A Case of Type 2 Diabetes Mellitus with Lung Cancer Suffered from Euglycemic Diabetic Ketosis Accompanied by Adrenal Insufficiency after Immune Checkpoint Inhibitors

A 74-year-old patient with type 2 diabetes mellitus received basal-bolus insulin, insulin secretagogues, and sodium glucose transporter 2 (SGLT2) inhibitors. After immune checkpoint inhibitor treatment for lung cancer, he suffered from depressed consciousness with a urinary ketone body (3+). When all hypoglycemic treatments were discontinued, his serum blood glucose remained at 121 mg/dL. He was diagnosed with euglycemic diabetic ketosis. Endocrine loading tests revealed isolated adrenocorticotropic hormone (ACTH) deficiency as an immune-related adverse event. It was suggested that euglycemic diabetic ketosis was induced by the self-suspension of insulin and insulin secretagogues, adrenal insufficiency, SGLT2 inhibitors, and carbohydrate intake shortage.

Sodium glucose transporter 2 inhibitors (SGLT2 inhibitors) are a new type of glucose-lowering drug.Tey can reduce blood glucose by inhibiting its reabsorption in proximal tubules and by promoting urinary glucose excretion [3].SGLT2 inhibitors are widely used in the clinical treatment of type 2 diabetes mellitus (T2DM).However, SGLT2 inhibitors may also cause euglycemic diabetic ketosis.It is a life-threatening emergency and is characterized by milder degrees of hyperglycemia with blood glucose levels of <200 mg/dL with severe metabolic acidosis [4].Euglycemic diabetic ketoacidosis is also induced by other factors, such as surgery, trauma, pregnancy, decreased caloric intake, heavy alcohol use, insulin use prior to hospital admission, or liver cirrhosis [4,5].However, there are no reports of euglycemic diabetic ketosis in T2DM associated with isolated ACTH defciency induced by irAEs.In this case report, we describe the clinical features of irAE-related euglycemic diabetic ketosis in T2DM.

Case Presentation
A 74-year-old man sufered from T2DM at 58 years of age.He was treated with basal-bolus insulin at a total daily dose of 0.58 units/kg/day, canaglifozin 100 mg/day, glimepiride 1 mg/day, metformin 1000 mg/day, and dulaglutide 0.75 mg/ week.His glucose control was poor, and his HbA1c level was 8.0-9.0%.He had a carbohydrate-rich diet.He also sufered from fatty liver.His body weight was 79 kg, and his body mass index was 25.8 kg/m 2 .His fasting serum C-peptide level was 0.76-1.57ng/mL, and his postprandial C-peptide level was 2.25-6.28ng/mL, indicating a normal to mild decrease in insulin secretion.
An abnormal lung mass was detected in regular medical checks provided by his company, and he was diagnosed with squamous cell carcinoma of the left lower lobe (clinical TNM stage T3N3M0 and NSCLC stage IIIC).He was treated with carboplatin, paclitaxel, nivolumab (anti-PD-1 antibody), and ipilimumab (anti-CTLA-4 antibody).Nivolumab and ipilimumab were regularly administered for maintenance treatment.
On the 8 th day of the 3 rd cycle of nivolumab and ipilimumab, he felt general fatigue, excessive daytime sleepiness, and appetite loss.On the 13 th day, those symptoms further worsened, and he discontinued injecting insulin and dulaglutide and taking all oral hypoglycemic agents.On the 19 th day, he was transported to the emergency room of our hospital with a high fever of 38.3 °C and a depressed level of consciousness, as assessed by the Glasgow Coma Scale (E4V3M5).
He received intravenous rehydration containing glucose, insulin, and antibiotic treatment, which are standard treatments for euglycemic diabetic ketosis and bacterial infection.However, severe unconsciousness and hypovolemic shock appeared on the 3 rd day of hospitalization.All 3 sets of blood and urine culture tests were negative.Terefore, we suspected that euglycemic diabetic ketosis was accompanied by adrenal insufciency.We started 5 consecutive days of intravenous hydrocortisone supplementation (80-150 mg/day) followed by twice-daily oral hydrocortisone supplementation (30 mg/day).His condition drastically improved, and his urinary ketone body concentration became negative on the 7 th day of hospitalization.A rapid ACTH test was performed on the 8 th day to confrm the diagnosis of adrenal insufciency (Table 1).Subsequently, a corticotropin-releasing hormone loading test was performed on the 10 th day and revealed secondary adrenal insufciency.Te levels of the other anterior pituitary hormones were normal (Table 1).Enhancement and dynamic magnetic resonance imaging of the pituitary showed no enlargement of the pituitary gland or stalk, mass formation, or infammation.We established a diagnosis of isolated ACTH defciency.We judged it to be an irAE and considered that euglycemic diabetic ketosis was secondarily provoked.According to the Common Terminology Criteria for Adverse Events v5.0 (CTCAEv5.0)[6], his irAE grade was evaluated as level 4, most severe or life-threatening.He lost 6.2 kg of body weight in 2 months.He was discharged on the 23 rd day while receiving hydrocortisone supplementation.His diabetes was well-controlled by basal-bolus insulin and weekly glucagon-like peptide-1 receptor agonist injection therapy (Figure 1).

