Factors Associated with Relapse of Type 2 Diabetes Mellitus after Laparoscopic Sleeve Gastrectomy in Japanese Subjects: A Subgroup Analysis of J-SMART Study.

INTRODUCTION: Laparoscopic sleeve gastrectomy (LSG) for morbidly obese patients often results in remission of type 2 diabetes (T2DM), but diabetes relapses in some of those patients. The frequency of T2DM relapse in Asians and the factors involved have not been adequately investigated. METHODS: The J-SMART study was conducted on 322 Japanese subjects with body mass index (BMI) ≥32 kg/m2 who underwent LSG at 10 accredited centers in Japan between 2011 and 2014. Of these, 82 T2DM subjects with diabetes in complete or partial remission at 1 year after LSG and followed postoperatively for 5 years were included in the subgroup analysis and classified into two groups: diabetes remission-maintained and diabetes relapse. RESULTS: The mean age of all included subjects was 49.2 years, median BMI was 41.5 kg/m2, and median HbA1c was 6.7%. Compared with the diabetes remission-maintained group, the diabetes relapse group at 5 years after LSG had significantly higher preoperative HbA1c, number of antidiabetic medications, and high-density lipoprotein cholesterol level; and lower BMI and homeostasis model assessment-beta cell function (HOMA-ß). As many as 83.0% of the subjects were able to achieve HbA1c <7% at 5 years after LSG, but 26.8% of the subjects had diabetes relapse. Preoperative HbA1c significantly contributed to diabetes relapse (odds ratio 1.54, p = 0.049). In addition, the diabetes relapse group tended to have lower percentage total weight loss (%TWL) at 1 year after LSG and higher percentage weight regain (%WR) from postoperative nadir weight, compared with the diabetes remission-maintained group. The hazard ratio for diabetes relapse was 3.14-fold higher in subjects with %TWL ≥20% and %WR ≥25%, and 5.46-fold higher in those with %TWL <20% and %WR ≥25%, compared with %TWL ≥20% and %WR <25%. CONCLUSION: While LSG provides a high remission rate for T2DM, relapse is not uncommon. Preoperative HbA1c, poor weight loss, and excess weight regain after LSG contribute to diabetes relapse, suggesting the importance of treatment strategies focusing on these factors.

Characteristics of Childhood Onset and Post-Puberty Onset Obesity and Weight Regain after Laparoscopic Sleeve Gastrectomy in Japanese Subjects: A Subgroup Analysis of J-SMART.

INTRODUCTION: The psychosocial background of subjects with severe obesity developed from childhood onset obesity (CO) and their outcomes after bariatric surgery have not been fully investigated. METHODS: 305 subjects were enrolled in the J-SMART study, which examined the effects of laparoscopic sleeve gastrectomy (LSG) in Japan, and categorized into two groups: CO defined as onset up to 13 years of age (CO group) and post-puberty onset obesity defined as onset after 13 years of age (PPO group). The subjects were followed up for at least 2 years and up to 5 years after LSG. Changes in physical parameters and remission of obesity-related comorbidities were assessed at 2 years after LSG. Weight regain (WR) was also assessed by evaluating the nadir weight after LSG and maximum weight thereafter during follow-up period. RESULTS: The mean postoperative follow-up period was 3.0 ± 1.1 years. 40.0% of the subjects had CO and these subjects had higher BMI and HOMA-ß and lower age, HbA1c, HDL cholesterol, and visceral/subcutaneous fat area ratio compared to those with PPO. The CO group was also characterized by having higher rates of mental retardation, developmental disorders, and obesity in either parent and lower rate of marriage compared to the PPO group. Two years after LSG, there were no differences in total weight loss and remission rates of diabetes, dyslipidemia, and sleep apnea syndrome between the two groups, although remission rate of hypertension was higher in the CO group. The CO group also had a higher rate of WR after LSG than the PPO group, with CO, BMI, mental disorder, and binge eating contributing to WR. CONCLUSION: This study suggests that CO might be associated with genetic and psychosocial factors. CO and PPO probably differ in pathogenesis and may require different treatment strategies.

Correction to: Metabolic surgery in treatment of obese Japanese patients with type 2 diabetes: a joint consensus statement from the Japanese Society for Treatment of Obesity, the Japan Diabetes Society, and the Japan Society for the Study of Obesity.

