Masqueraders: how to identify atypical diabetes in primary care

Illustrative case of monogenic diabetes

A 22-year-old female with no medical history presented to an occupational health clinic to obtain clearance for work-related travel. She denied any specific complaints, and her physical exam was within the normal limits with no signs of insulin resistance. Her body mass index (BMI) was 23 kg/m². She reported that multiple relatives in every generation were diagnosed with mild diabetes at a young age. Because routine urine analysis indicates glycosuria, she started checking her blood glucose utilizing a relative’s glucose meter. Her glucose checks revealed mild fasting and postprandial hyperglycemia. Her A1c (glycated hemoglobin) was 7.1%, her C-peptide was 1.4 ng/dL (normal range, 0.8–3.5 ng/dL) with corresponding fasting blood glucose of 128 mg/dL, and her GAD-65 Ab and islet antibodies were negative. She was started on glipizide with improvement in blood glucose to normal ranges. She was referred for genetic testing to confirm MODY.

Illustrative case of latent autoimmune diabetes of the adult (LADA)

A 38-year-old male with a medical history of T2DM was referred for worsening of A1c from 7.2% in March 2018 to 9.9% just 3 months later in June 2018. He was diagnosed with T2DM a year earlier when he was hospitalized for spine surgery. His blood glucose was elevated, and he was started on metformin postdischarge. Due to worsening of A1c, oral medications were titrated with addition of sulfonylurea and maximizing the metformin dose but with no significant improvement. He denied having a family history of diabetes. He presented with blood glucose varying from 70 to 420 mg/dL. On examination, he had no evidence of insulin resistance (acanthosis nigricans); his BMI was 21.5 kg/m². Labs indicated his C-peptide was 0.5 with corresponding plasma glucose of 239 mg/dL, elevated GAD-65 autoantibody titer (77 units/mL), and negative islet-cell antibody (ICA). He was started on basal-bolus insulin regimen, and his metformin and sulfonylurea were discontinued. His blood glucose readings improved, and his A1c improved to 7.1% in September 2018 and has remained in the target range with his A1c at 6.7% as of February 2021.

Illustrative case of ketosis prone diabetes (KPD, flatbush diabetes)

A 17-year-old black male with no medical history presented to the emergency room with vomiting for 1 day. He reported having a history of polyuria, polydipsia, and polyphagia for 2 weeks. He has a family history of T2DM in his maternal grandmother. On physical examination, his BMI was 30 kg/m², and he had acanthosis nigricans on the back of his neck. Initial labs indicated plasma glucose of 1,228 mg/dL (normal range, 100–125 mg/dL), bicarbonate of 17 mEq/L (normal range, 23–30 mEq/L), anion gap of 20 mEq/L (normal range, 3–10 mEq/L), arterial pH of 7.22 (normal range, 7.35–7.45), and beta-hydroxybutyrate elevated at 77.20 mmol/L (normal, less than 0.4 mmol/L). The patient was diagnosed as having DKA and had an A1c of 12.2%. He was diagnosed with new-onset diabetes with DKA. He was treated for DKA and discharged home on long-acting insulin glargine, rapid-acting insulin aspart, and metformin. When the patient was seen in follow-up 1 month after discharge, he was noted to have pre-meal and bedtime blood glucose within the target range and episodes of hypoglycemia between 61 and 67 mg/dL. A1c at this visit is 5.0%. Insulin glargine and aspart doses were reduced by 50%. On a 3-month follow-up visit, the A1c was 4.5%. Insulin was discontinued and metformin continued. The stimulated (mixed meal challenge) C-peptide was 9.45 ng/dL with corresponding glucose of 122 mg/dL; the GAD-65 Ab and islet-cell autoantibodies were negative. At 1-year follow-up, the patient continued to have A1c in the normal range on metformin and with lifestyle modifications.

