Latent Autoimmune Diabetes in Adults

The most prevalent type of diabetes is T2D, which accounts for approximately 90% to 95% of cases.1 Therefore, it is easy to suppose that middle-aged and older adults who present with new-onset diabetes have T2D. However, multiple recent studies indicate that between 5% and 10% of adults diagnosed with T2D may be misdiagnosed and may have LADA.2-5

LADA is considered a subset of T1D. In both T1D and LADA, the immune system attacks the insulin-producing β cells of the pancreas. However, in LADA, the disease progression is much slower than that of traditional T1D.5-8 One or more pancreatic autoantibodies will be positive and C-peptide typically will be low in patients with LADA.5 Individuals with LADA also tend to be slimmer than patients with T2D, although patients with LADA can be overweight or obese. 


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Patients with LADA have fewer metabolic features such as dyslipidemia and increased waist circumference and body mass index (BMI) than patients with T2D.3-5,8  Family or personal history of autoimmune diseases should prompt suspicion for LADA because the condition has a strong genetic component.5 Autoimmune thyroid disease (Hashimoto thyroiditis and Graves disease), pernicious anemia, and Addison disease are the most frequently co-occurring autoimmune diseases in patients with LADA.6,9

Like T2D, LADA usually occurs in adults, typically developing in those >30 years of age. As often seen with patients with T2D, patients with newly diagnosed LADA initially may not require insulin; however, with increase in β-cell failure, insulin therapy usually becomes necessary.  Family history of diabetes does not appear to play as big a role in LADA and may or may not be present.5,10

LADA Diagnosis

Primary care providers often are the first to diagnose and treat patients with new-onset diabetes. They can test for type when the diagnosis is uncertain. One or more positive autoantibodies confers the diagnosis of autoimmune diabetes.5,6 These tests often can be ordered together in an autoimmune diabetes panel. Autoantibodies include islet cell cytoplasmic autoantibodies, zinc transporter 8, insulin autoantibodies, insulinoma-associated-2 autoantibodies, and GAD65, which is the most prevalent of the autoantibodies in those with autoimmune diabetes.5

C-peptide, or connecting peptide, is produced in equal amounts with insulin in the β cell and is cleaved from proinsulin in the final step before insulin release.11 Because C-peptide is degraded more slowly than insulin and is not skewed by exogenous insulin,the C-peptide level is an excellent indicator of β-cell function.5,6,11    

In patients with T2D, C-peptide level is typically increased because this is a disease of insulin resistance and subsequent overproduction of insulin. In patients with LADA or T1D, C-peptide level will be low to undetectable.5,6,11 

Clues in the Case Presentation

Reviewing the patient’s presentation along with diabetes characteristics (Table 2), clues exist that would prompt the practitioner to suspect that this was not a typical case of T2D. The patient was of normal weight and presented acutely with classic symptoms of hyperglycemia more commonly seen in autoimmune diabetes: weight loss, polyphagia, and polydipsia. She had no family history of diabetes, but she did have a family and personal history of autoimmune thyroid disease.  The patient did not have any features of metabolic syndrome, which is prevalent in T2D; hypertension and dyslipidemia were absent, and her waist circumference was in a healthy range. Additionally, her HbA1c was markedly elevated, which is a more common initial presentation for patients with T1D or LADA than for those with T2D.5

Implications for the Primary Care Provider

Primary care providers should be aware of less common forms of diabetes and features that would prompt suspicion of an unusual diagnosis. If the patient does not seem to fit into a typical type of diabetes, then further investigation is imperative.12 (See sidebar for information on MODY, another rare type of diabetes).

