Update on Diabetes

ONE OF THE earliest diseases described in classical antiquity, diabetes has been a human malady throughout written history. The Egyptian physician Hesy-Ra wrote of a condition of too-frequent urination in 1552 B.C. The term “diabetes” — meaning “to siphon” — was first used in 250 B.C. by Apollonious of Memphis, an ancient Greek physician.¹ Four hundred years later, Greek physician Aretaeus described the condition as “the melting down of flesh and limbs into urine.” By the Middle Ages, the disease was formally known as diabetes mellitus (the Latin word for honey added to indicate the urine of patients was known to be sweet after it was observed ants were attracted to the urine of diabetics).²

In 1776, English physician Matthew Dobson noted there were two types of diabetics: those who perished in as little as five weeks, and those who lasted for decades, but were never cured.¹ His was the first classification of diabetes into types 1 and 2. In 1889, the first major advance in understanding and treating diabetes occurred when two doctors in Strasbourg, France, discovered that removing the pancreas from a dog led to symptoms of diabetes. Just over a decade later, German researcher Georg Zuelzer found injecting extract from the pancreas eased the symptoms of diabetes.² Then, in 1922, Canadian physician Frederick Banting successfully treated a diabetic dog with insulin extracted from another dog,² for which he shared the Nobel Prize in Medicine with John James Rickard Macleod, in whose laboratory the work was done.³ Soon after, a higher-quality insulin was extracted from cattle and made commercially available. The first synthetic insulin was produced in 1978.⁴

More than three millennia after diabetes was first described, we understand the mechanisms of the disease, and we can use insulin to stop it from killing patients in the short term. But, we still don’t have a cure or an effective way to prevent its onset. It remains a serious, debilitating disease that shortens lifespans and negatively impacts a patient’s quality of life.

What Is Diabetes?

Diabetes mellitus is any condition in which there is too much sugar in the bloodstream.⁵ It is generally caused by the pancreas not producing enough insulin, a protein used to stimulate the passage of glucose from the blood into the cells of surrounding tissues. In some cases, it is caused by insulin resistance, which occurs when the tissues of the body are unresponsive to the presence of insulin and, therefore, unable to extract glucose from the blood.

The Centers for Disease Control and Prevention (CDC) estimates 29 million (approximately 9 percent) Americans have some form of diabetes, and up to one-quarter of them are not yet diagnosed. More than one-third of adult Americans have prediabetes, 90 percent of whom are unaware of it.⁶ Further, a 2011 study published in the British journal The Lancet found rates of diabetes are rising across the globe.

The vast majority of patients (CDC estimates between 90 percent and 95 percent) with diabetes will develop the version known as type 2.⁷ Although less severe than type 1 because the pancreas still makes insulin, just not enough, and the body is less efficient at using it, 8 type 2 diabetes generally manifests during adulthood and can be treated with diet and exercise in its early stages.

Type 1 diabetes is an autoimmune disease that occurs when the body’s immune system mistakenly attacks the pancreas, destroying the beta cells that produce insulin.⁹ Typically appearing during childhood or adolescence, it is fatal within weeks if left untreated.

Even rarer than type 1 diabetes is a handful of other variants of the disease:

• Gestational diabetes: Expectant mothers may develop diabetes that goes away after delivery.¹⁰ Patients who have had gestational diabetes are at higher risk of developing type 2 diabetes later in life, as is the unborn child.
• Neonatal diabetes mellitus: With this rare condition (one in every 100,000 to 500,000), the baby develops diabetes in the first six months of life. In about half of these cases, the condition is permanent.¹¹ When the condition persists, it is called permanent neonatal diabetes mellitus. In the other half whose condition subsides, it is known as transient neonatal diabetes mellitus.
• Maturity-onset diabetes of the young (MODY): This form of diabetes is hereditary and is caused by one of a handful of mutations that prevent the pancreas from producing enough insulin.¹¹
• Cystic-fibrosis-related diabetes: Patients with cystic fibrosis often develop diabetes when the thick mucus the body produces in response to the disease causes scarring of the pancreas, interfering with production of insulin.¹²

• Diabetes can also manifest as a symptom or complication of other diseases, ranging from Cushing’s syndrome to hemochromatosis, pancreatic cancer and hyperthyroidism.¹³

While the discovery that insulin can be used to manage the disease changed the prognosis of type 1 diabetes from one of imminent death to a chronic disease, mortality rates for diabetics remain much higher than for the general population. Even when being successfully managed with insulin, diet and exercise, diabetes continues to exact a toll on the circulatory system, nervous system, kidneys and eyes.¹⁴ It is the leading cause of both amputation and adult-onset blindness in the U.S.⁶

Diabetes was the seventh-leading cause of death in the U.S. in 2015 (79,835 deaths were attributed primarily to diabetes), and was listed as a contributing cause of death on another 252,806 death certificates.¹⁵ It is generally thought that types 1 and 2 diabetes shorten lifespan by about 20 years and 10 years, respectively.¹⁶ However, some recent studies show modern treatment regimens may be significantly lowering mortality.¹⁷

Causes ofDiabetes Researchers do not yet fully understand how or why most cases of diabetes develop. Type 1 diabetes has been shown to be an autoimmune disorder, but the specific triggers — whether environmental or reaction to an infection — are not yet fully known. Type 2 diabetes, accounting for the vast majority of diabetes cases, is thought to be the result of several factors, from genes to lifestyle.¹³ It is the least understood manifestation of the disease.

