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Case Studies
A 25-year-old graduate student originally presented to you with symptoms of a UTI. An urinanalysis showed signs of infection, as well as glycosuria. You prescribed a 3-day course of trimethoprim-sulfamethoxazole and ordered a comprehensive metabolic panel, which came back normal for lipid levels and renal and liver function but showed an A1C of 7.1.
You examine the patient again and note that she is of normal weight (BMI=23), has never smoked, and is currently using no prescription medications other than a daily combination oral contraceptive (3 mg drospirenone/0.02 mg estradiol). She reports having an occasional glass of wine at dinner and sometimes several beers or mixed drinks at weekend parties. She shows no overt symptoms of ketoacidosis. All cardiovascular and neurologic signs are within normal range, including a blood pressure of 110/70.
When you question the patient about family history, she reports that her father, now aged 48, was diagnosed with Type 2 diabetes in his early 30s, which she says never surprised anyone in the family since he was always overweight and rarely exercises. She says her father’s elderly uncle also has diabetes, presumably Type 2. More puzzling to her is a “painfully thin” older brother, who was diagnosed with Type I diabetes in his early twenties, although he reputedly often goes days at a time without needing insulin therapy.
Next Steps
You strongly suspect that this patient may have some form of MODY (Maturity Onset Diabetes of the Young). What would be your next steps in diagnosing and treating her?
1. How to confirm MODY
2. How to treat MODY
Continue to Management Options
Diagnosis of MODY
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.
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References
Treatment of MODY
The basic principles of the treatment of MODY are much easier than the diagnosis. This is because most patients are not diagnosed in the first place, either because clinicians don't know the family history or because they don't even consider MODY as a possibility.
This patient most likely has hepatic nuclear factor 1-a (HNF-1 alpha) MODY, also referred to as MODY-3. This is a transcription factor MODY, the type characterizing about 2/3 of all MODY patients and accounting for 61% of all MODYs.1 All transcription factor MODY patients involve genetic defects in insulin secretion; thus, insulin sensitizers (including metformin) are not indicated. As with type 1 diabetes, patients with MODY are classically thin and insulin sensitive already (although with the increasing epidemic of obesity we do now see overweight and obese MODY patients as well).
HNF-1-alpha MODY patients respond well and are quite sensitive to sulfonylureas. However, as with patients with type 2 patients, over time they lose their response to these agents and require insulin. Since HNF-1-alpha MODY patients are not ketosis-prone, ketoacidosis is not a concern. While we don’t have studies guiding us to which insulin regimens are most effectivem, I have found most of these patients require traditional basal-bolus insulin after failing sulfonlureas. From a theoretical perspective, it may be that basal insulin with daytime sulfonylurea may work well during the transition to more severe beta-cell deficiency.
It is now clear that patients with MODY can get the microvascular complications associated with type 2 diabetes;thus, glycemic targets should not be different. The exception to this is those patients who are diagnosed with glucokinase MODY (MODY-2). This type of MODY is the second most common, comprising 22% of all MODY patients.1 Their hyperglycemia is quite mild and in general no therapy is required (except perhaps during pregnancy). This patient’s A1C of 7.1%, however, is higher than would be expected for a glucokinase MODY patient, and, again, from what we know she sounds more likely to have MODY-3.
Of course, treatment would vary if the patient turned out to have yet another form of MODY, but this is also highly unlikely from what we have been told. While other types of MODY have been described, only HNF-4 a is seen in any significant numbers, comprising 4% of all MODY patients.1 Furthermore, as with MODY-3, this less common form of MODY is initially treated with sulfonylreas followed by insulin.
Down the line, other forms of therapy might also be considered, especially considering that the beta-cell lesion of MODY is obviously different than the lesions seen in either type 1 or type 2 diabetes. It is intriguing to consider how a GLP-1 agonist or DPP-4 inhibitor might both lower glucose and potentially spare beta-cell function over time. I am not aware of any anecdotal experiences with this approach, but perhaps some of our readers can enlighten us on this topic.
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