Discussion
We reported the case of a patient with T2DM and NSCLC who sufered from euglycemic diabetic ketosis and adrenal insufciency caused by isolated ACTH defciency as an irAE.Tis is the frst reported case in which euglycemic diabetic ketosis associated with adrenal insufciency was recognized in a T2DM patient with residual insulin secretion.To date, three reports have recognized diabetic ketoacidosis with isolated ACTH defciency as an irAE [7][8][9].All patients had type 1 diabetes mellitus accompanied by isolated ACTH defciency.Namely, in these patients, diabetic ketoacidosis developed in a background of absolute insulin defciency.However, in our patient, euglycemic diabetic ketosis developed in a patient with a preserved insulin secretion capacity.
Several clinical factors were suggested to induce euglycemic diabetic ketosis in T2DM patients with residual insulin secretion.It might be true that irAE-related isolated ACTH defciency created an opportunity to develop euglycemic diabetic ketosis.However, that alone was not sufcient for the development of diabetic ketosis because it could not cause insulin defciency [10].In addition to irAErelated isolated ACTH defciency, self-suspension of insulin injection and insulin secretagogues, SGLT2 inhibitors, and carbohydrate intake shortage might have contributed to the development of euglycemic diabetic ketosis.Next, we describe the mechanism that is presumed to underlie the development of euglycemic diabetic ketosis in our patient in detail (Figure 2).
Te self-suspension of insulin injection and insulin secretagogues may have accelerated insulin defciency.Te patient required a large dose of insulin plus insulin secretagogues to control his blood glucose as usual.During sick days, the demand for insulin increases due to decreased insulin sensitivity [11].Six days of consecutive selfsuspension would certainly promote insulin defciency.
Adrenal insufciency, SGLT2 inhibitors, and carbohydrate intake shortage might keep blood glucose levels lower.Cortisol plays a role in stimulating gluconeogenesis and inhibiting glycogenesis to prevent hypoglycemia [12,13].Tus, adrenal insufciency leads to hypoglycemia [12].SGLT2 inhibitors lower blood glucose levels by inhibiting the reabsorption of glucose in proximal tubules and by 2 Case Reports in Endocrinology promoting urinary glucose excretion [3].Te half-life of canaglifozin in T2DM repeatedly administered at 100 mg/ day is 11.8 ± 3.2 hours [14].However, the prolonged infuence of SGLT2 inhibitors and delayed recovery from euglycemic diabetic ketoacidosis have been reported, even at 6-10 days [15,16].Uenishi et al. reported that dehydration and a decreased renal function were one of the reasons for the prolonged infuence of SGLT2 inhibitors [15], as was also shown in our patient.Carbohydrates are the main source of glucose, and it is well known that a carbohydrate-restricted diet reduces blood glucose levels [17].Our patient had a medical record of fasting serum C-peptide level of 0.76 ng/ mL at 102 mg/dL of blood glucose.So, insulin secretion had been inhibited during adrenal insufciency.
Taken together, at frst, self-suspension of insulin injection and insulin secretagogues led to relative insulin defciency, Case Reports in Endocrinology resulting in the increased production of ketone bodies.Second, adrenal insufciency, SGLT2 inhibitors, and carbohydrate intake shortage kept blood glucose levels lower despite insulin defciency.Finally, pancreatic β cells cannot compensate for decreased insulin secretion, resulting in temporary severe insulin defciency.Temporary severe insulin defciency promotes lipolysis, the delivery of free fatty acids to the liver, ketogenesis, and ultimately, euglycemic diabetic ketosis [4,5] (Figure 2).In addition to temporary severe insulin defciency, the upregulation of glucagon secretion contributes to the overproduction of ketone bodies although serum glucagon levels were not measured.Te administration of SGLT2 inhibitors stimulates the secretion of glucagon, which is mediated by a decrease in insulin secretion [5] or a direct efect of SGLT2 inhibitors on pancreatic α-cells [18].
Our patient showed diabetic ketosis due to hypoinsulinemia but not diabetic ketoacidosis.McNulty et al. [19] reported a case of newly diagnosed type 1 diabetes mellitus with Addison's disease, which showed only diabetic ketosis and did not progress to diabetic ketoacidosis.Sheung et al. [20] reported that the degree of acidosis was very mild in diabetic ketoacidosis caused by self-discontinuation of insulin injection   Case Reports in Endocrinology in type 1 diabetes mellitus with Addison's disease.It was speculated that ketone body synthesis due to insulin defciency were partly ofset by adrenal insufciency [19,20].
In conclusion, we reported the case of a patient with T2DM who was treated with ICIs for NSCLC and developed euglycemic diabetic ketosis due to several clinical factors.It is necessary for healthcare professionals to recognize that such patients have a high risk of developing euglycemic diabetic ketosis.

Figure 2 :
Figure 2: Diagram of the development of euglycemic diabetic ketosis.

Table 1 :
Patient laboratory data from the time of administration and the results of endocrine loading tests.