Search

OBJECTIVE: In type 2 diabetes, the significant pathological change in pancreatic islets is amyloid deposits. Its major component is islet amyloid polypeptide (IAPP). The objective of this study was to evaluate the possibility that the effect of the IAPP genotype on β-cell dysfunction in type 2 diabetes is modified by variations in plasma glucose levels. METHODS: Participants from the Toon Genome Study underwent a 75 g OGTT for the diagnosis of glucose tolerance and the evaluation of insulin secretion. We examined the effect of a SNP, rs77397980, on β-cell function by analyzing an interaction (statistics) between the IAPP genotype and AUC glucose. RESULTS: The ratio of the C-allele carriers was essentially the same among subjects with normal glucose tolerance, impaired glucose tolerance and diabetes. In subjects with diabetes, along with an increase in AUC glucose, fasting insulin remained constant in the T/T homozygotes and appeared to decrease in the C-allele carriers. A homeostasis model assessment (HOMA)-IR appeared to be increased in the former and decreased in the latter. In subjects with diabetes stratified into cases with higher AUC glucose than the median, fasting insulin and HOMA-IR were lower in the C-allele carriers than in the T/T homozygotes. An interaction between the IAPP genotype and AUC glucose was indicated in the effect on HOMA-IR. CONCLUSIONS: The possibility that the association between IAPP genotype and basal insulin level is modified by variation in plasma glucose, resulting in a decreased basal insulin in type 2 diabetes, cannot be excluded. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00523-4.

We herein report the clinical course of a 56-year-old Japanese patient with slowly progressive type 1 diabetes mellitus, metabolic syndrome, non-alcoholic fatty liver disease, and severe insulin resistance. The patient’s intravenous glucose tolerance test indicated marked reductions in insulin sensitivity and endogenous insulin secretion. Accordingly, administration of ipragliflozin l-proline, a sodium-glucose cotransporter 2 inhibitor, promoted improvements in insulin sensitivity and blood glucose levels, as well as a decrease in visceral fat, improvement in dyslipidemia, and decrease in hepatic lipid content, suggesting the potential efficacy of sodium-glucose cotransporter 2 inhibitors for obese patients with type 1 diabetes mellitus exhibiting insulin resistance.

IntroductionWe investigated trends in the proportion of diabetes treatment and glycemic control, which may be altered by recent advances in insulin and non-insulin drugs, in Japanese patients with type 2 diabetes.Research design and methodsA serial cross-sectional study was performed using a multicenter large-population database from the Japan Diabetes Clinical Data Management study group. Patients with type 2 diabetes who attended clinics belonging to the study group between 2002 and 2018 were included to examine trends in glycated hemoglobin A1c (HbA1c) by treatment group using multivariable non-linear regression model.ResultsThe proportion of patients with insulin only decreased from 15.0% to 3.6%, patients with insulin+non-insulin drugs increased from 8.1% to 15.1%, patients with non-insulin drugs increased from 50.8% to 67.0%, and those with no drugs decreased from 26.1% to 14.4% from 2002 to 2018, respectively. The HbA1c levels of each group, except for no drugs, continued to decrease until 2014 (unadjusted mean HbA1c (%) from 2002 to 2014: from 7.89 to 7.45 for insulin only, from 8.09 to 7.63 for insulin+non-insulin, and from 7.51 to 6.98 for non-insulin) and remained unchanged thereafter. Among insulin-treated patients, use of human insulin decreased, use of long-acting analog insulin increased, and concomitant use of non-insulin drugs increased (from 35.1% in 2002 to 80.9% in 2018), which included increased use of dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide 1 receptor agonists, and the persistently high use of metformin.ConclusionsDuring the past two decades, combined use of insulin and non-insulin drugs increased and glycemic control improved and leveled off after 2014 in Japanese patients with type 2 diabetes. Further studies of the trend in association with age and factors related to metabolic syndrome are necessary to investigate strategies aiming at personalized medicine in diabetes care.

AIMS: The current study evaluated patient demographics and clinical characteristics that associated with HbA1c reduction following addition of one oral antidiabetic drug (OAD) to DPP4i monotherapy. METHODS: A retrospective study was conducted using CoDiC database. Adult T2DM patients treated with sitagliptin monotherapy for ≥ 6 months and adding one OAD were extracted. Association between patient characteristics at the time of add-on OAD and following HbA1c reduction was assessed. RESULTS: Of 444 included patients, mean age was 62 years and 33% were female. All add-on OAD classes demonstrated further HbA1c reduction (p

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) in Japan. The clinical course and factors related to the progression of DKD to ESRD are important issues when treating patients with DKD.Ninety-one type 2 diabetic patients with DKD that had progressed from chronic kidney disease (CKD) stages G1-3 on their initial clinical visit to ESRD were enrolled. The decline in the estimated glomerular filtration rate (eGFR) was analyzed and the initial clinical factors that influenced the decline rate were explored.There was a linear decline in eGFR before progression to ESRD, with a median annual decline rate (∆eGFR) of 9.2 mL/min/1.73 mIn addition to the common risk factors, initial eGFR, HDL-C, and TBil were identified as novel risk factors for ESRD. These risk factors may differ between patients with early and advanced stages of CKD.

In type 2 diabetes (T2D), the most significant pathological change in pancreatic islets is amyloid deposits, of which a major component is islet amyloid polypeptide (IAPP), also called amylin. IAPP is expressed in β-cells and co-secreted with insulin. Together with the inhibitory effects of synthetic human IAPP (hIAPP) on insulin secretion, our studies, using hIAPP transgenic mice, in which glucose-stimulated insulin secretion was moderately reduced without amyloid deposit, and hIAPP gene-transfected β-cell lines, in which insulin secretion was markedly impaired without amyloid, predicted that soluble hIAPP-related molecules would exert cytotoxicity on β-cells. Human IAPP is one of the most aggregation-prone peptides that interact with cell membranes. While it is widely reported that soluble hIAPP oligomers promote cytotoxicity, this is still a hypothesis since the mechanisms are not yet fully defined. Several hIAPP transgenic mouse models did not develop diabetes; however, in models with backgrounds characterized for diabetic phenotypes, β-cell function and glucose tolerance did worsen, compared to those in non-transgenic models with similar backgrounds. Together with these findings, many studies on metabolic and molecular disorders induced by risk factors of T2D suggest that in T2D subjects, toxic IAPP oligomers accumulate in β-cells, impair their function, and reduce mass through disruption of cell membranes, resulting in β-cell failure. IAPP might be central to β-cell failure in T2D. Anti-amyloid aggregation therapeutics will be developed to create treatments with more durable and beneficial effects on β-cell function.

Aims/Introduction We carried out an observational cohort study to examine the relationship between the efficacy of oral antidiabetic drugs and clinical features in type 2 diabetics. Materials and Methods We analyzed the CoDiC® database of the Japan Diabetes Data Management Study Group across 67 institutions in Japan. In a total of 3,698 drug‐naïve patients who were initiated with metformin, dipeptidyl peptidase‐4 inhibitor (DPP‐4i) or sulfonylurea (SU) from 2007 to 2012, we evaluated body mass index (BMI) and hemoglobin A1c (HbA1c). The patients were stratified according to their clinical features, and matched using a propensity score to adjust for baseline factors. Results HbA1c was reduced with all drugs, with the largest effect elicited by DPP‐4i and the smallest by SU (P = 0.00). HbA1c increased with SU after 6 months in the patients stratified by an age‐of‐onset of 25 (P = 0.00). The reduction in HbA1c was larger in patients with HbA1c of ≥8%, compared with that in patients with HbA1c of

