Current clinical state of type 1 diabetes in Saitama prefecture.

Introduction: In Japan, epidemiological studies on type 1 diabetes (T1D) have mainly focused on the disease in childhood. Meanwhile, limited information is available regarding the clinical features of adolescent and adult T1D. Therefore, we aimed to investigate their current clinical state in Saitama prefecture near Tokyo, Japan. Materials and methods: We conducted a cross-sectional, hospital-based, multicenter study. Eight institutions participated in the study, all of which treated relatively large numbers of T1D patients. We identified 1241 T1D patients aged 16 or over: 814 with acute-onset T1D (AT1D), 362 with slowly progressive insulin-dependent diabetes mellitus (SPIDDM), and 65 with fulminant T1D (FT1D). Based on the patient's medical records, various clinical parameters and complications were investigated. Results: Of 1241 patients, 739 (59.5%) were females. Among all patients, the median age, onset age, and disease duration were 51, 38, and 13 years, respectively. The patients had a median BMI of 22.6 kg/m2, and 26.1% were obese, corroborating previous nationwide surveys. Moreover, the median HbA1c was 7.8%, similar to previous nationwide surveys. Among patients with AT1D, SPIDDM, and FT1D, 85.6%, 72.1%, and 81.5% carried out multiple daily insulin injection, respectively, while 10.3%, 2.2%, and 18.5% were subject to continuous subcutaneous insulin infusion. The proportions of retinopathy, nephropathy, and neuropathy were 26.3%, 20.8%, and 21.5%. Conclusions: The glycemic control in T1D patients in Saitama was equivalent to that observed in previous nationwide surveys. Moreover, approximately one-quarter of T1D patients had obesity. Future studies should address whether our findings reflect those throughout Japan. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-021-00557-8.

Early introduction of very small amounts of multiple foods to infants: A randomized trial.

BACKGROUND: We investigated whether multiple food allergies could be safely prevented by simultaneously administering very small amounts of multiple foods. METHODS: Infants 3-4 months old with atopic dermatitis from 14 primary care pediatric clinics in Japan were enrolled in this randomized, placebo-controlled trial. The infants were administered either mixed allergenic food powder (MP) containing egg, milk, wheat, soybean, buckwheat, and peanuts, or placebo powder (PP). The amount of powder was increased in a stepwise manner on weeks 2 and 4, and continued until week 12. The occurrence of food allergy episodes after powder intervention was assessed at 18 months old. This trial was registered with the University Hospital Medical Information Network Clinical Trials Registry (number UMIN000027837). RESULTS: A total of 163 participants were randomly allocated to either the MP group (n = 83) or the PP group (n = 80). The incidence of food allergy episodes by 18 months was significantly different between the MP and PP groups (7/83 vs. 19/80, respectively; risk ratio 0.301 [95% CI 0.116-0.784]; P = 0.0066). Egg allergies were reduced in the MP group. In addition, food allergy episodes from any of the other five foods were significantly reduced, although the reductions in those due to individual foods were not significant. CONCLUSIONS: Gradually increasing the intake of very small amounts of multiple foods in early infancy can safely reduce the incidence of egg allergies. Other foods may also suppress food allergies, but no definitive conclusions could be reached.

Time in range correlates glycated albumin measured immediately after 2 weeks of continuous glucose monitoring.

AIMS: Time in range (TIR), an index of glycemic control and also blood glucose fluctuation, obtained from continuous glucose monitoring (CGM), has been increasing its importance along with the spread of CGM in recent years. For a while, glycated albumin (GA) has been also used as a glycemic control index during about 2-weeks in routine clinical practice. It has not yet been confirmed under optimal condition whether TIR and GA correlates. Clarification of the correlation between TIR and GA, which was measured immediately after 2-weeks of CGM, might be a finding that further supports the utility of TIR. METHODS: GA was measured at the conclusion of 2-week CGM in 71 diabetes outpatients at our hospital, and the correlation between GA and indices such as TIR obtained from CGM was statistically analyzed. RESULTS: It was found that TIR and time above range (TAR) were significantly correlated with GA. Upon performing multiple regression analysis, TIR, TAR and BMI. indicated a significant regression coefficient with respect to GA. CONCLUSIONS: These findings further support the utility of TIR as a marker of glycemic control that it might also be correlated with GA, and also suggest a relation between GA and blood glucose fluctuation.

Efficacy and safety of liraglutide monotherapy compared with metformin in Japanese overweight/obese patients with type 2 diabetes.

