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Curr Opin Endocrinol Diabetes Obes. Author manuscript; available in PMC 2021 June 01.
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Published in final edited form as:

Curr Opin Endocrinol Diabetes Obes. 2020 June ; 27(3): 140–145. doi:10.1097/
MED.0000000000000537.

Glucose Metabolism in Cushing Syndrome

Anu Sharma1, Adrian Vella2
1Division of Diabetes and Endocrinology, University of Utah School of Medicine, Salt Lake City,
UT
2Division
of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo College of Medicine,
Rochester, MN
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Abstract
Purpose of review—Impairment of glucose metabolism is commonly encountered in Cushing’s
syndrome. It is the source of significant morbidity and mortality even after successful treatment of
Cushing’s. This review is to understand the recent advances in understanding the pathophysiology
of diabetes mellitus from excess cortisol.

Recent findings—In vitro studies have led to significant advancement in understanding the
molecular effects of cortisol on glucose metabolism. Some of these findings have been translated
with human data. There is marked reduction in insulin action and glucose disposal with a
concomitant, insufficient increase in insulin secretion. Cortisol has a varied effect on adipose
tissue, with increased lipolysis in subcutaneous adipose tissue in the extremities, and increased
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lipogenesis in visceral and subcutaneous truncal adipose tissue.

Summary—Cushing’s syndrome results in marked impairment in insulin action and glucose

disposal resulting in hyperglycemia. Further studies are required to understand the effect on
incretin secretion and action, gastric emptying, and its varied effect on adipose tissue.

Keywords
Glucose metabolism; secondary diabetes; diabetes mellitus; Cushing’s syndrome; cortisol

Introduction
Glucose metabolism is frequently impaired (43%–84%)1–3 in Cushing’s syndrome (CS) 2,4
resulting in an increased risk of metabolic syndrome4 and cardiovascular death5,6.
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Individuals with CS have twice as high mortality compared to controls (HR 2.3, 95% CI
1.8–2.9) with persistence of impaired glucose metabolism7 and increased risk for myocardial
infarction even after treatment for CS (HR 4.5 the year after diagnosis, decreasing to HR 3.7
during long term follow up)6. In fact, even in mild autonomous cortisol excess (or
subclinical ACTH independent CS), the prevalence of diabetes mellitus was 18.1% with an

Author of correspondence: Anu Sharma, MBBS, 615 Arapeen Drive Ste 100, Salt Lake City, UT 84108, Ph 801-581-7761,
anu.sharma@hsc.utah.edu.
Conflicts of interest
AS has no conflicts of interest.
 Sharma and Vella Page 2

increased risk of cardiovascular events compared to nonfunctioning adrenal tumors (15.5%

vs 6.4% respectively)8. This highlights the importance of understanding the cardiovascular
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risks associated with cortisol excess and the need to institute early treatment to decrease
excess mortality.

Glucose metabolism is a complex biochemical process that requires multiple interacting

factors to function effectively in order to achieve euglycemia. Insulin secretion is defined as
the β-cell secretory response to the circulating glucose concentration. Equally important is
insulin action, which is commonly referred to as insulin sensitivity or insulin resistance. This
is defined as the ability of insulin to remove glucose from the blood stream by stimulation of
uptake into peripheral tissues, suppression of lipolysis and decreasing endogenous glucose
production. Physiologically, cortisol plays a small role in stimulating gluconeogenesis and
inhibiting glycogenesis thereby preventing hypoglycemia9. In addition cortisol stimulates
lipolysis and proteolysis which provides oxidative substrates for metabolism 10. Excess
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cortisol amplifies these processes, in addition to impairing insulin secretion and action with
resultant hyperglycemia.

In this review, we will describe the pathophysiology of impaired glucose metabolism in CS

which is summarized in Table 1. Given the rarity of CS (0.2–5 people/million per year11,12),
most of our in-depth understanding of how cortisol affects glucose metabolism stems from
exogenous glucocorticoid data.

Insulin Secretion
Insulin secretion is primarily controlled by glucose. Glucose transporter 2 (GLUT2) serves
as the β-cell’s glucose sensor. Once glucose enters the β-cell, it is phosphorylated by
glucokinase and enters several pathways to increase insulin gene transcription, insulin gene
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translation with formation of insulin secretory granules and insulin granule exocytosis 13.
Approximately 7% of insulin granules are “docked” or linked to the β-cell plasma
membrane and are readily available to be released in response to glucose 14. The rest of
insulin granules require mobilization to the plasma membrane, priming and fusion for
release 15. These are referred to as “undocked” and belong to the reserve pool.