In type 2 diabetes (T2D), the most significant pathological change in pancreatic islets is amyloid deposits, of which a major component is islet amyloid polypeptide (IAPP), also called amylin. IAPP is expressed in β-cells and co-secreted with insulin. Together with the inhibitory effects of synthetic human IAPP (hIAPP) on insulin secretion, our studies, using hIAPP transgenic mice, in which glucose-stimulated insulin secretion was moderately reduced without amyloid deposit, and hIAPP gene-transfected β-cell lines, in which insulin secretion was markedly impaired without amyloid, predicted that soluble hIAPP-related molecules would exert cytotoxicity on β-cells. Human IAPP is one of the most aggregation-prone peptides that interact with cell membranes. While it is widely reported that soluble hIAPP oligomers promote cytotoxicity, this is still a hypothesis since the mechanisms are not yet fully defined. Several hIAPP transgenic mouse models did not develop diabetes; however, in models with backgrounds characterized for diabetic phenotypes, β-cell function and glucose tolerance did worsen, compared to those in non-transgenic models with similar backgrounds. Together with these findings, many studies on metabolic and molecular disorders induced by risk factors of T2D suggest that in T2D subjects, toxic IAPP oligomers accumulate in β-cells, impair their function, and reduce mass through disruption of cell membranes, resulting in β-cell failure. IAPP might be central to β-cell failure in T2D. Anti-amyloid aggregation therapeutics will be developed to create treatments with more durable and beneficial effects on β-cell function.

Aims/Introduction To assess the efficacy and safety of sitagliptin compared with α-glucosidase inhibitors in Japanese patients with type 2 diabetes inadequately controlled by metformin or pioglitazone alone. Materials and Methods In the present multicenter, randomized, open-label, parallel-group, active-controlled, non-inferiority trial, 119 patients aged 20–79 years with type 2 diabetes who had glycated hemoglobin 6.9–8.8% on stable metformin (500–1,500 mg/day) or pioglitazone (15–30 mg/day) alone were randomly assigned (1:1) to receive the addition of sitagliptin (50 mg/day) or an α-glucosidase inhibitor (0.6 mg/day voglibose or 150 mg/day miglitol) for 24 weeks. The primary end-point was change in glycated hemoglobin from baseline to week 12. All data were analyzed according to the intention-to-treat principle. Results After 12 weeks, reductions in adjusted mean glycated hemoglobin from baseline were −0.70% in sitagliptin and −0.21% in the α-glucosidase inhibitor groups respectively; between-group difference was −0.49% (95% confidence interval −0.66 to −0.32, P

The aim of the present study was to determine whether the dipeptidyl peptidase (DPP)-4 inhibitor could repair pancreatic β-cell dysfunction and insulin resistance. Ten subjects with type 2 diabetes who had never received DPP-4 inhibitor treatment were enrolled in the study. Just before and 3 months after twice-daily administration of vildagliptin (50 mg tablets), insulin secretion and insulin sensitivity were estimated using 2-compartment model analysis of C-peptide kinetics and insulin-modified minimal model parameters, respectively. The first-phase insulin secretion (CS1) was determined as the sum of the C-peptide secretion rate (CSR) from 0 to 5 min (normal range 6.8–18.5 ng/ml/min). The whole-body insulin sensitivity index (SI) was calculated using a minimal model software program (normal range 2.6–7.6×10 −4 /min/μU/ml). After vildagliptin treatment, reductions in mean (± SE) HbA1c were noted (43.28±1.53 vs. 40.98±1.77 mmol/mol; p=0.019). Vildagliptin treatment increased the area under the curve for the C peptide reactivity (CPR) (AUC CPR ; 26.66±5.15 vs. 33.02±6.12 ng/ml · 20 min; p=0.003) and CS1 (0.80±0.20 vs. 1.35±0.38 ng/ml/min; p=0.037) in response to an intravenous glucose load. ­Vildagliptin treatment significantly increased SI (0.46±0.27 vs. 1.21±0.48×10 −4 /min/μU/ml; p=0.037). The long-term administration of vildagliptin improved CS1 and Si suggesting that this drug has the capacity to repair impairments in pancreatic β-cell function and insulin resistance in type 2 diabetes.

Aims/Introduction We evaluated the long‐term efficacy of insulin regimens in patients with type 2 diabetes mellitus and poor glycemic control despite oral antidiabetic drugs (OAD). Materials and Methods We carried out a propensity score‐matched cohort study using the CoDiC® database of the Japan Diabetes Data Management Study Group across 54 institutions in Japan from 2005 to 2010. A total of 10,854 patients on OAD in 2005 were studied, and 1,253 patients (11.5%) were treated with insulin until 2010. The changes in insulin regimens and glycated hemoglobin (HbA1c) levels were analyzed over this study period. Results Propensity score matching showed no differences in the baseline patient characteristics. A total of 96 patients transferred to insulin, and HbA1c gradually and significantly decreased in the patients on a twice‐daily premixed preparation of rapid‐acting human‐insulin analogs (twice‐daily MIX) and basal–bolus therapy with rapid‐acting human‐insulin analogs (RA) plus long‐acting insulin analog (LA; P

We examined whether the rate of eating was associated with the body mass index and glycemic control status in Japanese patients with type 2 diabetes (50% women, mean±SD age 59.4±7.5 years). Rapid eating was significantly associated with body mass index (p=0.047). The body mass index of those who reported eating quickly was 0.8 kg/m² higher than in individuals who reported eating at medium speed even after adjustment for known confounders. No significant association was observed between the rate of eating and HbA(1c). Our findings suggest an association between self-reported rapid eating and an elevated body mass index in patients with type 2 diabetes.

To clarify the detailed clinical features and HLA subtype in the patients with fulminant type 1 diabetes, we investigated consecutive 250 case records registered to the committee of the Japan Diabetes Society between 2000/7/15 and 2006/6/30. After the classification with age at onset or gender, clinical data and HLA DR were evaluated. As a result, the prevalence of male patients, BMI, HbA 1c and ALT levels at the onset increased significantly according to the elder quartile, but no other data showed any significant difference. Only age at onset and blood glucose level were significantly higher in male patients than in female patients without pregnancy by multivariate analysis. The distribution of HLA DR was not different in any subtype by gender or age at onset. Our present study revealed common feature in clinical and HLA-DR status regardless of age and gender within fulminant type 1 diabetes except pregnant women.

Objective: We tested the hypothesis that insulin therapy rather than sulfonylurea (SU) treatment is preferable to reverse or preserve β-cell function among patients with slowly progressive insulin-dependent (type 1) diabetes (SPIDDM) or latent autoimmune diabetes in adults. Methods: This multicenter, randomized, nonblinded clinical study screened 4089 non-insulin-dependent diabetic patients for glutamic acid decarboxylase autoantibodies (GADAb). Sixty GADAb-positive non-insulin-requiring diabetic patients with a 5-yr duration or shorter of diabetes were assigned to either the SU group (n = 30) or the insulin group (n = 30). Serum C-peptide responses to annual oral glucose tolerance tests were followed up for a mean of 57 months. The primary endpoint was an insulin-dependent state defined by the sum of serum C-peptide values during the oral glucose tolerance test (ΣC-peptide) less than 4 ng/ml (1.32 nmol/liter). Results: The progression rate to an insulin-dependent state in the insulin group (three of 30, 10%) was lower than that in the SU group (13 of 30, 43%; P = 0.003, log-rank). Longitudinal analysis demonstrated that ΣC-peptide values were better preserved in the insulin group than in the SU group. Multiple regression analysis demonstrated that insulin treatment, a preserved C-peptide response, and a low GADAb titer at entry were independent factors in preventing progression to an insulin-dependent state. Subgroup analysis suggested that insulin intervention was highly effective for SPIDDM patients with high GADAb titers [≥10 U/ml (180 World Health Organization U/ml)] and preserved β-cell function [ΣC-peptide ≥ 10 ng/ml (3.31 nmol/liter)] at entry. No severe hypoglycemic episodes occurred during the study. Conclusions: Insulin intervention to preserve β-cell function is effective and safe for patients with SPIDDM or latent autoimmune diabetes in adults.