Illustrative case of secondary diabetes

A 43-year-old male presented with a 1-month history of polyuria, polydipsia, and weight loss. As part of his evaluation, he was found to be hyperglycemic with a glucose of 420 mg/dL, and he had ketosis but minimal acidosis. His medical history included alcohol abuse and recurrent pancreatitis with four previous hospitalizations. He had been sober for 9 months and was told that there is permanent damage to his pancreas. After the patient was stabilized on treatment, he was evaluated for type 1 diabetes. His C-peptide was low but detectable at 0.45 ng/dL, with a corresponding glucose value of 160 mg/dL, and his auto-antibody panel (GAD-65, ICA, insulin autoantibodies [IAA]) was negative. Due to the significant hyperglycemia and pancreatitis, he was managed on a basal and bolus insulin regimen.

Maturity-onset diabetes of the young (MODY)

Monogenic diabetes includes both MODY and neonatal diabetes mellitus. Neonatal diabetes will not be discussed in this manuscript. Approximately 500,000 people in the United States have MODY [8]. While its name reflects the clinical presentation, MODY, it does not accurately depict pathogenesis or the necessary treatment. MODY is caused by the autosomal-dominant transmission of a single mutated gene. To date, there have been 14 genetic mutations linked to MODY [9]. The most common forms of MODY are HNF1A MODY-3 and GCK MODY-2 gene mutations and result in abnormal vesicle packaging or release of insulin, which leads to a milder form of diabetes [9]. Because it is not a metabolic disease similar to T2DM, people with MODY are not likely to have dyslipidemia. They are more likely to be thin and without the comorbidities seen with T2DM. As a result, many people with MODY are misdiagnosed with T1DM and are started on insulin, many for the rest of their life. However, C-peptide levels are measurable and indicative of some production of insulin while they do not have GAD-65 antibodies [10].

A physician should consider MODY if an asympto-matic person presents with mild hyperglycemia and has a strong family history of similar diabetes presentation (with at least three generations represented in an autosomal-dominant pattern). The autosomal-dominant transmission identifies MODY as the form with the strongest familial pattern [9]. People with MODY will not have measures of autoimmunity or dyslipidemia, and they should have measurable insulin production. People with monogenic diabetes are often identified at the time of other screening such as a physical exam or during obstetrical care.

Monogenic diabetes is typically more difficult to diagnose because patients are often underweight to normal-weight children or young adults, although age is not predictive [9, 10]. They usually do not experience insulin resistance or metabolic syndrome, as in the case of typical T2DM. Therefore, there is the assumption that they have T1DM. However, if correctly diagnosed, these patients can be taken off insulin. Table 2 demonstrates the clinical comparison between MODY, T1DM, T2DM, KPD, and secondary diabetes.

Latent autoimmune diabetes of the adult (LADA)

LADA is a form of T1DM that is most commonly diagnosed between 30 and 50 years of age in people with a normal BMI (less than 25) [10]. Because it is an autoimmune disease, one of the main risk factors for LADA is a personal or family history of autoimmune disorders. The Immunology of Diabetes Society defines LADA by three criteria: adult-age onset, no need for immediate insulin therapy, and presence of islet-cell autoantibody [10, 11]. The impairment of beta cells in patients with LADA is a slower process compared to T1DM, which is why patients with LADA do not need insulin right away. By definition, people with LADA can go at least 6 months after diagnosis before they are so insulinopenic that they require insulin to live [11]. Because it is an autoimmune disease, metabolic syndrome characteristics are seen less commonly with LADA. An interesting finding with LADA is the earlier presentation of microvascular complications, such as neuropathy and retinopathy [11], as compared to T1DM, which may be due to a longer period of subclinical hyperglycemia. Many individuals with LADA are misdiagnosed with T2DM because of adult onset. However, a common feature is poor control on standard type 2 therapy or inadequate control until started on insulin.