Glucocorticoids affect insulin secretion directly and indirectly. The effect is also dependent
on the dose of glucocorticoids as well as, the duration of exposure16. In vitro studies show a
direct inhibition of insulin secretion possibly due to decreased transcription of factors
required to activate the secretory process in response to cytoplasmic Ca2+ 17. In vivo studies,
however, reveal compensatory mechanisms in response to glucocorticoid exposure. While
there is decreased production of NADP, cAMP and inositol phosphate production 17, there is
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concomitant upregulation of parallel cAMP signaling pathways18 and increased number of

docked secretory granules19. Interestingly, pancreatic islets express 11beta-hydroxysteroid
dehydrogenase type 1 (11β-Hsd1) which influences both insulin20 and glucagon secretion21.
The main action of glucagon is stimulation of hepatic glucose output via increased
gluconeogenesis and glycogenolysis with concomitant suppression of glycolysis and
glycogenesis. Glucagon secretion is regulated by intra-islet glucose concentration, intra-islet
insulin signaling, paracrine stimulation of somatostatin via insulin, with minor contributions

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by incretins and the autonomic nervous system 22–24. Dexamethasone treated rats were
found to have increased α-cell mass, higher glucagon receptor content with resultant
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hyperglucagonemia 25. The hyperglycemia found was reversed with blockade of the
glucagon receptor 25 suggesting a potential role for targeting glucagon and its receptor in the
treatment of hyperglycemia in CS.

In an attempt to understand the effect of cortisol under human physiologic conditions,

Kamba et al26 performed a population based study in Japan to investigate the association
between cortisol and β cell function. Utilizing the homeostasis model assessment (HOMA)
they calculated crude estimates for insulin secretion (HOMA-β) and insulin resistance
(HOMA-R). Higher cortisol levels were associated with decreased insulin secretion
(p=0.03). In contrast, when a supra-physiological dose of glucocorticoid was administered
(prednisolone 30 mg daily for 15 days), insulin secretion was increased as measured by the
insulinogenic index after a meal27. In addition, glucocorticoids increase hepatic insulin
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extraction which is more evident during an intravenous glucose challenge compared to an

oral glucose challenge 28. Page et al29 performed the most robust study comparing 7
individuals with Cushing’s disease (CD) to 10 healthy participants utilizing the minimal
model analysis with a frequently sampled insulin modified intravenous glucose tolerance test
(FSIGTT). While first phase insulin secretion was similar, second phase insulin secretion
was found to be enhanced in CD 29. This increase, however, was not appropriate for the
prevailing decrease in insulin action 29.

Insulin Action
The compensatory increase in insulin secretion found in long term glucocorticoid exposure
is likely in response to the profound decrease in insulin action. Glucocorticoids impair
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insulin sensitivity at multiple sites in the liver, muscle and adipose tissue30.

When insulin binds to hepatocytes, it decreases hepatic glucose output or endogenous

glucose production (EGP) via inhibition of gluconeogenesis. Glucocorticoids upregulate
forkhead box O1 (FOXO1) with increased expression of MAP kinase phosphatase-3
(MKP-3)31. This results in activation of hepatic gluconeogenesis by increased transcription
of key regulatory enzymes (phosphoenolpyruvate32 and glucose-6-phosphatase (G6P) 33).
Human studies, however, show a more complex interaction between glucocorticoids and
EGP. Rooney et al performed a human study utilizing the euglycemic glucose clamp with
glucose tracers to study the effect of cortisol on G6P34. EGP was suppressed with high
insulin infusion despite increased G6P cycle activity. Hyperglycemia was thought to result
from impaired glucose disappearance. This study was then replicated in 8 individuals with
Cushing’s disease which confirmed the finding of impaired insulin action due to reduced
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glucose disposal 35.

Glucocorticoids also indirectly increase hepatic glucose output through elevated free fatty
acid concentrations (FFA). As mentioned above, glucocorticoids upregulate FOXO1. This
enhances hepatocyte lipid accumulation via several pathways (MKP-3, PPAR-γ, FAS, SCD1
and ACC2)36,37 leading to hepatic steatosis. Newly synthesized lipids are converted to

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diacylglycerol38 and ceramides39, both being implicated in the development of decreased

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hepatic insulin action.