A mild increase in liver enzyme levels is sometimes observed in patients with diabetic ketosis or ketoacidosis. The aim of the present study was to assess the cause and prevalence of the elevation of liver transaminase levels in fulminant and acute-onset type 1 diabetic patients experiencing diabetic ketosis or ketoacidosis.We analyzed data on the liver transaminase levels of 108 patients over 18 years of age with newly diagnosed type 1 diabetes complicated by ketosis or ketoacidosis. The data were collated from a nationwide survey on fulminant type 1 diabetes and retrospective medical records.Thirty-two (60.4%) out of the 53 patients suffering from fulminant type 1 diabetes were detected with transient elevation of liver transaminase (TELT) levels during the first month after initiation of insulin therapy; in the case of acute-onset type 1 diabetes, such an observation was noted in 16 (29.1%) out of 55 patients. Fatty liver was diagnosed in 20% of the patients, and 65% of these patients exhibited TELT. The dosage of insulin injected in these patients was significantly high.High blood glucose and fatty liver may influence the elevation of liver transaminase levels during the treatment of new-onset type 1 diabetes.

Impaired insulin secretion and decreased insulin sensitivity are the main pathophysiologic features responsible for development of hyperglycemia in type 2 diabetes mellitus. Insulin resistance is often associated with increased adipose tissue mass. To examine which variables influence insulin sensitivity, we compared metabolic parameters, serum resistin, leptin, and adiponectin concentrations to the insulin sensitivity, obtained by frequently sampled intravenous glucose tolerance test using the minimal model analysis, in 113 Japanese patients with type 2 diabetes mellitus. Duration of diabetes, fasting plasma glucose, fasting insulin, homeostasis model assessment of insulin resistance index, and serum resistin concentration were significantly higher in the insulin-resistant subgroup compared with the insulin-sensitive subgroup and correlated with insulin sensitivity. Stepwise regression analysis also identified these parameters as independent regulators of insulin sensitivity. The present study reconfirmed that fasting insulin level or homeostasis model assessment of insulin resistance would be a surrogate measure of insulin resistance and demonstrated that insulin resistance increases progressively after the onset of overt diabetes and that the serum resistin level is associated with insulin sensitivity, suggesting that resistin plays an important role in the development of insulin resistance in Japanese patients with type 2 diabetes mellitus.

The number of diabetic patients has been increasing in Japan and consequently diabetic complications are the most important target to be prevented through improving glycemic control. In order to describe the glycemic control status and treatment of diabetic patients by specialists in Japan over three years, from 2000 to 2002, we examined HbA1c, other laboratory data and the modality of drug therapy in the study population, 8170 in 2000, 11,831 in 2001, and 16,934 in 2002. Patients were registered at clinics and hospitals that were members of the Japan Diabetes Clinical Data Management Study Group (JDDM). HbA1c levels, other laboratory data, and details of drug therapy were collected and analyzed using SPSS and MS Access. The mean HbA1c levels were essentially unchanged during the study periods, ranging from 7.9% to 7.8%, and from 7.1% to 7.0%, in type 1 and type 2 diabetic patients, respectively. In type 2 diabetes, the frequency of oral hypoglycemic agents (OHA) use increased from 44.9% to 51.4%, while the use of diet-only therapy decreased from 29.9% to 25.4% over the study period. Although the systolic blood pressure was slightly above target, the mean blood pressure and the mean lipid profile were mostly within the treatment goals set by the Japan Diabetes Society. This first report from a large scale study of the daily management of diabetes in Japan revealed that the average HbA1c level was superior to most of the results reported from other countries. Nonetheless, 66% of the patients still had HbA1c levels and half of the patients had other laboratory parameters including blood pressure and lipid profile that were greater than those recommended by the Japan Diabetes Society. The nature of diabetes drug therapy in Japan has gradually changed as new drugs have appeared in the market.

The objective of this study was to characterize the clinical and immunogenetic features of Japanese pregnancy-associated fulminant type 1 diabetes (PF). A group of patients with PF was compared with a group of patients of child-bearing age with fulminant type 1 diabetes that was not associated with pregnancy (NPF) in a nationwide survey conducted from 2000-2004.The clinical characteristics of the 22 patients in the PF group were compared with those of the 48 patients in the NPF group. Human leukocyte antigen (HLA) class II DR and DQ genotyping of 17 PF and 20 NPF patients was performed.Arterial pH was significantly lower (P = 0.0366), and amylase values tended to increase in PF patients compared with NPF patients (P = 0.0515). In 22 PF patients, 18 developed disease during pregnancy (26.3 wk; range, 7-38), whereas four cases occurred immediately after delivery (10.5 d; range, 7-14 d). Twelve cases that developed during pregnancy resulted in stillbirth (67%), and five of the six fetal cases that survived were delivered by cesarean section. The haplotype frequency of HLA DRB1*0901-DQB1*0303 in PF was significantly higher than those in NPF (P = 0.0244) and controls (P = 0.0001), whereas that of DRB1*0405-DQB1*0401 in NPF was significantly higher than those in PF (P = 0.0162) and controls (P0.0001).The clinical symptoms of PF patients were more severe than those of NPF patients, and the prognosis of their fetuses was extremely poor. The type 1 diabetes-susceptible HLA class II haplotype is distinct in PF and NPF patients, suggesting that different HLA haplotypes underlie the presentation of PF or NPF.

To address the possibility that the partial disruption of Glucagon-like peptide-1 (GLP-1) signaling could cause diabetes, we tried to detect the mutation in GLP-1 receptor (GLP-1R) gene in the population with type 2 diabetes. Genomic DNA was extracted from 36 unrelated Japanese type 2 diabetic subjects and directly sequenced for the GLP-1R gene. For the detected polymorphisms, 791 patients with type 2 diabetes and 318 controls were screened by polymerase chain reaction-restricted fragment length polymorphism and association study was carried out. Five missense and four silent variants were detected in the GLP-1R gene. There were no significant differences in the frequencies of Pro7Leu, Arg44His and Leu260Pro polymorphism between the diabetic and control groups. And also there were no significant differences in body mass index (BMI), onset age and fasting IRI among the wild type, heterozygote and homozygote of these variants in diabetic patients. Thr149Met mutation was detected in one case among 791 type 2 diabetes patients, but not in control subjects. The patient with this mutation exhibited impairment of both insulin secretion, insulin sensitivity and glucose effectiveness, which may be partially explained by Thr149Met mutation in GLP-1R, though family linkage analysis and function analysis remain to be examined.

In 1996, we designed a randomized multicenter study to assess the effects of small doses of insulin on beta cell failure in slowly progressive type 1 diabetes (the Tokyo Study). We report here the preliminary results of this study. Glutamic acid decarboxylase 65 antibody (GADA)-positive patients were randomly divided into 2 groups: one group received insulin (Ins group), the other a sulfonylurea (SU group). Fifty-four patients (24 Ins group, 30 SU group) were analyzed at the end of a 4-year period. All patients underwent a 75 g oral-glucose test (O-GTT) every 6-12 months. The insulin-dependent stage was defined based on an integrated value of serum C-peptide levels on O-GTT ( summation operator CPR; sum of CPR at 0, 30, 60, 90, and 120 min) below 4.0 ng/mL. The summation operator CPR in the SU group decreased progressively from 22.0 +/- 10.6 to 11.3 +/- 7.5 ng/mL over the 48-month period (p /= 10 ng/mL), the proportion of SU group subjects who progressed to IDDM was significantly higher than that of the Ins group (7/28, 25% vs. 0/21, 0%, p = 0.015). Among subjects with a high GADA titer (>/=0 U/mL), 9/14 (64.3%) of the SU group, but only 2/16 (12.5%) of the Ins group, developed IDDM (p = 0.0068). As to those with a high GADA titer and a preserved C-peptide response, SU group subjects progressed to IDDM (7/12, 58.3%) more frequently than Ins group subjects (0/14, 0%) (p = 0.0012). In summary, our results suggest that small doses of insulin effectively prevent beta cell failure in slowly progressive type 1 diabetes. We recommend avoiding SU treatment and instead administering insulin to NIDDM patients with high GADA titer.

