[A case of repeated severe hypoglycemia caused by accidental ingestion of sulfonylurea in an elderly patient].

An 81-year-old man was being treated with oral medication for chronic heart failure and epilepsy. He had no history of diabetes, cirrhosis, or gastric surgery. He was admitted to our hospital due to disturbance of consciousness. His blood glucose level was 6 mg/dl, with a relatively high insulin level (14.4 µU/ml). Computed tomography and a 48 h fasting test showed no signs of insulinoma. There were no signs of reactive hypoglycemia, insulin autoimmune syndrome, or adrenal insufficiency. His wife had been taking medication for diabetes, including sulfonylurea. She had dementia, and he managed her medication. Since his medication was found in his wife's medicine box, we considered the possibility that he might have taken sulfonylurea by mistake. We asked his daughter to manage their medicine. However, one month later, he was admitted to our hospital again with severe hypoglycemia. His wife's HbA1c value and estimated glomerular filtration rate were 6.9% and 30 ml/min/1.73 m2. We asked his wife's home doctor to stop sulfonylurea prescription, and the hypoglycemia did not recur, with his wife's level of HbA1c remaining stable.Elderly individuals and patients with an impaired renal function are prone to hypoglycemia from sulfonylurea. In elderly households, there is a possibility of accidental ingestion of oral hypoglycemic agents by other family members living with the patient. It is therefore necessary to understand and manage the medications of family members living together. It is also important to avoid prescribing medications with a high risk of hypoglycemia to elderly patients.

TYK2 Promoter Variant Is Associated with Impaired Insulin Secretion and Lower Insulin Resistance in Japanese Type 2 Diabetes Patients.

Accumulating evidence has suggested that viral infection causes type 1 diabetes due to direct ß-cell damage and the triggering of autoimmune reactivity to ß cells. Here, we elucidated that the tyrosine kinase 2 (Tyk2) gene, encoding an interferon receptor signaling molecule, is responsible for virus-induced diabetes in mice, and its promoter variant confers a risk of type 1 diabetes in humans. This study investigated the relationship between a TYK2 promoter variant (TYK2PV) and insulin secretion in type 2 diabetes patients. TYK2PV status was determined using direct DNA sequencing and its associations with fasting insulin, C-peptide, and homeostatic model assessment of insulin resistance (HOMA-IR) were evaluated in type 2 diabetes patients without sulfonylurea or insulin medication. Of the 172 patients assessed, 18 (10.5%) showed TYK2PV-positivity. Their body mass index (BMI) was significantly lower than in those without the variant (23.4 vs. 25.4 kg/m2, p = 0.025). Fasting insulin (3.9 vs. 6.2 µIU/mL, p = 0.007), C-peptide (1.37 vs. 1.76 ng/mL, p = 0.008), and HOMA-IR (1.39 vs. 2.05, p = 0.006) were lower in those with than in those without the variant. Multivariable analysis identified that TYK2PV was associated with fasting insulin ≤ 5 µIU/mL (odds ratio (OR) 3.63, p = 0.025) and C-peptide ≤ 1.0 ng/mL (OR 3.61, p = 0.028), and also lower insulin resistance (HOMA-IR ≤ 2.5; OR 8.60, p = 0.042). TYK2PV is associated with impaired insulin secretion and low insulin resistance in type 2 diabetes. Type 2 diabetes patients with TYK2PV should be carefully followed in order to receive the appropriate treatment including insulin injections.

FIB-4 index-based surveillance for advanced liver fibrosis in diabetes patients.

Liver fibrosis is associated with lifestyle-related diseases, including diabetes. The identification of diabetic patients with severe liver fibrosis is important, but a simple and reliable diagnostic procedure remains to be determined. We conducted an observational study to evaluate the performance of a FIB-4 index-based screening strategy for the diagnosis of advanced liver fibrosis in patients with diabetes or prediabetes. Two hundred and forty-two patients underwent abdominal imaging in our Study. According to the abdominal imaging findings, fatty liver, liver cirrhosis, and hepatocellular carcinoma were defined, and their association with FIB-4 index evaluated. The prevalences of liver cirrhosis and hepatocellular carcinoma in patients with a high (≥ 2.67; liver cirrhosis: 42.9%, hepatocellular carcinoma: 14.3%) FIB-4 index were significantly higher than in those with an intermediate (1.3 ≤ FIB-4 < 2.67; liver cirrhosis: 1.6%, hepatocellular carcinoma: 0.8%) or low FIB-4 index (< 1.3; liver cirrhosis: 1.2%, hepatocellular carcinoma: 0%). The diagnostic accuracy, specificity, and sensitivity of the FIB-4 index for the diagnosis of liver cirrhosis or hepatocellular carcinoma were 84.3%, 85.5%, and 89.3%, respectively, with an optimized cut-off value of 2.96 (sensitivity = 0.86, specificity = 0.98). Using an optimized cut-off value, FIB-4 index might be useful to identify liver cirrhosis or hepatocellular carcinoma in diabetes patients with high diagnostic accuracy.

