Anti-integrin αvß6 autoantibodies are a potential biomarker for ulcerative colitis-like immune checkpoint inhibitor-induced colitis.

BACKGROUND: No specific biomarker for immune checkpoint inhibitor (ICI)-induced colitis has been established. Previously, we identified anti-integrin αvß6 autoantibodies in >90% of patients with ulcerative colitis (UC). Given that a subset of ICI-induced colitis is similar to UC, we aimed to clarify the relationship between such autoantibodies and ICI-induced colitis. METHODS: Serum anti-integrin αvß6 autoantibody levels were compared between 26 patients with ICI-induced colitis and 157 controls. Endoscopic images of ICI-induced colitis were centrally reviewed. Characteristics of anti-integrin αvß6 autoantibodies in the ICI-induced colitis patients were compared with those of UC patients. RESULTS: Anti-integrin αvß6 autoantibodies were found in 8/26 (30.8%) patients with ICI-induced colitis and 3/157 (1.9%) controls (P < 0.001). Patients with anti-integrin αvß6 autoantibodies had significantly more typical UC endoscopic features than those without the autoantibodies (P < 0.001). Anti-integrin αvß6 autoantibodies in ICI-induced colitis patients were associated with grade ≥3 colitis (P = 0.001) and steroid resistance (P = 0.005). Anti-integrin αvß6 autoantibody titers correlated with ICI-induced colitis disease activity. Anti-integrin αvß6 autoantibodies of ICI-induced colitis exhibited similar characteristics to those of UC. CONCLUSIONS: Anti-integrin αvß6 autoantibodies may serve as potential biomarkers for the diagnosis, classification, risk management, and monitoring the disease activity, of ICI-induced colitis.

Genetic Pathogenesis of Inflammation-Associated Cancers in Digestive Organs.

Epidemiological, clinical, and biological studies convincingly demonstrate that chronic inflammation predisposes to the development of human cancers. In digestive organs, inflammation-associated cancers include colitis-associated colorectal cancers, Helicobacter pylori-associated gastric cancer, as well as Barrett's esophagus and esophageal adenocarcinoma associated with chronic duodenogastric-esophageal reflux. Cancer is a genomic disease, and stepwise accumulation of genetic and epigenetic alterations of tumor-related genes leads to the development of tumor cells. Recent genome analyses show that genetic alterations, which are evoked by inflammation, are latently accumulated in inflamed epithelial cells of digestive organs. Production of reactive oxygen and aberrant expression of activation-induced cytidine deaminase, a nucleotide-editing enzyme, could be induced in inflamed gastrointestinal epithelial cells and play a role as a genomic modulator of inflammation-associated carcinogenesis. Understanding the molecular linkage between inflammation and genetic alterations will open up a new field of tumor biology and provide a novel strategy for the prevention of inflammation-associated tumorigenesis.

Comparison of sitagliptin with nateglinide on postprandial glucose and related hormones in drug-naïve Japanese patients with type 2 diabetes mellitus: A pilot study.

AIMS/INTRODUCTION: Dipeptidyl peptidase-4 inhibitors and glinides are effective in reducing postprandial hyperglycemia. However, little information is available on the comparative effects of the two drugs on the levels of postprandial glucose. The aim of the present study was to compare the effects of sitagliptin and nateglinide on meal tolerance tests in drug-naïve patients with type 2 diabetes mellitus. MATERIALS AND METHODS: The study participants were 19 patients with type 2 diabetes mellitus, which was inadequately controlled by diet and exercise. An open-label, prospective, cross-over trial was carried out to compare the effects of single-dose sitagliptin and nateglinide on the postprandial glucose level and its related hormones during meal tests. RESULTS: The change in area under the curve (AUC) of glucose from 0 to 180 min (AUC0-180 min) during the meal test by nateglinide was similar to that by sitagliptin. As expected, the change in active glucagon like peptide-1 was significantly higher after a single-dose of sitagliptin than nateglinide. Then, insulin secretion relative to glucose elevation (ISG) (ΔISG0-180 min: ΔAUC0-180 min insulin/AUC0-180 min glucose) was significantly enhanced by nateglinide compared with sitagliptin. Conversely, glucagon level (ΔAUC0-180 min glucagon) was increased by administration of nateglinide, whereas the glucagon level was reduced by administration of sitagliptin. CONCLUSIONS: The effects of sitagliptin on postprandial glucose levels were similar to those of nateglinide in drug-naïve type 2 diabetes patients. However, the induced changes in insulin, active glucagon-like peptide-1 and glucagon during meal loading suggest that reduction of postprandial hyperglycemia was achieved by the unique effect of each drug.

Sitagliptin Improves the Impaired Acute Insulin Response during a Meal Tolerance Test in Japanese Patients with Type 2 Diabetes Mellitus: A Small-Scale Real-World Study.