The direct effect of glucocorticoids on adipose tissue vary depending on the duration of
exposure, concentration and the location of adipose tissue being studied (visceral vs
subcutaneous). A pathognomonic physical finding in CS is increased truncal adipose tissue
mass with atrophy of both muscle and fat in the extremities. The exact underlying molecular
difference between the effects of glucocorticoids on visceral as opposed to subcutaneous
adipose tissue is yet to be fully determined. Glucocorticoids stimulate lipolysis in
subcutaneous adipose tissue 40,41 but induces lipogenesis in visceral adipose tissue, with its
action augmented by insulin 42–44. This seemingly site specific variation in activity is likely
linked to its actions on intracellular hormone sensitive lipase 45, intravascular lipoprotein
lipase 45, and AMP-activated protein kinase (AMPK) 46. The result is overall increase in free
fatty acid turnover with an overall decrease in insulin action.
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Glucose disappearance
Glucose disappearance refers to the ability of peripheral tissue to uptake circulating glucose
for metabolism. Muscle is the primary source for glucose disposal, accounting for 70–80%
of the body’s glucose use 36. Cortisol plays an important role in the myocyte’s ability to
clear glucose. Physiologically, glucocorticoids are important in maintaining euglycemia
during fasting or starvation by increased proteolysis which releases amino acids that serve as
precursors for hepatic gluconeogenesis. In addition, there is impaired recruitment of GLUT4
to the cell surface resulting in decreased glucose uptake. In the presence of excess
glucocorticoids, these processes are amplified.

Glucocorticoids decrease phosphorylation of the insulin receptor which is required for it to

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bind to insulin receptor substrate 1 (IRS1) to activate insulin receptor signaling47.

Downstream signaling is also impaired by decreasing the activity of phosphinositide-3-
kinase (PI3K)48 resulting in disruption of glycogen synthase activity 49. Glucocorticoids
decrease GLUT4 translocation and exocytosis both directly 50 and indirectly due to defective
insulin receptor signaling 51. The net result of excess cortisol is hyperglycemia due to a
significant decrease in glucose disappearance 29,35.

Glucose Effectiveness
Glucose effectiveness refers to the ability of glucose to stimulate its own uptake and
suppress EGP. There is limited data pertaining to effect of glucocorticoids on glucose
effectiveness. Nielsen et al studied 8 healthy subjects under a somatostatin and insulin clamp
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using a glucose infusion to simulate postprandial rise in glucose52. Each subject served as
their own control (hydrocortisone vs saline infusion). There was a significant decrease in
both insulin action and glucose effectiveness implicating both to be significant contributors
to hyperglycemia.

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Other Factors Influencing Glucose Metabolism

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Targeting incretins and their receptors play an important role in the management of type 2
diabetes mellitus. Pharmacological management targeting incretins potentiate the β-cell
response to food intake and hyperglycemia. In addition, there is slowed gastric emptying and
decreased appetite. In dexamethasone treated rats, the secretory responsiveness of L cells to
a meal was decreased 53. While there is suggestion that glucocorticoids mildly affect the
insulinotropic effect of incretins 54,55, it is unclear what physiologic role incretins play in the
regulation of glucose metabolism in CS.

Bone produces several factors that affect glucose homeostasis. Secretion of osteocalcin56
and expression of thioredoxin-interacting protein (TXNIP) 57 are both altered in the
presence of chronic glucocorticoids in mice, contributing to decreased insulin sensitivity.
The nervous system also contributes to decreased insulin sensitivity. Neuropeptide Y
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expression is increased in the presence of glucocorticoids which potentiated impaired insulin

action. This impairment was reversed by hepatic sympathetic denervation58. Secretion of
growth hormone, thyrotropin releasing hormone and gonadotropin hormones are impaired in
chronic hypercortisolism. Growth hormone deficiency59, hypothyroidism60 and
hypogonadism61 have all been implicated in altered glucose metabolism.

Lastly, expression of 11β-Hsd1 is increased in the presence of chronic glucocorticoid

exposure62. 11β-Hsd1 converts cortisone to cortisol. In the presence of hydrocortisone, 30
healthy adults showed increased hepatic 11β-Hsd1 activity with impaired suppression of
EGP 63. This suggests that hepatic cortisol exposure exacerbates altered glucose metabolism
by a deleterious positive feedback loop. 11β-Hsd1 is also present in adipose tissue. Adipose-
specific 11β-Hsd1 knock out mice treated with glucocorticoids were protected from
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circulating fatty acid excess and hepatic steatosis suggesting a crucial role of adipose tissue
11β-Hsd1 in the development of metabolic derangements in CS 64.

