The Relationship of Mitochondrial Dysfunction and the Development of Insulin Resistance in Cushing’s Syndrome

Authors Ježková J, Ďurovcová V, Wenchich LHansíková H, Zeman J, Hána V, Marek J, Lacinová Z, Haluzík M, Kršek M

Received 18 March 2019

Accepted for publication 13 June 2019

Published 19 August 2019 Volume 2019:12 Pages 1459—1471

DOI https://doi.org/10.2147/DMSO.S209095

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Melinda Thomas

Peer reviewer comments 3

Editor who approved publication: Dr Antonio Brunetti

 

Jana Ježková,1 Viktória Ďurovcová,1 Laszlo Wenchich,2,3 Hana Hansíková,3 Jiří Zeman,3Václav Hána,1 Josef Marek,1 Zdeňka Lacinová,4,5 Martin Haluzík,4,5 Michal Kršek1

1Third Department of Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic; 2Institute of Rheumatology, Prague, Czech Republic; 3Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic; 4Institute of Medical Biochemistry and Laboratory Diagnostic, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic; 5Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic

Correspondence: Jana Ježková
Third Department of Medicine, First Faculty of Medicine, Charles University and General University Hospital, U Nemocnice 1128 02 Praha 2, Prague, Czech Republic
Tel +420 60 641 2613
Fax +420 22 491 9780
Email fjjezek@cmail.cz

Purpose: Cushing’s syndrome is characterized by metabolic disturbances including insulin resistance. Mitochondrial dysfunction is one pathogenic factor in the development of insulin resistance in patients with obesity. We explored whether mitochondrial dysfunction correlates with insulin resistance and other metabolic complications.

Patients and methods: We investigated the changes of mRNA expression of genes encoding selected subunits of oxidative phosphorylation system (OXPHOS), pyruvate dehydrogenase (PDH) and citrate synthase (CS) in subcutaneous adipose tissue (SCAT) and peripheral monocytes (PM) and mitochondrial enzyme activity in platelets of 24 patients with active Cushing’s syndrome and in 9 of them after successful treatment and 22 healthy control subjects.

Results: Patients with active Cushing’s syndrome had significantly increased body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR) and serum lipids relative to the control group. The expression of all investigated genes for selected mitochondrial proteins was decreased in SCAT in patients with active Cushing’s syndrome and remained decreased after successful treatment. The expression of most tested genes in SCAT correlated inversely with BMI and HOMA-IR. The expression of genes encoding selected OXPHOS subunits and CS was increased in PM in patients with active Cushing’s syndrome with a tendency to decrease toward normal levels after cure. Patients with active Cushing’s syndrome showed increased enzyme activity of complex I (NQR) in platelets.

Conclusion: Mitochondrial function in SCAT in patients with Cushing’s syndrome is impaired and only slightly affected by its treatment which may reflect ongoing metabolic disturbances even after successful treatment of Cushing’s syndrome.

Keywords: Cushing’s syndrome, insulin resistance, mitochondrial enzyme activity, gene expression

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Active Cushing’s disease is characterized by increased adipose tissue macrophage presence

Journal of Clinical Endocrinology and Metabolism — Lee IT, et al. | February 07, 2019

Using immunohistochemistry, researchers determined whether adipose tissue (AT) inflammation in humans is associated with chronic endogenous glucocorticoid (GC) exposure due to Cushing’s disease (CD).

Abdominal subcutaneous AT samples were evaluated for macrophage infiltration and mRNA expression of pro-inflammatory cytokines in 10 patients with active CD and 10 age, gender and BMI- matched healthy subjects.

The presence of AT macrophages, a hallmark of AT inflammation, increases chronic exposure to GCs due to CD. AT inflammation can, therefore, be the source of systemic inflammation in these patients, which in turn can contribute to obesity, insulin resistance and cardiovascular disease. In patients with CD, PCR showed no differences in mRNA expression of any analyzed markers.

Read the full article on Journal of Clinical Endocrinology and Metabolism

SteroTherapeutics Receives FDA Orphan-Drug Designation

PHILADELPHIA, April 04, 2018 — SteroTherapeutics, a privately held biopharmaceutical company developing therapies focused on metabolic diseases including non-alcoholic steatohepatitis (NASH), announced today that the U.S. Food and Drug Administration has granted orphan drug designation for ST-002 in the treatment of nonalcoholic fatty liver disease, nonalcoholic steatosis and hyperglycemia in patients with Cushing’s syndrome.

