Looking for a Zebra: Pay Attention for Signs of Atypical Diabetes

Miriam E. Tucker

August 17, 2021

It's important to be alert for signs that a person with diabetes might be among the minority, of around 5%, who have an atypical type, as the correct diagnosis can have major implications for their management. 

About 90% of people with diabetes have type 2 and another 5% have type 1.

The remaining 5% — 1 in every 20 patients with diabetes — has another type, which can be difficult to distinguish from the more common types. These include monogenic diabetes and diabetes that is secondary to other conditions including diseases of the exocrine pancreas, endocrinopathies, or infections, drug or chemical-induced, or other genomic syndromes associated with diabetes.

In a talk on August 12 at the virtual meeting of the Association of Diabetes Care & Education Specialists, Ji Chun, an endocrine physician assistant in Orange County, California, described examples of atypical diabetes, when to suspect that a patient might have it, and how making the right diagnosis affects management. He also discussed latent autoimmune diabetes of adulthood (LADA), a form of type 1 that is often misdiagnosed as type 2 because of its slower and later age of onset.

"Routine screening to find these 5% zebras will not be cost-effective, so we need to pay attention to those who present with unusual features...Early recognition of these uncommon causes of hyperglycemia can change the course of disease and patients' quality of life," Chun emphasized.

He presented the case of an actual patient, a 51-year-old woman referred to him with new-onset diabetes. She had an A1c of 10.6%, fasting glucose of 290 mg/dL, body mass index (BMI) of 27 kg/m2, and blood pressure of 132/78 mmHg, and was taking lisinopril 10 mg/day but had no significant dyslipidemia.

Her primary care physician had diagnosed her with type 2 diabetes and had started her on metformin 1000 mg twice a day. Ultimately, that diagnosis wasn't the whole story (see box).

What Happened to the Case?

When Chun first saw his patient, he prescribed her basal insulin and instructed her on titration. She also self-initiated a low-carbohydrate diet. When she returned a week later, she had a dramatic improvement in glucose levels and had lost 7 pounds in addition to the 7 pounds she'd lost after being diagnosed. She complained of nausea and diarrhea, so Chun switched her to extended-release metformin, then lowered her metformin dose.

She self-discontinued the insulin after having one episode of hypoglycemia, then stopped taking the metformin as her glucose numbers were good and she still had diarrhea. When she returned to see Chun after about 2-3 weeks, she'd lost another 10 pounds and continued to report nausea and diarrhea despite being off metformin.

That's when Chun became alarmed.

He ordered a CT of her abdomen, which revealed pancreatic cancer. She died within 4 months after he first saw her.

Pancreatic cancer should be suspected when there is:

  • Rapid onset or worsening of diabetes without known cause

  • Abnormal weight loss

  • Abnormal liver/biliary tests and/or jaundice

But even then, Chun said, "these are all late signs of pancreatic cancer and the prognosis is very bad and they deteriorate very fast."

He's actually had seven such patients referred to him for diabetes management who he diagnosed with pancreatic cancer. Four have died.

However, "I do have three who did surprisingly well. We caught them at an earlier stage, and to my knowledge they're still alive...Remember these signs, and if you see them, be sure to screen them or alert your team member to do so."

LADA: Several Clues Signal the Need for Autoantibody Testing

Neither age nor body weight is a reliable indicator of even the two common types of diabetes, as heavier youth are now developing type 2 and adults of any body size can develop type 1.

"Since more and more patients are gaining weight and metabolic syndrome is so prevalent, we tend to default patients who present with diabetes into type 2 diabetes without having a second guess," Chun noted, adding that the most diagnostic confusion and misclassification usually arise in people who develop diabetes between the ages of 20 and 40 years. 

LADA, also known as type 1.5 diabetes, is an autoimmune condition that progresses more slowly to insulin dependence than does classic type 1. But taken together, 60% of patients who develop LADA or classic type 1 do so after the age of 20 years.

Features that signal the possibility of autoimmune diabetes include:

  • Younger age (< 40 years)

  • Leaner (BMI < 25 kg/m2)

  • Personal or family history of an autoimmune disorder

  • More acute presentation/catabolic state

  • Unresponsive to non-insulin therapy

  • Rapid progression to insulin therapy

In these situations, autoantibody testing is indicated. Chun recommended ordering tests for antibodies to glutamic acid decarboxylase (GAD) and one other, usually either islet cell or zinc transporter 8 autoantibody. Insulin autoantibodies can be ordered, but not in patients who are already taking insulin because autoantibodies can develop to exogenous insulin, he noted.

C-peptide can also be ordered as a supplemental test to assess beta-cell reserve, but it's not diagnostic and should only be measured after glucotoxicity is resolved (< 225 mg/dL). A positive autoantibody test plus C-peptide < 1.0 ng/mL signals that the person has type 1 diabetes/LADA and needs basal-bolus insulin therapy. 

