K. Matsuoka

A Subtype of Diabetes Mellitus Associated with a Mutation of Mitochondrial DNA

BACKGROUND Several families have been described in which a mutation of mitochondrial DNA, the substitution of guanine for adenine (A-->G) at position 3243 of leucine transfer RNA, is associated with diabetes mellitus and deafness. The prevalence, clinical features, and pathophysiology of diabetes with this mutation are largely undefined. METHODS We studied 55 patients with insulin-dependent diabetes mellitus (IDDM) and a family history of diabetes (group 1), 85 patients with IDDM and no family history of diabetes (group 2), 100 patients with non-insulin-dependent diabetes mellitus (NIDDM) and a family history of diabetes (group 3), and 5 patients with diabetes and deafness (group 4) for the mutation. We also studied the prevalence and characteristics of diabetes in 39 patients with a syndrome consisting of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes who were known to have the mutation and 127 of their relatives (group 5). RESULTS We identified 16 unrelated patients with diabetes associated with the A-->G mutation: 3 patients from group 1 (6 percent), 2 patients from group 3 (2 percent), 3 patients from group 4 (60 percent), and 8 patients from group 5 (21 percent). We also identified 16 additional subjects who had diabetes and the mutation among 42 relatives of the patients with diabetes and the mutation in groups 1, 2, 3, and 4 and 20 affected subjects among the 127 relatives of the patients in group 5. Diabetes cosegregated with the mutation in a fashion consistent with maternal transmission, was frequently (in 61 percent of cases) associated with sensory hearing loss, and was generally accompanied by impaired insulin secretion. CONCLUSIONS Diabetes mellitus associated with the A-->G mutation at position 3243 of mitochondrial leucine transfer RNA represents a subtype of diabetes found in both patients with IDDM and patients with NIDDM in Japan.

Role of Glycemic Control and Blood Pressure in the Development and Progression of Nephropathy in Elderly Japanese NIDDM Patients

OBJECTIVE To investigate the role of glycemic control and blood pressure in the development and progression of nephropathy and to suggest goals for glycemic control and blood pressure for the prevention of nephropathy in elderly Japanese NIDDM patients. RESEARCH DESIGN AND METHODS A total of 123 age- and diabetes duration-matched elderly Japanese NIDDM patients (aged 60−75 years; 74 normoalbuminuric and 49 microalbuminuric) were retrospectively studied for 6 years. RESULTS The group that developed microalbuminuria from normoalbuminuria (group NM: n = 24) showed a higher 6-year mean HbA1c than the group that remained normoalbuminuric (group NN: n = 50; 9.0 ± 0.8 vs. 8.1 ± 0.8%, P < 0.01) in spite of no significant difference in 6-year mean blood pressure (MBP). On the other hand, the group that progressed from microalbuminuria to overt proteinuria (group MP: n = 26) showed a higher 6-year MBP than the group that remained microalbuminuric (group MM: n = 23; 106 ± 5 vs. 95 ± 6 mmHg, P < 0.01) in spite of no significant difference in 6-year mean HbA1c. The cutoff level of HbA1c separating group NN from group NM was 8.5% (normal range ≤ 6.5%), and that of MBP separating group MM from group MP was 100 mmHg. CONCLUSIONS Glycemic control is a more potent factor than blood pressure level on the development of microalbuminuria. However, as far as the progression of microalbuminuria to overt proteinuria is concerned, hypertension is the most crucial factor in elderly NIDDM patients. Suggested goals for glycemic control and blood pressure level for the prevention of nephropathy in elderly Japanese patients are an HbA1c of ≤8.5% (equivalent to 7.8% in the current measurement of stable HbA1c; normal range ≤5.8%) and an MBP of ≤ 100 mmHg.