OBJECTIVE— To describe the clinical and immunologic characteristics of fulminant type 1 diabetes, a novel subtype of type 1 diabetes, we conducted a nationwide survey. RESEARCH DESIGN AND METHODS—History and laboratory data, including islet-related autoantibodies, were examined in 222 patients with fulminant and nonfulminant type 1 diabetes in our hospitals in addition to another 118 patients with fulminant type 1 diabetes located outside our hospitals in Japan. RESULTS—In our hospitals, of the 222 patients studied, 43 (19.4%) were diagnosed with fulminant type 1 diabetes, 137 (61.7%) were classified as having autoimmune type 1 diabetes, and 42 were type 1 diabetic subjects who were not fulminant and did not have anti-islet antibodies. An additional 118 fulminant patients outside our hospitals were enrolled, making a total of 161 fulminant type 1 diabetic subjects (83 male and 78 female subjects; 14 children/adolescents and 147 adults) identified from all over Japan. (In 2000, the average incidence was three cases per month.) Flu-like symptoms and pregnancy were more frequently observed in the fulminant than in the autoimmune group (P < 0.001). In the fulminant patients, 4.8% were positive for anti-GAD antibodies and none were positive for anti–islet antigen 2 antibodies. CONCLUSIONS—Fulminant type 1 diabetes is a distinct subtype and accounts for ∼20% of the ketosis-onset type 1 diabetes cases in Japan. Flu-like symptoms are characteristic of disease onset. Metabolic derangement is more severe in this subtype than in autoimmune type 1 diabetes.

Diabetes mellitus with the mitochondrial DNA 3243(A-G) mutation is reported to represent 0.5-2.8% of the general diabetic population. Since the characterization of diabetes with the mutation is still incomplete, we undertook a nation-wide case-finding study of genetically defined patients using questionnaires in Japan. One hundred and thirteen Japanese diabetic patients with the mutation were registered and analyzed. The patients had a high prevalence of maternal inheritance of diabetes and deafness, short and thin stature, and showed an early middle-aged onset of diabetes and deafness. Eighty-six percent of the patients required insulin therapy due to the progressive insulin secretory defect. Glucose intolerance of the mothers was associated with an early middle-aged onset of diabetes, reduction in the insulin secretory capacity, early requirement of insulin therapy, and increases in the daily insulin dose. The heteroplasmic concentrations of the 3243 mutation in leukocytes were low and declined with aging. The patients had advanced microvascular complications, and mitochondria-related complications such as cardiomyopathy, cardiac conductance disorders, neuromuscular symptoms, neuropsychiatric disturbance, and macular pattern dystrophy. Thus, this study has revealed that: (1) diabetes mellitus with the 3243 mutation is a subtype of diabetes mellitus with mitochondria-related complications; and (2) insulin secretory ability is more severely impaired in the patients whose mothers were glucose intolerance.

Polymorphisms in beta-cell transcription factor genes, Ala45Thr in the NeuroD1 gene and Arg121Trp in the Pax4 gene, have been reported. To clarify the role of these mutations in the pathogenesis of late-onset diabetes, we examined the insulin secretion and sensitivity in diabetic patients carrying the homozygous mutation in the NeuroD1 gene or Pax4 gene. We screened for the polymorphisms in NeuroD1 and Pax4 genes in 296 late-onset diabetic patients and 177 unrelated control subjects over 60 years of age. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) followed by direct sequencing. Acute insulin secretion was evaluated using a 2-compartment model analysis of C-peptide kinetics after intravenous glucose load (CS1). Insulin sensitivity was estimated by the insulin-modified minimal model analysis (Si). Four diabetic patients carried the homozygous mutation (Thr/Thr) in the NeuroD1 gene and 3 patients carried the homozygous mutation (Trp/Trp) in the Pax4 gene, while both homozygous mutations were not detected in the control subjects. In patients A, B, C, and D with homozygous mutations in NeuroD1, CS1 (normal range, 6.8 to 18.5 ng/mL/min) was 0.508, 1.481, 1.223, and 1.584 ng/mL/min, respectively, and Si (normal range, 2.6 to 7.6 x 10(-4)/min/[microU/mL]) was 0.727, 3.31, 3.79, and 0.00 x 10(-4)/min/(microU/mL), respectively. In patients X, Y, and Z with homozygous mutation in Pax4, CS was 0.418, 0.208, and 1.279 ng/mL/min, respectively, and Si was 1.11, 2.88, and 0.00 x 10(-4)/min/(microU/mL), respectively. Since acute insulin secretion in response to glucose was markedly impaired and insulin resistance was varied in the patients carrying the homozygous mutations in the NeuroD1 and Pax4 genes, the mutations are ones of the factors involved in the beta-cell dysfunction and do not relate to the insulin resistance. These homozygous mutations appear to play a part in the pathogenesis of beta-cell defect in about 2.5% of Japanese patients with late-onset diabetes.

Severe resistance to subcutaneous insulin but sensitivity to intravenous insulin persisted for 11 years in a 23-year-old diabetic woman. Several therapeutic trials revealed that (1) intravenous regular insulin improved her metabolic control; (2) continuous subcutaneous infusion (CSII) treatment with regular insulin or insulin lispro caused hyperglycemic period with hypoinsulinemia and hypoglycemic period with hyperinsulinemia alternately; (3) adding heparin to insulin lispro in CSII resulted in dramatic increase of serum insulin level and improvement of glycemic control; and (4) regular insulin plus heparin in CSII could not increase serum insulin level and thus the glycemic values was not improved. From these results, the patient followed the insulin lispro plus heparin protocol and obtained a better glycemic control without any adverse events. Effectiveness of this therapy may lead us to further understanding of pathophysiology of this syndrome.

We tried to characterize the clinical features associated with glucose metabolism in the development of diabetes. Study subjects were glucose-tolerant subjects without a family history of diabetes (normal glucose tolerance [NGT]1 group, n = 15) and with a first-degree diabetes relative (NGT2, n = 9), 12 subjects with impaired glucose tolerance (IGT), and 13 subjects with type 2 diabetes mellitus (DM). The first phase C-peptide secretion (CS1), insulin sensitivity (Si), and glucose effectiveness (Sg) were assessed by the combination of C-peptide 2-compartment model and minimal model analyses. Using these parameters, each group was characterized: CS1 was decreased in NGT2 and IGT compared with NGT1 and further decreased in DM; Si was not different among NGT1, NGT2, and IGT, whereas Si was decreased in DM; CS1 x Si value was decreased in NGT2 compared with NGT1 and decreased in IGT, DM, progressively; Sg was decreased in IGT and DM compared with NGT1 and NGT2. CS1 x Si and Sg values could segregate each group distinctively, although it had a large variety of phenotypes. CS1 x Si value and Sg are assumed to represent the contributions of insulin-dependent and independent mechanisms to glucose tolerance, respectively, and thus, both mechanisms should play an important role in the characterization of pathophysiologic phenotypes of the subjects with various degrees of glucose tolerance.

