Shojiro Sawada

Background: Hyperglycemic hyperosmolar syndrome (HHS) is a severe complication of diabetes, and is triggered by infection, use of corticosteroids, non-adherence to medications, and acute diseases. Despite advances in diabetes management, the clinical features and outcomes of patients with HHS remain unclear. This study aimed to investigate the clinical characteristics and prognoses of patients with HHS at a university hospital in Japan. Methods: This retrospective cohort study analyzed 84 consecutive patients diagnosed with HHS between 2018 and 2023. Patients with HHS were classified into “isolated HHS” and “mixed diabetic ketoacidosis (DKA)/HHS” groups based on established criteria. A subgroup analysis further divided the isolated HHS group into those with and without metabolic acidosis. Clinical data were collected from electronic medical records. Results: The median age of patients with HHS was 75 years, with infections (51.2%) being the most common trigger. Approximately 70% of patients did not receive diabetes medication. The isolated HHS group had a significantly higher 30-day mortality rate (26.0%) than the mixed DKA/HHS group (0%). In the isolated HHS group, those with metabolic acidosis showed markedly worse outcomes, with a 30-day mortality rate of 54.6% versus 20.7% in those without acidosis. Conclusion: HHS predominantly affects elderly patients and is often associated with poor diabetes management. The isolated HHS group had a worse prognosis than the mixed DKA/HHS group, and the presence of metabolic acidosis other than ketoacidosis significantly increased mortality. Regular blood glucose monitoring and appropriate diabetes medications are crucial for preventing the development of HHS.

Lipopolysaccharides are components of Gram-negative bacteria. The relationship between blood lipopolysaccharide levels and health status has mainly been investigated in Europe, and there is a lack of information about Asia, particularly Japan. This study aimed to investigate the relationship between blood lipopolysaccharide levels and health status in the Japanese. We conducted two cross-sectional studies in 36 healthy subjects (Study 1) and 36 patients with abnormal glucose metabolism (AGM; Study 2). The plasma lipopolysaccharide concentration in healthy subjects was positively correlated with body mass index. The plasma lipopolysaccharide concentration in AGM patients was obviously higher than that in healthy subjects. Furthermore, in AGM patients, the plasma lipopolysaccharide concentration was positively correlated with C-peptide, fasting plasma glucose levels, triglycerides, and stage of diabetic nephropathy. The plasma lipopolysaccharide concentration was also negatively correlated with 20/(C-peptide × fasting plasma glucose), an indicator of insulin resistance, and high-density lipoprotein cholesterol. In particular, the correlation between plasma lipopolysaccharide concentration and triglycerides in AGM patients was maintained in multiple regression analyses adjusted for age, sex, or body mass index. These results suggest a possible role of lipopolysaccharides in obesity in healthy subjects and in the deterioration of triglyceride metabolism in AGM patients in the Japanese population.

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Background: Bariatric surgery is effective for the treatment of patients with morbid obesity and type 2 diabetes mellitus (T2DM), for body weight loss and glycemic control. However, in Japan, there has been no previous report of the effectiveness bariatric surgery in a case of morbid obesity associated with acute onset type 1 diabetes mellitus (T1DM), in which pancreatic β-cells were destroyed and endogenous insulin was depleted. Case presentation: A 36-year-old woman with morbid obesity and T1DM, diagnosed when she was 6 years, was admitted for bariatric surgery. At her first consultation, she had a body weight of 106.7 kg and a body mass index of 42.2 kg/m². Her HbA1c level was 9.0%, with a required daily insulin dose of 75 units. She underwent laparoscopic sleeve gastrectomy. At 1 year after surgery, her body weight had decreased to 81.0 kg and her body mass index to 32.2 kg/m². In addition, her daily required dose of insulin had decreased to 24 units, with an improvement in her HbA1c level to 7.7%. Conclusions: Although further evidence needs to be accumulated, including long-term outcomes, laparoscopic sleeve gastrectomy may provide an effective treatment for patients with morbid obesity and T1DM for body weight loss, improvement in HbA1c level, and insulin dose reduction.