[This corrects the article DOI: 10.1007/s13340-021-00551-0.].

Correction to: Metabolic surgery in treatment of obese Japanese patients with type 2 diabetes: a joint consensus statement from the Japanese Society for Treatment of Obesity, the Japan Diabetes Society, and the Japan Society for the Study of Obesity.

[This corrects the article DOI: 10.1007/s13340-021-00551-0.].

A Clinical Case of Insulinoma Presenting with Postprandial Hypoglycemia in a Patient with a History of Gastric Bypass Surgery.

A 61-year-old man with a history of total gastrectomy for cancer with Roux-en-Y reconstruction showed severe postprandial hypoglycemia accompanied by endogenous hyperinsulinemia. Abdominal ultrasonography and contrast-enhanced computed tomography showed no abnormal findings in the pancreas. A selective arterial secretagogue injection test showed the marked induction of serum immunoreactive insulin when calcium was injected into the splenic artery. A pathological analysis following distal pancreatectomy with splenectomy revealed a pancreatic neuroendocrine microadenoma containing insulin-producing cells in the resected pancreas. This case highlights the importance of carefully evaluating refractory and severe hypoglycemia in patients with a history of gastric surgery to exclude insulinoma.

Metabolic surgery in treatment of obese Japanese patients with type 2 diabetes: a joint consensus statement from the Japanese Society for Treatment of Obesity, the Japan Diabetes Society, and the Japan Society for the Study of Obesity.

Bariatric surgery has been shown to have a variety of metabolically beneficial effects for patients with type 2 diabetes (T2D), and is now also called metabolic surgery. At the 2nd Diabetes Surgery Summit held in 2015 in London, the indication for bariatric and metabolic surgery was included in the "algorithm for patients with type T2D". With this background, the Japanese Society for Treatment of Obesity (JSTO), the Japan Diabetes Society (JDS) and the Japan Society for the Study of Obesity (JASSO) have formed a joint committee to develop a consensus statement regarding bariatric and metabolic surgery for the treatment of Japanese patients with T2D. Eventually, the consensus statement was announced at the joint meeting of the 38th Annual Meeting of JSTO and the 41st Annual Meeting of JASSO convened in Toyama on March 21, 2021. In preparing the consensus statement, we used Japanese data as much as possible as scientific evidence to consider the indication criteria, and set two types of recommendation grades, "recommendation" and "consideration", for items for which recommendations are possible. We hope that this statement will be helpful in providing evidence-based high-quality care through bariatric and metabolic surgery for the treatment of obese Japanese patients with T2D. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00551-0.

Background characteristics and diabetes remission after laparoscopic sleeve gastrectomy in Japanese patients with type 2 diabetes stratified by BMI: subgroup analysis of J-SMART.

AIM: The J-SMART study was the first national survey of Japanese patients undergoing laparoscopic sleeve gastrectomy (LSG). We performed a subgroup analysis of J-SMART focusing on the differences in patient background and diabetes remission between patients with BMI 32-34.9 kg/m2 and those with higher BMI. METHODS: In this multi-institutional retrospective study at 10 certified bariatric institutions, 203 Japanese with type 2 diabetes (T2D) and BMI of 32 kg/m2 or higher were analyzed (mean age: 49.2 years, BMI: 43.8 kg/m2, HbA1c: 7.6%). Patients were stratified into five groups according to preoperative BMI. RESULTS: Background characteristics in BMI 32.0-34.9 group were higher adjusted HbA1c, higher visceral/subcutaneous fat area ratio, higher prevalence of diabetic retinopathy, higher frequency of insulin use and lower serum C-peptide. Although 2-year percent total weight loss (21.7%) and diabetes complete remission (CR) rate (52.4%) were lower in BMI 32.0-34.9 group, diabetes improvement rate was 81.0%, and the decrease in HbA1c and number of antidiabetic drugs were comparable or greater than those with higher BMI. Higher BMI and no insulin use were significant independent predictors of diabetes CR. No significant independent predictor was identified for diabetes improvement. CONCLUSION: The patients with 32-34.9 kg/m2 were characterized by more severe visceral obesity, T2D and the complications, and lower intrinsic insulin secretion capacity. LSG should be considered as a treatment option for patients with BMI 32-34.9 kg/m2, to improve diabetes control.

Bucillamine-induced gigantomastia with galactorrhea and hyperprolactinaemia.

