Prevalence of GORD (gastro-oesophageal reflux disease) in Type 2 diabetes and a comparison of clinical profiles between diabetic patients with and without GORD.

AIMS: To examine the incidence of gastro-oesophageal reflux disease (GORD) and its associated factors in patients with Type 2 diabetes mellitus (Type 2 DM). METHODS: In 859 Type 2 DM outpatients, we conducted a QUEST inquiry and considered those showing a QUEST score of 4 or higher as having GORD. We surveyed clinical variables (physical findings, gender, age, duration of disease, glycated haemoglobin (HbA(1c)), type of oral glucose-lowering agent, presence or absence of insulin therapy, complications, and presence or absence of agents that may be associated with GORD [Ca channel blocker (CCB) anti-platelet agents]) to investigate their association with the onset of GORD. RESULTS: We analysed 813 subjects, of whom 56.6% were male. The mean age was 63.7 +/- 11.3 years and HbA(1c) 7.2 +/- 1.2%. The incidence of GORD was 29.0% (n = 221). GORD was positively correlated with body weight, body mass index (BMI) and HbA(1c). It was negatively correlated with age, serum creatinine and proportion of patients treated with pioglitazone or CCB. In addition, GORD was more common in females. The incidence of GORD was significantly higher in younger patients. CONCLUSIONS: Previous studies have suggested a relationship of GORD with pioglitazone/CCB. However, the results of this study do not support this; these agents may not induce GORD.

Prevalence of A-to-G mutation at nucleotide 3243 of the mitochondrial tRNA(Leu(UUR)) gene in Japanese patients with diabetes mellitus and end stage renal disease.

The A-to-G mutation at nucleotide 3243 of the mitochondrial tRNA(Leu(UUR)) gene (mt.3243A>G) is associated with both diabetes mellitus and myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Recently, this mutation was found in three diabetic subjects with progressive kidney disease, suggesting that it may be a contributing factor in the development of kidney disease in patients with diabetes. The aim of this study was to evaluate the contribution of this mutation to the development of end stage renal disease (ESRD) in patients with diabetes. The study group consisted of 135 patients with diabetes and ESRD. The control group consisted of 92 non-diabetic subjects with ESRD who were receiving hemodialysis. The mt.3243A>G mutation was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We found the mt.3243A>G mutation in eight patients (8/135; 5.9%), all of whom were initially diagnosed with type II diabetes. Five of the eight patients were subsequently also diagnosed with MELAS. We did not find the mutation in any of the 92 nondiabetic subjects with ESRD. The prevalence of this mutation was 6.5-fold higher in patients with diabetes and ESRD than in those with diabetes alone (8/135 vs 5/550, respectively; chi2 = 13.704; P = 0.0002). The mt.3243A>G mutation may be a contributing genetic factor in the development of ESRD in Japanese patients with diabetes.

Glutamic acid decarboxylase autoantibodies in stiff-man syndrome and insulin-dependent diabetes mellitus exhibit similarities and differences in epitope recognition.

Glutamic acid decarboxylase (GAD) is an autoantigen in two autoimmune diseases, insulin-dependent diabetes mellitus (IDDM) and stiff-man syndrome (SMS). However, most individuals with one of these diseases do not have the other disease. Prior studies have suggested that the natures of the GAD Abs associated with each of these diseases are different, which may have implications for the autoimmune pathogenesis. We have compared the GAD autoantibody profile and have mapped GAD protein epitope regions in the two diseases using an immunoprecipitation assay with recombinant GAD 65 and GAD 67 proteins, GAD protein fragments, and synthetic GAD peptides, as well as chimeric GAD proteins. Our results indicate that individuals with SMS have GAD Abs in 100- to 500-fold higher titer than individuals with IDDM. The population of GAD Abs in SMS sera is quite complex and includes those that recognize at least three GAD 65 epitope regions located between amino acids 1-16, 188-442, and 442-563. These types of GAD Abs are not found in IDDM sera. All SMS sera also had Ab specificity that binds GAD 67 in a region highly homologous to amino acids 188-442 of GAD 65. In contrast to prior studies that used immunoblotting to measure GAD Abs, we find GAD Abs in SMS sera also target two conformation-dependent regions of GAD 65, one located in the middle and one near the C-terminus of the protein. These two regions of the GAD 65 protein are similar to regions targeted by GAD 65-specific Abs found in individuals with IDDM. These results indicate that although disease-specific epitopes may exist, there is also overlap in the humoral response between the two diseases.

