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Twenty-five million Americans have type 2 diabetes, 2 to 3 million have type 1 diabetes, and between 500,000 and 750,000 have monogenic diabetes (Philipson 2010), which includes maturity onset diabetes of the young or MODY (see sidebar, page 9).
Subspecialists like monogenic diabetes expert Louis H. Philipson, MD, PhD, would like to retire the term “MODY.”
“Maturity-onset diabetes of the young makes it seem like these patients are getting type 2 diabetes earlier, and that’s not what’s going on,” says Philipson. “They’re getting diabetes because they have specific defects in their beta cells based on a single gene mutation, and each gene mutation has its own characteristics. Almost all of them result in decreased insulin secretion without increased insulin resistance. The name MODY was created primarily to distinguish these syndromes from type 1 diabetes, with its associated complete absence of insulin. But it’s much more informative to say what that gene mutation is. MODY is better referred to as monogenic diabetes.”
But MODY is still in common usage. It’s also easier to say “MODY 3” than “HNF4a gene mutation.”
There’s no shortage of information about monogenic diabetes, and the search continues for additional gene mutations that cause it. But many primary care physicians and endocrinologists are unaware of this condition and how to diagnose and treat it.
The prevalence of monogenic diabetes is estimated at 1 to 3 percent of all diabetes cases in the United States (Philipson 2010). As the incidence of type 2 diabetes continues to skyrocket, awareness of monogenic diabetes is also growing.
Louis H. Philipson, MD, PhD, professor in the Department of Medicine, University of Chicago Pritzker School of Medicine and director of the Kovler Diabetes Center, estimates that only 10 percent of Americans with monogenic diabetes are correctly diagnosed.
“Endocrinologists and diabetes specialists cannot see all patients with diabetes,” Philipson notes. “There are just too many of them and not enough of us.”
Fortunately, seeing Philipson is how Maribeth, a 45-year-old suburban Chicago high school art teacher, and her son Dylan finally received appropriate treatment.
Maribeth e-mailed Philipson when her mother called her about a radio interview featuring 6-year-old Lilly Jaffe, another of Philipson’s monogenic diabetes patients. Lilly’s tale sounded similar to what Maribeth and Dylan were experiencing back in 2007.
Married with four children, Maribeth’s first two pregnancies were uneventful, but when she was carrying Dylan in 2001, she was diagnosed with gestational diabetes.
“During my fourth pregnancy, I was diabetic from the beginning, and it was very difficult to control,” she recalls. “Between diabetes and high blood pressure, I was put on bed rest the last three months.”
Maribeth was checking her blood glucose up to 12 times a day as her physician and her nutritionist tried unsuccessfully to control what they thought was type 2 diabetes using injectable insulin and oral antihyperglycemics and moderating her diet.
“I felt so bad that my husband and I were thinking that I probably had just a few years to live,” she says. “My [blood glucose] numbers were going up and down, and I was so tired all the time — just exhausted.”
Meanwhile, Dylan, age 5 at the time, was constantly thirsty, urinating frequently, losing weight, and not looking well. His fasting blood glucose was borderline high, but he tested negative for type 1 diabetes glutamic acid decarboxylase antibodies. Dylan’s pediatric endocrinologist advised watchful waiting.
Then, a second pediatric endocrinologist established that Dylan’s hemoglobin A1c scores were between 6 and 7 (10 to 12 or higher are typical of newly diagnosed type 1 diabetes), but his post-meal blood glucose levels were high. A regimen of diluted insulin injections was prescribed, but the breakthrough came when this physician suspected monogenic diabetes and sent a blood sample to Athena Diagnostics for genetic analysis.
When Athena confirmed that Dylan had a glucokinase mutation (MODY2), the rest of the family was tested for this dominantly inherited disease. Maribeth and Dylan were the only family members with monogenic diabetes. The pediatric endocrinologist had facilitated a definitive diagnosis with a genetic test, but “didn’t quite know how to treat Dylan,” in Maribeth’s words. She and her husband were considering an implantable insulin pump for Dylan. That’s when she heard about Philipson’s radio interview.
“We went down to the University of Chicago to see Dr. Philipson, and it was just amazing because he knew just what was going on with me and with my son,” she recalls.
She admits to misgivings when Philipson recommended discontinuing all her and her son’s medications. Dylan appeared to be stable and thriving on diluted insulin injections, but Maribeth was on multiple medications and still “feeling lousy.”
Working with Maribeth’s nutritionist, along with endocrinologist Robert Sobel, MD, both at Chicago’s Northwestern Memorial Hospital, Philipson weaned Maribeth and Dylan off all medications, even though Maribeth was still gaining weight. Today, Dylan is thriving and Maribeth is on once-a-day liraglutide [rDNA origin] injection (Victoza) and a controlled diet. Says Maribeth, “I
A correct diagnosis of monogenic diabetes could save payers and employers a significant amount of money.
feel like I’ve been given a second chance at life.”
“As a nonprogressive disease with near-normal average blood sugars, the accepted treatment for most patients with a GCK mutation causing MODY2 is to do nothing,” Philipson says. “Yet, we see over and over again patients on four or five drugs or on insulin, and kids on four shots a day or insulin pumps. These patients are not obese or have any evidence of autoimmunity and often have a family history with a similar kind of picture, and if you treat them with insulin or other medications, their average blood sugar hardly changes.”
So why is Maribeth on liraglutide? Although Philipson says that Maribeth would do very well without it, Sobel, a former student of Philipson’s, “is OK with me being on it,” says Maribeth.
Maribeth and Dylan are lucky. The other monogenic diabetes subtypes, the more common of which are referred to as transcription factor diabetes, aren’t as easy to treat.
A mutation in the HNF4A gene (MODY1) is associated with severe progressive hyperglycemia and microvascular disease, and a mutation in HNF1A (MODY3) also includes hypertension and abnormal lipids. A mutation in HNF1B (MODY5) is characterized by severe progressive hyperglycemia, renal abnormalities, and genital malformations, and may require replacing endocrine and exocrine pancreatic functions. Both HNF4A (MODY1) and HNF1A (MODY3) are responsive to inexpensive oral sulfonylurea therapy.
“Sulfonylureas are the absolute cheapest, oldest form of treating diabetes, says Philipson. The HNF1A and HNF4A subtypes are particularly responsive, he says, requiring very small doses of sulfonylurea. “For these folks, it certainly would be easier to treat them with a pill that would be about 100-fold less expensive than insulin therapy.”
Diagnosis and treatment of monogenic diabetes is clearly beneficial for patients, but it also can be good for physicians, employers, and payers.
If you’re a physician, you’ll treat your patients more effectively and develop an even bigger reputation for diagnostic acumen. If you’re an employer or a payer, a correct diagnosis of monogenic diabetes matters because a typical regimen for type 1 and type 2 diabetes typically includes a blood glucose meter, multiple anti-hyperglycemic drugs, and injectable insulin. And that’s not counting office consults and emergency room visits for hypoglycemic episodes. Multiply that by a potential 1.4 million mis-diagnosed Americans, and you’re talking real money.
“We need to get the word out,” says Philipson. “Train the generalists as best we can, see patients who are not doing well, and send them back to the generalists to continue taking care of them.”