What Causes Blood Sugar to Rise in Non-Diabetics?

High blood sugar or glucose, also called hyperglycemia, occurs when there is too much sugar in the blood. High blood sugar is the primary symptom that underlies diabetes, but it can also occur in people who don’t have type 1 or type 2 diabetes, either because of stress or trauma, or gradually as a result of certain chronic conditions.

It is important to manage high blood sugar, even if you don’t have diabetes, because elevated blood glucose can delay your ability to heal, increase your risk of infections, and cause irreversible damage to your nerves, blood vessels, and organs, such as your eyes and kidneys. Blood vessel damage from high blood sugar also increases your risk of heart attack and stroke.

Non-Diabetic Hyperglycemia and Prediabetes

You are considered to have impaired glucose tolerance or prediabetes if you have a fasting glucose level between 100–125 mg/dL, and hyperglycemia if your fasting blood glucose level is greater than 125 mg/dL, or greater than 180 mg/dL one to two hours after eating.

The body obtains glucose mainly through carbohydrate consumption, but also through the breakdown of glycogen to glucose—a process called glycogenolysis—or conversion of non-carbohydrate sources to glucose—called gluconeogenesis—that primarily occurs in the liver.

While 50% to 80% of glucose is used by the brain, kidneys, and red blood cells for energy, the remaining supply of glucose is used to produce energy. It is stored as glycogen in the liver and muscles, and can be tapped into at a later time for energy or converted into fat tissue.

In healthy people, blood glucose levels are regulated by the hormone insulin to stay at a steady level of 80–100 mg/dL. Insulin maintains steady blood sugar by increasing the uptake and storage of glucose and decreasing inflammatory proteins that raise blood sugar when there is an excess of glucose in the blood.

Certain conditions can increase your blood glucose levels by impairing the ability of insulin to transport glucose out of the bloodstream. When this occurs, you develop hyperglycemia, which puts you at an increased risk of prediabetes, diabetes, and related complications.

Common Causes

Cushing’s Syndrome

Cushing’s syndrome results from excess secretion of the adrenocorticotropic hormone, a hormone produced in the anterior portion of the pituitary gland that causes excess cortisol to be produced and released from the adrenal glands. Pituitary adenomas, or tumors of the pituitary gland, are the cause of Cushing’s syndrome in more than 70% of cases, while prolonged use of corticosteroid medication can also significantly increase the risk.

People with Cushing’s syndrome are at an increased risk of developing impaired glucose tolerance and hyperglycemia as a result of increased levels of cortisol throughout the body. Cortisol is a hormone that counteracts the effects of insulin by blocking the uptake of glucose from the bloodstream, thereby increasing insulin resistance and maintaining high blood sugar levels. Elevated cortisol levels also partially decrease the release of insulin from where it is produced in the pancreas.

Approximately 10% to 30% of people with Cushing’s syndrome will develop impaired glucose tolerance, while 40% to 45% will develop diabetes.

Corticosteroid medication is often prescribed to decrease inflammation throughout the body, but can lead to the development of Cushing’s syndrome and hyperglycemia because it activates specific enzymes that increase the conversion of non-carbohydrate molecules into glucose (gluconeogenesis). Corticosteroids also disrupt pancreatic cell function by inhibiting cell signaling pathways involved in the release of insulin from the pancreas.

Read other causes at https://www.verywellhealth.com/causes-blood-sugar-rise-in-non-diabetics-5120349

Long-acting Signifor Has Similar Safety Profiles as Twice-daily Treatment in Cushing’s Patients, Trial Showed

A long-acting, once-a-month treatment of Signifor (pasireotide) normalized cortisol levels in 40% of patients with Cushing’s disease whose disease had recurred after surgery, or who were not candidates for surgery, according to new data from a Phase 3 trial.

The safety profiles of the once-monthly regimen proved to be similar to standard twice-daily Signifor treatments, researchers found.

The study, “Efficacy and safety of once-monthly pasireotide in Cushing’s disease: a 12 month clinical trial,” was published in the journal The Lancet Diabetes & Endocrinology.

Novartis‘ Signifor in its twice-daily injection formulation has already been approved for treating Cushing’s in the U.S. and elsewhere.

The 12-month, Phase 3 trial (NCT01374906) was conducted at 57 sites in 19 countries. The study included 150 patients with Cushing’s whose cortisol levels had risen or not dropped at all after surgery, or who were unable to undergo surgery.

Between Dec. 28, 2011, and Dec. 9, 2014, participants were randomized to receive either 10 mg or 30 mg of Signifor every four weeks, via an injection to the muscle. If, after four months of therapy, cortisol urinary levels (mUFC) were 50% greater than the upper normal limit, the dose could be increased from 10 mg to 30 mg, or from 30 mg to 40 mg. It could also be increased after seven, nine, or 12 months if the mUFC concentration was greater than normal.

