Glucose Metabolism in Cushing Syndrome

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 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.

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 death^5,6. 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 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 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 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 year^11,12), most of our in-depth understanding of how cortisol affects glucose metabolism stems from exogenous glucocorticoid data.

Table 1.

Factors affecting Glucose Metabolism with excess cortisol

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
	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 hormone; FSH – follicle stimulating hormone; LH – luteinizing hormone; GLUT4 – glucose transporter type 4

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 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 Ca^{2+ 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 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 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 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 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 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 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 diacylglycerol³⁸ and ceramides³⁹, both being implicated in the development of decreased 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.

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 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 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.

Other Factors Influencing Glucose Metabolism

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

Key Points.

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.

Abbreviations:

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

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

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

ACC2

Acetyl-CoA carboxylase 2

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