“We are pursuing a drug that has a very real potential to become the optimal agent of choice and a standard of care for these Cushing’s patients,” said Manohar Katakam Ph. D., CEO of SteroTherapeutics. “Our clinical trial will target multiple critical metabolic-related outcomes including the reduction of triglycerides, insulin resistance, weight loss, and the prevention and/or abrogation of hepatic steatosis and fibrosis.”

“The FDA’s orphan-drug designation for Fluasterone highlights the significant unmet and underserved needs for treatment in these individuals,” added Dr. Katakam. “We look forward to realizing the benefits and promise of this potential for Fluasterone in Cushing’s syndrome patients.”

The Orphan Drug Act became law in 1983. Fewer than 5,000 applicants have received this designation, according to the FDA website. Rare conditions are often described as orphan diseases or disorders when there are few or no treatment options. There are approximately 7,000 known orphan diseases.

The FDA’s Orphan Drug Designation program provides orphan status to drugs and biologics which are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the United States.

The designation allows the sponsor of the drug to be eligible for various incentives, including a seven-year period of U.S. marketing exclusivity upon regulatory approval of the drug, as well as tax credits for clinical research costs, annual grant funding, clinical trial design assistance, and the waiver of Prescription Drug User Fee Act (PDUFA) filing fees.

Cushing syndrome occurs when a patient’s body is exposed to high levels of the hormone cortisol over a long period of time (chronic hypercortisolemia) . Cushing syndrome, sometimes called hypercortisolism, affects 15,000 to 20,000 patients in the United States.

Too much cortisol can produce some of the hallmark signs of Cushing syndrome — a fatty hump between a patient’s shoulders, a rounded face, and pink or purple stretch marks on the skin. Cushing syndrome can also result in high blood pressure, bone loss and upper body obesity, increased fat around the neck, and relatively slender arms and legs. Diabetes is frequently a complication found in Cushing’s syndrome patients. These patients also develop nonalcoholic fatty disease and steatosis as a result of the chronic hypercortisolism.

About SteroTherapeutics

SteroTherapeutics, a Philadelphia, PA area based company, is focused on developing novel therapies for significant unmet needs in metabolic disease including liver diseases.

SteroTherapeutics lead products have been proven in previous human studies to possess a strong safety profile and established mechanisms of action. The company’s strategic intent is to focus on understanding disease pathways and how to safely treat and restore an optimal quality of life.  SteroTherapeutics is managed by a veteran team that has significant experience in the pharmaceutical and biotechnology industry. The team has specific experiences in the development, manufacturing and commercialization of small molecule and biologics based products.

INVESTOR RELATIONS CONTACT:
Tony Schor, Investor Awareness, Inc. on behalf of
SteroTherapeutics, LLC
tschor@sterotx.com/ (847) 945-2222 ext. 221

From https://www.econotimes.com/SteroTherapeutics-Receives-FDA-Orphan-Drug-Designation-1236099

Bruising easily and gaining weight? Don’t mistake high blood pressure for this syndrome

By Olivia Lerche June 30th, 2017

Cushing’s sydnrome [sic]: Condition can have the same symptoms as high blood pressure

The condition is a hormonal disorder caused by prolonged exposure to the hormone cortisol – which can be caused by taking steroids. Cortisol regulates metabolism and immune response in the body.

Other people develop Cushing’s syndrome because their bodies produce too much cortisol.

It is most common in adults aged between 20 and 50 although women are almost three time [sic] as likely to be diagnosed.

While the condition is rare and only affects around one in every 50,000 people – the syndrome can affect people with type 2 diabetes, obese and have poorly controlled blood sugar levels.

The condition is also more common in people with high blood pressure.

Cushing’s syndrome – also called hypercortisolism – can cause a number of symptoms.These can include:
Weight gain
Thinning skin which can bruise easily
Reddish-purple stretch marks on the arms, legs, breasts, thighs, stomach and buttocks
It can also cause the face to become rounder – causing fat to deposit on the face
Muscle or bone weakness is also a sign of the condition
A loss of libido – decreased interest in sex – is also a symptom

Cushing's sydnrome: Condition can have the same symptoms as high blood pressureGETTY

Cushing’s sydnrome [sic]: Condition has similar symptoms as high blood pressure and metabolic syndrome

However, other symptoms can include excess hair on the face, irregular periods, severe fatigue, high blood pressure, high blood sugar irritability or depression and even a fatty deposit between the shoulders.The National Institute of Diabetes and Digestive and Kidney Diseases said: “Metabolic syndrome – a combination of problems that includes excess weight around the waist, high blood pressure, abnormal levels of cholesterol and triglycerides in the blood, and insulin resistance-also mimics the symptoms of Cushing’s syndrome.”Cushing’s syndrome often develops as a side effect of treatment with corticosteroids.

