DM has been higher in patients with SCS than in cases of nonfunctioning adenoma or controls (, , , , , , ), but these data were not confirmed by other studies that found much the same prevalence of these comorbidities in SCS as in the overall series of AI and in the general population (, -).”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [200] Rossi, 2000, Subclinical Cushing’s syndrome in patients with adrenal incidentaloma: clinical and biochemical features, J Clin Endocrinol Metab

      Not checked in the free run.

    • cites [201] Tauchmanovà, 2002, Patients with subclinical Cushing’s syndrome due to adrenal adenoma have increased cardiovascular risk, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [203] Terzolo, 2005, Subclinical Cushing’s syndrome in adrenal incidentalomas, Endocrinol Metab Clin North Am source

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    • cites [207] Terzolo, 2002, Adrenal incidentaloma: a new cause of the metabolic syndrome?, J Clin Endocrinol Metab source

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    • cites [210] Emral, 2003, Prevalence of subclinical Cushing’s syndrome in 70 patients with adrenal incidentaloma: clinical, biochemical and surgical outcomes, Endocr J source

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    • cites [211] Morelli, 2010, Subclinical hypercortisolism: correlation between biochemical diagnostic criteria and clinical aspects, Clin Endocrinol (Oxf) source

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    • cites [220] Morelli, 2014, Long-term follow-up in adrenal incidentalomas: an Italian multicenter study, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overall, diabetes or impaired glucose tolerance was identified in 20% to 25% of patients with adrenal incidentaloma and subclinical Cushing syndrome and was related to age, adenoma size, midnight cortisol level, and plasma cortisol after dexamethasone suppression.

    “Overall, DM or IGT was identified in % to % of patients with AI and SCS and was related to patients' age (), the size of their adenomas, their midnight cortisol level, and their plasma cortisol level after suppression with dexamethasone ().”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [219] Muscogiuri, 2011, The size of adrenal incidentalomas correlates with insulin resistance. Is there a cause-effect relationship?, Clin Endocrinol (Oxf) source

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    • cites [211] Morelli, 2010, Subclinical hypercortisolism: correlation between biochemical diagnostic criteria and clinical aspects, Clin Endocrinol (Oxf) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Results suggest chronic mild hypercortisolism, as in subclinical Cushing syndrome, may be associated with the clinical phenotype of insulin resistance syndrome, or alternatively adrenal incidentaloma may be an unrecognized manifestation of metabolic syndrome.

    “The results of these studies suggest that chronic mild hypercortisolism, as in SCS, may be associated with the clinical phenotype of IR syndrome or, alternatively, that AI may be per se an unrecognized manifestation of metabolic syndrome.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Ketoconazole has been used worldwide for more than 30 years to lower circulating cortisol in Cushing syndrome, although only retrospective studies have reported its use.

    “Ketoconazole has been used worldwide for more than  years to lower circulating cortisol levels in CS, although only retrospective studies have reported on its use to date.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    At doses higher than 4 g daily, mitotane has an adrenolytic effect, inducing cellular necrosis, so it is indicated mainly in adrenal cancer.

    “At doses higher than  g daily, mitotane also has an adrenolytic effect, inducing cellular necrosis, so it is indicated mainly in adrenal cancer ().”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [265] Mancini, 2010, Treatment of Cushing disease: overview and recent findings, Ther Clin Risk Manag source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Available data do not support large-scale screening for Cushing syndrome in type 2 diabetes but may suggest case-finding for hypercortisolism in diabetic patients with certain features.

    “Available data consequently do not support largescale screening for CS in patients with type  DM but may suggest a case-finding approach for hypercortisolism in diabetic patients with certain features (i.e., uncontrolled DM despite appropriate treatment, drug-resistant hypertension, Cushingoid appearance, central obesity, osteoporosis, or polycystic ovary syndrome) (, ).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [245] Leibowitz, 1996, Pre-clinical Cushing’s syndrome: an unexpected frequent cause of poor glycaemic control in obese diabetic patients, Clin Endocrinol (Oxf) source

      Not checked in the free run.