A high-molecular-weight form of insulin-like growth factor-2 (IGF-2), known as “big” IGF-2, is occasionally produced by various tumor types, leading to hypoglycemia. Although solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm, it has been estimated that 4–6% of SFT patients develop hypoglycemia due to circulating big IGF-2. The mean time elapsed from tumor detection until the onset of hypoglycemia is reportedly less than one year (8.5 ± 1.9 months). A 68-year-old man was hospitalized for exacerbation of recurring hypoglycemic episodes. He had been diagnosed with an SFT 17 years before the onset of hypoglycemia, and the SFT had already been very large at that time. The tumor, which was non-resectable and refractory to chemotherapies, had slowly increased in size since the initial diagnosis. Half a year before the hypoglycemic episodes manifested, another tumor, adjacent to the left kidney, was newly identified. Fluorodeoxyglucose positron emission tomography-computed tomography scanning, revealed the left peri-renal tumor to show much higher fluorodeoxyglucose uptake than the preexisting SFT, suggesting that it was unlikely to be a metastasis from the SFT. Abundant serum big IGF-2 was detected by western immunoblot analysis, indicating it to be the cause of the hypoglycemia. Since the 17 years between SFT detection and the onset of IGF-2-induced hypoglycemia was an extremely long period as compared with those in previous reports, we initially suspected that the new, peri-renal tumor had produced big IGF-2, but transcatheter arterial embolization of its feeding arteries did not suppress hypoglycemia. Notably, by measuring the tumor volume doubling time, the peri-renal tumor growth was shown to be markedly accelerated in parallel with exacerbation of the hypoglycemia. The patient died of heart failure 21 months after the onset of hypoglycemia. Unexpectedly, autopsy revealed that big IGF-2 had been produced only by the preexisting SFT, not the peri-renal tumor, and that the peri-renal tumor was a dedifferentiated liposarcoma. We should keep in mind that even a long-inactive SFT can undergo transformation to produce big IGF-2, which then acts on both insulin and IGF-1 receptors, possibly leading to both hypoglycemia and the development/growth of another tumor, respectively.

Summary: Bariatric surgery is associated with a high remission rate of type 2 diabetes mellitus. However, it is unclear whether patients showing remission of diabetes actually have normal blood glucose levels throughout the day. We therefore performed continuous glucose monitoring (CGM) in 15 ambulatory patients showing remission of diabetes after laparoscopic sleeve gastrectomy (LSG) without or with duodenojejunal bypass (DJB) at the time of diabetic remission (12.9 ± 1.8 months after bariatric surgery). The definition of remission of diabetes was based on the American Diabetes Association criteria. The mean, SD, and coefficient of variation (CV) of glucose calculated from CGM were 6.2 ± 0.6 mmol/L, 1.5 ± 0.4 mmol/L, and 23.7 ± 6.2%, respectively. These values were higher than those of healthy participants without diabetes previously reported. The percentages of time spent above 10.0 mmol/L and below 3.9 mmol/L were 2.6 (IQR 0‐5.0)% and 0 (IQR 0‐8.0)%, respectively. Thus, patients with remission of diabetes after LSG or LSG/DJB still had substantial periods of hyperglycemia and hypoglycemia throughout the day. Therefore, we must manage patients with diabetes carefully, even after apparent remission of type 2 diabetes in response to bariatric surgery.

Insulin injection, especially with insulin analogs, occasionally induces the production of insulin antibodies with high binding capacity and low affinity, similar to the insulin autoantibodies characteristic of insulin autoimmune syndrome (IAS). Production of these “IAS-like” insulin antibodies causes marked glycemic fluctuations with postprandial hyperglycemia and fasting hypoglycemia. A 66-year-old man with a 27-year history of diabetes was admitted because of marked glycemic fluctuations. Human insulin treatment had been initiated at age 56, followed by multiple daily injections of insulin analogs 5 years later. After the initial year of insulin analog treatment, the patient began to experience frequent morning hypoglycemic attacks and day-time hyperglycemia. Marked hyperinsulinemia (4500 μU/mL) and high titers of insulin antibodies (80.4%) with high binding capacity and low affinity indicated that IAS-like insulin antibodies were causing severe glucose fluctuations. Altering insulin formulations (insulin aspart → regular human insulin→ insulin lispro) proved to be ineffective. After several therapeutic trials, cessation of exogenous insulin and addition of mitiglinide to liraglutide with voglibose finally attenuated glycemic fluctuations with increased postprandial insulin secretion. Continuous glucose monitoring revealed improvement of morning hypoglycemia and postprandial hyperglycemia with smaller mean amplitude of glycemic excursion. Therefore, compared to exogenously injected insulin, endogenously secreted insulin directly and rapidly acts on hepatocytes and suppresses postprandial glucose output. Proper enhancement of postprandial endogenous insulin aimed at suppressing postprandial glucose output without stimulating excessive glucose uptake in the periphery is potentially useful for treating diabetes with insulin antibody-induced glycemic instability.