Mutations of the hepatocyte nuclear factor 4 alpha (HNF-4alpha) gene have been demonstrated in maturity-onset diabetes of the young (MODY) 1 families. To investigate the possibility that the HNF-4alpha gene contributes to the onset of non-insulin-dependent diabetes mellitus (NIDDM) in Japanese patients, we screened all exons and flanking introns of this gene for mutations in 100 patients with NIDDM diagnosed after 25 years of age. We identified two missense mutations: M49V in exon 1c and T1301 in exon 4; and two nucleotide substitutions in introns: cytosine to thymidine at -5 nt in intron 1b and adenine to thymidine at -21 nt in intron 5. We screened an additional 220 diabetic subjects for the polymorphism in intron 1b. The c/t substitution in intron 1b was associated with NIDDM. This substitution in the polypyrimidine tract, an important cis-acting element directing intron removal, is likely to influence pre-mRNA splicing of this gene. T1301 in exon 4 was observed in only two diabetic subjects. This mutation could influence the conformation of this peptide, resulting in changes in ligand binding domain function. M49V in exon 1c was found in both diabetic and non-diabetic subjects; isoforms HNF-4alpha 4, 5, and 6 with this mutation may impair glucose metabolism in tissue. In contrast to the primary cause of nonsense and missense mutations of the HNF-4alpha gene in MODY1, the nucleotide substitution in intron 1b may partially contribute to development of NIDDM in combination with other genetic and environmental factors.

Cytokines induce apoptosis in pancreatic beta cells, but the exact mechanisms and sequence of events are not clear. Here, we investigate a role for tumor necrosis factor alpha (TNF-alpha) in the apoptosis of beta cells. Using the ribonuclease (RNase) protection assay and the reverse transcriptase-polymerase chain reaction (RT-PCR) method, we confirmed that TNF receptor 1 (TNFR1), TNFR1-associated death domain protein (TRADD), Fas receptor-associated intracellular protein with death domain (FADD), and FADD-like interleukin-1beta-converting enzyme (FLICE) were expressed in the pancreatic beta cell line, MIN6 cells. Fluorescent microscopic examination using Hoechst 33342 dye (Sigma, St Louis, MO) demonstrated that TNF-alpha induced time- and dose-dependent apoptotic nuclear changes in these beta cells. In situ end-labeling (ISEL) DNA analysis revealed that 10 nmol/L TNF-alpha generated new 3'-OH DNA strand breaks. Moreover, qualitative assessment of the induced DNA damage on agarose gels showed that 10 nmol/L TNF-alpha produced characteristic apoptotic patterns of DNA fragments formed by internucleosomal hydrolysis of static chromatin. In addition, C2-ceramides and natural ceramides dispersed in a solvent mixture of ethanol and dodecane induced characteristic features of apoptosis in MIN6 cells, mimicking TNF-induced DNA damage. We also determined endosomal ceramide production after TNF-alpha (10 nmol/L) treatment in MIN6 cells using the diacylglycerol kinase assay. These results suggest that TNF-alpha can cause apoptosis in pancreatic beta cells through TNFR1-linked apoptotic factors, TRADD, FADD, and FLICE, and TNF-induced ceramide production may be involved in the pathways.

The ras-mitogen-activated protein kinase (MAPK) cascade plays an important role not only in the mitogenic signal transduction pathway but also in the development of cancer, and it is believed to be one of the important regulators in normal hepatocytes and hepatocellular carcinoma. The aim of this study was to determine the role of insulin receptor substrate-1 and the MAPK cascade in rats with hepatocellular carcinoma induced by 3'-methyl-4-dimethylamino-azobenzene (3'-MeDAB).Liver cancer was induced in rats by feeding 3'-MeDAB, and the changes in expression of IRS-1 and MAPK were analyzed in tumorous, non-tumorous and control liver.Expression of insulin receptor substrate-1 (IRS-1) showed a 1.4-fold increase at protein level in the tumors (p0.01), but the tyrosine phosphorylation of IRS-1 did not differ between the tumor and control liver. Expression of MAPK and its activity were elevated 4.5-7.5-fold (p0.01) and 4.6-fold (p0.01) in the tumor compared with control liver. In non-tumorous lesions from rats fed with 3'-MeDAB, expression of MAPK, but not IRS-1, increased significantly (p0.01). Between tumorous and adjacent non-tumorous lesions, there was a significant difference in MAPK expression (p0.05) and activities (p0.05).The increased expression of MAPK may play an important role in the progression or initiation of HCC in this rat model.

We investigated the influence of the angiotensin-converting enzyme (ACE) gene on the onset and/or progression of diabetic nephropathy in 62 Japanese patients with non-insulin-dependent diabetes mellitus (NIDDM; type II diabetes). Because a number of factors are believed to be involved in the onset and/or progression of diabetic nephropathy, especially in patients with NIDDM, we selected the patients with well-matched risk factors, duration of disease, glycemic control, blood pressure, and others. All patients had normal renal function and none were receiving ACE inhibitors. Patients were divided into three groups according to albumin excretion rate (AER): group A, patients with an AER less than 15 microg/min (n = 29); group B, patients with an AER between 15 and 70 microg/min (n = 19); and group C, patients with an AER greater than 70 microg/min (n = 14). The glucose disposal rate was estimated using a euglycemic hyperinsulinemic clamp. We determined the mean glucose disposal rate in 132 patients with NIDDM (6.49 mg/kg/min). Patients with a glucose disposal rate less than the mean rate were considered to have a high degree of insulin resistance (n = 36). The presence of an insertion/deletion (I/D) polymorphism of the ACE gene was determined by the polymerase chain reaction method. Among patients with a high degree of insulin resistance, diabetic nephropathy was present in 2 of 11 patients with the II genotype of the ACE gene compared with 19 of 25 patients with the ID or DD genotype (P = 0.0024). The prevalence of diabetic nephropathy was greater in patients with both significant insulin resistance and the D allele (19 of 25) than in the remaining patients (14 of 37; odds ratio, 5.20). These results suggest that the ACE gene influences the onset and/or progression of diabetic nephropathy in patients with NIDDM with significant insulin resistance.

Cyclic adenosine 5′diphosphate-ribose (cADPR) is thought to have a second messenger role in insulin secretion through mobilisation of Ca2 +. As human lymphocyte antigen CD38 has both ADP-ribosyl cyclase and cADPR hydrolase activity, it may be important in glucose-induced insulin secretion in islets. Thirty one randomly selected Japanese patients with Type II diabetes mellitus who had first-degree and/or second-degree relative(s) with Type II diabetes mellitus were screened for mutations of this gene using single-stranded conformation polymorphism. Two variant patterns in exon 3 and exon 4 of the CD38 gene were identified. The variant in exon 3 resulted in an amino acid substitution from Arg140 (CGG) to Trp (TGG). The Arg140Trp mutation was observed in 4 of 31 patients, and allele frequencies were significantly different in patients and the control subjects (p = 0.004). One patient with this mutation has two missense mutations on beta cell/liver glucose transporter (GLUT2) gene; her mother, who has impaired glucose tolerance, also has this mutation on the CD38 gene and one missense mutation on the GLUT2 gene. Enzyme activity studies using COS-7 cells expressing the Arg140Trp mutation showed a reduction in ADP-ribosyl cyclase and cADPR hydrolase activity of around 50 %. The Arg140Trp mutation on CD38 thus appears to contribute to the development of Type II diabetes mellitus via the impairment of glucose-induced insulin secretion in the presence of other genetic defects. [Diabetologia (1998) 41: 1024–1028]

We herein report the case of a patient with slowly progressive type 1 diabetes and insulin independence lasting for >10 years despite the detection of continuously elevated glutamic acid decarboxylase autoantibody titers. We monitored the patient's clinical course and analyzed his endogenous insulin secretion and sensitivity using an intravenous glucose tolerance test (IVGTT) and oral glucose tolerance test (OGTT). His body mass index remained at approximately 22, while his serum C-peptide immunoreactivity level gradually decreased. The level of insulin secretion was significantly higher on the OGTT than the IVGTT. The patient's insulin sensitivity was within the normal limits. These results suggest that maintaining a lifestyle sufficient to preserve insulin secretion and/or normal insulin sensitivity is important and that β-cell responsiveness to incretins may, in part, contribute to insulin independence.

