Decreased islet amyloid polypeptide staining in the islets of insulinoma patients.

Islet amyloid polypeptide (IAPP) is a factor that regulates food intake and is secreted from both pancreatic islets and insulinoma cells. Here, we aimed to evaluate IAPP immunohistochemically in islets or insulinoma cells in association with clinical characteristics. We recruited six insulinoma patients and six body mass index-matched control patients with pancreatic diseases other than insulinoma whose glucose tolerance was confirmed to be normal preoperatively. IAPP and IAPP-insulin double staining were performed on pancreatic surgical specimens. We observed that the IAPP staining level and percentage of IAPP-positive beta cells tended to be lower (p = 0.1699) in the islets of insulinoma patients than in those of control patients, which might represent a novel IAPP expression pattern under persistent hyperinsulinemia and hypoglycemia.

Preoperative hemoglobin A1c is associated with postoperative bleeding after vitrectomy for vitreous hemorrhage in patients with diabetic retinopathy.

We previously reported that a high HbA1c level 3 months before vitrectomy for vitreous hemorrhage or a large preoperative decrease in the HbA1c level over 3 months tended to increase the risk of rebleeding in diabetic retinopathy patients evaluated between 2010 and 2014. Here, we aimed to confirm these results with an extended study period and an increased number of operated eyes. This study included 121 diabetic patients who were admitted to Osaka University Hospital between 2010 and 2019 and who underwent vitrectomy for vitreous hemorrhage. Binomial logistic regression analysis was performed with the presence of postoperative bleeding as the outcome. The present study showed that the duration of the operation was associated with rebleeding (odds ratio = 1.02, p = 0.0016). A high HbA1c level just before vitrectomy tended to be associated with the bleeding (odds ratio = 1.27, p = 0.05), while preoperative HbA1c changes were not associated with rebleeding. The results of this study suggest that a high preoperative HbA1c level just before vitrectomy, not a decrease in HbA1c levels, in addition to the duration of the operation may increase the risk of postoperative bleeding after vitrectomy in diabetic retinopathy patients.

Consumption of two meals per day is associated with increased intrapancreatic fat deposition in patients with type 2 diabetes: a retrospective study.

INTRODUCTION: This study aimed to identify the associations between lifestyle factors and intrapancreatic fat deposition in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The participants were 185 patients with type 2 diabetes who were hospitalized at Osaka University Hospital between 2008 and 2020 and underwent abdominal CT during hospitalization. Information regarding lifestyle factors, including the number of meals consumed per day, snacking habits, exercise habits, exercise at work, smoking habits, alcohol intake, insomnia, sleep apnea syndrome, and night-shift working, was acquired from self-administered questionnaires or medical records. We measured the mean CT values for the pancreas (P), liver (L), and spleen (S), and the visceral fat area (VFA), and quantified intrapancreatic and liver ectopic fat accumulation as P-S and L-S, respectively. RESULTS: After adjustment for age, sex, hemoglobin A1c, and body mass index (BMI), participants who consumed two meals per day had significantly lower P-S (higher intrapancreatic fat deposition, p=0.02) than those who consumed three meals per day. There were no significant associations between the number of meals consumed and liver ectopic fat accumulation and VFA (p=0.73 and p=0.67, respectively). CONCLUSIONS: Patients with diabetes who consumed two meals per day showed greater intrapancreatic fat deposition than those who consumed three meals per day, even after adjustment for BMI. These findings support the current guideline for diabetes treatment that skipping meals should be avoided.

Genetic assessment using whole-exome sequencing for a young hypertriglyceridemic patient with repeated acute pancreatitis.

