"Preserved" glucagon secretion in fulminant type 1 diabetes.

Mixed-meal tolerance tests were carried out after an overnight fast. Healthy control participants (■), type 1A diabetespatients (○) and fulminant type 1 diabetic patients (▲). Data are presented as the mean ± standard error of the mean.

Taurine improves glucose tolerance in STZ-induced insulin-deficient diabetic mice.

Blood glucose levels fluctuate considerably in diabetic patients with reduced secretion of endogenous insulin. We previously reported that glucagon is secreted excessively in these patients and that taurine increases glucagon secretion in vitro. Therefore, we hypothesized that glucose tolerance would further deteriorate when taurine was administered to diabetic mice incapable of insulin secretion. We generated four groups of streptozotocin (STZ)-treated C57BL/6J mice (STZ-mice): STZ-mice without taurine treatment (STZ-Con), STZ-mice treated with 0.5% (w/v) taurine (STZ-0.5% Tau), STZ-mice treated with 1% (w/v) taurine (STZ-1% Tau), and STZ-mice treated with 2% (w/v) taurine (STZ-2% Tau). Mice were treated for 4 weeks, and then, we evaluated glucose tolerance, pancreatic ß-cell area and α-cell area, pancreatic insulin and glucagon content, and daily blood glucose variability. As a result, following the administration of taurine, glucose tolerance improved, both pancreatic ß- and α-cell area increased, and both insulin and glucagon content increased. In the 1% taurine administration group, blood glucose variability decreased. These unexpected results suggest that taurine improves glucose tolerance, in spite of its subsequent increased glucagon production, partly by increasing pancreatic ß-cells and insulin production in vivo.

Antibody to CMRF35-Like Molecule 2, CD300e A Novel Biomarker Detected in Patients with Fulminant Type 1 Diabetes.

AIMS/HYPOTHESIS: Fulminant type 1 diabetes (FT1D) is a distinct subtype of type 1 diabetes and is fatal without immediate diagnosis and treatment. At present, there are no biomarkers for early and predictive detection of FT1D. METHODS: First, we analyzed a total of 6 serum samples from 3 patients with FT1D (1 sample in the acute and 1 in the sub-acute phases from each patient) by seromic analysis. Second, titres of the antibody were measured by ELISA in sera from 30 patients with FT1D (both in the acute and sub-acute phases), 13 patients with FT1D in the chronic phase, 32 patients with autoimmune type 1 (type 1A) diabetes (T1AD), 30 patients with type 2 diabetes (T2D), 23 patients with autoimmune thyroid disease (AITD) and 31 healthy control subjects (HC). RESULTS: Seromic analysis revealed 9 antibodies which showed high signals from all 3 patients with FT1D in the acute phase. Among them, the titre of anti-CD300e antibody was significantly higher in FT1D patients in the acute phase than that in T1AD, T2D, AITD patients and HC, as determined by ELISA (P<0.01, respectively). The titre of anti-CD300e antibody was also higher in FT1D in the acute phase than that in the sub-acute phase (P = 0.0018, Wilcoxon signed-rank test). The titre of anti-LGALS3 antibody in FT1D patients in the acute phase did not differ from that in patients with FT1D in the sub-acute phase, T1AD, T2D, AITD and HC. CONCLUSION/INTERPRETATION: The titre of a novel antibody, anti-CD300e, was high in sera from patients with FT1D. This antibody might be a diagnostic marker and provide new insight into the pathogenesis of FT1D.

Possible contribution of taurine to distorted glucagon secretion in intra-islet insulin deficiency: a metabolome analysis using a novel α-cell model of insulin-deficient diabetes.