Identification of glutamic acid decarboxylase autoantibody heterogeneity and epitope regions in type I diabetes.

Glutamic acid decarboxylase (GAD) is an autoantigen of the islet cell antibodies (ICAs) present in type I diabetes. GAD autoantibodies are also found in patients with stiffman syndrome and in certain ICA-positive individuals who rarely develop diabetes on long-term follow-up. This latter subset of ICA has been termed restricted or beta-cell-specific ICA because the antibodies react with only the beta-cells of the islet. By immunoprecipitation of recombinant GAD65 and GAD67 protein and protein fragments, 83% of sera from individuals with new-onset diabetes or prediabetes (n = 30) had GAD65 autoantibodies, but only 26% had GAD67 autoantibodies. In contrast, all restricted ICA sera (n = 6) had both GAD65 and GAD67 autoantibodies. In both types of sera, the binding of GAD67 autoantibodies could be blocked by preincubation of the serum with GAD65 and GAD67, but the binding of GAD65 autoantibodies could not be blocked by preincubation with GAD67. The titer of GAD65 autoantibodies was much higher in the restricted ICA sera (titer > 1:1,000) than in the sera from individuals with new-onset diabetes or prediabetes (titer < 1:100) and was reflected by the greater amount of GAD65 protein immunoprecipitated by restricted ICA sera (2.61 +/- 1.39 U) compared with sera from individuals with new-onset diabetes (0.51 +/- 0.34 U). The restricted ICA sera immunoprecipitated equimolar amounts of GAD65 protein fragments, suggesting a non-conformational or linear epitope; epitope mapping localized the major epitope region to amino acids 361-442 and a second minor epitope region to amino acids 1-195.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of the clinical course of 130 Japanese non-insulin-dependent diabetic patients undergoing dialysis.

To clarify the characteristics of diabetic nephropathy (DN) in Japanese patients with non-insulin-dependent diabetes (NIDDM), we analyzed the clinical course of 130 such patients who began dialysis treatment due to DN between 1978 and 1988 at the Diabetes Center of Tokyo Women's Medical College. Analysis of the clinical course prior to attending the Diabetes Center revealed that 64 (49.2%) of the patients neglected or discontinued their initial treatment for diabetes until the development of diabetic complications because of the lack of symptoms. The average duration of untreated diabetes in these patients was 10.7 +/- 4.6 years. The biggest problem for NIDDM patients was the absence of symptoms until the development of diabetic complications.

Clinical profile of Japanese dialysis patients with diabetic nephropathy, diagnosed as having diabetes before the age of thirty.

Diabetic nephropathy is the leading cause of death in young diabetic patients. There are a large number of patients with non-insulin-dependent diabetes mellitus (NIDDM) who are diagnosed before the age of 30 in Japan. We investigated 36 patients with young-onset diabetes who started dialysis between 1978 and 1987 in our hospital. Of the 36 patients, 12 (33.3%) were classified as having insulin-dependent diabetes mellitus (IDDM), 22 (61.1%) had NIDDM, and 2 (5.6%) could not be classified clinically. The percentages of the different types of diabetes in our series of dialysis patients were almost identical with those in Nagai's series of 551 diabetic patients diagnosed before the age of 30 at the Diabetes Center of Tokyo Women's Medical College from 1976 to 1981. The present study showed the young-onset NIDDM in Japan was associated with almost the same incidence of end-stage diabetic nephropathy as was IDDM. However, the number of NIDDM patients diagnosed under 30 years of age was almost double that of IDDM patients. Thus, we have to pay greater attention to the development of diabetic nephropathy in young-onset NIDDM patients than has been thought necessary in the past.