Knowing the type of diabetes helps guide pharmacologic therapy and aids in the delay or prevention of diabetes complications. For patients with LADA, basal/bolus insulin is considered the mainstay of treatment, although it may not be needed initially.13 Recent evidence suggests that medications such as dipeptidyl peptidase-4 (DPP-4) inhibitors and/or GLP-1 receptor agonists may help preserve β-cell function and delay the need for intensive basal or bolus therapy though these medications are considered investigational and are not yet approved by the US Food and Drug Administration for patients with T1D or LADA.14-17 Metformin may be considered in the treatment of patients with LADA if insulin resistance is a concern. Medications that stimulate insulin production, such as sulfonylurea agents, are thought to hasten the demise of remaining functioning β cells and generally should be avoided.14,18

As the disease advances, a patient with LADA will progress to full insulin dependence and warrants close follow-up. When starting insulin therapy in patients with T1D or LADA, the dosage typically is weight based and ranges from 0.4 to 1.0 units/kg/d. Basal insulin requirements classically are 50% of the total daily dose. The remaining insulin is used for mealtime coverage of carbohydrates and as a bolus to correct hyperglycemia.13 Patients with LADA may be insulin-sensitive, so starting slowly and titrating upward based on response is advised. Management with an endocrinology provider is appropriate.

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Proper diagnosis is essential because it ensures that patients are appropriately educated about their disease including sick-day rules (including frequently checking blood glucose and ketone levels) and the potential for ketoacidosis. A correct diagnosis also ensures that patients have access to technologies such as insulin pumps and continuous glucose monitors that often are not covered by insurance for patients with T2D but are covered for patients with LADA. A diagnosis of LADA diagnosis alerts the provider to screen patients appropriately for other autoimmune diseases and leads to heightened awareness of both patient and provider when considering the health of the family.5,6,18

Jennifer L. Deltour, MSN, FNP-C, BC-ADM, is a nurse practitioner in primary care and endocrinology with Asante Physician Partners Family Medicine and Asante Physician Partners Endocrinology in Medford, Oregon.

References

  1. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2020. Atlanta, GA: Centers for Disease Control and Prevention, US Department of Health and Human Services; 2020.
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  3. Pozzilli P, Pieralice S. Latent autoimmune diabetes in adults: current status and new horizonsEndocrinol Metab. 2018;33(2):147-159.
  4. Thomas NJ, Lynam AL, Hill AV, et al. Type 1 diabetes defined by severe insulin deficiency occurs after 30 years of age and is commonly treated as type 2 diabetesDiabetologia. 2019;62(7):1167-1172.
  5. Carlsson S. Etiology and pathogenesis of latent autoimmune diabetes in adults (LADA) compared to type 2 diabetesFront Physiol. 2019;10:320.
  6. American Diabetes Association. 2. Classification and diagnosis of diabetes: Standards of Medical Care in Diabetes-2020Diabetes Care. 2020;43(suppl 1):S14-S31.
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  10. Hjort R, Alfredsson L, Andersson T, et al. Family history of type 1 and type 2 diabetes and risk of latent autoimmune diabetes in adults (LADA)Diabetes Metab. 2017;43(6):536-542.
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  13. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2020Diabetes Care. 2020;43(suppl 1):S98-S110.
  14. Buzzetti R, Pozzilli P, Frederich R, Iqbal N, Hirshberg B. Saxagliptin improves glycaemic control and C-peptide secretion in latent autoimmune diabetes in adults (LADA). Diabetes Metab Res Rev. 2016;32(3):289-296.
  15. Chatzianagnostou K, Iervasi G, Vassalle C. Challenges of LADA diagnosis and treatment: lessons from 2 case reportsAm J Ther. 2016;23(5):e1270-e1274.
  16. Pozzilli P, Leslie RD, Peters AL, et al. Dulaglutide treatment results in effective glycaemic control in latent autoimmune diabetes in adults (LADA): a post-hoc analysis of the AWARD-2, -4 and -5 trialsDiabetes Obes Metab. 2018;20(6):1490-1498.
  17. Zhao Y, Yang L, Xiang Y, et al. Dipeptidyl peptidase 4 inhibitor sitagliptin maintains β-cell function in patients with recent-onset latent autoimmune diabetes in adults: one year prospective study. J Clin Endocrinol Metab. 2014;99(5):E876eE880.
  18. Kreider KE. The diagnosis and management of atypical types of diabetes. J Nurse Practition. 2019;15(2):171-176.