Diabetes was at the top of the differential diagnosis list upon presentation. This patient was likely to have type 1 diabetes at presentation, as defined by fasting glucose >126 or postprandial glucose >200, or hemoglobin A1c of 6.5% or greater and insulin deficiency, as well as clinical signs of an insulin deficiency syndrome (polyuria, polydipsia, weight loss, ketoacidosis . We had discovered all of these features by the time of her follow up visit, except testing for C-peptide was not done for insulin deficiency. The patient’s polyphagia with weight loss and nocturnal enuresis are all clinical features of type 1 diabetes at diagnosis and not type 2 diabetes. The patient’s report of presyncopal symptoms also fit with volume depletion caused by osmotic diuresis due to hyperglycemia. In contrast, patients with type 2 diabetes are often asymptomatic at presentation .
Another diagnostic consideration was overtreatment of her hypothyroidism. Her weight loss, increased appetite, urinary frequency, and more rapid heartbeat could have been explained by hyperthyroidism . However, her elevated TSH was consistent with under treatment and subsequent free T-4 was normal.
In a patient with multiple autoimmune diseases, the clinician should have a higher index of suspicion that the patient could present with an additional autoimmune disease. Our patient could be classified as having one of the polyglandular autoimmune syndromes (PAS), specifically PAS IIIa [6, 15]. These syndromes are divided into PAS I, II, and III. While juvenile PAS I is quite rare, PAS II commonly presents in the third or fourth decade in women, and has a prevalence of 1:20,000. The main difference between PAS III and PAS II is the absence of adrenal cortical involvement causing adrenal insufficiency in PAS III, while this is present in PAS II. Autoimmune thyroiditis (Graves’ disease or Hashimoto’s thyroiditis) and type 1 diabetes, when occurring together, are defined as autoimmune polyglandular syndrome type IIIa . Notably, there is often a long time interval between the manifestation of the first and second component disease of PAS II, which often comprises years to decades. Perhaps our patient may later develop adrenal insufficiency given she has both type 1 diabetes and autoimmune thyroid disease, which may suggest an underlying genetic predisposition to PAS II. PAS II can also include features of adrenal insufficiency, hypoparathyroidism, primary hypogonadism, and other manifestations . Clinicians need to be on the lookout for these associated diseases [6, 16, 17].
Experts recommend serologic and functional screening for these associated diseases in patients with a monoglandular autoimmune disease at diagnosis and during follow-up appointments at least every 2 years [6, 16]. Although diabetes-associated autoantibodies can be obtained to predict individuals at risk for developing type 1 diabetes, methods to delay or prevent disease onset are not promising. Immunosuppressive agents (such as cyclosporine, rituximab, abatacept), which come with a variety side effects, have been evaluated to prevent or delay type 1 diabetes and shown limited to no impact. For the few drugs that appear to have some effect, not all patients respond and for those who do, the effects are often short-lived. Although there is limited evaluation of beta-cell prevention or preservation in LADA patients, one study using a GAD-alum formulation demonstrated a relative preservation of C-peptide release for 5 years, with limited side effects. Still, the benefit of screening diabetes-associated autoantibodies prior to diagnosis remains controversial [7, 18]. Given that our patient has type 1 diabetes and thyroid disease, screening may include functional assessment of adrenal failure, primary hypogonadism, hypoparathyroidism, type A autoimmune gastritis with or without pernicious anemia, and celiac disease.
After identification of autoimmune thyroid disease, screening for diabetes (such as oral glucose tolerance testing) should have been implemented and could have led to earlier detection in our patient. Our patient was started on insulin at diagnosis and given that her presentation was more consistent with type 1 diabetes versus early onset LADA. Insulin is often started in patients who have weight loss or dehydration in the setting of hyperglycemia or if they have evidence of increased ketogenesis as evidenced by ketonuria or acidosis; our patient met all of these criteria aside from the acidosis and thus we started her on insulin [4, 9]. Interestingly, our patient may have had LADA for years before this clinical presentation, causing her beta cell mass to decrease, which resulted in having more features of type 1 diabetes than other adult patients with LADA, who do not require insulin at diagnosis [4, 7]. Previously, a blood glucose had not been checked to screen for diabetes. If her clinicians had been more mindful of the relationship between autoimmune thyroid disease and diabetes, perhaps they would have checked her blood sugar sooner (despite her appearance as a fit, healthy female), diagnosed LADA, and potentially delayed her progression to insulin dependence through early treatment.