Gigantomastia is characterised by excessive breast growth and can occur as a rare, drug-induced adverse event. D-penicillamine is the most frequent cause of drug-induced gigantomastia. Only one case of gigantomastia due to bucillamine, an analogue of D-penicillamine, has been reported so far. We herein report a case of bucillamine-induced gigantomastia presenting with acute enlargement of the bilateral breasts and accessory breast tissue in the axillae 7 months after the start of bucillamine therapy. Awareness about this rare adverse event is important since bucillamine is still widely used in Japan and Korea.

Background characteristics and postoperative outcomes of insufficient weight loss after laparoscopic sleeve gastrectomy in Japanese patients.

AIM: Laparoscopic sleeve gastrectomy (LSG) is becoming popular in Japan, but insufficient weight loss is often observed in patients after LSG. We investigated the effect of LSG on obesity-related comorbidities and identified the background characteristics of Japanese patients with insufficient weight loss after LSG. METHODS: In this multi-institutional retrospective study at 10 certified bariatric institutions, 322 Japanese patients who underwent LSG with a follow-up period of more than 2 years were analyzed. Anthropometry, obesity-related comorbidities and psychosocial background data were collected. Weight loss was expressed as 2-year percent total weight loss (%TWL). RESULTS: Mean age, body weight, body mass index (BMI) and glycated hemoglobin were 46.9 years, 119.2 kg, 43.7 kg/m2 and 7.1%, respectively. Prevalence of mental disorders was 26.3%. Mean BMI declined to 30.3 kg/m2 at 2 years and %TWL was 29.9%. Improvements in the markers and prevalence of obesity-related comorbidities were observed. Remission rates of diabetes, dyslipidemia and hypertension were 75.6%, 59.7% and 41.8%, respectively. %TWL at the respective cut-off level of diabetes remission was 20.8%. Lower remission rates of diabetes in patients with %TWL <20%, and less calorie restriction and higher prevalence of mental disorders (46.9%) in patients with %TWL <15% were observed. Frequencies of %TWL <15% and <20% were 6.5% and 18.5%, respectively. CONCLUSION: %TWL 20% was a candidate cut-off point of insufficient weight loss for diabetes remission after LSG, and mental disorders might be relevant to intractable obesity in Japanese patients.

Clinical outcomes of 20 Japanese patients with insulinoma treated with diazoxide.

Diazoxide is recognized as an effective medical treatment for insulinoma. However, due to its adverse effects, such as fluid retention, it is sometimes difficult to employ diazoxide at an effective dose in clinical practice. This study aimed to clarify the clinical factors, which may affect efficacy and safety of the diazoxide treatment. We retrospectively evaluated the medical records of 20 patients with insulinoma including 4 malignant cases. The patients were divided into two groups according to the presence or absence of favorable outcomes or adverse effects, and the clinical features of both groups were compared. Diazoxide was effective and ineffective in each 9 patients, respectively. In other 2 cases, the efficacy could not be determined. In the effective group, all patients had benign insulinoma. Additionally, the tumor size determined by imaging test was tended to smaller than the ineffective group but not statistically significant when malignant cases were excluded (p = 0.065). Fluid retention was observed more frequently in females than in males (p = 0.025). Five patients displayed unacceptable thrombocytopenia within a few weeks after the administration of diazoxide. In these patients, the diazoxide dose was significantly higher than that in the other patients [400 mg/day (250-500 mg/day) vs. 225 mg/day (50-425 mg/day), p = 0.027]. These findings may be informative in determining the indication and dose of diazoxide against insulinoma. In addition, a careful evaluation of platelet count would be required for a few weeks after the initiation of diazoxide treatment.

IgG4-related Hypophysitis with Subtle Hypopituitarism in an Elderly Diabetic Patient: Is Treatment or Observation Preferable?

A 70-year-old man with diabetes mellitus presented with an enlarged pituitary stalk in 2014. IgG4-related parotitis and submandibular sialoadenitis were diagnosed in 2012. He denied any symptoms related to a pituitary mass. His visual field was intact, and his hypopituitarism was subtle. The serum IgG4 level was elevated. A lip biopsy revealed strong fibrosis and hyper-infiltration of IgG4-positive plasma cells. Based on these findings, IgG4-related hypophysitis was diagnosed. The patient was carefully followed without specific intervention. His clinical condition showed no change until December 2016, suggesting a stable, natural course. Care should be taken when considering glucocorticoid therapy, especially for elderly diabetic patients, given possible side effects.