Pieralice and Pozzilli [12] developed a predictive model for identifying LADA based on measurement of GAD-65 Ab and C-peptide measurement to confirm the diagnosis and determine the treatment protocol. Some of the clinical risks associated with LADA include BMI of less than 25 kg/m², younger than 50 years of age, acute hyperglycemia symptoms at onset, and personal or family history of autoimmune disorders. Patients with two or more of these risk factors should be considered high risk for LADA. A positive GAD-65 Ab measurement should be an indicator of LADA. A patient with mild risk and one risk factor along with a low C-peptide value should be an indicator to test GAD-65 Ab [12]. Similarly, the new The Rare and Atypical Diabetes Network (RADIANT) trial aims to create a descriptive guide detailing the genetic and clinical presentation for all of the atypical forms of diabetes, including LADA [13]. Table 3 demonstrates the clinical comparison between T1DM, LADA, T2DM, KPD, and secondary diabetes.

Ketosis prone diabetes (KPD)

KPD is a form of T2DM and is defined by recurrent episodes of ketoacidosis. The mechanism of development and the progression of the illness is not well understood [14], but glucose toxicity and lipotoxicity leading to beta cell desensitization has been hypothesized [15]. KPD is seen more often in overweight and obese black males with a family history of T2DM [16]. KPD is generally diagnosed when patients are admitted to the hospital with ketoacidosis. They present with acute-onset hyperglycemia and some impairment of beta cell function and insulin insensitivity. What is unique about KPDM is that after resolution of ketoacidosis, patients can often be in remission (normal glucose levels with no medications) for months to years after initial episode and diagnosis, although they are prone to recurrent spontaneous ketoacidosis. KPDM may not always be associated with measures of autoimmunity such as GAD-65 or anti-islet-cell autoantibodies.

Balasubramanyam et al. [17] and Sjöholm [18] have classified patients with KPD based on the presence or absence of autoantibodies and the presence or absence of beta cell function measured soon after resolution of initial DKA episode. There are four general subtypes of KPD in this Aβ classification scheme:

1. A−β−, autoantibody negative and with absent β-cell function;

2. A+β−, autoantibody positive and with absent β-cell function;

3. A−β+, autoantibody negative and with present β-cell function;

4. A+β+, autoantibody positive and with present β-cell function [17, 18].

A−β− and A+β− KPD have permanent and complete beta cell failure and thus require long-term insulin. A−β+ KPD have preserved beta cell function and do not require insulin for long-term survival. A+β+ KPD may either have preserved beta cell function or have progressive beta cell failure, which will determine long-term insulin requirement.

Secondary diabetes

Secondary diabetes results as a consequence of other medical issues that affect the pancreas. In conditions like pancreatitis, pancreatic cancer, and cystic fibrosis, the beta islet-cell function becomes impaired [19]. This beta islet-cell impairment leads to a lack of insulin production and subsequent insulin dependence. Patients with secondary diabetes may initially present with the underlying primary problem, such as chronic or recurrent pancreatitis, pancreatic cancer, or new-onset T1DM. In the case of an older patient with pancreatic cancer presenting with weight loss or otherwise unexplained deterioration of glycemic control, secondary diabetes should certainly be considered. The key features that make this different is that they will look like they have T1DM and will not make sufficient insulin to control glucose, but there will be no measures or risk of autoimmunity. One important clinical warning is to make sure that physicians do not confuse secondary diabetes with T2DM. Those with secondary diabetes need insulin as treatment to live like T1DM. Another key finding is that any person who presents as new-onset T1DM after the age of 50 years should be evaluated for secondary forms of diabetes such as pancreatic cancer [19].

Other causes of secondary diabetes can be hereditary hemochromatosis, atypical antipsychotics, glucocorticoids, or posttransplant diabetes (also called new-onset diabetes after transplantation, or NODAT) due to immunosuppressive medications and endocrine disorders (Cushing’s syndrome). These conditions will not be discussed in this manuscript.

Future directions in atypical diabetes

With awareness of atypical diabetes on the rise, there have been new efforts to accurately diagnose people with the other forms of diabetes. The RADIANT trial is a national multicenter trial with the aim to categorize people with atypical forms of diabetes. This National Institutes of Health (NIH)-funded trial seeks to provide a specific diagnosis to nearly 2,000 people with atypical diabetes. More information can be found at https://www.nih.gov/news-events/news-releases/nih-funds-first-nationwide-network-study-rare-forms-diabetes [13].