Glycemic instability is a serious problem in patients with insulin-deficient diabetes, and it may be due in part to abnormal endogenous glucagon secretion. However, the intracellular metabolic mechanism(s) involved in the aberrant glucagon response under the condition of insulin deficiency has not yet been elucidated. To investigate the metabolic traits that underlie the distortion of glucagon secretion under insulin deficient conditions, we generated an αTC1-6 cell line with stable knockdown of the insulin receptor (IRKD), i.e., an in vitro α-cell model for insulin-deficient diabetes, which exhibits an abnormal glucagon response to glucose. A comprehensive metabolomic analysis of the IRKD αTC1-6 cells (IRKD cells) revealed some candidate metabolites whose levels differed markedly compared to those in control αTC1-6 cells, but also which could affect the glucagon release in IRKD cells. Of these candidates, taurine was remarkably increased in the IRKD cells and was identified as a stimulator of glucagon in αTC1-6 cells. Taurine also paradoxically exaggerated the glucagon secretion at a high glucose concentration in IRKD cells and islets with IRKD. These results indicate that the metabolic alterations induced by IRKD in α-cells, especially the increase of taurine, may lead to the distorted glucagon response in IRKD cells, suggesting the importance of taurine in the paradoxical glucagon response and the resultant glucose instability in insulin-deficient diabetes.

The cytokeratin-18 fragment level as a biomarker of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus.

BACKGROUND: The serum cytokeratin-18 fragment (CK-18) concentration has been suggested to be a biomarker of nonalcoholic fatty liver disease (NAFLD), although its usefulness in patients with type 2 diabetes mellitus (T2DM) is unknown. METHODS: The study was divided into two parts. In the first cross-sectional study, a total of 200 patients with T2DM and 58 healthy control subjects were recruited. NAFLD was diagnosed using ultrasonography. In the subsequent longitudinal study, we evaluated the three-month change (Δ) in the CK-18 concentration and other parameters in 40 T2DM patients with NAFLD. RESULTS: The serum CK-18 values were significantly higher in the NAFLD group than in the nonNAFLD group among both diabetic and nondiabetic subjects. The CK-18 concentration was found to be an independent determinant of NAFLD and was positively correlated with the ultrasonography score and AST and ALT concentrations in the T2DM patients. Positive correlations were also identified between the CK-18 and transaminase concentrations in the T2DM and NAFLD cohorts. ΔCK-18 was found to be significantly associated with ΔBMI in the T2DM patients with NAFLD. CONCLUSIONS: A dose effect between the CK-18 concentration and the severity of NAFLD was found in the T2DM patients; thus, the CK-18 concentration is a potentially useful biomarker for assessing the efficacy of treatment and the improvement in NAFLD in patients with T2DM.

Glycaemic instability correlates with a hyperglucagonaemic response in patients with type 1 diabetes without residual beta-cell function.

We investigated the association between arginine-stimulated glucagon secretion (AUCIRG) and several parameters of glycaemic variability in 12 patients with type 1 diabetes without residual beta-cell function. AUCIRG positively correlated with the SD and mean amplitude of glycaemic excursions, thus glucagon might contribute to glycaemic instability, independent of endogenous insulin.

Glycated albumin to glycated hemoglobin ratio is a sensitive indicator of blood glucose variability in patients with fulminant type 1 diabetes.

BACKGROUND: Since serum albumin is glycosylated more rapidly than hemoglobin, it is possible that the glycated albumin (GA) to HbA1c ratio (GA: HbA1c ratio) is potentially a more sensitive indicator of blood glucose excursion than HbA1c. The aim of the present study was to assess the clinical usefulness of GA: HbA1c ratio as a marker of daily glucose excursions in patients with type 1 diabetes according to the subtypes; acute onset type 1A, fulminant and slowly progressive type 1 diabetes. METHODS: Fifty-six outpatients with type 1 diabetes [16 fulminant, 20 acute-onset type 1A and 20 slowly progressive (SPIDDM)] were recruited consecutively. Each patient performed self-monitoring of blood glucose at seven points a day. The associations among the daily profile of glucose and GA, HbA1c, GA: HbA1c ratio were examined across and within the subtypes of type 1 diabetes. RESULTS: GA and GA: HbA1c ratio were each independently correlated with mean amplitude of glucose excursion (MAGE) in patients with type 1 diabetes (F=27.53, p<0.001 and F=13.02, p<0.001, respectively). GA: HbA1c ratio was significantly higher in fulminant type 1 diabetic patients than in SPIDDM patients (3.5 ± 0.2 vs. 3.2 ± 0.5, p=0.015) and it was independently associated with MAGE within fulminant type 1 diabetes (F=21.2, p<0.001). CONCLUSION: In conclusion, the present study demonstrated that GA: HbA1c ratio could be a better marker for glycemic variability than HbA1c in type 1 diabetes, especially in fulminant type 1 diabetes.