Early Effects of Sleeve Gastrectomy on Obesity-Related Cytokines and Bile Acid Metabolism in Morbidly Obese Japanese Patients.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has wide-ranging positive effects on adipocytokine metabolism, bile acid profile, and chronic low-grade inflammation related to obesity. However, the early temporal changes in these markers following LSG have not been well investigated. This study aimed to evaluate the early effects of LSG on adipocytokines, bile acid profile, and inflammatory markers. METHODS: This was a nonrandomized prospective study examining morbidly obese Japanese patients undergoing LSG. Serial measurements of leptin, adiponectin, bile acids, fibroblast growth factor (FGF)-19, and inflammatory markers were performed preoperatively and 1 and 6 months after LSG. RESULTS: The study included ten patients (five females) with a mean age of 48.8 years and BMI 40.9 kg/m2. At baseline, 90% of the patients had T2DM, 70% had dyslipidemia, and 90% had hypertension. Patients lost 5.1 kg/m2 BMI at 1 month and 10.1 kg/m2 BMI at 6 months. The leptin levels sharply decreased, and FGF-19 increased significantly as early as 1 month postoperatively. Adiponectin levels showed an increasing trend at 1 month and a significant increase at 6 months. A significant decrease in high-sensitivity CRP and plasminogen activator inhibitor-1 was observed at 6 months. No significant changes were observed in interleukin (IL)-6, IL-8, tumor necrosis factor-α, serum amyloid A protein, or monocyte chemotactic protein-1 throughout the study. CONCLUSIONS: LSG improved the secretion of adipocytokines, increased FGF-19 secretion soon after surgery, and slowly ameliorated inflammation related to obesity through significant weight loss.

Effect of Ezetimibe on LDL-C Lowering and Atherogenic Lipoprotein Profiles in Type 2 Diabetic Patients Poorly Controlled by Statins.

BACKGROUND: There exists a subpopulation of T2DM in whom first-line doses of statin are insufficient for optimally reducing LDL-C, representing a major risk of CVD. The RESEARCH study focuses on LDL-C reduction in this population along with modifications of the lipid profiles leading to residual risks. METHODS: Lipid changes were assessed in a randomized, multicenter, 12-week, open-label study comparing a high-potency statin (10mg of atorvastatin or 1mg of pitavastatin) plus ezetimibe (EAT: n = 53) with a double dose of statin (20mg of atorvastatin or 2mg of pitavastatin) (DST: n = 56) in DM subjects who had failed to achieve the optimal LDL-C targets. Lipid variables were compared with a primary focus on LDL-C and with secondary focuses on the percentage of patients who reached the LDL-C targets and changes in the levels of RLP-C (remnant like particle cholesterol) and sd-LDL-C, two characteristic atherogenic risks of DM. RESULTS: The reduction of LDL-C (%), the primary endpoint, differed significantly between the two groups (-24.6 in EAT vs. -10.9 in DST). In the analyses of the secondary endpoints, EAT treatment brought about significantly larger reductions in sd-LDL-C (-20.5 vs. -3.7) and RLP-C (-19.7 vs. +5.5). In total, 89.4% of the patients receiving EAT reached the optimized treatment goal compared to 51.0% of the patients receiving DST. The changes in TC (-16.3 vs. -6.3) and non-HDL-C (-20.7 vs. -8.3) differed significantly between the two groups. CONCLUSION: Ezetimibe added to high-potency statin (10 mg of atorvastatin or 1 mg of pitavastatin) was more effective than the intensified-dose statin (20 mg of atorvastatin or 2 mg of pitavastatin) treatment not only in helping T2DM patients attain more LDL-C reduction, but also in improving their atherogenic lipid profiles, including their levels of sd-LDL-C and RLP-C. We thus recommend the addition of ezetimibe to high-potency statin as a first line strategy for T2DM patients with insufficient statin response. TRIAL REGISTRATION: The UMIN Clinical Trials Registry UMIN000002593.

Hyperosmolar hyperglycemic state in advanced amyotrophic lateral sclerosis.