The goal was to normalize average concentrations of free cortisol in the urine to less than or equal to the upper normal limit at month seven. It was met by 31 of the 74 patients in the 10 mg group (41.9%) and 31 of the 76 patients in the 30 mg group (40.8%).

The most common adverse events were hyperglycemia (high concentration of blood sugar), diarrhea, cholelithiasis (gall stones), diabetes, and nausea.

The researchers consider this treatment to be a good option for patients whose disease has returned after surgery, or who cannot undergo surgery. The long-lasting treatment schedule of one injection per month is more convenient for patients than the twice-daily subcutaneous injection, making it more likely that they would not discontinue treatment.

“Surgical resection of the causative pituitary adenoma is the first-line treatment of choice for most patients with Cushing’s disease, which leads to remission in greater than 75% of patients if done by an expert pituitary surgeon,” wrote Dr. Andre Lacroix, MD, a professor in the Department of Medicine at the University of Montreal teaching hospital, and colleagues.

“However, surgery is not always successful, and disease recurrence can occur several years after initial remission, while some patients refuse or are not candidates for surgery. As a result, many patients require additional treatment options.”

“Long-acting pasireotide normalized mUFC concentration in about 40% of patients with Cushing’s disease at month 7 and had a similar safety profile to that of twice-daily subcutaneous pasireotide,” the team wrote in the study.

“Long-acting pasireotide is an efficacious treatment option for some patients with Cushing’s disease who have persistent or recurrent disease after initial surgery or are not surgical candidates, and provides a convenient monthly administration schedule,” researchers concluded.

From https://cushingsdiseasenews.com/2017/10/31/long-acting-signifor-for-cushings-disease-has-similar-efficacy-and-safety-as-twice-daily-treatment/

Silibinin from milk thistle seeds as novel, non-invasive treatment strategy for Cushing Disease

Silibinin has an outstanding safety profile in humans and is currently used for the treatment of liver disease and poisoning. Scientists at the Max Planck Institute of Psychiatry in Munich discovered in collaboration with scientists from the Helmholtz Zentrum München in cell cultures, animal models and human tumor tissue that silibinin can be applied to treat Cushing Disease, a rare hormone condition caused by a tumor in the pituitary gland in the brain. The researchers have filed a patent and now plan clinical trials using silibinin as a non-invasive treatment strategy. Thus, in future, patients might not have to undergo brain surgery anymore.
Treatment with silibinin, a constituent of milk thistle seeds, alleviated symptoms of Cushing Disease in cell cultures, animal models and human tumor tissue. In future, patients might not have to undergo brain surgery anymore.

Cushing Disease, not to be confused with Cushing’s Syndrome, is caused by a tumor in the pituitary gland in the brain. The tumor secrets increased amounts of the stress hormone adrenocorticotropin (ACTH) followed by cortisol release from the adrenal glands leading to rapid weight gain, elevated blood pressure and muscular weakness. Patients are prone to osteoporosis and infections and may show cognitive dysfunction or even depression. In 80 to 85 % of the patients, the tumor can be removed by uncomfortable brain surgery. For inoperable cases, there is currently only one targeted therapy approved, which unfortunately causes intense side effects such as hyperglycemia in more than 20 % of the patients.

Scientists around Günter Stalla, endocrinologist at the Max Planck Institute of Psychiatry in Munich, have now discovered in cell cultures, animal models and human tumor tissue that a harmless plant extract can be applied to treat Cushing Disease. “Silibinin is the major active constituent of milk thistle seeds. It has an outstanding safety profile in humans and is already used for the treatment of liver disease and poisoning,” explains Marcelo Paez-Pereda, leading scientist of the current study published in the renowned scientific journal Nature Medicine. After silibinin treatment, tumor cells resumed normal ACTH production, tumor growth slowed down and symptoms of Cushing Disease disappeared in mice.

In 2013, the Max Planck scientists filed a patent on a broad family of chemical and natural compounds, including silibinin, to treat pituitary tumors. Compared to humans, where only 5.5 in 100,000 people worldwide develop Cushing Disease, this condition is very common in several pets. For example, 4 % of dogs and even 7 % of horses suffer from Cushing Disease. Thus, the researchers now plan to test special formulations with a very pure substance and slow release of the active component silibinin in clinical trials.