There is little information on direct comparison between metformin and glucagon-like peptide-1 (GLP-1) receptor agonists in the Asian population. This study examined the efficacy and safety of liraglutide monotherapy compared with metformin monotherapy in overweight/obese Japanese patients with type 2 diabetes (T2DM). The study was a 24-week, open-labeled, randomized controlled study. Overweight or obese patients with T2DM aged 20-75 years with suboptimal glycemic control were randomized to liraglutide or metformin monotherapy. The primary endpoint was change in HbA1c at week 24. Secondary endpoints included changes in daily glycemic profile, body weight, incidence of hypoglycemia and other adverse events. The study, which was originally planned to enroll 50 subjects in each group, was ended with insufficient recruitment. A total of 46 subjects completed the study, and analysis was conducted in this cohort. Reduction in HbA1c at week 24 was comparable between the metformin (n = 24) and liraglutide (n = 22) groups (-0.95 ± 0.80% vs. -0.80 ± 0.88%, p = 0.77), while the liraglutide group reached maximal reduction more rapidly than did the metformin group. There was no significant difference in weight gain or incidence of hypoglycemia between the groups. Diarrhea was more frequent in the metformin group, while constipation was more frequent in the liraglutide group. There was no significant difference in treatment satisfaction between the groups. In conclusion, liraglutide and metformin monotherapy showed similar reduction in HbA1c during 24 weeks, with no difference in weight gain or incidence of hypoglycemia in overweight or obese Japanese patients with T2DM.

Glycated albumin is not significantly correlated with body mass index in patients with acute-onset type 1 diabetes.

BACKGROUND: No previous reports have clarified the relationship between glycated albumin (GA) and BMI in patients with acute-onset type 1 diabetes. METHODS: We conducted a cross-sectional study evaluating the correlation between GA and BMI in 209 patients with acute-onset type 1 diabetes and in 159 patients with type 2 diabetes who were designated as the control group. The correlation between fasting serum C-peptide immunoreactivity (CPR) and GA or BMI was also evaluated to clarify the impact of insulin secretion capacity on the relationship between GA and BMI. RESULTS: GA was significantly inversely correlated with BMI in patients with type 2 diabetes (r=-0.317, p<0.001) but not in patients with type 1 diabetes (r=0.031, p=NS). In patients with type 2 diabetes, GA was significantly inversely correlated with fasting CPR, and BMI was significantly correlated with fasting CPR. In patients with type 1 diabetes, GA was significantly inversely correlated with fasting CPR (r=-0.291, p<0.001), but BMI was not correlated with fasting CPR (r=-0.010, p=NS). CONCLUSIONS: Unlike in patients with type 2 diabetes, GA was not significantly correlated with BMI in patients with acute-onset type 1 diabetes.

Effects of concomitant drugs on sitagliptin-mediated improvement in glycemic control in Japanese patients with type 2 diabetes.

AIMS: We investigated to clarify factors associated with the efficacy of sitagliptin, a dipeptidyl peptidase (DPP)-IV inhibitor, for glycemic control including the confounding effect of concomitant drugs in patients with type 2 diabetes. METHODS: We included type 2 diabetes patients with HbA1c levels of ≥7% who were not under insulin treatment and were administered sitagliptin (50mg/day for 6 months). Reduction or discontinuation of insulin sensitizers was not permitted during the study period. Outcomes included HbA1c level variations and attaining a target HbA1c level of <7%. Associated factors with each outcome were examined using multivariate analysis. RESULTS: Of the 313 patients enrolled in this study, 147 (47.0%) attained HbA1c levels of <7%. High baseline HbA1c levels were associated with HbA1c level variations but inversely associated with attaining the target HbA1c level of <7%. Concomitant use of an insulin sensitizer and a α-glucosidase inhibitor and maintenance of the baseline dose of concomitant drugs were significantly associated with each outcome. CONCLUSIONS: Our results suggest that concomitant sitagliptin administration (50mg/day) will improve glycemic control if treatment is initiated before HbA1c levels deteriorate. Other medication should be continued at initiation of sitagliptin administration.

Slowly progressive type 1 diabetes treated with metformin for five years after onset.

A 52-year-old man was diagnosed with slowly progressive type 1 diabetes (SPIDDM). We expected him to quickly progress to an insulin-dependent state due to a high anti-glutamic acid decarboxylase antibody titer (23.9 U/mL). At SPIDDM diagnosis, he was in a non-insulin-dependent state, with a fasting serum C-peptide immunoreactivity level of 2.5 ng/mL. Therefore, we prescribed metformin. His glycemic control remained stable, and his intrinsic insulin secretion capacity was maintained for five years. Although one case is insufficient to draw firm conclusions, this report suggests that metformin is a therapeutic choice for SPIDDM when the insulin secretion capacity is maintained.