Low CTLA-4 expression in CD4+ helper T-cells in patients with fulminant type 1 diabetes.

Fulminant type 1 diabetes is a novel subtype of type 1 diabetes characterized by a remarkably abrupt onset of insulin-deficient hyperglycemia. An accelerated immune reaction has been suggested as the cause of markedly rapid beta cell loss in this disease, but the precise mechanism has not been clarified. We analyzed the expression of cytotoxic T lymphocyte antigen 4 (CTLA-4) in CD4(+) helper T-cells in 16 patients with fulminant type 1 diabetes, 14 patients with type 1A diabetes, 10 patients with type 2 diabetes and 20 normal control subjects. There was a significant reduction in CTLA-4 expression in CD4(+) helper T-cells from patients with fulminant type 1 diabetes (P<0.05) compared with the other three groups. Low CTLA-4 expression was also observed in both CD4(+)CD25(high) T-cells and CD4(+)CD25(-) T-cells. There was a significant negative correlation between the proliferation of CD4(+)CD25(-) T-cells and the levels of CTLA-4. Intracellular expression of CTLA-4 in CD4(+) helper T-cells was not correlated with two CTLA-4 polymorphisms. In conclusion, the expression of CTLA-4 in CD4(+) helper T-cells was low in patients with fulminant type 1 diabetes.

Expression of toll-like receptors in the pancreas of recent-onset fulminant type 1 diabetes.

Fulminant type 1 diabetes, established in 2000, is defined as a novel subtype of diabetes mellitus that results from remarkably acute and almost complete destruction of pancreatic beta cells at the disease onset. In this study, we aimed to clarify the pathogenesis of fulminant type 1 diabetes with special reference to insulitis and viral infection. We examined pancreatic autopsy samples from three patients who had died soon after the onset of disease and analyzed these by immunohistochemistry and in situ-hybridization. The results were that both beta and alpha cell areas were significantly decreased in comparison with those of normal controls. Mean beta cell area of the patients just after the onset was only 0.00256 % while that of normal control was 1.745 %. Macrophages and T cells-but no natural killer cells-had infiltrated the islets and the exocrine pancreas. Although both of them had massively infiltrated, macrophages dominated islet infiltration and were detected in 92.6 % of the patients' islets. Toll-like receptor (TLR) 3, a sensor of viral components, was detected in 84.7+/- 7.0 % of T cells and 62.7+/- 32.3 % of macrophages (mean+/- SD) in all three patients. TLR7 and TLR9 were also detected in the pancreas of all three patients. Enterovirus RNA was detected in beta-cell positive islets in one of the three patients by in situ-hybridization. In conclusion, our results suggest that macrophage-dominated insulitis rather than T cell autoimmunity contributes to beta cell destruction in fulminant type 1 diabetes.

Fulminant type 1 diabetes as a model of nature to explore the role of C-peptide.

Patients with fulminant type 1 diabetes almost completely lack C-peptide even soon after the onset of the disease, and the deficiency continues for the rest of their life. Thus, fulminant type 1 diabetes could serve as a good model of nature to explore the physiological role of C-peptide. For example, patients with fulminant type 1 diabetes have diabetic chronic complications more frequently than those with classical autoimmune type 1 diabetes 5 years after the onset of diabetes, and the higher prevalence could be partly attributable to the complete lack of C-peptide in fulminant type 1 diabetes.