SH is regarded as benign and transient hyperglycemia during acute stress. Accumulating studies have demonstrated that SH was unrelated to T1DM, thus rendering routine confirmatory investigation unnecessary2, 3, 6–10. Furthermore, extreme SH (ESH), glucose levels ≥ 300 mg/dL, was rarely seen in children; and it was also unrelated to subsequent DM10. Crucially, previous studies showed the ESH subjects exhibited merely 13% ketonuria10. In view of this, ketonuria in our young boy might be taken as a feature of glucose dysregulation in that ketone body forms rapidly in insufficient insulin environment. However, the critical timing to elucidate the underlying etiopathology of SH was still inconclusive, the current latent T1DM case is thus an exceptional didactic experience worthy of attention.
In addition to AEBA per se, beta-2 agonists and corticosteroids also increase blood glucose mediated by promoting gluconeogenesis. Accordingly, previous studies regarding SH almost excluded beta-2 agonists and corticosteroids intervention2, 3, 8, 9; therefore, asthmatic children with underlying DM might be excluded and then underestimated. Interestingly, asthma and T1DM are both immune-mediated disease but their association was not fully clarified. It was reported that children with asthma increase the risk of subsequent T1DM development by 41% when compared to normal population11. To date, there were only two studies on a total of 33 asthmatic children exploring the relationship between transient hyperglycemia and asthma, but none of the subjects was diagnosed to have DM eventually7, 10.
Likewise, in our patient, bronchodilator and steroid might contribute to hyperglycemia and aggravate the severity of SH; hence, drug effect on glucose metabolism should be taken into consideration. Burgess C. et al. reported that only high doses of inhaled beta-2 agonist can significantly increase blood glucose to the peak level of 133 mg/dL after 5 hours of treatment in mild-to-moderate asthma subjects12. Another study showed that asthmatic patients had a peak value of glucose 293 mg/dL after 4 hours of combined treatment with beta-2 agonist and corticosteroid13. In the present case, extreme values of blood glucose were inconsistent with the time point of beta-2 agonists and corticosteroids intervention (Fig. 1). Moreover, the inexplicably higher glucose concentration (≥ 300 mg/dL) than those in previous studies, which together supported that dysglycemia of our case might be caused not only by acute stress and drug effect but also by underlying insulinopenia. In addition to peak blood glucose, the duration of SH could be another crucial clue for early detection of latent DM. It has been reported that 67% of ESH subjects normalized their blood glucose levels below 150 mg/dL within 48 hours and none of them was subsequently diagnosed with DM10. Similarly, Gupta et al. also demonstrated the restoration of SH could be observed within 24 hours in all enrolled children with illness and the result of oral glucose tolerance tests done for 86% participants were normal2. In the present case, blood glucose above 150 mg/dL was detected even at 48 hours after admission (Fig. 1), indicating that this prolonged SH might be caused by latent DM.
To elucidate the pattern of glucose fluctuation under psychiatric stress, T1DM animal models under a predator stress circumstance showed the SH was characterized as “fast and slow” pattern, in which blood glucose rapidly increased and slowly decreased thereafter14. Although we cannot fully extrapolate the animal results to humans, blood glucose levels of the present case indeed rapidly increased from 174 mg/dl to 400 mg/dL within 2 hours (9th -11th hours after admission), maintained peak levels above 400 mg/dL for 5 hours (11th -15th hours after admission) and then decreased slowly to 89 mg/dL (Fig. 1), suggesting a human “fast and slow” pattern along with prolonged SH course in insulinopenic status.
Although HbA1c was a pivotal biomarker of long-term glycemic control with the usefulness to reflect the cumulative glycemic history of the preceding two to three months15, it cannot tell GV to clinicians. It has been reported that GV was associated with diabetes complication and increased mortality rate in PICU16, 17. Hanefeld et al. monitored blood glucose values with continuous glucose measurement systems (CGMS) in abnormal glucose tolerance subjects and control ones and demonstrated a significantly higher amplitude of glucose excursion and standard deviation (SD) in those with abnormal glucose tolerance, suggesting higher GV18. Another study focusing on children with positive islet autoantibodies (high risk to future T1DM) revealed those with blood glucose above 140 mg/dL accounted for over 20% study time during a 5- to 7- day -period of CGMS monitor could be used to predict the future development of DM. Compared to patients with negative antibody, a higher SD of blood glucose was noted in those with positive islet autoantibodies19.
Owing to unconfirmed diagnosis of DM at admission, regular stick blood glucose test was performed for our patient to evaluate his GV under stress instead of real-time CGMS. Significant change of blood glucose was noticed initially after stress exposure; however, obvious variation unexpectedly existed after the resolution of acute stress (Fig. 1). This interesting finding illuminated persistent high GV after stress might be a potent risk factor for underlying T1DM, but further study with more patients is needed to confirm our current findings.
To our knowledge, there has been no prospective study exploring the difference in SH between diabetic and nondiabetic children. This first case highlights an important but still complex relationship between SH (glucose dysregulation) and subclinical T1DM (insulinopenia). We suggest that clinicians should be aware of pathological SH, particularly when it was characterized by features such as ESH (> 300mg/dl), high GV even after acute phase of illness, prolonged hyperglycemic duration (longer than 48 hours) or ketonuria (urine ketone ≥ 2+), all suggesting that dysglycemia might result from latent diabetes. Then further investigations to traditionally benign SH should be conducted even there were no clinical signs or symptoms of diabetes.