Usefulness of Revised Fasting Plasma Glucose Criterion and Characteristics of the Insulin Response to an Oral Glucose Load in Newly Diagnosed Japanese Diabetic Subjects

OBJECTIVE To examine the usefulness of the revised criterion for fasting plasma glucose (FPG) in the diagnosis of diabetes recommended by the American Diabetic Association (ADA) (126 mg/dl, 7 mmol/1), and to characterize insulin response during the 75-g oral glucose tolerance test (OGTT) in newly diagnosed Japanese diabetic subjects. RESEARCH DESIGN AND METHODS A series of 2,121 Japanese subjects underwent a 75-g OGTT (0–3 h) and were divided into three groups (normal glucose tolerance [NGT], impaired glucose tolerance [IGT], and diabetes mellitus [DM]) according to the current World Health Organization criteria. After the cutoff values of FPG that distinguish NGT and IGT from diabetes were analyzed, the usefulness of the ADA criterion for FPG was examined by comparing diagnostic parameters (sensitivity, specificity, and accuracy) with those for the cutoff value of 140 mg/dl. To assess insulin response, both the insulinogenic index (Islx), a marker of early secretion, and the area under the insulin response curve (AUCIns), a marker of total secretion, were compared between the DM, NGT, and 1GT groups. RESULTS First, the FPG cutoff value distinguishing NGT from diabetes was 109 mg/dl. An FPG of 126 mg/dl showed a higher sensitivity (0.52 vs. 0.31), the same specificity (1.00), and a higher accuracy (0.82 vs. 0.74) than an FPG of 140 mg/dl, and it had a higher specificity (1.00 vs. 0.86) with a slightly lower accuracy (0.82 vs. 0.85) than an FPG of 109 mg/dl. Second, the FPG cutoff value differentiating IGT from diabetes was 113 mg/dl. An FPG of 126 mg/dl showed a higher sensitivity (0.52 vs. 0.31) and accuracy (0.80 vs. 0.74) and a similar specificity (0.97 vs. 1.00) compared with an FPG of 140 mg/dl, and it had a higher specificity (0.97 vs. 0.82) with the same accuracy (0.80) as an FPG of 113 mg/dl. Third, the DM group showed the lowest Islx among the three groups at all FPG values. The AUCIns in the DM group increased along with FPG, reached the maximum level at an FPG of 110 mg/dl, and declined thereafter. AUCIns was higher in the DM group than in the NGT group at FPG values ≥100 mg/dl. CONCLUSIONS The revised ADA criterion for FPG of 126 mg/dl may improve diagnostic sensitivity without loss of specificity in Japanese diabetic subjects when compared with an FPG criterion of 140 mg/dl. Although early insulin secretion was impaired, total insulin secretion did not seem to be reduced in newly diagnosed Japanese diabetic subjects.

Usefulness of stable HbA1c for supportive marker to diagnose diabetes mellitus in Japanese subjects

To evaluate the adequacy and usefulness of the stable glycated hemoglobin (HbA(1c)) value of 6.5% suggested by the Japan Diabetic Society in 1999 for supportive diagnostic marker of diabetes, we assessed the sensitivity and specificity of an HbA(1c) value of 6.5% in patients who were newly diagnosed by the 75 g oral glucose tolerance test (75g-OGTT). A total of 866 Japanese subjects underwent the 75g-OGTT and HbA(1c) measurement (normal range: 4.3-5.8%). They were divided into three groups [normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and diabetes mellitus (DM)], using the WHO criteria, since no subject with impaired fasting glycemia (IFG) was observed. The cut-off value of HbA(1c) separating DM from NGT or DM from IGT on cumulative distribution curve analysis was 5.9% (sensitivity 0.76 and specificity 0.86) and 5.9% (sensitivity 0.76 and specificity 0.77), respectively. The sensitivity of an HbA(1c) of 6.5% for separation of DM from NGT or IGT by the same analysis was 0.49 and 0.49, respectively. Similarly, the specificity for separation of DM from NGT or IGT was 0.98 and 0.98, respectively. These results mean that 49% of diabetic subjects show an HbA(1c)> or =6.5%, and 51% have an HbA(1c) less than 6.5%, while only 2% of NGT and IGT subjects have an HbA(1c)> or =6.5%, and 98% have a value less than 6.5%. Therefore, the sensitivity of an HbA(1c) value of 6.5% in separating DM from NGT or IGT is low, and thus 6.5% is too high value to use when screening for diabetes. However, the specificity is very high, so an HbA(1c) of 6.5% is a useful supportive marker to diagnose diabetes.