Glucagon-Like Peptide-1 Receptor Agonist Prevented the Progression of Hepatocellular Carcinoma in a Mouse Model of Nonalcoholic Steatohepatitis.

Glucagon-like peptide-1 (GLP-1) receptor agonists are used to treat diabetes, but their effects on nonalcoholic steatohepatitis (NASH) and the development of hepatocellular carcinoma (HCC) remain unclear. In this study, mice with streptozotocin- and high-fat diet-induced diabetes and NASH were subcutaneously treated with liraglutide or saline (control) for 14 weeks. Glycemic control, hepatocarcinogenesis, and liver histology were compared between the groups. Fasting blood glucose levels were significantly lower in the liraglutide group than in the control group (210.0 ± 17.3 mg/dL vs. 601.8 ± 123.6 mg/dL), and fasting insulin levels were significantly increased by liraglutide (0.18 ± 0.06 ng/mL vs. 0.09 ± 0.03 ng/mL). Liraglutide completely suppressed hepatocarcinogenesis, whereas HCC was observed in all control mice (average tumor count, 5.5 ± 3.87; average tumor size, 8.1 ± 5.0 mm). Liraglutide significantly ameliorated steatosis, inflammation, and hepatocyte ballooning of non-tumorous lesions in the liver compared with the control findings, and insulin-positive ß-cells were observed in the pancreas in liraglutide-treated mice but not in control mice. In conclusion, liraglutide ameliorated NASH and suppressed hepatocarcinogenesis in diabetic mice. GLP-1 receptor agonists can be used to improve the hepatic outcome of diabetes.

PDCD4 Knockdown Induces Senescence in Hepatoma Cells by Up-Regulating the p21 Expression.

While the over-expression of tumor suppressor programmed cell death 4 (PDCD4) induces apoptosis, it was recently shown that PDCD4 knockdown also induced apoptosis. In this study, we examined the cell cycle regulators whose activation is affected by PDCD4 knockdown to investigate the contribution of PDCD4 to cell cycle regulation in three types of hepatoma cells: HepG2, Huh7 (mutant p53 and p16-deficient), and Hep3B (p53- and Rb-deficient). PDCD4 knockdown suppressed cell growth in all three cell lines by inhibiting Rb phosphorylation via down-regulating the expression of Rb itself and CDKs, which phosphorylate Rb, and up-regulating the expression of the CDK inhibitor p21 through a p53-independent pathway. We also found that apoptosis was induced in a p53-dependent manner in PDCD4 knockdown HepG2 cells (p53+), although the mechanism of cell death in PDCD4 knockdown Hep3B cells (p53-) was different. Furthermore, PDCD4 knockdown induced cellular senescence characterized by ß-galactosidase staining, and p21 knockdown rescued the senescence and cell death as well as the inhibition of Rb phosphorylation induced by PDCD4 knockdown. Thus, PDCD4 is an important cell cycle regulator of hepatoma cells and may be a promising therapeutic target for the treatment of hepatocellular carcinoma.

Re-evaluation of glycated hemoglobin and glycated albumin with continuous glucose monitoring system as markers of glycemia in patients with liver cirrhosis.

[This retracts the article DOI: 10.3892/br.2016.808.].

Influence of muscle fiber type composition on early fat accumulation under high-fat diet challenge.