To search for a possible relationship between islet amyloid polypeptide (IAPP)/amylin and the pathophysiology of non-insulin-dependent (type 2) diabetes mellitus (NIDDM), we examined the changes in IAPP contents in the pancreata of genetically obese and diabetic mice (C57BL/6J ob/ob and C57BL/KsJ db/db mice). In the male ob/ob mice, IAPP and insulin contents began to increase at 16 weeks and continued to increase. In the male db/db mice, IAPP content began to increase at 8 weeks of age and insulin content at 4 weeks. Both contents continued to increase until 16 weeks, but drastically decreased at 24 weeks. Immunohistochemical studies using anti-IAPP8–17 antibody showed the increase of islet cell mass and the heterogeneous immunoreactivity for IAPP in islet cells in the ob/ob mice at 24 weeks of age. In the db/db mice at the same age, the immunoreactivity was heterogeneous and weak in many islet cells. These results suggest that genetic factors that are important in the manifestation of NIDDM influence the capacity of β-cells to synthesize and secrete IAPP, and that IAPP synthesis and secretion change in the course of the disease.

Yagui K, Yamaguchi T, Kanatsuka A, Shimada F, Huang CI, Tokuyama Y, Ohsawa H, Yamamura K, Miyazaki J. Mikata A, Yoshida S, Makino H. Formation of islet amyloid fibrils in beta-secretory granules of transgenic mice expressing human islet amyloid polypeptide/amylin. Eur J Endocrinol 1995:132:487–96. ISSN 0804–4643 To investigate the relationship between human islet amyloid polypeptide (IAPP)/amylin expression and islet amyloid deposits in the pathogenesis of human non-insulin-dependent diabetes mellitus (NIDDM), we developed transgenic mice using a human IAPP cDNA connected to an insulin promoter. Ribonucleic acid blotting and immunohistochemistry revealed the expression of the transgene in the pancreatic beta cells. Immunogold electron microscopy showed that beta-secretory granules contained the human C-terminal flanking peptide of the IAPP precursor. Reverse-phase HPLC demonstrated human and mouse IAPP amide in the pancreas. Electron microscopy showed the accumulation of fibril-like material in a considerable number of beta-secretory granules. These results suggest that in transgenic mice, the human IAPP precursor is expressed in beta cells and becomes normally sorted into beta-secretory granules in which normal conversion to mature human IAPP takes place. The human IAPP molecules, because of their amyloidogenesis, aggregate into amyloid fibrils in secretory granules. Glucose tolerance was normal at 7 months old and islet amyloid was not observed. A longer time may be required for islet amyloid deposits and hyperglycemia to develop in mice. Our working hypothesis is that in human NIDDM, IAPP aggregates into amyloid fibrils in beta-secretory granules, and that the fibrils are released into the extracellular space and islet amyloid deposits become substantial with time. Azuma Kanatsuka, Second Department of Internal Medicine, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260, Japan

The beta-cell/liver glucose transporter (GLUT2) gene was screened for mutations using single-strand conformation polymorphism analysis (SSCP) in 30 Japanese subjects with non-insulin dependent diabetes mellitus (NIDDM). Analysis of all exons and adjacent intron regions identified six SSCP polymorphisms, three of which resulted in amino acid substitutions: V101I, T110I and G519E. The V101I and G519E, substitutions represent new polymorphisms in this gene. The six polymorphisms were observed in both NIDDM and control groups and there were no significant differences in allele frequencies between groups. A portion of the insulin receptor substrate 1 gene in 30 NIDDM subjects and in normal control subjects was also screened for mutations. Two SSCP variants that change the sequence of the protein, delta S686/687 (deletion of the codons for serine-686 and 687) and G972R, were identified in two different NIDDM subjects, both whom were also heterozygous for the V101I polymorphisms in GLUT2. The GLUT2 and IRS1 amino acid polymorphisms did not show a simple pattern of co-inheritance with NIDDM in the families of these subjects suggesting that neither polymorphism is sufficient to cause NIDDM but may increase diabetes-susceptibility through their interaction with other loci and environmental factors.

In order to elucidate the causal relationship between (Na(+)-K+)ATPase and diabetic nephropathy, we studied the erythrocyte (Na(+)-K+)ATPase activity in Type 2 diabetic patients, 20 with microalbuminuria and 27 without microalbuminuria and in 16 control subjects. (Na(+)-K+)ATPase activities in microalbuminuric patients (0.273 +/- 0.012 mumol Pi/mg protein/h, mean +/- SE) were significantly reduced compared with those without microalbuminuric patients (0.308 +/- 0.011 mumol Pi/mg protein/h, p < 0.05) and control subjects (0.330 +/- 0.011 mumol Pi/mg protein/h, p < 0.01). Microalbuminuric patients had higher systolic blood pressure (133 +/- 3 vs 124 +/- 3 mmHg, p < 0.05) and greater frequency of parental hypertension (50% vs 19%, p < 0.05) than those without microalbuminuria. (Na(+)-K+)ATPase activities in diabetic patients with hypertension were significantly reduced compared with those in diabetic patients without hypertension. Moreover, (Na(+)-K+)ATPase activities in diabetic patients with parental hypertension were significantly reduced compared with those in patients without parental hypertension. There was no difference in erythrocyte Na+ content between with and without microalbuminuria or hypertension or parental hypertension in diabetic patients. Erythrocyte Na+ content was significantly negatively correlated with (Na(+)-K+)ATPase activity in control subjects (r = -0.619, p < 0.05), but not in diabetic patients (r = -0.194). Plasma digitalis-like substances showed no correlation with (Na(+)-K+)ATPase activities in diabetic patients with microalbuminuria or hypertension or parental hypertension. We concluded that the reduction of erythrocyte (Na(+)-K+)ATPase activity may be related to a familial predisposition to arterial hypertension and may partly be responsible for the development of diabetic nephropathy in Type 2 diabetic patients.

Aberrant expression of the IAPP gene may be involved in the pathogenesis and islet amyloid formation of type 2 (non-insulin dependent) diabetes mellitus. We sequenced 536 basepairs in the 5′-upstream sequence of the gene of 35 Japanese with this disease and 3 patients with maturity-onset diabetes in the young. The sequences corresponding to both alleles of the gene were identical to one another and to the sequence of subjects without diabetes mellitus except for one allelic variation of ‘A’ and ‘C’ at the position −230. Analysis by allele specific polymerase chain reaction revealed no significant difference in frequency of the variation at this position between normal and type 2 diabetic subjects. We conclude that the 5′ region of the IAPP gene is highly conserved and only 1 DNA polymorphism is detected and that this polymorphism does not associate with type 2 diabetes mellitus.

Mutations were screened for in the glucokinase gene of 25 Japanese patients with Type 2 (non-insulin-dependent) diabetes mellitus. Each exon was scanned by electrophoresis of enzymatically amplified DNA segments under non-denaturing conditions and variants were sequenced. A variant pattern was detected in exon 5 of one patient. Direct sequencing of this exon revealed a single nucleotide substitution in codon 188 (GCT-->ACT) of one of two alleles resulting in the mutation of Ala188-->Thr, an invariant residue in the sequence of all mammalian glucokinases and hexokinases. This mutation was not found in 40 normal control subjects. The proband had been diagnosed with Type 2 diabetes at the age of 62 years. Four other members of her family have the same mutation and all have Type 2 diabetes or impaired glucose tolerance. The youngest age at diagnosis of Type 2 diabetes in these other members was 13 years, suggesting that her pedigree was maturity-onset diabetes of the young (MODY). All subjects with the Thr188 mutation show a decreased insulin secretory response during oral glucose tolerance testing. Mutations in the glucokinase gene associated with Type 2 diabetes have been previously identified in Caucasian (French and British) subjects. This study indicates that mutations in this gene are also implicated in the development of Type 2 diabetes in Asians. Further studies are required to determine the frequency of mutations in glucokinase among Japanese patients with Type 2 diabetes.

