Atypical diabetes: Case study 2
A 26-year-old female patient presents to you to establish diabetes care. She has a past medical history of irritable bowel syndrome. Her mother and sister were both diagnosed with diabetes in their 20s, for which the patient believes they are taking insulin. Her father does not have diabetes.
On physical exam, she has a body mass index of 23 kg/m2, blood pressure of 108/78 mmHg, respiratory rate of 16 breaths per minute, and a pulse of 74 beats per minute. She is not in acute distress and has no signs of insulin resistance. The rest of her exam is normal, including her thyroid.
Her HbA1c in the office today is 7.4% and her random glucose is 188 mg/dL. She has had a small breakfast.
Question 1. What type of diabetes does she most likely have?
- Type 1 diabetes
- Type 2 diabetes
- Latent autoimmune diabetes of the adult
- Monogenic diabetes of youth
- Secondary diabetes
Question 2. What laboratory tests would you like to order to confirm her diabetes type?
Choose all options that apply.
- Oral glucose tolerance test
- C-peptide coupled with a glucose test
- Glutamic acid decarboxylase and islet cell autoantibodies
- Lipid panel
This case has a number of unique features. The patient was diagnosed with diabetes at a young age, but not while in acute hyperglycemic crisis, and is not overweight or obese. She has no personal or family history of autoimmunity, but does have a strong family history of diabetes diagnosed as a young adult.
The best laboratory tests to determine what type of diabetes the patient has include a measure of endogenous insulin production (C-peptide coupled with a glucose test) and a measure of diabetes-related autoimmunity (glutamic acid decarboxylase [GAD] and islet cell autoantibodies). The C-peptide test informs us if her pancreatic beta cells are working normally and the islet cell autoantibodies help us to determine whether this is type 1 diabetes.
The patient’s comprehensive metabolic profile was mostly normal, other than a high glucose of 220 mg/dL. Her lipids were: Total cholesterol 168 mg/dL, high-density lipoprotein cholesterol 68 mg/dL, low-density lipoprotein cholesterol 90 mg/dL, and triglycerides 82 mg/dL. Her C-peptide was low–normal, despite a glucose of 220 mg/dL. Both her GAD and islet cell autoantibodies were negative.
A few things should jump out at you on reviewing this case.
- The patient has a strong family history of diabetes. This really reduces the likelihood of this being type 1 diabetes.
- There is evidence that she still makes insulin and no evidence of autoantibodies. This too makes type 1 diabetes less likely.
- Her lipid panel is normal. This makes this case less likely to be type 2 diabetes.
This young woman likely has monogenic diabetes of youth (MODY), previously known as maturity-onset diabetes of youth. MODY is a more accurate name than maturity-onset diabetes of youth, as it is actually a collection of autosomal dominant genetic conditions that lead to hyperglycemia and is typically present at a relatively young age .
There are 29 genetic mutations associated with atypical forms of diabetes, such as MODY, neonatal diabetes, mitochrochondrial diabetes, and lipodystrophy, of which 13 have been shown to be associated with MODY .
Table 1. Comparison of MODY with type 1 and type 2 diabetes
|Characteristic||MODY||Type 1 diabetes||Type 2 diabetes|
Age at diagnosis
Beta cell antibodies
|* For MODY types 1, 3, and 4.|
Hx=medical history; MODY=monogenic diabetes of youth; SU=sulfonylurea
The four features of MODY are:
- a strong family history of diabetes (typically three generations of autosomal inheritance can be shown);
- no evidence of insulin resistance;
- most often phenotypically normal; and
- no evidence of autoimmunity.
It is important to diagnose MODY for two reasons. First, most people with MODY are told that they have type 1 diabetes and will need insulin for life. This is not the case. Second, MODY is strongly hereditary and so a correct diagnosis can help with early and correct diagnosis of the condition in other family members and children.
There are about 500,000 people in the United States with MODY, about one-quarter of the number with type 1 diabetes and about one 50th of the number with type 2 diabetes . When clinical suspicion points to MODY, you should perform the above initial laboratory tests. If these tests do not point to type 1 diabetes or type 2 diabetes and you have observed the four features mentioned above, then you can consider specific tests for genetic mutations. These tests are expensive and are best used to confirm a diagnosis of MODY when it is less than certain.
In most cases, MODY can be treated with a low-dose sulfonylurea. Since patients with MODY make insulin but do not release it correctly, sulfonylurea resolves this issue. MODY-2 (see Box 1) can be treated with dietary modifications. For patients with MODY, a correct diagnosis helps to prevent unnecessary treatment and improves patient safety.
|Box 1. Most common types of MODY|
MODY=monogenic diabetes of youth
While there have been few developments in recent years, a recent study published in Nature has found a new genetic mutation that leads to a novel form of MODY . While this form (RFX6 protein-truncating variants) does not yet have a name, it is found in women 83% of the time and appears to have a later onset or penetrance .
There are many types of diabetes. When a patient does not have the usual phenotypical findings or dyslipidemia of type 2 diabetes, and there is no evidence of the failing insulin production markers of autoimmunity, you should consider an atypical form of diabetes. In this case, the family history, mild disease course, and the results of the laboratory tests suggest that this person likely has MODY. Specific genetic testing is available to confirm the diagnosis.
- Winters WE, Silverstein JH. Molecular and genetic bases for maturity onset diabetes of youth. Curr Opin Pediatr 2000;12:388–393.
- The search for Diabetes in Youth Study Group (SEARCH), Liese AD, D'Agostino RB Jr et al. The burden of diabetes mellitus among US youth: Prevalence estimates from the SEARCH for Diabetes in Youth Study. Pediatrics 2006;118:1510–1518.
- Patel KA, Jarno Kettunen, Markku Laakso et al. Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance. Nature Communications 2017;8:888.