Time-course changes in nerve conduction velocity (NCV) in type 2 diabetes.

AIM: Changes in NCV were surveyed over 10 years in type 2 diabetes patients to clarify the time-course relationships between NCV and retinopathy stage and between NCV and HbA1c. In addition, the natural course of diabetic sensorimotor polyneuropathy (DSPN) was discussed based on the findings. METHODS: Using a simple NCV measurement device, NCV (MCV and SCV) was measured once a year over 10 years in 474 patients with type 2 diabetes. These patients were grouped based on the retinopathy stage and HbA1c level in the course to investigate the time-course relationships between the retinopathy stage and NCV and between HbA1c and NCV. RESULTS: The retinopathy stage and NCV reduction were strongly correlated, and NCV decreased as retinopathy progressed. On comparison of time-course NCV among the retinopathy stages, continuity of NCV reduction along with the retinopathy progression was noted. Regarding the relationship between HbA1c and NCV, NCV reduction was moderate in the group maintaining HbA1c at a relatively favorable level, but morbid reduction of NCV could not be prevented even though favorable control was maintained. CONCLUSION: NCV reduction is strongly correlated with retinopathy progression from more than 10 years before its manifestation through reaching proliferative retinopathy. It was also suggested that NCV reduction can be attenuated by controlling blood glucose, but the reduction cannot be prevented completely. Based on these findings, DSPN is a progressive complication that starts from an early phase after onset of diabetes and steadily aggravates, keeping step with retinopathy aggravation, and it may be difficult to completely prevent the progression.

Insulin-like growth factor-1 (IGF-1)-derived peptide protects against diabetes in NOD mice.

Spontaneous diabetes in non-obese diabetic (NOD) mice results from beta-cell destruction by autoreactive T lymphocytes. Here, we report the significance of insulin-like growth factor-1 (IGF-1) peptide as a tool for the prevention of type 1 diabetes. Female NOD mice were immunized with a subcutaneous injection of IGF-1, glutamic acid decarboxylase (GAD), insulin or IGF-1-derived peptides (residues 8-23, 24-41 or 50-70) in incomplete Freund's adjuvant (IFA) or with IFA only as the control group at 4 weeks of age, and observed up to 36-37 weeks of age. Diabetes onset was significantly suppressed and delayed in the IGF-1 group as compared to the GAD, insulin and control groups (p<0.05), and it was significantly suppressed and delayed in the (50-70)IGF-1 group as compared to the (8-23)IGF-1 and control groups (p<0.02). Although the degree of insulitis in all treated mice was not significantly different, a significant number of IL-4-producing cells in response to IGF-1 peptides were detected in (50-70)IGF-1-treated mice in intracellular cytokine assay. In conclusion, IGF-1 peptide 50-70 immunizations of NOD mice suppressed and delayed diabetes onset, probably through amplification of the Th2-type response. It was suggested that IGF-1 peptide 50-70 immunization can be used as a tool for prevention of type 1 diabetes.

CXC chemokine ligand 10 neutralization suppresses the occurrence of diabetes in nonobese diabetic mice through enhanced beta cell proliferation without affecting insulitis.

We have shown that neutralization of IFN-inducible protein 10/CXCL10, a chemokine for Th1 cells, breaks Th1 retention in the draining lymph nodes, resulting in exacerbation in Th1-dominant autoimmune disease models induced by immunization with external Ags. However, there have been no studies on the role of CXCL10 neutralization in Th1-dominant disease models induced by constitutive intrinsic self Ags. So, we have examined the effect of CXCL10 neutralization using a type 1 diabetes model initiated by developmentally regulated presentation of beta cell Ags. CXCL10 neutralization suppressed the occurrence of diabetes after administration with cyclophosphamide in NOD mice, although CXCL10 neutralization did not significantly inhibit insulitis and gave no influence on the trafficking of effector T cells into the islets. Because both CXCL10 and CXCR3 were, unexpectedly, coexpressed on insulin-producing cells, CXCL10 was considered to affect mature and premature beta cells in an autocrine and/or paracrine fashion. In fact, CXCL10 neutralization enhanced proliferative response of beta cells and resultantly increased beta cell mass without inhibiting insulitis. Thus, CXCL10 neutralization can be a new therapeutic target for beta cell survival, not only during the early stage of type 1 diabetes, but also after islet transplantation.