Our objective was to describe cases of hyperosmolar hyperglycemic state (HHS) in advanced amyotrophic lateral sclerosis (ALS) patients and discuss its pathophysiology. Five ventilator-dependent patients with ALS, with no previous history of diabetes, showed development of marked hyperglycemia (plasma glucose levels of 755-1544 mg/dl) after preceding infectious episodes. All patients had severe generalized muscle wasting and tetraplegia. The initial manifestations of HHS were fever, drowsiness, or polyuria. Hydration and intravenous insulin therapy were markedly effective, resulting in favorable recovery without the necessity of chronic medication for hyperglycemia in all cases. Seventy-five grams oral glucose tolerance tests performed via feeding tubes in two patients after the successful treatment of HHS revealed increased insulin resistance and diminished early-phase insulin secretion with preserved total insulin secretion. In conclusion, a marked loss of skeletal muscle, the largest glucose consumer of the human body, with background abnormality of early-phase insulin secretion, might be a causative factor of HHS in advanced ALS.

Reversible respiratory failure due to rhabdomyolysis associated with cytomegalovirus infection.

A 58-year-old woman presented with muscle weakness, whole body myalgia, and dyspnea. On admission, neurological examination showed proximal muscle weakness in the extremities. The weakness gradually extended to the bulbar and respiratory muscles, necessitating an artificial ventilator. Serum CK level was markedly increased (33,774 IU/L; normal <150 IU/L) and myoglobinuria was noted in urinalysis. There was no sign of renal failure. Nerve conduction study was normal, but needle EMG showed myopathic changes in the weak muscles. Serological studies for virus titers showed more than a four-fold increase of cytomegalovirus (CMV) antibody titer during the disease course. The IgM anti-GM2 antibody was also elevated in the acute phase and decreased in the recovery phase. The muscle weakness and respiratory failure gradually improved after intravenous methylprednisolone administration, and the serum CK level was normalized in several days. CMV infection was thought to have played a central role in the rhabdomyolysis, leading to critical but reversible respiratory muscle paralysis.

Noninsulinoma pancreatogenous hypoglycemia syndrome: a rare case of adult-onset nesidioblastosis.

The most common cause of hyperinsulinemic hypoglycemia in adults is insulinoma. Nesidioblastosis is a rare, but well-recognized disorder of persistent hyperinsulinemic hypoglycemia in infancy, but adult-onset nesidioblastosis associated with hyperinsulinemic hypoglycemia, termed noninsulinoma pancreatogenous hypoglycemic syndrome (NIPHS), has been reported. Here, we describe an extremely rare case of NIPHS in an elderly man. A 78-year-old man was admitted to our hospital due to hypoglycemic coma. During the previous 3 months, he noticed excessive sweating at midafternoon. His low fasting plasma glucose level (27 mg/dl) and high immunoreactive insulin level (11.1 muU/ml) were consistent with the possible presence of insulinoma. Localizing studies including computed tomography of the abdomen and celiac arteriography were negative, but selective arterial calcium infusion (SACI) test suggested the presence of insulinoma in the body and tail of the pancreas. Surgical exploration by palpation and intraoperative ultrasonography failed to detect any mass in the pancreas, and 60% distal pancreatectomy was performed. Postoperatively, his hypoglycemic episodes completely disappeared. Histological examination of the resected pancreas revealed diffuse islet cell hyperplasia consistent with a pathological diagnosis of nesidioblastosis. Thus, our case is a very rare case of NIPHS, or adult-onset nesidioblastosis, in which SACI test was proven to be a useful diagnostic tool for localization of the pancreatic lesion.

High molecular weight form insulin-like growth factor II-producing mesenteric sarcoma causing hypoglycemia.

An 81-year-old woman presented with frequent episodes of hypoglycemia. Her serum level of insulin was normal, but her serum insulin-like growth factor (IGF)-II level was high. She was found to have a spindle cell sarcoma originated from the mesentery of the sigmoid colon, which was completely resected. Postoperatively, hypoglycemia ameliorated with concomitant reduction in serum IGF-II levels. Immunohistochemical study revealed positive immunostaining for IGF-II in tumor cells, and the abundant expression of IGF-II mRNA was demonstrated by RT-PCR. The presence of high molecular weight (HMW) form IGF-II in patient's serum was confirmed by immunoblotting. This is the first report of a patient with HMW form IGF-II-producing mesenteric sarcoma causing hypoglycemia.