Masqueraders: how to identify atypical diabetes in primary care

Diabetes mellitus is a complex set of conditions that impacts 34 million Americans. While type 1 diabetes, type 2 diabetes, and gestational diabetes are most frequently encountered, there are many other types of diabetes with which healthcare providers are less familiar. These atypical forms of diabetes make up nearly 10% of diabetes cases and can masquerade as type 1 or 2 diabetes mellitus (T1DM or T2DM), and the treatment may not be optimized if the diagnosis is not accurate. Atypical forms include monogenic diabetes (formally known as maturity-onset diabetes of the young [MODY]), latent autoimmune diabetes of the adult (LADA), ketosis-prone diabetes, and secondary diabetes. This paper will detail the defining characteristics of each atypical form and demonstrate how they can masquerade as type 1 or 2 diabetes mellitus. Gestational diabetes mellitus will not be discussed in this article.

Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry

Objectives There have been few large-scale studies utilizing exome sequencing for genetically undiagnosed maturity onset diabetes of the young (MODY), a monogenic form of diabetes that is under-recognized. We describe a cohort of 160 individuals with suspected monogenic diabetes who were genetically assessed for mutations in genes known to cause MODY. Methods We used a tiered testing approach focusing initially on GCK and HNF1A and then expanding to exome sequencing for those individuals without identified mutations in GCK or HNF1A. The average age of onset of hyperglycemia or diabetes diagnosis was 19 years (median 14 years) with an average HbA1C of 7.1%. Results Sixty (37.5%) probands had heterozygous likely pathogenic/pathogenic variants in one of the MODY genes, 90% of which were in GCK or HNF1A. Less frequently, mutations were identified in PDX1, HNF4A, HNF1B, and KCNJ11. For those probands with available family members, 100% of the variants segregated with diabetes in the family. Cascade genetic testing in families identified 75 additional family members with a familial MODY mutation. Conclusions Our study is one of the largest and most ethnically diverse studies using exome sequencing to assess MODY genes. Tiered testing is an effective strategy to genetically diagnose atypical diabetes, and familial cascade genetic testing identified on average one additional family member with monogenic diabetes for each mutation identified in a proband.

Identification of Atypical Diabetes Using Algorithms to Search the Electronic Medical Record

Background and Hypothesis: Atypical diabetes (DM) comprises phenotypically and potentially genotypically distinct forms of DM not fitting current sub-categories of classification. Understanding these rare and uncharacterized types of DM can potentially inform the application of personalized therapeutic approaches and is the emphasis of a recent NIH-funded Consortium focused on Rare and Atypical Diabetes (RADIANT). We aimed to employ informatic-based algorithms to identify potentially atypical DM cases from electronic medical records (EMR) to identify candidates for inclusion in RADIANT. Project Methods: Diabetic patients were identified based on two DM diagnostic codes, treatment with anti-diabetic medication, and two diagnostic labs elevated. We filtered for patients with BMI <25 at diagnosis and normal lipid profile. Charts were reviewed manually. Demographic and clinical data were extracted from EMR and entered into a REDCap database. SPSS was used for statistical analysis. Results: A total of 21,820 individuals met criteria for DM; 208 were identified as potentially atypical. Chart review was completed for 126 cases. Fifteen were deceased and removed from the final cohort. Of those remaining, 12 (11%) exhibited features consistent with atypical diabetes. The remainder were classified as typical T2D. No significant differences regarding ethnicity or diabetes complication status were identified between typical and atypical cases. Demographics of atypical cases were, 66% female, and 33% male. The average age of diagnosis was 46.8 ± 19.3 yrs. Average BMI was 23.7 ± 4.1. Atypical diabetes individuals were more likely to present with ketoacidosis (p=0.01) exhibiting a trend towards increased insulin use (50% vs. 14%; p=0.09). Conclusion: Our study suggests that using EMR may be effective in flagging phenotypically distinct forms of DM in real world settings, associated with a high false positive rate. Data suggests this form of atypical diabetes represents a small percentage of overall DM cases (0.05%). Future studies will focus on application of algorithms to identify other atypical diabetes subsets.

Atypical diabetes: a diagnostic challenge

In medical school, we learned how to classify diabetes according to different clinical characteristics. However, at the dawn of the precision medicine era, it is clear that today’s clinical reality does not always align well with textbook teachings. The terms juvenile versus elderly-onset diabetes, as well as insulin-dependent versus non-insulin-dependent diabetes, have become obsolete. Contrary to what is often taught severe ketoacidosis may occur in type 2 diabetes. Patients may also suffer from two or more forms of diabetes simultaneously or consecutively. Five authentic cases of diabetes with uncommon characteristics that pose diagnostic challenges are presented here.

Use of capillary ketones monitoring in treatment of mild ketotic crisis in people with ketosis-prone atypical diabetes

This study was carried out to assess the potential reduction in duration of intensive diabetic ketoacidosis treatment in adults with ketosis-prone atypical diabetes (KPD) when using capillary versus urinary ketones. In this cross-sectional study, we included 20 people with KPD presented at the National Obesity Center of the Yaoundé Central Hospital with hyperglycemic decompensation (random capillary glucose ≥13 mmol/L) and significant ketosis (ketonuria≥++) requiring intensive insulin treatment. In all subjects, intensive insulin treatment was initiated at 10 UI per hour with simultaneous measurement of capillary beta-hydroxybutyrate and ketonuria every 2 hours until disappearance of ketonuria. Time-to-disappearance of urine ketones was compared with the time-to-normalization of capillary β-hydroxybutyrate concentrations. Subjects were aged 46±13 years with a median duration of diabetes of 1.5 (IQR: 0–2.5) years. On admission, the mean blood glucose was 22.8±5 mmol/L and capillary ketones level was 2.9±2.7 mmol/L. The median time-to-disappearance of ketonuria was 5 (IQR: 3–8) hours compared with the time-to-normalization of capillary β-hydroxybutyrate of 4 (IQR: 2–6) hours, p=0.0002. The absolute difference in time-to-normalization of ketonuria versus ketonemia was 2 (IQR: 1–3) hours and the relative time reduction of treatment was 32.5%±18.0%. Our results suggested that the use of capillary ketones versus ketonuria would allow a significant reduction in duration of intensive insulin treatment by one third in people with KPD.

The combination of common neuroosteoarthropathy and diabetic dermatopathy in type 2 diabetes mellitus

Diabetic neuroosteoarthropathy (Charcots osteoarthropathy, DNAP, Charcots foot) is a common complication of diabetic neuropathy, which can be easily diagnosed in clinical practice and usually is corrected without leading to severe deformation of the affected joint in case of timely and adequate treatment. We present the result of long-term clinical observation of a patient with early development of complications of type 2 diabetes mellitus, diabetic dermatopathy, common DNOAP with damage to the joints of the feet, ankles, knees and elbows. A feature of the described clinical case is the prevalence of osteoarticular disorders with seizure of atypical diabetes zones knee and elbow joints, the defeat of which is more characteristic of other diseases (such as collagenoses and syphilis), as well as a combination of DNOAP with diabetic dermatopathy. It seems that the causes of such a common arthropathic process lie in the long course of diabetic neuropathy, which debuted long before the diagnosis of type 2 diabetes, as well as the development and progression of this patient in the last decade of observing diabetic nephropathy and associated secondary hyperparathyroidism. In the modern literature, descriptions of combinations of dermatopathies with other complications of diabetes mellitus are extremely rare, and references to a combination of common DNAP and diabetic bullosis have not been found.