INTRODUCTION: Several studies have shown that dipeptidyl peptidase-4 (DPP-4) inhibitors improve insulin secretion during oral glucose tolerance tests. However, the effects of DPP-4 inhibitors on impaired acute insulin responses in the postprandial state in real-world settings are unknown. Therefore, we evaluated the effects of sitagliptin on the acute insulin responses in Japanese patients with type 2 diabetes mellitus (T2DM) using meal tolerance tests. METHODS: Twenty-one patients with T2DM were given a test meal (460 kcal), and plasma glucose and insulin were measured at 0, 30, 60, 120, and 180 min after the meal. The insulinogenic index of all of these patients was below 43.2. The postprandial profiles were assessed at baseline and after 3 months of treatment with 50 mg/day sitagliptin after a meal (n = 11) or were untreated (control group; n = 10). This study was a prospective, open-label, non-blinded, non-randomized, clinical study. RESULTS: Sitagliptin significantly decreased the plasma glucose levels at 60, 120, and 180 min, and significantly increased the plasma insulin levels at 0 and 30 min. There were no significant changes in glucose or insulin in the control group. The insulinogenic index increased significantly in the sitagliptin group compared with the control group (+16.7 vs. +0.1, P < 0.005). However, homeostasis model assessment of insulin resistance and the insulin sensitivity index were not significant different between the two groups. CONCLUSION: Administration of sitagliptin at 50 mg/day after a meal improved the impaired acute insulin response and suppressed postprandial hyperglycemia. Whereas the study is rather small and the design is suboptimal as it is not randomized and not blinded, these results suggest that sitagliptin is effective in Japanese patients with T2DM, many of whom display impaired acute insulin responses after a meal.

Low serum galectin-3 concentrations are associated with insulin resistance in patients with type 2 diabetes mellitus.

BACKGROUND: Galectin-3 is a family of soluble beta-galactoside-binding lectins that play many important regulatory roles in inflammation. Galectin-3-deficient mice have been shown to exhibit excess adiposity, hyperglycemia, insulin resistance and systemic inflammation. We investigated the association between serum galectin-3 and insulin resistance in patients with type 2 diabetes using a glucose clamp method. METHODS: This was a cross-sectional study. Twenty patients (mean fasting plasma glucose 7.6 mmol/L, HbA1c 7.2%, BMI 28.1 kg/m(2)) underwent a meal tolerance test and glucose clamp test. Participants were given a test meal and plasma glucose and insulin were measured at 0, 30, 60, 120 and 180 min. The glucose disposal rate was measured during hyperinsulinemic-euglycemic glucose clamps. Serum galectin-3 levels were measured using the enzyme-linked immunosorbent assay method. RESULTS: The mean serum galectin-3 level was 5103 pg/ml. Galectin-3 levels correlated significantly with the glucose disposal rate (R = 0.71, P < 0.001), fasting insulin (R = -0.56, P < 0.01), homeostasis model assessment for insulin resistance (R = -0.52, P < 0.05), and the insulin sensitivity index (R = 0.62, P < 0.005). Galectin-3 levels also positively correlated with the serum adiponectin level (R = 0.61, P < 0.05), but not with the high-sensitive C-reactive protein and interleukin-6 and -10. CONCLUSIONS: These results suggest that low levels of serum galectin-3 are associated with insulin resistance in patients with type 2 diabetes.

Bezafibrate improves insulin resistance evaluated using the glucose clamp technique in patients with type 2 diabetes mellitus: a small-scale clinical study.

BACKGROUND: Bezafibrate is mainly used to treat hypertriglyceridemia. Studies have reported that bezafibrate also improves type 2 diabetes mellitus, but the mechanism has not been fully elucidated. We performed euglycemic hyperinsulinemic clamps (glucose clamp) and meal tolerance tests (MTT) to examine the effects of bezafibrate on insulin resistance in patients with type 2 diabetes mellitus. METHODS: Twelve Japanese patients with type 2 diabetes mellitus and dyslipidemia (mean age: 59.5 years; fasting plasma glucose: 7.95 mmol/L; hemoglobin A1c [HbA1c]: 7.3%; body mass index: 26.5 kg/m(2)) underwent a glucose clamp and MTT before and after 12 weeks of treatment with 400 mg/day bezafibrate. The glucose infusion rate was measured during the glucose clamp. The patients took a test meal (460 kcal) in the MTT. Plasma glucose and immunoreactive insulin levels were measured at 0 (fasting), 30, 60, 120, and 180 min. Serum C-peptide immunoreactivity, serum lipids, and liver function markers were also measured during the MTT. RESULTS: Bezafibrate significantly increased the mean glucose infusion rate from 5.78 ± 1.94 to 6.78 ± 2.52 mg/kg/min (p < 0.05). HbA1c improved from 7.30 ± 0.55% to 7.02 ± 0.52% (p < 0.05). In the MTT, fasting plasma glucose decreased from 7.95 ± 1.15 to 6.98 ± 1.07 mmol/L (p < 0.05). The area under the plasma glucose curve from 0 to 180 min decreased significantly from 29.48 ± 5.07 to 27.12 ± 3.98 mmol/h/L (p < 0.05), whereas immunoreactive insulin was unchanged. Furthermore, bezafibrate also significantly improved serum lipids, with decreases in triglyceride levels from 1.84 ± 0.88 to 1.14 ± 0.41 mmol/L (p < 0.05), low-density lipoprotein cholesterol levels from 3.56 ± 0.83 to 2.92 ± 0.55 mmol/L (p < 0.05), and remnant-like particle cholesterol levels decreased from 0.25 ± 0.16 to 0.14 ± 0.06 mmol/L (p < 0.05), and increases in high-density lipoprotein cholesterol levels from 1.50 ± 0.24 to 1.66 ± 0.29 mmol/L (p < 0.05). CONCLUSIONS: Bezafibrate improved glucose intolerance and peripheral insulin resistance in these Japanese patients with type 2 diabetes mellitus and dyslipidemia. Therefore, bezafibrate could be used to treat insulin resistance in patients with type 2 diabetes mellitus and dyslipidemia. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trials Registry, UMIN000012462.

