Enzyme-linked immunosorbent assay of 3 Screen Islet Cell Autoantibody in patients with autoimmune thyroid disease.

BACKGROUND: In recent years, the emergence of multiplex technology that can simultaneously measure multiple anti-islet autoantibodies has become particularly valuable for the staging and early diagnosis of immune-mediated type 1 diabetes (T1D). While it has been established that 20%-30% of T1D patients suffer from autoimmune thyroid disease (AITD), there is limited available data regarding the presence of anti-islet autoantibodies in AITD patients. Among commercially available anti-islet autoantibodies, glutamic acid decarboxylase 65 autoantibodies (GADAs) are often the first marker measured in general clinical practice. AIM: To investigate the frequency of anti-islet autoantibodies in AITD patients. METHODS: Our study involved four hundred ninety-five AITD patients, categorized into three distinct groups: AITD with T1D (n = 18), AITD with phenotypic type 2 diabetes (T2D) (n = 81), and AITD without diabetes (n = 396), and the enzyme-linked immunosorbent assay (ELISA) was employed to determine the frequencies of 3 Screen Islet Cell Autoantibody (3 Screen ICA), GADA, insulinoma-associated antigen-2 autoantibodies (IA-2As), and zinc transporter 8 autoantibodies (ZnT8As) within these groups. RESULTS: The frequency of 3 Screen ICA in AITD patients with T1D, T2D, and those without diabetes were 88.9%, 6.2%, and 5.1%, respectively, with no significant difference seen between the latter two groups. Notably, the frequency of 3 Screen ICA was 11.1% higher in AITD patients with T1D, 1.3% higher in AITD patients with T2D, and 1.1% higher in AITD patients without diabetes compared to GADA, respectively. Furthermore, 12.5%, 20.0%, and 20.0% of the 3 Screen ICA-positive patients were negative for GADA. Additionally, 1.3% of the AITD patients who tested negative for 3 Screen ICA in both the AITD with T2D and non-diabetic AITD groups were found to be positive for individual autoantibodies. Among the 3 Screen ICA-positive patients, there was a significantly higher proportion of individuals with multiple autoantibodies in AITD patients with T1D compared to those without diabetes (37.5% vs 5.0%, P < 0.05). However, this proportion was similar to that in AITD patients with T2D (20.0%). Nevertheless, there was no significant difference in 3 Screen ICA titers between AITD patients with T1D and those without diabetes (436.8 ± 66.4 vs 308.1 ± 66.4 index). Additionally, no significant difference in 3 Screen ICA titers was observed between Graves' disease and Hashimoto's thyroiditis in any of the groups. CONCLUSION: Our findings reveal that some AITD patients without diabetes exhibit 3 Screen ICA titers comparable to those in AITD patients with T1D. Thus, 3 Screen ICA outperforms GADA in identifying latent anti-islet autoantibody-positive individuals among AITD patients.

Development of type 1 diabetes in a patient treated with anti-interleukin-6 receptor antibody for rheumatoid arthritis.

Interleukin-6 is a pleiotropic cytokine that plays a pathogenic role in type 1 diabetes. Therefore, anti-interleukin-6 receptor antibody, tocilizumab, used for the treatment of rheumatoid arthritis, is considered a candidate for immune intervention in type 1 diabetes. Here, we report the case of a 73-year-old woman (HLA-DR9-DQ3 homozygote) with well-controlled rheumatoid arthritis who developed type 1 diabetes while receiving tocilizumab treatment. At 57 years-of-age, the patient was diagnosed with rheumatoid arthritis, for which she underwent tocilizumab therapy that enabled complete suppression of her joint inflammation. A total of 17 months after starting tocilizumab therapy, she noticed polydipsia, polyuria, general fatigue and weight reduction (-2 kg/month), and was diagnosed with type 1 diabetes with diabetic ketoacidosis based on an arterial pH of 7.26, serum ketone body of 7,437 µmol/L, blood glucose level of 925 mg/dL, glycated hemoglobin of 13.2% and the presence of anti-islet autoantibodies. This case report shows valuable insight regarding the effect of anti-interleukin-6 receptor antibody therapy on type 1 diabetes prevention.

Efficacy of omarigliptin, once-weekly dipeptidyl peptidase-4 inhibitor, in patients with type 2 diabetes.