OBJECTIVE—Resistin is an adipocyte-secreted cytokine associated with insulin resistance in mice. We previously reported that the G/G genotype of a resistin single nucleotide polymorphism (SNP) at −420 increases type 2 diabetes susceptibility by enhancing its promoter activity. The aim of the present study was to determine the relevance of SNP −120 in a large number of subjects. RESEARCH DESIGN AND METHODS— We examined 2,610 type 2 diabetic case and 2,502 control subjects. The relation between SNP −420 and the age of type 2 diabetes onset was further analyzed by adding 237 type 2 diabetic subjects with age of onset ≤40 years. RESULTS—When analyzed without considering subject age, the SNP −420 genotype was not associated with type 2 diabetes. Since we reported that the onset of type 2 diabetes was earlier in G/G genotype, we analyzed the data using a trend test for age intervals of 10 years. The frequency of G/G genotype differed among age grades in type 2 diabetes (P = 0.037) and appeared to be higher in younger grades. In type 2 diabetes, G/G genotype was more frequent in subjects aged CONCLUSIONS—The G/G genotype frequency of resistin SNP −420 appears to be increased in younger-onset type 2 diabetic subjects.

The purpose of this study was to investigate which pathophysiological and demographic characteristics of Japanese subjects with type 2 diabetes mellitus were associated with poor glycemic control and to propose a statistical model for predicting their glycemic control. A total of 220 subjects with type 2 diabetes mellitus were enrolled in this study. Frequently sampled intravenous glucose tolerance test was performed to determine the first-phase C-peptide secretion rate (CS1) and insulin sensitivity index. Multiple regression analysis in a stepwise manner was carried out to identify independent regulators of glycemic control. Upon stepwise linear regression analysis with hemoglobin A1c as a dependent parameter, fasting plasma glucose concentration (FPG), CS1, and onset age remained as predictors, explaining 41.0% of glycemic control. The young-onset group (onset ageor =48 years) had significantly higher hemoglobin A1c than the old-onset group (onset age48 years) (P = .0148), although the present age was significantly older in the old-onset group; and there were no significant differences in duration of diabetes, treatment, body mass index, FPG, fasting insulin level, homeostasis model assessment of insulin resistance, CS1, and log(insulin sensitivity index) between them. Worsening factors of glycemic control in Japanese subjects with type 2 diabetes mellitus were elevated FPG, impaired first-phase insulin secretion, and young age of onset of the disease. Because glycemic control in the subjects with young-onset diabetes tends to be worse, early and aggressive intervention should be required for those with young-onset diabetes to prevent long-term complications.

The aim of the present study was to assess the development of microangiopathy in patients with fulminant type 1 diabetes, a novel subtype of type 1B diabetes.In a nationwide survey, we followed 41 patients with fulminant type 1 diabetes and 76 age- and sex-matched patients with type 1A diabetes for 5 years. The following data were recorded every 12 months after the onset of diabetes: seven-point blood glucose concentrations, HbA1c level, urinary albumin excretion, serum C-peptide level, blood pressure, daily dosages of insulin, frequency of severe hypoglycaemic episodes, and neurological and fundoscopic examination.The 5-year cumulative incidence of microangiopathy was 24.4% in fulminant type 1 diabetes and 2.6% in type 1A diabetes. In longitudinal studies using the Kaplan-Meier method, the cumulative incidence of each form of microangiopathy was significantly higher in fulminant type 1 diabetes than in type 1A diabetes; retinopathy was 9.8% vs 0% (p=0.014), nephropathy 12.2% vs 2.6% (p=0.015) and neuropathy 12.2% vs 1.3% (p=0.010), respectively. Mean HbA1c levels were similar in the fulminant and type 1A diabetes groups during the follow-up periods. However, the mean M-value, mean insulin dosages and the frequency of severe hypoglycaemic episodes were significantly higher, and the mean postprandial C-peptide level was significantly lower in the fulminant type 1 diabetes group.These data suggest that patients with fulminant type 1 diabetes are a high-risk subgroup for diabetic microangiopathy associated with the lack of endogenous insulin secretion from the onset of diabetes.

Mutations in PAX4, a transcription factor involved in the beta-cell differentiation, could predispose to the development of type 2 diabetes mellitus. To clarify the role of PAX4 Arg121Trp mutation on the development of type 2 diabetes mellitus, we try to determine the clinical phenotype in diabetic subjects with this mutation. Study subjects consisted of 793 type 2 diabetic patients and 318 control subjects. Genotyping for Arg121Trp polymorphism was performed by Invader assay. Clinical phenotype was determined in diabetic subjects including 20 Trp121 carriers and 142 wild-type subjects using a combination of 2-compartment model of C-peptide kinetics and minimal model analysis during intravenous glucose tolerance test. We detected 3 Trp/Trp, 51 Arg/Trp, and 739 Arg/Arg in diabetic subjects, and 16 Arg/Trp and 302 Arg/Arg in control subjects. The frequency of Trp121 allele was 3.59% and 2.51% in diabetic and control groups, respectively (P = .19). Rate of insulin users was higher in Trp121 carriers compared with the wild-type group (42.5% vs 25.0%, P = .0046). First-phase C-peptide secretion was significantly decreased in the diabetic subjects with Trp121 allele compared with the patients with wild type (P = .0048), whereas there were no significant differences in insulin sensitivity and glucose effectiveness between the groups. Arg121Trp mutation in PAX4 gene could be associated with beta-cell dysfunction in Japanese subjects with type 2 diabetes mellitus.

To clarify the actual usage of insulin preparations and their effectiveness on glycaemic control in patients with Type 1 diabetes mellitus in Japan, we analyzed clinical data collected via CoDiC, an electronic system for diabetes data collection and management, at 28 institutes. Of 18,470 diabetic patients registered with CoDiC in June, 2003, 12,279 patients were being treated with insulin preparations and/or oral hypoglycemic agents, with 861 of these patients having Type 1 diabetes mellitus and 11,418 patients having Type 2 diabetes. Three analytical surveys were carried out with the Type 1 diabetes patients. Study I: Cross-sectional survey on the treatment in 2002. Six hundred and thirteen patients received intensive conventional insulin treatment (ICT). The number of patients receiving rapid-acting insulin analogue (RA) was greater than that of patients receiving regular insulin (R). Serum CPR was lower in the patients with ICT than in the patients with conventional insulin treatment (CT). Study II: Survey on the changes in the actual usage and clinical effectiveness of insulin preparations, based on the data input in 2001 and 2002. The number of patients with ICT using RA insulin markedly increased. Study III: Analysis of the participants' clinical course over the 18-month period of the study from the time of first consultation. The dose of insulin increased during the term. The average HbA1c level fell drastically and reached to 7.5% over the first 9 months of the study and then remained between a range of 7.5% and 8% for the rest of the study period. In conclusion, ICT is actively performed and the RA insulin analogues are widely used in Type 1 diabetic patients in Japan. Basal-bolus therapy should be used to treat Type 1 diabetic patients with postprandial serum CPR of less than 0.5 ng/ml. It is difficult to obtain the ideal glycaemic control in Type 1 diabetic patients with the currently available insulin preparations.