Due to the paucity of data, the optimal initial treatment of latent autoimmune diabetes in adults (LADA) is not established. Studies treating recently-diagnosed LADA patients with dipeptidyl peptidase 4 (DPP-4) inhibitors suggest that these may postpone loss of beta cell function, although these findings are not convincing and need to be confirmed in larger randomized trials. Despite its widespread use in type 2 disease, there are no studies evaluating the impact of metformin alone in patients with LADA. However, use of sulfonylureas is discouraged due to rapid deterioration of beta cells . To date, the evidence suggests that patients with LADA should be initially treated with insulin when glycemic control declines to a level indicating need for antidiabetic treatment [7, 19].
Unfortunately, treatment of T1DM remains an ongoing challenge. Tight control with intensive insulin treatment leading to reduced complications is often hindered by increased hypoglycemia and weight gain. Physiologic insulin strategies with rapid-acting analog insulins and insulin pumps combined with continuous glucose monitoring systems have shown improved glycemic control and decreased side effects. Use of adjunctive therapies, with non-insulin therapies, can be considered for patients with type 1 diabetes failing to achieve glycemic control on insulin [5, 9, 20].
Pramlintide, an amylin analog, is the only FDA-approved adjunctive therapy for type 1 diabetes. Use is limited due to concerns with tolerability and the need for administration by multiple daily injections or an infusion pump [5, 20]. Evidence suggests that adding metformin to insulin therapy may reduce insulin doses and improve metabolic control in overweight type 1 diabetic patients [20, 21]. Promising data is available for glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors due to their potential protection of beta cells and suppression of glucagon release . More clinical data exist for GLP-1 agonists which show a substantial reduction in post-prandial glucose excursions, weight and daily insulin requirements [20, 22, 23]. Sodium–glucose cotransporter 2 (SGLT2) inhibitors provide insulin-independent glucose lowering by inhibiting glucose reabsorption in the proximal renal tubule. The FDA has warned about the risk of ketoacidosis occurring in the absence of significant hyperglycemia in patients receiving these medications; thus, patients should be counseled on maintaining adequate hydration and monitored for ketoacidosis [20, 24]. Furthermore, patients should be warned that the FDA recently issued a boxed warning for increased risk for leg and foot amputation for one SGLT2 inhibitor, Canagliflozin. A clear benefit has not been demonstrated with use of thiazolidinediones (TZDs) in type 1 patients and the many potential side effects make it a less appealing option for add-on therapy. Use of metformin, GLP-1 agonists, DPP-4 inhibitors, and SGLT2 inhibitors may be considered safe and effective add-on therapy to insulin although large clinical trials are needed before routine use in this population . Our patient may have benefited from one of these therapies, which highlights that primary care providers need a broader understanding of acceptable treatment options for patients with LADA.
A previous autoimmune disease in a given patient increases the chance of another autoimmune disease in that same patient, and therefore there should be a low threshold for screening for concomitant autoimmune diseases. Screening and regular follow-up should be performed to detect other endocrine deficiencies before the development of potentially severe acute (such as adrenal crisis or ketoacidosis) or chronic complications (such as microvascular damage in type 1 diabetes). Early awareness of patients having LADA may result in more regular and targeted follow-up and a quicker transition to insulin if not initiated at diagnosis. The mainstay of therapy is insulin replacement, although tight control with intensive insulin is challenging. Insulin resistance is increasingly recognized as a barrier to ideal glycemic control in LADA, thus non-insulin therapies can be considered at early diagnosis or more commonly as add-on to insulin.