BACKGROUND: Omarigliptin is one of several once-weekly dipeptidyl peptidase-4 inhibitors (DPP-4is). Despite the high frequency of switching from various daily DPP-4is to omarigliptin in actual clinical practice, data regarding its efficacy in patients with type 2 diabetes (T2D) after switching are limited. AIM: To analyze the efficacy of omarigliptin in Japanese patients with T2D who had previously received treatment with other glucose-lowering agents. METHODS: Forty-nine T2D patients treated for the first time with omarigliptin were recruited retrospectively and divided into four groups defined as either add-on or switched from daily DPP-4is: switched from linagliptin, switched from sitagliptin, and switched from vildagliptin. During a 3-mo follow-up, the clinical parameters among these groups were assessed and compared, with the impact of the switch on glycemic variability as measured by continuous glucose monitoring also being evaluated in the switched groups. RESULTS: Hemoglobin A1c levels saw a significant decrease of -0.32% ± 0.41% in the add-on group (P = 0.002). However, the other groups' variables depended on the pre-switch daily DPP-4i: switched from linagliptin, -0.05% ± 0.22%; switched from sitagliptin, -0.17% ± 0.33%; and switched from vildagliptin, 0.45% ± 0.42%, which saw significant worsening (P = 0.0007). Multivariate logistic regression analysis revealed that switching from vildagliptin to omarigliptin was independently associated with worsening glycemic control (P = 0.0013). The mean and standard deviation of sensor glucose value, the mean amplitude of glycemic excursions, and the mean of daily difference significantly improved when switching the patient from either linagliptin or sitagliptin to omarigliptin. However, in patients switched from vildagliptin, not only did the glucose variability indices see no improvements, the mean of daily difference even underwent significant worsening. CONCLUSION: Administering omarigliptin as add-on therapy or switching to it from sitagliptin and linagliptin, but not vildagliptin, improves glycemic control and thus should help in decision making when selecting DPP-4is for T2D patients.

Characterization of patients with diabetes who were incidentally found to be glutamic acid decarboxylase autoantibody-positive by bridging-type enzyme-linked immunosorbent assay.

This study aimed to characterize diabetic patients incidentally found to be positive for glutamic acid decarboxylase autoantibodies (GADA) in general practice. Using bridging-type enzyme-linked immunosorbent assay, we screened 1,040 patients with phenotypic type 2 diabetes for GADA, finding 25 (2.4%) to be positive. However, on retesting, with a median interval of 19 days, 44% of GADA-positive patients turned negative (Disappearing Group). The mean age at diabetes onset was significantly higher (P < 0.05) and GADA titers at first determination were significantly lower (P < 0.001) in the Disappearing Group compared with the Persistent Positive Group. On initial screening, all patients in the Disappearing Group had GADA titers of <6.5 U/mL. The current study showed that a portion of phenotypic type 2 diabetic patients incidentally identified as GADA-positive were falsely positive, and that to avoid the misclassification, remeasurement of GADA is essential in cases showing very low titers.

Statin-induced autoimmune hepatitis in patients with type 1 diabetes: A report of two cases and literature review.

Statins are widely used medications for the treatment of hypercholesterolemia, as well as prevention of cardiovascular disease. We report two patients with type 1 diabetes who developed autoimmune hepatitis after the administration of statin. The first patient developed the marked elevation of liver enzymes 6 months into atorvastatin therapy. The second patient developed liver dysfunction 8 months after the initiation of rosuvastatin therapy. Liver biopsies in both patients showed either portal, interface and lobular hepatitis or a piece-meal necrosis with lymphocytes and plasma cell infiltration that were compatible with autoimmune hepatitis. Then, both patients were started on prednisolone, to which they responded well. Liver biopsy is to be considered for type 1 diabetes patients if there is no improvement of liver dysfunction after discontinuation of statins.

Discrepancy of glutamic acid decarboxylase 65 autoantibody results between RSR radioimmunoassay and enzyme-linked immunosorbent assay in patients with type 1 diabetes is related to autoantibody affinity.

AIM/INTRODUCTION: Autoantibodies to the 65 kDa isoform of glutamic acid decarboxylase (GADA) are a valuable diagnostic and predictive marker for type 1 diabetes. Recently, it has been reported that a significant proportion of sera in the commercial RSR radioimmunoassay (RIA) that have tested positive for GADA have then turned negative in RSR enzyme-linked immunosorbent assay (ELISA) tests in patients with type 1 diabetes. The present study aimed to investigate whether the GADA result discrepancies between RSR-RIA and RSR-ELISA are related to autoantibody affinity. METHODS: GADA affinity was measured by a competitive binding experiment using unlabeled recombinant human GAD65 in 12 discordant samples (5 RIA[+]/ELISA[-] and 7 RIA[-]/ELISA[+] sera). Furthermore, the effect of the initial incubation time on the GADA positivity was also examined using the ELISA test. RESULTS: GADA affinities were >1010  L/mol in two of five RIA(+)/ELISA(-) and all of seven RIA(-)/ELISA(+) sera. After an initial incubation time longer than the recommended 1 h, the GADA titer in three of five RIA(+)/ELISA(-) sera and all RIA(-)/ELISA(+) sera increased 1.6- to 100-fold. However, the titer in 12 GADA-negative sera from healthy controls remained unchanged after the longer incubation. The increment ratio of GADA titer was positively correlated with GADA affinity (r = 0.991, P < 0.001). CONCLUSIONS: The RSR-RIA test identifies both high- and low-affinity GADA, whereas the RSR-ELISA test identifies only high-affinity GADA. A longer initial incubation time in the RSR-ELISA test increases the sensitivity of GADA with the same specificity in patients with type 1 diabetes.

