The key to this case is recognizing our patient is not presenting with typical type 1 DM–or at least if she has that disease, diabetes was found before the advent of overt insulin deficiency. That certainly can occur with type 1 diabetes, especially when the patient seeks medical care for an issue that is unrelated to the diabetes (maybe the UTIs in our patient), with the diabetes being incidentally discovered. Still she provides intriguing history of a brother who is diagnosed with type 1 diabetes, but goes days without insulin. Particularly tantalizing is the wording of the case “…often goes for days at a time without needing insulin…” That could imply the blood glucose level does not change throughout that time. In other words, it’s not that he has enough c-peptide remaining that he doesn’t go into DKA or otherwise get overly sick. Instead, it sounds like nothing happens whether he’s on or off the insulin.
So the medical detective in you comes out. The list of causes of diabetes is very long–not just type 1 and type 2 diabetes, but also many endocrinopathies such as Cushing’s, acromegaly and hyperthyroidism, cystic fibrosis, other pancreatic diseases, hemochromatosis, and numerous rare or not so rare genetic syndromes. Could our patient have one of these? Most of these illnesses have distinguishing extra-pancreatic features along with the diabetes. What about our patient–what do we know?
1) She is not overweight or metabolic, nor are there obvious illnesses beyond the UTIs and the diabetes.
2) Three generations of male and female family members are affected.
3) No distinguishing extra-pancreatic feature for any rare diabetes syndrome is described in her or a family member.
4) Her brother has a diagnosis of type 1 diabetes that may be questionable.
5) On the other hand, her father sounds like fairly typical type 2 diabetes, and we know little to nothing about her father’s uncle.
What don’t we know? A lot. We need much more information about her family to see if there is a clear genetic pattern, in the case of MODY an autosomal dominant inheritance. How did the other family members present, at what ages, what therapies were they treated with, and what was their clinical course over time in terms of therapy and microvascular complications? So back to our patient. Could this be type 2 diabetes? Seems highly doubtful but not impossible. A research group at Yale University has extensively studied young (close in age to our patient) offspring of two parents with type 2 diabetes, when they are still normally glucose tolerant. They are highly insulin resistant–you might expect that. Otherwise, however, they are normal weight with an average BMI of 23, and there are no other distinguishing features such as hypertension or hyperlipidemia.1,2 So based on what we know about her father and his uncle, there could be an insulin-resistance form of type 2 diabetes in the family (maybe even her brother), but I doubt it.
Could it be early type 1 diabetes? Absolutely, and I would test for the autoimmune markers for type 1 diabetes that are available in my institution, recognizing that the testing may be negative even with type 1 diabetes. Our institution typically screens for only 1 marker–GAD 65 antibody–but some specialized research centers test a panel of several markers that gives a lower false negative rate.
Could it be MODY? Yes, in that this young woman loosely fits the clinical features of a family with a possible autosomal dominant pattern of young onset diabetes (that description is usually defined as requiring at least one member, in this case the patient herself, with diabetes onset before 25 years of age) with generally normal weight and insulin independence at diagnosis. Indeed the concept of MODY began with Steve Fajans in the 1960s to explain the medical enigma of the time of a family he was following with childhood and adolescent diabetes that was not insulin dependent.3 That was particularly interesting because at that time, childhood diabetes was by definition type 1 diabetes as the typical type of metabolic-based type 2 diabetes was unimaginable in children or adolescents. And MODY has been one of the great genetic success stories, with six or more genetic varieties identified.3-5 Collectively this is a beta-cell disease, with all of the mutated genes affecting beta-cell function (glucokinase, which is the glucose sensing enzyme within beta-cells that regulates glucose-stimulated insulin secretion) or mass and survival (PDX-1 and several hepatic nuclear factors). So it makes sense the patients are not obese or obviously insulin resistant, and they present like early type 1 diabetes but with relative rather than absolute insulin deficiency–i.e., without a predisposition for ketosis or need for insulin therapy at diagnosis.
How to diagnose MODY? Frankly that’s a hard question to answer. The first step is identify a patient with a family that fits the general description, including evidence for a multigenerational autosomal dominant pattern of inheritance. Also clinical features may suggest the subtype–quite mild hyperglycemia that is stable over many years is typical for glucokinase mutations, stable modest hyperglycemia that is highly sensitive to sulfonylurea therapy suggests HNF-1 alpha mutation, and HNF-1 beta mutations have modest to severe hyperglycemia that is progressive and is often accompanied by cystic renal disease. C-peptide testing may be helpful to distinguish type 1 DM from MODY, with stimulated values in MODY patients typically exceeding the very low to absent c-peptide levels in type 1 diabetes. Alternatively a group from the UK has written extensively on the urinary c-peptide-to-creatinine ratio as an easy practical diagnostic method, although it remains a research tool.6 Genetic testing is also available from research institutions and a few commercial labs, but the general rule of thumb is to test only if it will make a clinical difference in that patient or family. Also, it is not surprisingly that research institutions that do their own MODY testing are strong advocates of genetic testing.7,8 In contrast, I have found commercial lab testing not particularly helpful–the samples I have sent have all come back negative. So my approach now is to test for autoimmune markers of type 1 diabetes and stimulated c-peptide. If suggestive of MODY I decide whether to stop insulin for a trial with a sulfonylurea.