Polymorphism of the solute carrier family 12 (sodium/chloride transporters) member 3, SLC12A3, gene at exon 23 (+78G/A: Arg913Gln) is associated with elevation of urinary albumin excretion in Japanese patients with type 2 diabetes: a 10-year longitudinal study

Aims/hypothesisWe have shown previously that the SLC12A3 +78G/A polymorphism in exon 23 (Arg913Gln) was a new candidate for conferring susceptibility to diabetic nephropathy. The aim of this study was to confirm the effect of this polymorphism on the elevation of urinary albumin excretion in type 2 diabetic patients.MethodsWe retrospectively studied 264 Japanese patients with type 2 diabetes over a ten-year period. The subjects were classified into two groups: (1) persistent normoalbuminuria or microalbuminuria, or improvement from microalbuminuria to normoalbuminuria (group N); and (2) progression from normoalbuminuria to microalbuminuria or overt proteinuria, or progression from microalbuminuria to overt proteinuria (group P). They were assessed for association with the +78G/A polymorphism.ResultsThe frequency of the +78A allele was significantly higher in group N than in group P (10% vs 1%, p=0.021). By logistic regression analysis and discriminant analysis, the substituted allele was shown to be an independent factor correlating negatively to the elevation of albumin excretion (p=0.043 and 0.022, respectively).Conclusions/interpretationThe SLC12A3 +78A(+) genotype may have a protective effect against the development and/or progression of diabetic nephropathy in Japanese type 2 diabetic patients.

ACE Inhibitors and Diabetic Nephropathy

Nineteen-ninety-three was a banner year for the demonstration of beneficial effects of interventions on outcomes in patients with diabetes and, in particular, with diabetic nephropathy. The Collaborative Study Group studying the effects of treatment with angiotensinconverting enzyme (ACE) inhibitors on the progression of diabetic nephropathy reported strongly positive results (1), hard on the heels of the publication of the results of the Diabetes Control and Complications Trial (DCCT) (2).

Association of aldehyde dehydrogenase with inheritance of NIDDM

SummaryTo investigate the influence of the mitochondrial aldehyde dehydrogenase 2 (ALDH2) genotype on the clinical features of diabetes, 212 Japanese patients with non-insulin-dependent diabetes mellitus (NIDDM) (154 males and 58 females aged 17–83 years; mean age 58.2 years) were investigated. Genotyping of ALDH2 was performed by the polymerase chain reaction — restriction fragment length polymorphism (PCR-RFLP) method. The pattern of inheritance of diabetes and various clinical parameters was compared between active and inactive ALDH2 groups. Of the 212 subjects, 120 had active ALDH2 and 92 had inactive ALDH2. The percentage of patients with a diabetic mother was higher in the inactive ALDH2 group (32.6%) than in the active ALDH2 group (19.2%) (p<0.05). The prevalence of proliferative retinopathy was lower in the inactive ALDH2 group than in the active ALDH2 group (p<0.05). However, other clinical parameters showed no difference. We conclude that maternal inheritance of diabetes was common in the inactive ALDH2 group. The finding is suggestive of a relationship between alcohol intolerance and inheritance of diabetes. We speculate that the interaction between mitochondrial DNA and ALDH2 inactivity causes an increase of mitochondrial DNA mutations or deletions, thereby inducing the maternal inheritance of diabetes. The relationship of the ALDH2 genotype with proliferative retinopathy is interesting, because it resembles that of chlorpropamide alcohol flushing with severe diabetic retinopathy. The interaction of aldehyde dehydrogenase isoenzymes might have an aetiological role, since aldehyde dehydrogenase 1 plays an important part in oxidation of retinal to retinoic acid. However, the number of affected patients with proliferative retinopathy was small, hence, our result should be considered as a preliminary finding.