Researchers believe gestational diabetes is caused by a combination of hormonal changes during pregnancy, genetic predisposition and overall health factors.¹³ MODY and neonatal diabetes mellitus are both monogenic forms of the disease caused when a single gene mutation prevents the body from producing or reacting appropriately to insulin.

In rare instances when diabetes is the result of another disease, such as with cystic fibrosis-related diabetes, the underlying health issue is the immediate cause. These include:

• Cancer of or physical trauma to the pancreas, negatively impacting its ability to produce insulin;
• Cushing’s syndrome causing the body to produce too much cortisone, which lessens the ability of the liver and skeletal muscles to respond to insulin;¹⁸
• Acromegaly (a disorder caused when the pituitary produces too much growth hormone), which overstimulates production of insulin and, in rare cases, induces insulin resistance;
• Hemochromatosis (a disorder caused when the body stores too much iron), which can cause organ damage, including to the pancreas; and
• Certain drugs that can either harm the beta cells that produce insulin in the pancreas, or disrupt insulin’s normal activity in the body. These include niacin (vitamin B3), diuretics, anti-seizure drugs, psychiatric drugs, drugs that treat HIV, pentamidine, anti-rejection medications and glucocorticoids.¹³

Symptoms and Progression of Diabetes

Since the term “diabetes” is used to describe high blood sugar and not its underlying cause, all forms of diabetes will have similar symptoms. However, symptoms of type 1 diabetes typically manifest over a course of weeks, while type 2 diabetes may take years to become noticeable. Symptoms often include:¹³

• Frequent urination
• Increased thirst
• Hunger pangs
• Fatigue
• Numbness or tingling in the extremities
• Sores that will not heal
• Sudden weight loss
• Blurred vision

Even properly treated, diabetes is a progressive disease. Over time, the risks of complications include:¹⁴

• Cardiovascular disease: High levels of glucose in the bloodstream cause damage to blood vessels over time. Diabetics have a higher risk of experiencing a heart attack or stroke.
• Kidney disease: The same blood vessel damage that can cause cardiovascular disease can also damage the kidneys, up to and including kidney failure requiring dialysis or transplant.
• Nerve damage: Damage to the capillaries that feed nerves can lead to loss of feeling in the hands and feet (and ultimately tissue damage that may require amputation to prevent infection), as well as problems with digestion. Men may suffer erectile dysfunction.
• Impaired vision: Deteriorating blood vessels can lead to a damaged retina. Diabetics are also at higher risk of cataracts and glaucoma.
• Impaired hearing: Blood vessel damage can affect the inner ear. Side effects of gestational diabetes may include preeclampsia in the mother, and excess growth and low blood sugar in the developing child, as well as an increased risk for the child to develop type 2 diabetes later in life.¹⁴

Symptoms for the above side effects and complications will manifest as the diabetes progresses, and will be consistent with those diseases.

Diagnosing Diabetes

The American Diabetes Association recommends screening the following individuals for diabetes and prediabetes, with or without symptoms: ¹⁹

• Everyone 45 and older, with a retest every three years, and
• Anyone with a body mass index above 25 if they have any additional risk factors, including a sedentary lifestyle, high blood pressure, high cholesterol, a history of ovarian cysts or having delivered a baby that weighed more than 9 pounds.

Prediabetes is defined as having a higher-than-normal blood sugar count, but not as high as full-blown type 2 diabetes.

Certain ethnic groups have a higher incidence of diabetes, including African Americans, Alaskan natives, native Americans, Asian Americans, Latinos and Pacific Islanders (including Hawaiians).¹³

Hyperthyroidism, an autoimmune disease, is another risk factor. Indeed, any time a patient is dealing with an autoimmune disease, he or she is at a higher risk for developing other autoimmune diseases. And, while no causal link between hyperthyroidism and type 1 diabetes has yet been discovered, there is a high correlation.²⁰

All pregnant women should be tested for gestational diabetes, rechecked throughout pregnancy and checked after giving birth to ensure blood sugar levels have returned to normal levels.²¹

A diabetes diagnosis can be made using the glycated hemoglobin (A1C) blood test, which measures a patient’s average blood sugar level. For pregnant patients and those with a nonstandard version of hemoglobin in whom the A1C test may not be accurate, other blood sugar tests can be performed.