    • cites [263] Nieman, 2008, The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline, J Clin Endocrinol Metab source

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  • May combine two claims.

    Premisecitation

    Patients cured of Cushing disease with normal serum and urinary cortisol for at least 5 years have a higher prevalence of atherosclerosis than healthy controls and maintain abnormalities typical of active Cushing disease, such as obesity, hypertension, impaired glucose tolerance, hyperlipidemia, and hypercoagulability.

    “As demonstrated by Colao et al. () in , patients cured of CD who have normal serum and urinary cortisol levels for at least  years have a higher prevalence of atherosclerosis than healthy controls and maintain several clinical and biochemical abnormalities typical of active CD, such as obesity, hypertension, IGT, hyperlipidemia, and hypercoagulability.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [191] Colao, 1999, Persistence of increased cardiovascular risk in patients with Cushing’s disease after five years of successful cure, J Clin Endocrinol Metab

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    No cases of confirmed subclinical Cushing syndrome emerged among 933 diabetic outpatients in India; patients with clinical signs suggestive of hypercortisolism were excluded a priori.

    “It is worth noting that no cases of confirmed SCS emerged among a population of  diabetic outpatients forming another large series in a recent study in India (); in this study, however, patients with clinical signs suggestive of hypercortisolism (easy bruising, facial plethora, proximal muscle weakness, and/or striae) were excluded a priori from the evaluation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [259] Budyal, 2015, Is it worthwhile to screen patients with type 2 diabetes mellitus for subclinical Cushing’s syndrome?, Endocr Connect source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Normalization of cortisol after surgery and/or radiotherapy is generally followed by resolution of glucose metabolism impairment because hypercortisolism causes hyperglycemia.

    “The normalization of cortisol levels after surgery and/or radiotherapy is generally followed by the resolution of patients' glucose metabolism impairment because their hypercortisolism is responsible for their hyperglycemia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Surgery and radiotherapy for Cushing disease can cause hypopituitarism, including GH deficiency, which if untreated may alter glucose metabolism and raise cardiovascular risk.

    “Both treatments can cause hypopituitarism (including GH deficiency) that, left untreated, may alter glucose metabolism and raise patients' cardiovascular risk ().”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [266] Gola, 2005, Clinical review: Growth hormone and cardiovascular risk factors, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Although 0.7% is too low in absolute terms to support widespread screening, it means Cushing syndrome is much more common than previously believed given the high prevalence of type 2 diabetes.

    “Although this figure is too low in absolute terms to support the efficacy of widespread screening, it means that CS is much more common than previously believed, considering the high prevalence of type  DM in the general population.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The frequency of Cushing syndrome in an unselected type 2 diabetes population was too low compared with false-positive results to make routine screening applicable, given high cost-effectiveness and lack of specific tests.

    “On the other hand, the frequency of CS identified in an unselected population of type  DM patients was too low compared with the number of false-positive results to make a routine screening strategy applicable in practice (), given its high cost-effectiveness and the lack of specific tests for diagnosing CS, especially in patients with a slightly elevated cortisol secretion and SCS ().”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [260] Tabarin, 2011, Pros and cons of screening for occult Cushing syndrome, Nat Rev Endocrinol source

      Not checked in the free run.

    • cites [261] Krarup, 2012, Do patients with type 2 diabetes mellitus have an increased prevalence of Cushing’s syndrome?, Diabetes Metab Res Rev source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Controlling hypercortisolism is the first step toward improving glucose metabolism in endogenous Cushing syndrome, but different treatments may affect diabetes outcome regardless of how well cortisol excess is corrected.

    “Controlling hypercortisolism is the first step toward improving glucose metabolism in patients with endogenous CS, but different treatments for hypercortisolism may affect the outcome of diabetes, regardless of how well cortisol excess is corrected (, , , , , , ).”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [1] Arnaldi, 2003, Diagnosis and complications of Cushing’s syndrome: a consensus statement, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [12] Mazziotti, 2011, Diabetes in Cushing syndrome: basic and clinical aspects, Trends Endocrinol Metab source

      Not checked in the free run.