We investigated effects of weight loss from diet and exercise regimen in obese subjects with normal fasting plasma glucose or impaired glucose tolerance (IGT) on insulin release capacity and insulin sensitivity. Eight subjects were recruited among visceral obesity patients (4 men, 4 women; age range, 24 to 57 years; body mass index [BMI], 32.8 to 60.3 kg/m(2)). All were admitted to Chiba University Hospital for 2 weeks, were treated with a tapering 5,023 to 2,930 kJ diet, and were given exercise equivalent to 628 kJ/d. For assessments, we used a combination of C-peptide secretion rate determination and minimal model analysis as previously reported. BMI and visceral fat area (V) significantly decreased (BMI on initiation v after intervention, 43.0 +/- 3.2 v 40.3 +/- 3.1 kg/m(2), P.05; V, 224 +/- 22 v 188 +/- 22 cm(2); P.05). Fasting immunoreactive insulin (F-IRI) and leptin concentrations decreased significantly. Capacity for insulin release in response to glucose increased in all subjects (first-phase insulin secretion [CS1], 4.66 +/- 4.05 v 6.81 +/- 4.57 ng/mL/5 min, P.05), but the insulin sensitivity index (S(i)) did not change significantly. These data suggest that weight reduction early in development of type 2 diabetes can oppose progression of diabetes by improving capacity for insulin release.

Insulin resistance is a major cause of type 2 diabetes mellitus (T2DM). Resistin, an adipocyte-secreted hormone, antagonizes insulin. Transgenic mice that overexpress the resistin gene (Retn) in adipose tissue are insulin-resistant, whereas Retn (−/−) mice show lower fasting blood glucose, suggesting that the altered Retn promoter function could cause diabetes. To determine the role of RETN in human T2DM, we analyzed polymorphisms in its 5′ flanking region. We found that the −420G/G genotype was associated with T2DM (397 cases and 406 controls) (P=.008; adjusted odds ratio = 1.97 [by logistic regression analysis]) and could accelerate the onset of disease by 4.9 years (P=.006 [by multiple regression analysis]). Meta-analysis of 1,888 cases and 1,648 controls confirmed this association (P=.013). Linkage disequilibrium analysis revealed that the −420G/G genotype itself was a primary variant determining T2DM susceptibility. Functionally, Sp1 and Sp3 transcription factors bound specifically to the susceptible DNA element that included −420G. Overexpression of Sp1 or Sp3 enhanced RETN promoter activity with −420G in Drosophila Schneider line 2 cells that lacked endogenous Sp family members. Consistent with these findings, fasting serum resistin levels were higher in subjects with T2DM who carried the −420G/G genotype. Therefore, the specific recognition of −420G by Sp1/3 increases RETN promoter activity, leading to enhanced serum resistin levels, thereby inducing human T2DM.

Fulminant type 1 diabetes, which is characterised by a markedly acute onset of diabetes and an absence of islet-related autoantibodies, accounts for 20% of type 1 diabetes in Japan. We aimed to clarify the contribution of the HLA subtype to fulminant type 1 diabetes in Japanese.We determined the serological subtypes of HLA-A, -DR and -DQ in 115 patients with fulminant type 1 diabetes, 98 patients with typical type 1A diabetes and 190 normal control subjects.The frequency of HLA-DR4, but not DR9, was significantly higher in fulminant type 1 diabetes, while those of HLA-DR1, DR2, DR5 and DR8 were significantly lower than those in controls. In contrast, DR9 but not DR4 was more frequent and DR2 was extremely rare in typical type 1A diabetes. Haplotype analysis revealed that DR4-DQ4 was significantly more frequent, and both DR2-DQ1 and DR8-DQ1 were less frequent in fulminant diabetes. In type 1A diabetes, DR2-DQ1 was extremely rare while DR9-DQ3 was significantly more frequent. In the combination analysis, the homozygotes of DR4-DQ4 in fulminant type 1 diabetes and DR9-DQ3 in typical type 1A diabetes indicated high odds ratios (13.3 and 13.3, respectively).Our results suggest that class II HLA contributes to the development of fulminant type 1 diabetes. Susceptibility and resistance of the HLA subtype to type 1 diabetes are distinct between fulminant and typical autoimmune type 1 diabetes.

In 1996, we designed a randomized multicenter study to assess the effects of small doses of insulin on beta cell failure in slowly progressive type 1 diabetes (the Tokyo Study). We report here the preliminary results of this study. Glutamic acid decarboxylase 65 antibody (GADA)-positive patients were randomly divided into 2 groups: one group received insulin (Ins group), the other a sulfonylurea (SU group). Fifty-four patients (24 Ins group, 30 SU group) were analyzed at the end of a 4-year period. All patients underwent a 75 g oral-glucose test (O-GTT) every 6-12 months. The insulin-dependent stage was defined based on an integrated value of serum C-peptide levels on O-GTT ( summation operator CPR; sum of CPR at 0, 30, 60, 90, and 120 min) below 4.0 ng/mL. The summation operator CPR in the SU group decreased progressively from 22.0 +/- 10.6 to 11.3 +/- 7.5 ng/mL over the 48-month period (p0.001 vs. baseline). The summation operator CPR in the Ins group was unchanged. Among the SU group, 30% of subjects (9/30) progressed to IDDM, while 8.3% of Ins group subjects (2/24) progressed to IDDM (p = 0.087). With regard to the subjects who had a preserved C-peptide response ( summation operator CPR/= 10 ng/mL), the proportion of SU group subjects who progressed to IDDM was significantly higher than that of the Ins group (7/28, 25% vs. 0/21, 0%, p = 0.015). Among subjects with a high GADA titer (/=0 U/mL), 9/14 (64.3%) of the SU group, but only 2/16 (12.5%) of the Ins group, developed IDDM (p = 0.0068). As to those with a high GADA titer and a preserved C-peptide response, SU group subjects progressed to IDDM (7/12, 58.3%) more frequently than Ins group subjects (0/14, 0%) (p = 0.0012). In summary, our results suggest that small doses of insulin effectively prevent beta cell failure in slowly progressive type 1 diabetes. We recommend avoiding SU treatment and instead administering insulin to NIDDM patients with high GADA titer.

To describe the clinical and immunologic characteristics of fulminant type 1 diabetes, a novel subtype of type 1 diabetes, we conducted a nationwide survey.History and laboratory data, including islet-related autoantibodies, were examined in 222 patients with fulminant and nonfulminant type 1 diabetes in our hospitals in addition to another 118 patients with fulminant type 1 diabetes located outside our hospitals in Japan.In our hospitals, of the 222 patients studied, 43 (19.4%) were diagnosed with fulminant type 1 diabetes, 137 (61.7%) were classified as having autoimmune type 1 diabetes, and 42 were type 1 diabetic subjects who were not fulminant and did not have anti-islet antibodies. An additional 118 fulminant patients outside our hospitals were enrolled, making a total of 161 fulminant type 1 diabetic subjects (83 male and 78 female subjects; 14 children/adolescents and 147 adults) identified from all over Japan. (In 2000, the average incidence was three cases per month.) Flu-like symptoms and pregnancy were more frequently observed in the fulminant than in the autoimmune group (P0.001). In the fulminant patients, 4.8% were positive for anti-GAD antibodies and none were positive for anti-islet antigen 2 antibodies.Fulminant type 1 diabetes is a distinct subtype and accounts for approximately 20% of the ketosis-onset type 1 diabetes cases in Japan. Flu-like symptoms are characteristic of disease onset. Metabolic derangement is more severe in this subtype than in autoimmune type 1 diabetes.

We examined the clinical characteristics of type 2 diabetes mellitus (T2D) patients requiring insulin therapy and evaluated the efficacy of adding insulin therapy regimens to oral anti-diabetic drugs. Members of the Japan Diabetes Data Management Study Group across 55 institutes specializing in diabetes entered their clinical data into the CoDiC® database. Of 19,800 patients treated with oral drugs from 1 May to 31 July 2006, we analyzed the data from 15,589 patients whose data input was continued until 31 July 2009. A total of 1,014 patients out of those studied were started on insulin therapy during 2006–2009. Age and age-of-onset were lower in the insulin-initiated patients compared with patients who continued on oral drugs (P