Treating Diabetes

The first course of treatment for every case of diabetes is to institute a healthy diet and maintain regular exercise. Depending on the type of diabetes, this may be augmented with daily glucose testing and insulin. Other medications may also be used to help manage symptoms of associated conditions such as high blood pressure or cholesterol.

Those with type 1 diabetes will require insulin to regulate their blood sugar since their pancreas is not producing any insulin. Insulin use requires a testing kit so patients can monitor their blood sugar levels on a daily or more frequent basis and adjust the insulin doses accordingly.²²

Type 2 diabetes and gestational diabetes patients are often able to control their disease with diet and exercise alone. However, over time, these patients are more likely to require insulin. And, if the expectant mother’s blood sugar can’t be regulated successfully with diet and exercise, insulin may be prescribed.

A healthy diet — one low in processed sugars and trans fats — can help the body self-regulate blood pressure and cholesterol, and prevent swings in blood sugar levels.²² Combining a dietary plan with regular exercise can also help maintain a healthy weight, which will help slow the onset of any complications. Since exercise helps the body move more sugar from the bloodstream to muscle cells, regular exercise increases the body’s efficiency by encouraging more insulin production and by making the body more receptive to insulin.²³

Some patients may be prescribed drugs to promote more insulin production or slow the liver’s production of glucose. Metformin is usually the first drug prescribed for type 2 diabetes to slow the production of glucose. It may also be used for those with prediabetes to reduce the risk of developing diabetes.²³

In very rare cases, a pancreatic transplant may be called for if patients with type 1 diabetes cannot be successfully managed with insulin. However, due to the side effects of the lifelong anti-rejection drugs, this is typically only recommended when a kidney transplant is already scheduled.²³

Neonatal diabetes can be treated with insulin or glibenclamide, which promotes the production of more insulin in the pancreas.²⁴ For those whose diabetes is the result of another underlying issue, treatment will have to be coordinated with treatment of the original condition. However, controlling blood sugar levels is critical no matter the original cause.

Preventing Diabetes

CDC estimates fully a third of adults have prediabetes. Healthy meals, regular exercise and weight control are the best methods for reducing the risk of developing full-blown type 2 diabetes.²⁵ And, there is some evidence that metformin may further reduce the risk, but this remains under study. CDC has launched the National Diabetes Prevention Program (www.cdc.gov/diabetes/prevention/index.html), which provides a host of materials physicians can use when treating patients.

There is no way to prevent type 1 diabetes or any type of diabetes with a genetic cause. However, the risk of developing gestational diabetes can be reduced with the same methods used for prediabetes. For instances of diabetes caused by other conditions, controlling those diseases remains the best course for reducing the risk of developing diabetes as a complication.

Ongoing Research

Given how widespread diabetes is and the serious complications arising from it, it is no surprise there are thousands of ongoing studies looking at prevention, treatment and cures. ClinicalTrials.gov listed more than 12,000 diabetes-related studies either recently completed or ongoing as of early fall 2017.

Among the more interesting studies is a potential vaccine entering clinical trials in 2018 that would target an enterovirus thought to play a critical role in triggering type 1 diabetes in children.²⁶ And, a possible cure for type 1 diabetes is the goal of a study looking at whether a combination of the anti-rejection drug anti-thymocyte globulin and the anti-cancer drug pegylated G-CSF can help restore insulin production.²⁷

Hundreds of new approaches to treatment are also being studied:

A Brazilian study is looking at whether regular exercise can restore blood vessel performance.²⁸ And, a U.S. study is investigating whether an electronic device can use visible light to measure biomarkers in the skin to diagnose diabetes without the need to draw blood.²⁹

Intravenous immune globulin (IVIG) is being studied to see if it can relieve symptoms of diabetes-related neuropathy (nerve disease). The University of Toronto was recruiting volunteers at press time for a study of the efficacy of IVIG in treating peripheral neuropathy in diabetics.³⁰ A 2010 study conducted at Nagoya University in Japan showed patients with multifocal diabetic neuropathy gained significant pain relief with IVIG therapy (however, those with symmetric neuropathy did not).³¹ And, a team at the University of Verona in Italy found that IVIG was effective in quickly relieving pain in patients with diabetic lumbosacral radiculoplexus neuropathy.³²

A California pharmaceutical company is studying their proposed new drug, Sotagliflozin (or LX4211), to see if it can help lower insulin resistance.³³

Also under review are the efficacy of public education campaigns and better training for medical professionals.

Looking Ahead

Although diabetes was one of the first diseases identified in history, having been with us since biblical times, there is no cure or vaccine for the disease yet. While promising leads are in the pipeline that will hopefully bring new treatments and perhaps even a cure, for now, physicians will continue to work with patients to construct healthy approaches to managing the disease, minimizing its complications and extending a high quality of life for as many years as possible.