Silibinin: Mode of action

“We knew that Cushing Disease is caused by the release of too much ACTH. So we asked ourselves what causes this over production and how to stop it,” says Paez-Pereda. In their first experiments, the researchers found tremendously high amounts of the heat shock protein 90 (HSP90) in tumor tissue from patients with Cushing Disease. In normal amounts, HSP90 helps to correctly fold another protein, the glucocorticoid receptor, which in turn inhibits the production of ACTH. “As there are too many HSP90 molecules in the tumor tissue, they stick to the glucocorticoid receptor,” explains Paez-Pereda. “We found that silibinin binds to HSP90 thus allowing glucocorticoid receptor molecules to dissolve from HSP90. With silibinin, we might have discovered a non-invasive treatment strategy not only for the rare Cushing Disease but also for other conditions with the involvement of glucocorticoid receptors, such as lung tumors, acute lymphoblastic leukemia or multiple myeloma,” concludes Paez-Pereda.

From http://www.psych.mpg.de/2034377/PM1507

Cushing’s syndrome vs simple obesity. How can a needle be found in the haystack?

Endocrinology Today 02/2015; 4(1):30-35.

Clinical recognition of Cushing’s syndrome should generally follow from the observation of a constellation of compatible clinical features that progress over time. Screening for Cushing’s syndrome in patients with individual features of the metabolic syndrome, such as obesity, hypertension and hyperglycaemia, is not recommended.

Early diagnosis reduces unnecessary suffering and the ultimate lifetime sequelae of Cushing’s syndrome. Confirmation involves the demonstration of biochemical hypercortisolism, and the extent of diagnostic testing needs to be based on the degree of clinical suspicion.
Read the whole article here, in PDF format

Higher Doses of ‘Abortion Pill’ Safe in Cushing’s?

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

LAS VEGAS — Higher doses of mifepristone for Cushing’s disease (Korlym) weren’t associated with increases in serious adverse events, researchers reported here.

Korlym is a glucocorticoid receptor antagonist better known as RU-486, or the “abortion pill.” It was approved for treating hyperglycemia associated with Cushing’s disease in 2012.

In an analysis of data from the SEISMIC trial, Dat Nguyen, MD, and colleagues found that similar percentages of patients had serious adverse events across all doses of the drug, reported.

They also reported at the American Association of Clinical Endocrinologists meeting here, that the proportion of the four most common adverse events — headache, fatigue, nausea, and hypokalemia — fell off after 10 weeks of the 24-week trial.

“Recent prescription data indicate that many physicians are not titrating beyond 300 mg per day, potentially limiting patients’ clinical response,” the researchers said.

The 2012 approval was based on the SEISMIC study, which followed 50 Cushing’s disease patients over 24-weeks in an open-label format. It found that daily doses improved blood sugar control and reduced insulin requirements.

Clinicians participating in the trial were told they could titrate beyond the starting dose of 300 mg a day. To look at the relationship between dose and safety, as well as response, Nguyen and colleagues looked at data on 40 of the patients who responded to therapy.

Most of them (90%) were taking at least 600 mg a day, 68% were taking at least 900 mg per day, and 44% took 1,200 mg daily.

Most of the responders (85%) had their initial clinical response at a dose of at least 600 mg daily.

Overall, there were 26 serious adverse events:

  • 10 at the 300 mg dose
  • 8 at the 600 mg dose
  • 3 at the 900 mg dose
  • 3 at the 1200 mg dose
  • 2 while off drug

 

When the researchers adjusted for the number of patients who had ever reached a given dose, the frequency of serious adverse events was similar across doses:

  • 10% of patients at 300 mg
  • 16% of patients at 600 mg
  • 15% of patients at 900 mg
  • 14% of patients at 1200 mg

 

The four most common adverse events decreased after week 10 – although that tracked an increase in dose (mean 588 mg/day before week 10 versus 895 mg/day thereafter).

Nguyen and colleagues concluded that higher doses of mifepristone weren’t associated with increases in serious adverse events or in the most common adverse events – and that better response was seen with higher doses.

Korlym was developed by Corcept Therapeutics of Menlo Park, Calif., as an orphan drug given that it is is believed only 5,000 patients are eligible for treatment. That gave the company 7 years of exclusive rights to market the agent for Cushing’s disease.

The label limits the drug’s indication to patients with endogenous Cushing’s disease who have type 2 diabetes or glucose intolerance and aren’t candidates for surgery, or failed to respond to surgical intervention.

The drug doesn’t reduce cortisol production but prevents it from binding to its receptor – an action separate from its blockade of the progesterone receptor, which makes it an effective agent in abortion.

Since the daily doses are in the same range as those used to induce abortion, the drug is contraindicated in pregnant women. It also carries a boxed warning that the drug will terminate a pregnancy.

From http://www.medpagetoday.com/MeetingCoverage/AACE/45790

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