The proinsulin/insulin (PI/I) ratio is reduced by postprandial targeting therapy in type 2 diabetes mellitus: a small-scale clinical study.

BACKGROUND: An elevated PI/I ratio is attributable to increased secretory demand on ß-cells. However, the effect of postprandial targeting therapy on proinsulin level is unknown. We evaluated the metabolic effect of glinide and sulfonylurea (SU) using the meal tolerance test (MTT). METHODS: MTT was applied to previously untreated Type 2 Diabetes Mellitus (T2DM) subjects. Twenty-two participants were given a test meal (450 kcal). Plasma glucose and insulin were measured at 0 (fasting), 30, 60, 120, and 180 min. Serum proinsulin and C-peptide immunoreactivity (CPR) were measured at 0 and 120 min. Postprandial profile was assessed at baseline and following 3 months treatment with either mitiglinide or glimepiride. RESULTS: Plasma glucose level at 30, 60, 120, and 180 min was significantly improved by mitiglinide. Whereas, glimepiride showed a significant improve plasma glucose at 0, 180 min. Peak IRI shifted from 120 to 30 min by mitiglinide treatment. The pattern of insulin secretion was not changed by glimepiride treatment. Whereas mitiglinide did not affect the PI/I ratio, glimepiride tended to increase the PI/I ratio. Moreover, although mitiglinide did not affect PI/I ratio as a whole, marked reduction was noted in some patients treated by mitiglinide. PI/I ratio was reduced significantly in the responder group. The responder subgroup exhibited less insulin resistance and higher insulinogenic index at baseline than non-responders. Moreover, the triglyceride level of responders was significantly lower than that of non-responders. CONCLUSIONS: Mitiglinide improved postprandial insulin secretion pattern and thereby suppressed postprandial glucose spike. In T2DM patients with low insulin resistance and low triglyceride, mitiglinide recovered impaired ß-cell function from the viewpoint of the PI/I ratio. TRIAL REGISTRATION UMIN-CTR: UMIN000010467.

Seasonal variation in myopia progression and axial elongation: an evaluation of Japanese children participating in a myopia control trial.

PURPOSE: To investigate the seasonal variations in myopia progression and axial elongation in Japanese children. METHODS: Ninety-two children who were enrolled in a myopia-control trial and wearing single vision or progressive addition lenses were included in the analyses (mean ± SD age 11.4 ± 1.7 years, mean spherical equivalent refractive error -4.40 ± 1.38 D). Refractive error and axial length were measured every 6 months for 1.5 years by non-cycloplegic autorefraction and partial coherence interferometer, respectively. Myopia progression and axial elongation for each 6-month interval were calculated by subtracting the measure at the end of the interval from that at the beginning. Seasons were classified as summer, winter or others, based on mid-day of the 6-month period between visits. RESULTS: Myopia progression was not significantly influenced by the season. After adjusting study groups (type of spectacles), years and age at the baseline, the mean (±SE) myopia progression was 0.35 ± 0.04 D for summer, 0.28 ± 0.06 D for winter and 0.38 ± 0.04 D for the others. In contrast, axial elongation was significantly influenced by the season, and the mean axial elongation was 0.137 ± 0.010 mm for summer, 0.170 ± 0.013 mm for winter and 0.163 ± 0.008 mm for the others. The seasonal variation in axial elongation, however, was smaller than that previously reported overseas. CONCLUSIONS: In Japanese children myopia progression did not slow in summer. Although axial elongation slightly decreased in summer, myopia progression seems to be fairly stable throughout the year.