GAD-reactive T cells were mainly detected in autoimmune-related type 1 diabetic patients with HLA DR9.

Type 1 diabetes mellitus (T1DM) is considered to be a T cell-mediated disease, and many reports suggest that some HLA types, especially HLA DR4 and DR9, convey susceptibility to T1DM in Japanese. We investigated the association between T cell reactivity against GAD and HLA types in "islet-associated autoantibody-positive" T1DM in Japanese. Blood samples were obtained from 36 "autoantibody-positive" type 1 diabetic patients with HLA DR4 or DR9 and 23 type 2 diabetic patients with HLA DR4 or DR9 as controls. They were divided into three groups, DR4/9, DR4/X, and DR9/X groups. In each HLA type group, GAD-reactive IFN-gamma-producing CD4(+) cells were assessed by means of intracellular cytokine staining for flow cytometry. Type 1 diabetic patients with HLA DR9/X had significantly higher numbers of GAD-reactive IFN-gamma-producing CD4(+) cells as compared to type 1 diabetic patients with DR4/X or DR4/9 (P < 0.05) and all type 2 diabetic patients. There was no significant difference in the number of GAD-reactive IFN-gamma-producing CD4(+) cells between type 1 diabetic and type 2 diabetic patients belonging to the DR4/X and DR4/9 groups. There was an association between T cell reactivity against GAD and HLA DR9 in Japanese type 1 diabetes.

Relationship between beta cell mass of NOD donors and diabetes development of NOD-scid recipients in adoptive transfer system.

BACKGROUND: There is controversy about the way the beta cell mass is reduced in type 1 diabetes. One view is that a gradual fall in beta cell mass begins soon after the onset of insulitis. Another view is that a sudden wave of beta cell destruction occurs just before the onset of diabetes. To clarify how the beta cell mass is reduced, we performed adoptive transfer experiments and examined the relationship between the pancreatic status of NOD donors and the time taken to transfer diabetes into NOD-scid recipients. METHODS: We killed 18-week-old female NOD mice (n = 20), removed their spleen, and transferred splenocytes into 5-week-old female NOD-scid mice (n = 60). The relationship between the pancreatic status of donors and the time taken to transfer diabetes into recipients was assessed. As pancreatic status, we measured insulin content and severity of insulitis. RESULTS: There was no linear correlation between the pancreatic status of donors and the time taken to transfer diabetes into recipients. NOD donors who needed 7 or more weeks to transfer diabetes in NOD-scid recipients had similar levels of insulin content or severity of insulitis as those of NOD donors who could not transfer diabetes. On the other hand, NOD donors who needed 6 or less weeks to transfer diabetes in recipients had similar levels of insulin content or severity of insulitis as those of diabetic NOD mice. CONCLUSIONS: According to our observations, beta cell mass seems to be preserved until just before the onset of diabetes and decreased dramatically within a few weeks.

Detection of GAD-reactive CD4+ cells in so-called "type 1B" diabetes.

OBJECTIVE: Although the majority of type 1 diabetes is considered to be type 1A, some patients with type 1 diabetes have no islet-associated autoantibody in their serum. This type of type 1 diabetes has usually been diagnosed as type 1B on the basis of islet-associated autoantibody-negativity. In this study, we tried to demonstrate the existence of islet-associated antigen-specific T cells in type 1 diabetes without islet-associated autoantibody. RESEARCH DESIGN AND METHODS: Peripheral blood samples were obtained from 110 Japanese diabetic patients, including 15 type 2 diabetic patients. Measurement of islet-associated antigen-specific cytokine response was performed by intracellular cytokine staining for flow cytometry. RESULTS: The number of GAD-reactive IFN-gamma-producing CD4+ cells in 50,000 CD4+ cells in diabetics with type 1B (113.6 +/- 34.6, median 45), type 1A (132.4 +/- 33.3, median 25), and LADA (154.4 +/- 44.1, median 20) was higher than that in type 2 diabetics (0.3 +/- 0.3, median 0) and control subjects (3.8 +/- 2.4, median 0). When the normal upper limit of the number of GAD-reactive CD4+ cells was set at the mean + 3SD of values in control subjects, at least half (52.4%) of the so-called "type 1B" patients were positive for GAD-reactive IFN-gamma-producing CD4+ cells, a significantly larger proportion than that in type 2 diabetics (0%; p < 0.001). CONCLUSIONS: Assessment of T cell reactivity against islet-associated antigen may contribute to the diagnosis of "autoimmune-related" type 1 diabetes.