Hypertriglyceridemia is caused not only by environmental factors but also by genetic factors. Severe hypertriglyceridemia is prone to complications of acute pancreatitis. Here, we report a whole-exome sequencing (WES) analysis for a young hypertriglyceridemic patient with recurrent acute pancreatitis and the patient's mother. A 28-year-old hypertriglyceridemic female was admitted to our hospital. At 23 years old, a health checkup clarified her hypertriglyceridemia. At the age of 26 and 27, she had repeated acute pancreatitis with severe hypertriglyceridemia (serum triglyceride level were 3,888 mg/dL and 12,080 mg/dL, respectively). The patient's BMI was 29.0 kg/m2, and blood samples under fibrate medication showed triglyceride 451 mg/dL and HbA1c 7.2%. Type V dyslipidemia became more apparent at postprandial state. The WES analysis showed that the patients had two heterozygous variants in Apolipoprotein A5 (APOA5) gene (p.G185C and p.V153M), a heterozygous variant in Apolipoprotein E (APOE) gene (p.R176C), three heterozygous variants in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene (p.T1220I, p.R1453W and p.V470M). On the other hand, her mother, who had moderate hypertriglyceridemia without acute pancreatitis, had a heterozygous variant in APOA5 gene (p.G185C) and two heterozygous variants in CFTR gene (p.T1220I and p.V470M). These results suggest that the more severe pathology of the patient than her mother might be due to the possible compound heterozygous APOA5 variants, the heterozygous APOE variant, and the possible compound heterozygous CFTR variants. In this case, WES analyses were useful to evaluate not only the causative genes of hypertriglyceridemia (APOA5 and APOE) but also the genes involved in the development of acute pancreatitis (CFTR) simultaneously.

Motivation for Treatment Correlating Most Strongly with an Increase in Satisfaction with Type 2 Diabetes Treatment.

INTRODUCTION: We previously reported several factors that cross-sectionally correlate with treatment satisfaction in Japanese patients with type 2 diabetes visiting diabetes clinics. The aim of this study is to identify factors associated with longitudinal changes in treatment satisfaction in patients with type 2 diabetes. METHODS: The study included 649 patients with type 2 diabetes treated with oral glucose-lowering agents who completed the first questionnaire in 2016. The collected data included scores from the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and other parameters regarding diabetes treatment. We analyzed 1-year longitudinal changes in DTSQ scores and investigated factors associated with these changes. RESULTS: Univariate linear regression analyses showed that changes in body weight, adherence to diet therapy, adherence to exercise therapy, cost burden, motivation for treatment, regularity of mealtimes, and perceived hypoglycemia correlated with changes in DTSQ scores. On the basis of multiple linear regression analyses, a decrease in hypoglycemia (ß ± SE = - 0.394 ± 0.134, p = 0.0034), cost burden (ß ± SE = - 0.934 ± 0.389, p = 0.017), and an increase in treatment motivation (ß ± SE = 1.621 ± 0.606, p = 0.0077) correlated with DTSQ score increases, suggesting that motivation for treatment had the strongest impact on score increases. Subgroup analyses revealed that an increase in motivation for treatment most significantly correlated with a DTSQ score increase in obese and poor glycemic control groups, regardless of age. CONCLUSION: This is the first longitudinal study clarifying that an increase in motivation for treatment most strongly correlates with an increase in DTSQ score in patients with type 2 diabetes.

Whole-exome Sequencing Analysis of a Japanese Patient With Hyperinsulinemia and Liver Dysfunction.

Hyperinsulinemia is often observed in obese subjects because of insulin resistance, but it may occur in nonobese subjects with unknown etiology. A 72-year-old man was admitted to our hospital for the examination of hyperinsulinemia, reactive hypoglycemia, and liver dysfunction. The patient's body mass index was 23.7 kg/m2, but he had an elevated visceral fat area (125 cm2). His laboratory data showed mildly elevated liver enzymes, whereas plasma fasting glucose and serum insulin levels were 91 mg/dL and 52.3 µU/mL, respectively. In a 75-g oral glucose tolerance test, the serum insulin level reached the highest value of 1124 µU/mL at 180 minutes. There was no obvious etiology except for mild liver steatosis shown by liver biopsy. We suspected genetic abnormalities related to hyperinsulinemia. We performed whole-exome sequencing (WES) analyses and identified a heterozygous nonsense variant p.R924X in the insulin receptor (INSR) gene, a novel heterozygous missense variant p.V416M in the AKT1 gene, and a novel hemizygous missense variant p.R310Q in the PHKA2 gene, which is the causative gene of hepatic injury as glycogen storage disease type IX. It was speculated that the INSR gene variant, in addition to visceral fat accumulation, was the main cause of hyperinsulinemia and reactive hypoglycemia, and the remaining 2 variants were also partly responsible for hyperinsulinemia. WES analysis revealed candidate gene variants of hyperinsulinemia and hepatic-type glycogenosis. Thus, WES analysis may be a useful tool for clarifying the etiology when unexplained genetic pathophysiological conditions are suspected.

