A Case of Autoantibody Negative Pediatric Diabetes Mellitus With Marked Insulin Resistance Concomitant With COVID-19: A Novel Form of Disease?

Martinez, Alfonso Hoyos; Hicks, Kelly Anne; Moorjani, Tracy Patel; Bell, Jennifer; Lin, Yuezhen

Background: SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) receptor to enter human cells. This receptor is avidly expressed in the pancreatic islets, suggesting the virus may target β-cell function. 17% of adults with COVID-19 have evidence of pancreatic injury. There is a direct relation between insulin resistance and COVID-19 severity and mortality with patients with higher insulin resistance presenting with higher inflammatory response. Fulminant type 1 diabetes (fT1D) has abrupt onset of symptoms with insulinopenia without evidence of autoimmunity, usually preceded by viral illness. Clinical case: A 12-year-old Hispanic male presented with a week history of polyuria, polydipsia, headache, and fatigue but no weight loss, fever, cough, anosmia, or diarrhea. Laboratory testing revealed new onset diabetes with DKA with HbA1C 11.3%, blood pH 7.04, glucose 381 mg/dL, C-peptide 0.6 ng/mL, β-hydroxybutyrate 8.2 mmol/L, and a positive nasopharyngeal PCR for SARS-CoV-2 but no elevation of inflammatory markers (CRP, ESR and ferritin). There was evidence of mild pancreatic injury (lipase 179 U/L, n:15-110 U/L), and all autoantibodies for autoimmune diabetes were negative. He was pubertal (Tanner 3), non-obese (BMI Z score -0.3) and without acanthosis nigricans. Past medical and family history were non-contributory. He was treated with IV insulin at 0.1 u/kg/h until DKA resolved within 24 h then transitioned to subcutaneous insulin at 1 u/kg/day. He did not have signs of systemic inflammatory response, need for respiratory support, or glucocorticoids but had persistent hyperglycemia prompting an increase of insulin dosing and resumption of IV insulin. His insulin requirements continued to increase up to 4 u/kg/d with sustained hyperglycemia indicative of an exceptional state of insulin resistance. On Day 6 of admission metformin was initiated, on Day 9 insulin requirements declined and he was discharged on an insulin regimen close to 1.5 u/kg/d. Eventually metformin was discontinued on Day 20 after diagnosis without rebound in insulin requirements. On Day 28 he had improved glycemic control (HbA1c 8.8%) at insulin doses more appropriate for his age and pubertal status (0.9 u/kg/d). Clinical lessons: We report a case of autoantibody negative diabetes with pancreatic injury and marked insulin resistance unrelated to systemic inflammatory response associated with COVID-19. The clinical presentation was reminiscent of fT1D with the exception of exceptional insulin resistance. This is perhaps a novel form of diabetes mellitus not otherwise classified. Although the pathophysiology remains obscure, it is plausible that it is mediated by direct islet injury. Notably, there was a discordance between the severity of illness and insulin resistance suggesting an intrinsic effect of SARS-CoV-2 on glucose hemostasis.