OBJECTIVE: To investigate whether differences in muscle fiber types affect early-stage fat accumulation, under high fat diet challenge in mice. METHODS: Twelve healthy male C57BL/6 mice experienced with short-term (6 weeks) diet treatment for the evaluation of early pattern changes in muscular fat. The mice were randomly divided into two groups: high fat diet (n = 8) and normal control diet (n = 4). Extra- and intra-myocellular lipid (EMCL and IMCL) in lumbar muscles (type I fiber predominant) and tibialis anterior (TA) muscle (type II fiber predominant) were determined using magnetic resonance spectroscopy (MRS). Correlation of EMCL, IMCL and their ratio between TA and lumbar muscles was evaluated. RESULTS: EMCL increased greatly in both muscle types after high fat diet. IMCL in TA and lumbar muscles increased to a much lower extent, with a slightly greater increase in TA muscles. EMCLs in the 2 muscles were positively correlated (r = 0.84, p = 0.01), but IMCLs showed a negative relationship (r = -0.84, p = 0.01). In lumbar muscles, high fat diet significantly decreased type I fiber while it increased type II fiber (all p≤0.001). In TA muscle, there was no significant fiber type shifting (p>0.05). CONCLUSIONS: Under short-time high fat diet challenge, lipid tends to initially accumulate extra-cellularly. In addition, compared to type II dominant muscle, Type I dominant muscle was less susceptible to IMCL accumulation but more to fiber type shifting. These phenomena might reflect compensative responses of skeletal muscle to dietary lipid overload in order to regulate metabolic homeostasis.

Re-evaluation of glycated hemoglobin and glycated albumin with continuous glucose monitoring system as markers of glycemia in patients with liver cirrhosis.

Liver cirrhosis (LC) is frequently accompanied by glucose intolerance. The present study was designed to determine whether glycated hemoglobin A1c (HbA1c) and glycated albumin (GA) were predictive markers of glycemia, as determined by a continuous glucose monitoring system (CGMS), in patients with LC. A total of 30 patients with LC, including 3, 19, 5, 2 and 1 with LC due to hepatitis B virus, hepatitis C virus, non-alcoholic steatohepatitis, alcohol and unknown causes, respectively, were assessed by CGMS. The average, maximum and minimum blood glucose (BG) levels were measured by CGMS, and correlated with HbA1c and GA. The average, maximum and minimum BG in these individuals were 142±38.7, 209.3±65.7 and 85.1±25.4 mg/dl, respectively. HbA1c was significantly correlated with average BG (r=0.447, P=0.015) and maximum BG (r=0.523, P=0.004). In addition, GA was significantly correlated with average BG (r=0.687, P<0.001) and maximum BG (r=0.648, P<0.001). Neither HbA1c nor GA was significantly correlated with minimum BG. Correlation analysis yielded formulas by which HbA1c and GA were predictive of average BG in individuals with LC: Average BG=19.2 × HbA1c (%) + 36.5 and average BG=6.6 × GA (%) + 13.0, respectively. In conclusion, HbA1c and GA showed significant correlations with average and maximum BG, as determined by CGMS. The derived formulas allow for estimates of average BG based on HbA1c and GA, and may contribute to the control of glycemia in patients with LC.

Pilot study of liraglutide effects in non-alcoholic steatohepatitis and non-alcoholic fatty liver disease with glucose intolerance in Japanese patients (LEAN-J).

AIM: Non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic syndrome, is associated with an increased risk of developing lifestyle-related diseases including type 2 diabetes, cardiovascular disease and cerebral vessel disease. No current drug therapy provides the ideal effects of decreasing hepatic inflammation while simultaneously improving liver fibrosis. Liraglutide is a glucagon-like peptide-1 receptor agonist that affects the histological findings in patients with non-alcoholic steatohepatitis (NASH). This study was conducted to evaluate the effect and action of liraglutide for biopsy-proven NASH. METHODS: After lifestyle modification intervention for 24 weeks, subjects whose hemoglobin A1c levels failed to improve to less than 6.0% and/or whose alanine aminotransferase levels were not lower than baseline, received liraglutide at 0.9 mg/body per day for 24 weeks. RESULTS: Of 27 subjects, 26 completed the lifestyle modification intervention. Nineteen subjects received liraglutide therapy for 24 weeks. Body mass index, visceral fat accumulation, aminotransferases and glucose abnormalities improved significantly. Repeated liver biopsy was performed in 10 subjects who continued liraglutide therapy for 96 weeks. Six subjects showed decreased histological inflammation as determined by NASH activity score and stage determined by Brunt classification. We saw no significant adverse events during therapy with liraglutide. CONCLUSION: Our pilot study demonstrated that treatment with liraglutide had a good safety profile and significantly improved liver function and histological features in NASH patients with glucose intolerance.