Maximum body mass index before onset of type 2 diabetes is independently associated with advanced diabetic complications.

INTRODUCTION: The maximum body mass index (BMI) before onset of type 2 diabetes (MBBO) might be used to estimate a patient's insulin secretion capacity. There have been few factors that can predict future diabetic complications at the time of diagnosis of diabetes mellitus. This study aimed to clarify the clinical usefulness of MBBO for predicting the development of advanced diabetic microvascular complications. RESEARCH DESIGN AND METHODS: This was a cross-sectional observational study. Of 1304 consecutively admitted patients with type 2 diabetes, we enrolled 435 patients for whom we could confirm their MBBO. Univariate and multivariate logistic regression analyses were performed to examine whether MBBO or BMI on admission was associated with advanced diabetic retinopathy or nephropathy. To evaluate the predictive performance of these indexes, we performed cross-validation in various models with MBBO or BMI and evaluated the areas under the curve (AUCs) yielded by these analyses. RESULTS: Univariate analyses suggested that MBBO was associated with advanced retinopathy and nephropathy, while BMI on admission was associated only with advanced nephropathy. In multivariate analyses, MBBO was significantly associated with advanced complications, while BMI on admission was not. For advanced diabetic retinopathy, the AUCs were 0.70-0.72, and for advanced nephropathy, the AUCs were 0.81-0.83. When comparing the AUCs among models, the models with MBBO sustained high predictive performance for diabetic complications. CONCLUSIONS: MBBO was independently associated with advanced diabetic complications, while BMI on admission was not. Diabetic microvascular complications in patients with high MBBO could progress more rapidly. At the time of the diagnosis of diabetes mellitus, MBBO would enable us to predict the progress of diabetic complications.

Amelioration of pancreatic fat accumulation in Japanese type 2 diabetes patients treated with sodium-glucose cotransporter 2 inhibitors: a retrospective study.

BACKGROUND: Prior reports have suggested that pancreatic fat is related to type 2 diabetes. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are expected to reduce ectopic fat accumulation. AIM: This study assessed the effect of SGLT-2 inhibitors on pancreatic and liver fat accumulations in patients with type 2 diabetes. MATERIALS AND METHODS: Retrospective analyses of indices of pancreatic and liver fat accumulations were conducted in 22 type 2 diabetes outpatients who were receiving SGLT-2 inhibitors for more than 12 weeks. The differences between the pancreatic (P) or liver (L) and splenic (S) computed tomography values were evaluated. RESULTS: Fatty pancreas was defined as P-S < -8 Hounsfield Unit (HU), and the number of patients with fatty pancreas was 11 (50%). Fatty pancreas significantly improved after SGLT-2 inhibitor use (median, -20.8; IQR, -34.8 to -14.3 HU vs. median, -14.6; IQR, -29.5 to -7.8 HU; p = 0.041). Fatty liver was defined as L-S ≤ 3.9 HU, and the number of patients with fatty liver was 11 (50%). Fatty liver significantly improved after SGLT-2 inhibitor use (median, -4.3; IQR, -23.0 to 3.0 HU vs. median, -0.7; IQR, -5.2 to 6.3 HU; p = 0.016). CONCLUSION: Pancreatic fat and liver fat accumulations might be reduced after treatment with SGLT-2 inhibitors in type 2 diabetes patients with intense cumulative fat depositions in these organs.

Coincidence of Large Adrenal Cyst and Prominent Hyporeninemic Hyperaldosteronism.

A 67-year-old Japanese woman who had end-stage renal disease was referred to our hospital for kidney transplantation. Abdominal CT revealed a large adrenal mass with inhomogeneity. She had a history of hospitalization for stroke and heart failure and exhibited prominent hyporeninemic hyperaldosteronism. Histological examination of the resected tumor with anti-CYP11B2 antibody indicated that she had a vascular endothelial cyst with primary aldosteronism (PA) due to multiple adrenocortical micronodules. This report implicates the pathological interaction between adrenal vascular cysts and PA-mediated vascular damage of the adrenal vein.

Digestibility in the gastrointestinal tract and migration to blood of ß'-component (Onk k 5), a major salmon roe IgE-binding protein.