    • cites [183] Faggiano, 2003, Cardiovascular risk factors and common carotid artery caliber and stiffness in patients with Cushing’s disease during active disease and 1 year after disease remission, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [186] Giordano, 2011, Metabolic and cardiovascular outcomes in patients with Cushing’s syndrome of different aetiologies during active disease and 1 year after remission, Clin Endocrinol (Oxf) source

      Not checked in the free run.

    • cites [190] Arnaldi, 2004, Cardiovascular risk in Cushing’s syndrome, Pituitary source

      Not checked in the free run.

    • cites [191] Colao, 1999, Persistence of increased cardiovascular risk in patients with Cushing’s disease after five years of successful cure, J Clin Endocrinol Metab

      Not checked in the free run.

    • cites [264] Baroni, 2016, Italian Society for the Study of Diabetes (SID)/Italian Endocrinological Society (SIE) guidelines on the treatment of hyperglycemia in Cushing’s syndrome and acromegaly, J Endocrinol Invest source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Cushing disease, the remission rate after neurosurgery is 65% to 90%, with a 10-year recurrence risk of 10% to 20%; macroadenomas have lower remission rates and earlier recurrence than microadenomas.

    “The remission rate after neurosurgery is in the range of % to %, with a risk of recurrence at  years ranging between % and %; for macroadenomas, the remission rate is lower, and recurrences tend to occur earlier than for microadenomas ().”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [265] Mancini, 2010, Treatment of Cushing disease: overview and recent findings, Ther Clin Risk Manag source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Patients with a history of Cushing disease carry a higher cardiovascular risk than the general population, albeit lower than patients with active disease.

    “These features mean that patients who have a history of CD carry a higher cardiovascular risk than the general population, albeit lower than in patients with active disease.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Premisenone given

    Diagnostic tests and cutoffs are important factors influencing the outcome of any screening.

    “Diagnostic tests and cutoffs are important factors influencing the outcome of any screening.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Diagnostic tests and cutoffs are important factors influencing the outcome of any screening.

  • May combine two claims.

    Premisenone given

    Most metabolic side effects mediated by the glucocorticoid receptor occur via transactivation, whereas most desired anti-inflammatory effects occur via transrepression.

    “Because most of the metabolic side effects mediated by GCR are via transactivation, whereas most of the desired anti-inflammatory effects are via transrepression, efforts have been made to separate these two modes of GCR activity.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cabergoline participates in appetite control.

    “Participation in appetite control a”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites a

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cabergoline inhibits prolactin release.

    “Inhibition of prolactin release”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites a

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Cortisol is the natural ligand for the glucocorticoid receptor in humans, and binding of cortisol or synthetic glucocorticoids results in metabolic and anti-inflammatory effects.

    “Cortisol is the natural ligand for GCR in humans, and the binding of cortisol or other synthetic GCs results in metabolic and anti-inflammatory effects.”
    Quote in the paperNot a substantial claim
43 of 43

  • The paper relies on this without support.

    Glucocorticoids circulate at 100- to 1000-fold higher plasma concentrations than aldosterone.

    “MRs have a similar affinity for aldosterone and cortisol (), but GCs circulate at to -fold higher plasma concentrations than does aldosterone.”

  • The paper relies on this without support.

    In brain and adipose tissue, mineralocorticoid receptors are high-affinity glucocorticoid receptors fully occupied by cortisol.

    “In other tissues, such as brain and adipose tissue, MRs are considered high-affinity GC receptors, fully occupied by cortisol.”

  • The paper relies on this without support.

    Diagnostic tests and cutoffs are important factors influencing the outcome of any screening.

    “Diagnostic tests and cutoffs are important factors influencing the outcome of any screening.”

  • The paper relies on this without support.

    Glucocorticoids induce diabetes mellitus.

    “Although GCs are well known to induce DM, no studies have specifically investigated the role of antidiabetic therapy in the treatment of hyperglycemia in patients with endogenous CS, and few studies have reported the effects of some antidiabetic agents in exogenous GC-induced hyperglycemia.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Diabetes in people with normal cortisol levels is characterised by increased fasting glucose, whereas secondary diabetes in hypercortisolemic patients can be better characterised by impaired glucose tolerance.