Development of Lobular Panniculitis Long After Completing the Personalized Peptide Vaccine Therapy.

BACKGROUND Personalized peptide vaccine therapy is regarded as a well-tolerated, safe and effective immunotherapy for patients with advanced cancers. Herein we report an exceptional case of a patient with advanced pancreatic cancer who developed delayed lobular panniculitis at sites corresponding to vaccine injections. CASE REPORT A 64-year-old Japanese female visited our clinic due to thirst and polydipsia; she was diagnosed as having type 2 diabetes. Simultaneously, she was diagnosed as having advanced pancreatic cancer; and a distal pancreatectomy and splenectomy were performed. Afterwards, she received adjuvant chemotherapy with titanium silicate-1 and personalized peptide vaccination using Montanide® ISA-51 by a subcutaneous injection to her abdomen over a total of 30 times. Thirteen months after the vaccine therapy had come to an end, lobular panniculitis appeared at the vaccination sites. At this point, corticosteroid was administered, resulting in significant improvement in the condition of the subcutaneous nodules. CONCLUSIONS This case report highlights the importance of careful patient explanation before initiation of cancer vaccine therapy about the possibilities of lobular panniculitis as an adverse event. It also highlights that it is important that physicians have a greater awareness of the possibility of panniculitis in patients with concerns regarding subcutaneous indurations even long after the end of peptide vaccine therapy.

Different effects of linagliptin and sitagliptin on blood pressure and renal function in Japanese patients with type 2 diabetes mellitus.

AIMS: To compare and evaluate effects of two DPP-4 inhibitors with different excretion routes on systemic and renal hemodynamics in Japanese patients with type 2 diabetes mellitus. METHODS: Seventy-three outpatients with type 2 diabetes who had been treated by 50 mg/day of sitagliptin (S) for at least 1 year were enrolled and prescribed 5 mg/day of linagliptin (L) instead of S for the next 1 year. RESULTS: After the initiation of S, the systolic and diastolic blood pressure decreased significantly. However, after switching to L for 1 year they increased significantly and returned to a comparable level as those before S treatment. The increase in serum creatinine or uric acid levels and the decrease in eGFR after S initiation were completely stopped or reversed after switching to L. The change in eGFR after the initiation of S was negatively correlated with the eGFR value at 1 year before switching. CONCLUSIONS: The administration of S had an obvious effect on the systemic or renal hemodynamics in contrast to the fact that the administration of L had no effect on these parameters. It is thus important to use these agents with different excretion routes, properly taking the patients' renal function into account.

Usefulness of carotid plaque (sum and maximum of plaque thickness) in combination with intima-media thickness for the detection of coronary artery disease in asymptomatic patients with diabetes.

AIMS/INTRODUCTION: The usefulness of markers of carotid plaque, such as sum (PS) and maximum (P-max) of the plaque thickness, in combination with intima-media thickness in the common carotid artery (CIMT) for the detection of obstructive coronary artery disease (CAD) was investigated in patients with type 2 diabetes without known CAD. MATERIALS AND METHODS: B-mode ultrasonographic scanning of the carotid artery and multislice computed tomography coronary angiography were carried out in 332 asymptomatic patients with type 2 diabetes. RESULTS: For the presence of obstructive CAD when incorporating PS or P-max to standard risk factors in a multiple logistic regression model, the classification ability in PS and P-max increased greatly (area under the curve [AUC] 0.827 vs 0.720 [net reclassification index {NRI} = 0.652, P < 0.01] and AUC 0.820 vs 0.720 [NRI = 0.775, P < 0.01], respectively), and it in CIMT increased slightly (AUC 0.740 vs 0.720, NRI = 0.230, P = 0.041). Furthermore, the classification abilities for a model with interaction terms between PS* or P-max* and CIMT were statistically larger than those for a model without interaction terms (AUC 0.833 vs 0.827 [NRI = 0.411, P < 0.01] and 0.823 vs 0.820 [NRI = 0.269, P < 0.05], respectively). Partitioning showed the patients in the values of the PS <2.6 mm and CIMT <0.725 mm (100%), or in P-max <2.1 mm and CIMT <0.725 mm (95.4%), did not have obstructive CAD, whereas those in the values of PS ≧2.6 mm, presence of hyperlipidemia and CIMT ≧0.675 mm (84%) or those in the value of P-max ≧2.1 mm and body mass index ≧24 (91.7%) had obstructive CAD. CONCLUSIONS: Although the P-max and PS in the carotid artery were useful as detectors of CAD, combining them with CIMT provided a much superior first-line screening method in detecting CAD in asymptomatic patients with diabetes.