The major allergen of chum salmon (Oncorhynchus keta) roe is the ß'-component (Onc k 5, ß'-c), which is a yolk protein and a fragment of vitellogenin. When yolk content containing ß'-c was orally administered to mice, ß'-c passed through the gastrointestinal tract and was excreted in feces without marked degradation. The direct administration of ß'-c to ligated jejunal and ileal loops showed that ß'-c was absorbed through the small intestine and transferred into the blood. Immunohistochemical staining showed that orally administered ß'-c was distributed from the apical side to the basal side of intestinal epithelial cells, suggesting that endocytosis may be involved in the intestinal absorption of ß'-c. In conclusion, ß'-c is absorbed along a large portion of the small intestine and circulates in the blood stream without significant digestion. The resistance of ß'-c to gastrointestinal digestion seems to contribute to its strong allergenicity.

Case of a novel PAX6 mutation with aniridia and insulin-dependent diabetes mellitus.

We present a case of a novel PAX6 heterozygous mutation with aniridia and insulin-dependent diabetes mellitus.To the best of our knowledge, this is the first case of its mutation with a complete loss of insulin secretory capacity. We believe that our letter will add new knowledge to diabetes mellitus associated with PAX6 mutations and might help us to understand the role of PAX6 in beta-cell development.

Hyperinsulinemia and Insulin Receptor Gene Mutation in Nonobese Healthy Subjects in Japan.

CONTEXT: Hyperinsulinemia is often observed in obese people, owing to their insulin resistance accompanied by visceral fat accumulation, but the frequency of hyperinsulinemia in nonobese people is not well known. Mutations in the insulin receptor gene are known to cause insulin resistance and hyperinsulinemia in type A insulin resistance syndrome, Rabson-Mendenhall syndrome, and Donohue syndrome. However, insulin receptor gene abnormalities have not been investigated in asymptomatic hyperinsulinemic subjects. PURPOSE: The aim of the current study was to investigate the prevalence of hyperinsulinemia in nonobese Japanese subjects and to examine the involvement of insulin receptor gene mutations. METHODS: We enrolled 11,046 subjects who received health checkups. From these, we extracted nonobese subjects (body mass index <25 kg/m2) who exhibited hyperinsulinemia (serum fasting immunoreactive insulin ≥15 µU/mL). Genetic analysis was performed for the insulin receptor gene in 11 nonobese subjects with hyperinsulinemia. RESULTS: The prevalence of hyperinsulinemia without apparent diabetes in nonobese subjects was 0.4% (33/8630). In the 11 analyzed subjects, two novel heterozygous nonsense mutations were detected [c.2106 T>G (p.Y702X) and c.2779-2780 GC>A]. The prevalence of insulin receptor gene mutations was 18.2% (2/11). CONCLUSIONS: To our knowledge, this is the first report of the prevalence of hyperinsulinemia in nonobese healthy subjects. We identified two novel mutations in the insulin receptor gene. These findings indicate that mutations in the insulin receptor gene may be related to fasting hyperinsulinemia, and insulin receptor gene screening may be useful for determining the cause of unexplained hyperinsulinemia.

An Impaired Awareness of Hypoglycemia Improved After Vitamin B12 Treatment in a Type 1 Diabetic Patient.

An impaired awareness of hypoglycemia is a serious problem in diabetic patients, which can lead to life-threatening severe hypoglycemia. Recurrent hypoglycemia attenuates the function of the central, mainly hypothalamic, nervous system and it causes an impaired awareness of hypoglycemia. Vitamin B12 deficiency is also associated with the dysfunction of central nervous system. We report a 72-year-old type 1 diabetic patient with vitamin B12 deficiency whose impaired awareness of hypoglycemia improved after 4 weeks of vitamin B12 administration with an increased counter-hormone secretion in response to hypoglycemia. We should recognize vitamin B12 deficiency as one of the causes of an impaired awareness of hypoglycemia in diabetic patients.

Blood staining of the cornea in Hansens disease

Blood staining of the cornea was studied by light and electron microscopy: a 55-year-old male with Hansen's disease had blood staining of the cornea due to intracorneal hemorrhage; he received a partial-thickness keratoplasty following 1 year after the onset of the staining. The excised specimens revealed deposits of degraded erythrocytes in the stroma. Numerous dense granules, probably of erythrocytic breakdown products, were phagocytosed by macrophages as well as parenchymal cells. The presence of macrophages was limited to the middle part of the stroma in which newly formed vessels were remarkable.