    “while diabetes in people with normal CORT levels is characterised by increased fasting glucose, a static metric by all means, secondary diabetes in hypercortisolemic patients can be better characterised by impaired glucose tolerance, a medical test that is intrinsically dynamic ( 14, 15 ).”

    From Dynamic modulation of glucose utilisation by glucocorticoid rhythms in health and disease (2020) · cites this paper as [15]

    The Essential Points and ‘Screening for DM in Patients With CS’ sections (pages not provided) say fasting glucose may be normal in Cushing syndrome and that an oral glucose tolerance test is preferable for detecting impaired glucose metabolism. They do not establish the contrasting claim that diabetes in people with normal cortisol levels is characterised by increased fasting glucose. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Cortisol stimulates liver gluconeogenesis and glycogenolysis.

    “and by stimulating liver gluconeogenesis and glycogenolysis ( 4, 15 ).”

    From Dynamic modulation of glucose utilisation by glucocorticoid rhythms in health and disease (2020) · cites this paper as [15]

    The “GC-induced hepatic metabolic disorders” section says glucocorticoids exacerbate liver gluconeogenesis and hepatic glucose output. It does not state that they stimulate hepatic glycogenolysis; the passage about glycogen concerns synthesis in muscle, not breakdown in the liver. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • An OGTT may not be performed when a patient's fasting glucose is normal, leading to an underestimation of the prevalence of diabetes in hypercortisolism.

    “This is important in view of the fact that an OGTT may not be performed when a patient's fasting glucose is normal, thus leading to an underestimation of the prevalence of diabetes in hypercortisolism ( 15 ).”

    From Dynamic modulation of glucose utilisation by glucocorticoid rhythms in health and disease (2020) · cites this paper as [15]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

  • Incorrect prevalence in the Chiodini screening cohort

    Minor

    The table reports 30 cases among 294 patients, which is 10.2%, not 9.4%.

    Reported 9.4 · recomputed 10.204082

1 of 1

Cites

Flagged first, then by citations

20 of the 383 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Boyle, 1993, Cushing’s disease, glucocorticoid excess, glucocorticoid deficiency, and diabetes, Diabetes Res, 1, 301
  2. 2006, Insulin sensitivity in patients with adrenal incidentaloma [in Serbian], Srp Arh Celok Lek, 134, 315

Cited by

Sorted by citations

Related

Authors
Scaroni, C., Zilio, M., Foti, M., & Boscaro, M.
Affiliations
  • University of Padua (IT)
  • Department of Cell Physiology & Metabolism, Centre Médical Universitaire, 1 Rue Michel Servet, 1211 Genèva, Switzerland
ORCID
Venue
Endocrine Reviews
Publisher
The Endocrine Society
Published
2017-03-20
Volume
38
Issue
3
Pages
189-219
ISSN
  • 0163-769X (ISSN-L)
  • 1945-7189
DOI
10.1210/er.2016-1105
OpenAlex
W2621858797
Semantic Scholar
8c0496e85c53fd1dd9e21c5d85f1fdab54f725cc
Cited by
140
References
383
Citations by year
2026: 16 · 2025: 20 · 2024: 13 · 2023: 17 · 2022: 19 · 2021: 21 · 2020: 14 · 2019: 12 · 2018: 5 · 2017: 2
FWCI
1.32
Type
journal article
Language
en
Open access
Locations
  • Endocrine Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • INFM-OAR (INFN Catania) (submittedVersion, cc-by)
  • Padua Research Archive (University of Padova) (submittedVersion)
Funders
  • Eli Lilly and Company
  • Pfizer
  • Viropharma
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Keywords
Cushing's syndrome, glucose metabolism, hypercortisolism, glucocorticoid excess, diabetes mellitus, glucose homeostasis, subclinical Cushing's syndrome, glycemic control
MeSH terms
Animals, Blood Glucose, Cushing Syndrome, Glucocorticoids, Humans, Hydrocortisone, Insulin Resistance, Signal Transduction, Glucose Metabolism Disorders

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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