Adding of Sitagliptin on Insulin Therapy Effectively and Safely Reduces a Hemoglobin A1c Level and Glucose Fluctuation in Japanese Patients with Type 2 Diabetes.

Aims. Efficacy and safety of DPP-4 inhibitor, sitagliptin, add-on therapy to insulin were investigated in Japanese patients with type 2 diabetes. Subjects and Methods. Two hundred and sixteen patients (126 men, 65 ± 12 years old, BMI 24.9 ± 4.5, means ± S.D.) who had been treated by insulin alone or insulin combined with other oral hypoglycemic agents (OHAs) were recruited, and sitagliptin was added for 3 months. Results. HbA1c was significantly decreased after 3 months of add-on therapy as a whole (8.56 ± 1.50% to 7.88 ± 1.25%, P < 0.0001). Body weight did not change and insulin dosage was significantly (P < 0.0001) decreased for 3 months. Furthermore, day-to-day glucose variability was significantly reduced (18.3 ± 9.1 to 16.1 ± 8.1%, P < 0.05). In stepwise multiple regression analysis on ΔHbA1c as an outcome variable, the higher baseline HbA1c value and a preserved CPR were selected as significant predictive variables. Fifteen patients complained of mild hypoglycemia without any assistance during 3 months of sitagliptin add-on, while no severe hypoglycemic episode was reported. Conclusions. Add-on of sitagliptin to ongoing insulin therapy effectively reduced either HbA1c level or glucose fluctuation and could be a practical and well-tolerated alternative to treat Japanese patients with type 2 diabetes who had been inadequately controlled by insulin with or without other OHAs.

Usefulness of sum of the thickness of plaque in the carotid artery for predicting the presence and the extent of the coronary artery disease in patients with type 2 diabetes mellitus without known coronary artery disease.

AIMS: The usefulness of the sum of plaque thickness in the carotid artery (plaque score; PS), as a prediction of coronary artery disease (CAD) was investigated in patients with type 2 diabetes mellitus. METHODS: B mode ultrasonographic scanning of the carotid artery and multislice computed tomography (MSCT) coronary angiography were performed in 227 diabetic patients without known cardiac disease. RESULTS: The PS was useful to predict the presence of diseased [nonobstructive and obstructive] CAD (≧3 segments) and obstructive (≧50%) CAD with cut-off value of 3.5mm (area under curve: 0.745 and 0.782, respectively), according to a receiver operating characteristics curve analysis. A multivariate logistic analysis of baseline risk factors showed that the PS was independent risk factor for the prediction of diseased and obstructive coronary artery disease (R(2)=0.2165, p<0.0001 and R(2)=0.2265, p<0.0001, respectively). The PS was most significant predictor of the number of diseased and obstructive segments of the coronary artery in a multiple regression analysis (R(2)=0.2022, p<0.0001 and R(2)=0.2209, p<0.0001, respectively). CONCLUSIONS: The PS in the carotid artery was useful for the prediction of the presence and the extent of CAD, and was most important as a screening test for the identification of a high risk group of asymptomatic diabetic patients.

Long-term efficacy of sitagliptin for the treatment of type 2 diabetic patients in Japan.

We studied the efficacy of sitagliptin in type 2 diabetic patients of our outpatient clinics. Since December in 2009, 164 patients have been treated by sitagliptin for their management of diabetes. HbA1c decreased by 0.8% in all patients without any change in mean body weight after 3 months. However, actually HbA1c did not decrease in 30 patients, and more than half of patients showed weight gain to some extent. Patients were classified according to the reduction of HbA1c and analyzed based on this category. Baseline characters such as age, gender, duration of diabetes, BMI, concomitantly used oral hypoglycemic agents and the score for life-style assessment were not related to glucose-lowering effect of sitagliptin. Ninety eight patients whose HbA1c had decreased after 3 months were further followed-up for another 3 months. Among them 45 patients showed some relapsing of HbA1c after 6 months, and they were compared with 53 patients without relapsing. More cases had been switched from α-glucosidase inhibitor (α-GI) and the score for life-style assessment was lower in relapsing patients compared to those in patients without relapsing. In conclusion, clinicians should keep the fact in mind that the individual variation of glucose-lowering effects and the possibility of relapsing exist during sitagliptin treatment, and that concern about life-style is still a quite important issue to prevent weight gain and the relapsing of blood glucose control.