Systemic administration of IL-18 promotes diabetes development in young nonobese diabetic mice.

IL-18 is now identified as a pleiotropic cytokine that acts as a cofactor for both Th1 and Th2 cell development. Type 1 diabetes is considered a Th1-type autoimmune disease, and to date, the suppressive effect of exogenous IL-18 on the development of diabetes has been reported in 10-wk-old nonobese diabetic (NOD) mice. In the present study we administered exogenous IL-18 systemically in 4-wk-old NOD mice using i.m. injection of the IL-18 expression plasmid DNA (pCAGGS-IL-18) with electroporation. Contrary to previous reports, the incidence of diabetes development was significantly increased in NOD mice injected with pCAGGS-IL-18 compared with that in control mice. Systemic and pancreatic cytokine profiles deviated to a Th1-dominant state, and the the frequency of glutamic acid decarboxylase-reactive IFN-gamma-producing CD4(+) cells was also high in the IL-18 group. Moreover, it was suggested that the promoting effect of IL-18 might be associated with increased peripheral IL-12, CD86, and pancreatic IFN-inducible protein-10 mRNA expression levels. In conclusion, we demonstrate here that IL-18 plays a promoting role as an enhancer of Th1-type immune responses in diabetes development early in the spontaneous disease process, which may contribute to elucidating the pathogenesis of type 1 diabetes.

Assessment of beta cell mass and oxidative peritoneal exudate cells in murine type 1 diabetes using adoptive transfer system.

Because it is controversial how the beta cell mass is reduced during the disease process in type 1 diabetes, we transferred splenocytes from Non-obese diabetic (NOD) to NOD-scid mice and evaluated the relation between the status of the pancreas in donors and the time taken to transfer diabetes to the recipients. We also evaluated the usefulness of assessment of the proportion of oxidative peritoneal exudate cells (PEC) as a novel marker of disease activity in this system. We examined the proportion of oxidative PEC, pancreatic insulin content and pancreatic histology in 16-18-week-old female NOD mice (donors), and transferred their splenocytes into 5-week-old female NOD-scid mice (recipients). After the onset of diabetes in NOD-scid recipients, we assessed the relation between insulin content (or severity of insulitis) of NOD donors and the time taken to transfer diabetes to NOD-scid recipients. The insulin content of "diabetes-prone" donors whose disease status was considered to be just before the onset of diabetes ("malignant" donors) was the same as that of diabetic mice, whereas the insulin content of "diabetes-prone" donors excluding "malignant" donors ("benign" donors) was the same as that of "non-diabetes-prone" donors. Because its proportion of oxidative PEC was inversely correlated with the severity of insulitis, we then evaluated the relation between the proportion of oxidative PEC and the time taken to transfer diabetes. "Malignant" donors had less proportion of oxidative PEC (< 10%), as compared to "benign" and "non-diabetes-prone" donors. These results suggest that a marked reduction of beta cell mass occurs at the very late prediabetic stage, and assessment of the proportion of oxidative PEC is useful to evaluate disease activity in type 1 diabetes.

T-cell function in anti-GAD65(+)diabetes with residual beta-cell function.

We have recently reported that in patients with anti-glutamic acid decarboxylase (GAD) 65(+)diabetes with residual beta-cell function, most with a 'high-titer' (>10U/ml) required insulin within 5 years, whereas most with a 'low-titer' (1.3-9.9U/ml) did not need insulin for over 15-20 years after the onset. We therefore examined T-cell function to evaluate the difference between the high-titer and low-titer groups. Interleukin (IL)-10 production upon polyclonal activation was significantly lower in the high-titer group than in the low-titer group. The serum level of interferon-inducible protein-10 (IP-10) was higher in the high-titer than the low-titer group. Although GAD65-reactive CD4(+)cells in the periphery were detected in both groups, a significant positive correlation between serum IP-10 level and the number of GAD65-reactive CD4(+)cells was observed only in the high-titer group. Therefore, it has been speculated that the co-existence of GAD65-reactive IFN-gamma-producing CD4(+)cells and a high serum IP-10 level may be important for rapid disease progression as seen in the high-titer group. Based upon these results, T-cell function is considered to be different between the high-titer and low-titer groups in anti-GAD65(+)diabetes with residual beta-cell function, supporting our previous findings regarding the clinical outcome of insulin-dependence in the two groups.