Efficacy of low-dose metformin in japanese patients with type 2 diabetes mellitus

Abstract The goal of this study was to examine the antihyperglycemic effect of low-dose metformin in nonobese and obese Japanese patients with type 2 diabetes mellitus. After 3 months of reeducation and stabilization of diet therapy (25 kcal/kg of ideal body weight), metformin treatment was initiated. We administered metformin (500 to 750 mg daily) as monotherapy (n = 11) or in combination with a sulfonylurea (n = 14). After 6 months of treatment, the fasting plasma glucose level (mean ± SD) decreased from 190 ± 42 mg/dL to 155 ± 37 mg/dL and the glycated hemoglobin A 1c level (mean ± SD) from 8.8 ± 1.2% to 7.4 ± 1.0% in the monotherapy group. These same variables decreased from 218 ± 60 mg/dL to 162 ± 30 mg/dL and from 9.5 ± 1.2% to 8.4 ± 1.2% in the combination therapy group. All of these changes were statistically significant. Our results demonstrate that even low doses of metformin can improve hyperglycemia in Japanese patients with type 2 diabetes mellitus.

Acute metabolic cataract as a first manifestation of diabetes mellitus in a 12-year-old girl.

To the Editor: We report a case of juvenile cataract and Type 2 diabetes in a 26-year-old female (154 cm, 51 kg). A sibling of her mother had impaired glucose tolerance. Polydipsia and leg paresthesia were apparent in this patient with cataract since the age of 10, and she was diagnosed with diabetes at the age of 12. On her first visit, her intelligence and physical examination results were normal, except for bilateral cataracts (an unusual manifestation in a 12-year-old girl). Ptosis, ophthalmoplegia and hearing loss were not observed. Her fasting plasma glucose concentration was 25.3 mmol/l, and her HbA1c was 20.1%. Other laboratory examination data were normal. She began intensive insulin treatment and 4 months later her HbA1c rapidly decreased to 5.9%, and the leg paresthesia disappeared. She underwent successful bilateral cataract extraction with intraocular lens implantation. Four years later, she stopped insulin therapy and has been under excellent control (HbA1c 6.0%) with oral hypoglycaemic agents, and she has been free of symptoms. Neuroimaging findings at the globus pallidus are a sign of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) or mitochondrial diabetes. In this patient, high intensity areas in the bilateral globus pallidus were noted on T1-weighted magnetic resonance imaging at the age of 18 (Fig. 1). However, she was not recognised as showing signs of mitochondrial disease, because the results of detecting mitochondrial DNA (mtDNA) mutation at position 3243 were negative in the laboratories, where the cut-off degree of heteroplasmy ranged from 0.2 to 1%. Informed consent was obtained and the study was approved by the local ethics committee of Saiseikai Central Hospital. Other important data, as to whether other family members had considerable mitochondrial DNA mutation, were not available. A new technology using real-time PCR with a TaqMan Probe was introduced in Diabetologia [1], which can quantify as little as 0.001% of the 3243 mtDNA mutation in blood cells.

Insulin Resistance and Atherosclerosis in Branch Retinal Vein Occlusion

PURPOSE To investigate insulin resistance and atherosclerotic change in patients with branch retinal vein occlusion (BRVO). SUBJECTS Sixty-three patients with BRVO, 859 age- and sex-matched control subjects without BRVO who received the 75-g oral glucose tolerance test (OGTT), and 53 control subjects, in whom carotid artery intima-media thickness (IMT) was measured by high-resolution ultrasonography, were included in this study. RESULTS The area under the curve of immunoreactive insulin in plasma during the OGTT was higher in patients with BRVO than in control subjects without BRVO, both when comparing individuals with normal glucose tolerance (P=.013) and when comparing individuals with impaired glucose tolerance (P<.005). Patients with BRVO showed greater IMT than control subjects, but the differences were significant only in the group aged 50-59 years and in the group older than 70 years. CONCLUSIONS Insulin resistance may play some role in the onset or progression of BRVO.