Corticosteroids are widely used to reduce inflammation and treat autoimmune conditions  – where the immune system malfunctions and attacks healthy tissue – such as rheumatoid arthritis, Crohn’s disease and lupus.

Cushing's sydnrome: Condition can have the same symptoms as high blood pressureGETTY

Cushing’s sydnrome [sic]: Condition can have the same symptoms as high blood pressure

Metabolic syndrome also mimics the symptoms of Cushing’s syndrome

However, the condition can be hard to diagnose because of the similarity to high blood pressure.To diagnose the disease, patients will usually need to have a saliva test, urine test and blood test to measure cortisol levels in the body.To treat the condition, patients will usually have to decrease the levels of steroids they are taking.

However, there are complications if the condition is left untreated.

It can lead to high blood pressure and increase the risk of heart disease and stroke.

Other Diseases

forums

Many of the people who post on the message boards suffer from other diseases, as well as Cushing’s. These links help to provide some information about these diseases.

~A ~

Acanthosis nigricans
This Topic on the Message Boards.

Acromegaly
This Topic on the Message Boards.

Addison’s Disease
This Topic on the Message Boards.

Adrenoleukodystrophy
This Topic on the Message Boards.


~B ~

Barrett’s esophagus


~C ~

Carney Complex
This Topic on the Message Boards.
New Support Group for Carney Complex.

Central Serous Retinopathy
This Topic on the Message Boards.

Congenital Adrenal Hyperplasia (CAH)
This Topic on the Message Boards.

Conn’s Syndrome
This Topic on the Message Boards.

Craniopharyngioma
This Topic on the Message Boards.


~D ~

Diabetes insipidus
This Topic on the Message Boards.


~E ~

Ectopic ACTH Syndrome
This Topic on the Message Boards.

Empty Sella
This Topic on the Message Boards.


~F ~

Fibromyalgia
This Topic on the Message Boards.


~G ~

Gigantism
This Topic on the Message Boards.


~H ~

Hirsuitism
This Topic on the Message Boards.

Hyperprolactinemia
This Topic on the Message Boards.

Hyperthyroidism
This Topic on the Message Boards.

Hypoalderostonism
This Topic on the Message Boards.

Hypocalcemia
This Topic on the Message Boards

Hypopituitarism
This Topic on the Message Boards.

Hypothyroidism
This Topic on the Message Boards.


~I ~

Insulin Resistance
This Topic on the Message Boards.


~K ~

Kidney Disease
This Topic on the Message Boards.


~L ~

Lyme Disease
This Topic on the Message Boards.


~M ~

Madelung’s Disease
This Topic on the Message Boards.

Menopause
This Topic on the Message Boards.

MEN Type 1
This Topic on the Message Boards.

Myasthenia Gravis
This Topic on the Message Boards.


~N ~

Nelson’s Syndrome
This Topic on the Message Boards.


~O ~

Osteopenia
This Topic on the Message Boards.

Osteoporosis
This Topic on the Message Boards.


~P ~

Panhypopituitarism
This Topic on the Message Boards.

PCOS
This Topic on the Message Boards.

Perimenopause
This Topic on the Message Boards.

Pheochromocytoma
This Topic on the Message Boards.

Pituitary dwarfism
This Topic on the Message Boards.

Premature menopause
This Topic on the Message Boards.

Primary pigmented nodular adrenocortical disease (PPNAD)
This topic on the Message Boards

Prolactinoma
This Topic on the Message Boards.

Pseudo Cushing’s
This Topic on the Message Boards


~R ~

Rathke’s cleft cyst
This Topic on the Message Boards.

ROHHAD (Rapid-Onset Obesity With Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation Presenting in Childhood)
This Topic on the Message Boards


~S ~

Sheehan’s Syndrome
This Topic on the Message Boards.

Stein-Leventhal Syndrome
This Topic on the Message Boards.


~T ~

Thymoma
This Topic on the Message Boards.

Thyroid Gland Disorders
This Topic on the Message Boards.

Turner’s Syndrome
This Topic on the Message Boards.


~V ~

Von Hippel-Lindau disease
This Topic on the Message Boards.


~Z ~

Zollinger-Ellison Syndrome

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