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MODY: An Insulin Sensitive Form Of Monogenic Diabetes Often Misdiagnosed As Type 2

Jan 8, 2008

MODY: An Insulin Sensitive Form Of Monogenic Diabetes Often Misdiagnosed As Type 2 Janet Ruhl, Type 2 1998-2006, MODY 2006-2007

MODY: An Insulin Sensitive Form Of Monogenic Diabetes
Often Misdiagnosed As Type 2
Janet Ruhl, Type 2 1998-2006, MODY 2006-2007

NIH statistics reveal that almost 20% of all people diagnosed with Type 2 diabetes are not overweight. Some of these people have little or no response to the drugs that lower insulin resistance like metformin or Actos. And while some of these people can control their blood sugar with a very low carb diet, others find that even when they eat very few grams of carbohydrate their blood sugars remain significantly higher than normal.

Despite their diagnoses, many of these people don’t have Type 2 diabetes at all. Instead they may have a third kind of diabetes–a diabetes caused by one of several different genetic flaws that affect the beta cell’s ability to secrete insulin in response to rising blood glucose levels.

For historical reasons this kind of diabetes is currently called MODY, which an acronym for “Mature Onset Diabetes of the Young.” The name is unfortunate, as research conducted in the past five years has made it clear that MODY can be diagnosed in people up to 55 years old and that the “mature onset diabetes” it refers to is not the insulin resistant “adult onset” diabetes we now call “Type 2.” People with MODY, unlike those with classic Type 2 diabetes, are extremely sensitive to insulin.

MODY is monogenic–you only need one defective gene to develop the disorder–so doctors have long believed that people who did not have a parent diagnosed with diabetes could have MODY. This is one reason why many normal weight people with diabetes who otherwise fit the profile for MODY do not get tested for it.

But this belief also turns out to be false. Now that gene testing has become easy and relatively cheap, researchers who have tested relatives of people diagnosed with MODY have discovered that a significant number of these relatives carry the MODY genes but maintain blood sugar levels that do not meet the diagnostic criteria for diabetes.

It appears that environmental factors can modify the expression of the MODY genes so that they can produce anything from pre-diabetes to a diabetes that produces blood sugars so high that it is misdiagnosed for Type 1.

That said, people with MODY usually have some close family members who have been diagnosed with some form of diabetes, either Type 1 or Type 2, even if neither parent has been diagnosed.

The salient points to keep in mind when considering whether MODY might explain a particular patient’s diabetes are these:

1. People with MODY are extremely sensitive to insulin. A dose of as little as two units may have a strong effect on their blood sugar.

2. People with MODY, no matter how high their blood sugars might be after meals, may have near normal fasting C-peptide levels. This is because the defects characteristic of MODY does not affect basal insulin secretion but only the ability to secrete insulin as blood sugars rise after eating.

3. People with MODY do not have GAD or islet antibodies. Though people with severe expressions of MODY genes may be misdiagnosed in their teens with Type 1 diabetes, they can be distinguished from true Type 1s by the very low doses of insulin they need and the lack of the autoimmune antibodies.

4. People with MODY may respond extremely strongly to sulfonylurea drugs. These drugs are often prescribed as the appropriate treatment for MODY. However, these drugs¬† are most effective for people whose severe expression of these genes causes blood sugars high enough to be mistaken for Type 1 diabetes. For those whose MODY is milder, even 1/4 of a 1 mg tablet of Amaryl may cause a dramatic hypo. For these people the use of very small doses of insulin–no more than 2 to 4 units per meal–is more effective and more easily tailored to varying food intake.

5. MODY should always be suspected in a woman of normal weight who develops gestational diabetes early in a pregnancy and who tests negative for autoimmune antibodies. This is often how MODY first reveals itself.

6. The different forms of genetic diabetes that are lumped together under the heading of MODY have different complication profiles. The two most common forms are MODY-3 caused by a defect in HNF1-a and MODY-2 caused by a defect in the glucokinase gene GCK.

People with MODY-3 usually have very low renal thresholds for glucose and may spill glucose when their blood sugars do not go much over 140 mg/dl. The gene that causes MODY-3 also causes kidney malformations of varying severity. So all patients with MODY-3 should be seen by competent nephrologist. Both MODY-3 and MODY-1 if untreated cause blood sugars high enough to cause the typical microvascular complications of diabetes.

MODY-2 is reputed to be “mild”–i.e. it does not seem to cause microvascular complications. Because of this, most doctors tell people who carry this gene that they need no treatment. However, some families carrying this gene report that several thin, fit family members have had fatal heart attacks in their mid-50s despite having no previous history of heart disease. Now that we know that even mildly elevated A1cs raise the risk of heart attack significantly doctors should be more aggressive about normalizing the blood sugars of people with MODY-2. Lowering carbohydrates may be all that is needed, but if it isn’t, very low doses of insulin might be called for.

7. The new incretin drugs may be very effective for people with MODY because GLP-1 stimulates insulin secretion in a way that bypasses the broken genes. GLP analogs like Byetta are probably a safer alternative to drugs that inhibit DPP-4 like Januvia and Galvus because DPP-4 inhibition also may have impacts on the immune system that are not yet well understood. Because all these drugs are so new, the most prudent strategy might be to wait until their side effect profiles and long-term safety is better understood. Very low dose insulin combined with carbohydrate restriction is probably safer for the present.

8. Though there are currently six MODY genes for which companies offer commercially available gene testing, researchers believe there may be dozens more MODY genes that have not yet been identified. Researchers at Joslin Diabetes Center and the University of Chicago are currently running studies to identify more of these genes.