Treatment
The first-line treatment would be to surgically target the underlying cause of CS. In some
cases however, it takes time to locate the source, making treating underlying glucose
abnormalities a priority to decrease overall morbidity and mortality. With the exception of
pasireotide, and to a lesser extent other somatostatin analogues (because of their suppression
of insulin secretion), all medical therapeutic options that decrease cortisol will aid in
improving glycemic control 36. While there is ongoing research targeting specific defects
found in glucocorticoid induced diabetes (e.g. 11β-Hsd1 inhbition65 and glucocorticoid
receptor modulators66, the current approach should be similar to the stepwise approach
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adopted for type 2 diabetes: lifestyle modification, metformin, therapies targeting

postprandial insulin secretion and action, and specific metabolic derangements (e.g.
hypertriglyceridemia and dyslipidemia) 67,68.

Conclusion
CS results in impaired glucose metabolism primarily through a decrease in insulin action
and reduction in glucose disposal. While there is a compensatory increase in insulin

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secretion, it is insufficient to overcome the significant alteration in insulin receptor signaling

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in the liver and peripheral tissues. Varied effects on adipose tissue results in both lipolysis
and lipogenesis accounting for the characteristic body fat distribution noted in CS. More
studies are needed to understand the effect of excess cortisol on incretins, gut mobility/
metabolism, the nervous system and bone.

Acknowledgments
Financial support and sponsorship

None

AV is an investigator in an investigator-initiated study sponsored by Novo Nordisk. He has consulted for XOMA,
vTv Therapeutics, Sanofi-Aventis, Novartis and Bayer in the past 5 years.

Abbreviations:
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CS Cushing’s syndrome

CD Cushing’s disease

ACTH Adrenocorticotrophic hormone

HR hazard ratio

CI confidence interval

NADP Nicotinamide adenine dinucleotide phosphate

cAMP cyclic adenosine monophosphate

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GLUT2 glucose transporter 2

GLUT4 Glucose transporter 4

HOMA Homeostatic Model Assessment

HOMA-β Homeostatic Model Assessment of insulin secretion

HOMA-R Homeostatic Model Assessment of insulin resistance

FSIGTT Frequently sampled intravenous glucose tolerance test

FOXO1 Forkhead box O1

G6P Glucose 6 phosphate

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EGP Endogenous glucose production

MKP-3 MAP kinase phosphatase-3

PPAR-γ Peroxisome proliferator-activated receptor gamma

FAS Fatty acid synthase

SCD1 Stearoyl-CoA desaturase

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ACC2 Acetyl-CoA carboxylase 2

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AMPK AMP-activated protein kinase

FFA Free fatty acid

IRS1 Insulin receptor substrate 1

PI3K phosphinositide-3-kinase

TXNIP thioredoxin-interacting protein

11β-Hsd1 11beta-hydroxysteroid dehydrogenase type 1

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Key Points
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1. Impaired glucose metabolism is prevalent in Cushing’s syndrome.

2. Cushing’s syndrome causes a significant reduction in insulin sensitivity and

glucose disappearance (peripheral uptake of glucose).

3. Excess cortisol induces both lipolysis and lipogenesis.

4. Metabolic derangements from excess cortisol significantly increases overall

morbidity and mortality even after successful treatment of Cushing’s
syndrome.
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Table 1.

Factors affecting Glucose Metabolism with excess cortisol

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Factor Organ Molecular Change

Insulin Secretion Pancreas ↑cAMP signaling

↑insulin

↑glucagon

Gut ↓GLP-1

Insulin Action Liver ↑MKP-3, ↑FOXO1

↑11β-Hsd1

Adipose Tissue ↑MKP-3, ↑FOXO1,↑PPAR-γ

↑NADPH

Bone ↑osteocalcin

↑TXNIP
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Brain ↑NPY

Pituitary ↓GH, ↓TSH, ↓FSH/LH

Glucose disappearance Muscle ↓insulin receptor signaling

↓glycogen synthase

↓GLUT4

Glucose effectiveness Liver ↓glucose stimulated glucose uptake

Glucagon suppression Pancreas ↑α-cell mass

↑glucagon receptors

Gastric emptying Gut unknown

MKP-3 - MAP kinase phosphatase 3; FOXO1 – forkhead box O1; 11β-Hsd1 – 11 β hydroxysteroid type 1; PPAR-γ - peroxisome proliferator-
activated receptor gamma; TXNIP - thioredoxin-interacting protein; NPY – neuropeptide Y; GH – growth hormone; TSH – thyrotropin stimulating
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hormone; FSH – follicle stimulating hormone; LH – luteinizing hormone; GLUT4 – glucose transporter type 4
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Curr Opin Endocrinol Diabetes Obes. Author manuscript; available in PMC 2021 June 01.