Recognition of Monogenic Diabetes Can Dramatically Alter Treatment

There are many single-gene mutations of either beta-cell function or insulin receptors that cause hyperglycemia.

Maturity-onset diabetes of youth (MODY) is a set of mutations of beta-cell function that accounts for about 1%-2% of all diabetes, but more than 80% of cases are undiagnosed or misdiagnosed as either type 1 or type 2. Approximately 1% of presumed type 1 and 4%-5% of type 2 diabetes diagnosed in adults younger than 45 years of age is actually monogenic diabetes.

While 1%-2% doesn't seem like a lot, it means that most clinicians who see a large number of patients with diabetes will have a few with MODY that they may not recognize.

"I know I'm missing some of these patients," Chun commented.

The diagnosis of MODY is important because it can dramatically alter treatment, depending on the type. Six types account for 99% of MODY cases and types 1-3 for more than 90%.

In type 2, hyperglycemia is mild and stable and doesn't lead to microvascular or macrovascular complications, so these patients don't need any treatment.  

In types 1 and 3, glycemic control does tend to worsen and they can develop complications, but they tend to respond very well to sulfonylureas and don't need insulin.

"With the proper diagnosis they could be on just once a day oral medication instead of intensive insulin therapy. Does that make a difference? Oh yes," Chun said.  

Type 5 presents similarly to 1 and 3 but doesn't respond as well to sulfonylureas, so these patients do need insulin early on. Still, because inheritance is 50%, having the correct diagnosis can be helpful to family members.

Monogenic diabetes should be suspected with the following:

  • Diabetes onset < 6 months of age

  • Diabetes without typical features of type 1 or type 2 (ie, negative autoantibodies, nonobese, especially with a strong family history of diabetes)

  • Stable/mild fasting hyperglycemia (100-150 mg/dL) and stable A1c (5.6%-7.6%), especially if nonobese

Genetic panels can be costly, in the $5000-$6000 ballpark. But some private genetic testing companies offer tailored testing at a lower price, around $200-$900, depending how many different genes are being tested, Chun said.

With Some Endocrinopathies, Hyperglycemia May Be the Only Sign

There are many endocrine disorders other than diabetes that can cause secondary hyperglycemia.

But with some of these, the primary diagnosis may not be obvious and "hides behind the diagnosis of diabetes," Chun said.

Individuals with endogenous hypercortisolism/Cushing syndrome will have hyperglycemia but may not exhibit the obvious classical signs, including moon-shaped face, fat pad on the back of the neck (buffalo hump), thin and/or purple striated skin, easily bruised, and pendulous abdomen with thin extremities. Or, those signs can be subtle.

Those with milder cases of endogenous hypercortisolism may simply present with hyperglycemia, hypertension, depression, and/or fatigue, "just like anyone else we see on a daily basis," Chun noted.

Here, an index of suspicion is warranted if a patient diagnosed with diabetes has advancing disease despite adherence to lifestyle intervention and pharmacotherapy, refractory hyperglycemia, and hypertension despite polypharmacy.  

Asking a patient to show you an older photo of themselves — commonly available today on cell phones — may allow you to appreciate the subtle physical changes over time, he advised.  

For those in whom Cushing syndrome is suspected, tests for endogenous hypercortisolism include:

  • 1 mg overnight dexamethasone suppression test — the most sensitive

  • Midnight salivary cortisol

  • 24-hour urine free cortisol

A random cortisol test should not be used to screen for hypercortisolism, he noted.

Acromegaly is another endocrinopathy that can cause secondary hyperglycemia and may be missed. The condition is due to excess growth hormone secretion, most commonly from pituitary adenomas. By the time they're diagnosed, most of these tumors are large (> 1 cm). 

Early signs of acromegaly are usually nonspecific, such as fatigue, weakness, mood changes, and hypogonadism. Hallmark signs such as enlarged hands, feet, and facial features usually don't appear until later, which explains why most cases are diagnosed long after onset. Before-and-after photos can be helpful here as well.

Screening should be for insulin-like growth factor-1 (IGF-1), not a random growth hormone test, due to the high false-negative rate with the latter.

Exocrine Disorders of the Pancreas: "Bronze Diabetes" and Cancer

Hemochromatosis, a condition of iron overload, can lead to toxicity in many parenchymal organs including the pancreas. It has an incidence of 1 per 200-500 people, mostly of northern European origin.

The iron can also deposit in skin causing hyperpigmentation and leading to the term "bronze diabetes." In addition, patients may have elevated liver enzymes, an enlarged heart, hypogonadism, fatigue, and joint pain.

Transferrin saturation and ferritin should be screened for.

Pancreatic cancer can also be the culprit, as with the patient case.

Chun has reported being on an advisory board for Novo Nordisk and is an employee of Corcept Therapeutics.

Virtual meeting of the Association of Diabetes Care & Education Specialists. Presented August 12, 2021.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR's Shots blog, and Diabetes Forecast magazine. She is on Twitter: @MiriamETucker.

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