Y. Atsumi

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).

Diabetes With the 3243 Mitochondrial tRNALeu(UUR) Mutation: Characteristic neuroimaging findings

OBJECTIVE To investigate the basis of central nervous system dysfunction in diabetes associated with the 3243 mitochondrial tRNA mutation, we studied neuroimaging findings in patients with this disease. RESEARCH DESIGN AND METHODS We screened 205 diabetic patients. Those patients who had the 3243 mutation in leukocytes or muscle were enrolled. All the subjects underwent computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and N-isopropyl-p-[123I]iodoamphetamine ([123I]IMP) single-photon emission computed tomography (SPECT) of the brain. RESULTS None of the nine subjects with the 3243 mutation had the typical clinical picture of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, and none had neurological focal signs. CT or MRI revealed diffuse brain atrophy in three patients (33%) and cerebellar atrophy in one (11%). Abnormal high intensity areas were observed on MRI in five patients (56%). The overall prevalence of brain abnormalities was 56% (5 of 9) on CT and 78% (7 of 9) on MRI scans. MRA revealed no stenotic lesions. SPECT showed reduced accumulation of [123I]IMP in the right or left parieto-occipital region in eight patients (89%). CONCLUSIONS Reduced accumulation of [123I]IMP in the parieto-occipital cortex was found in a high proportion of our subjects on SPECT. This imaging finding might be characteristic of diabetes associated with the 3243 mitochondrial tRNA mutation and may be a sign of latent central nervous system dysfunction.

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.

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.

Finger infection resulting from self-monitoring of blood glucose and a new Aid for reducing risk

contacted personally, and pediatricians, contacted through the Pediatric Society, were also included as a primary source of data. The secondary source was a school survey completed by the teachers in 303 public and private schools, including elementary, high, and technical schools. Each reported case was confirmed by an interview with a member of the family. Between 1978 and 1992, 25 new cases of IDDM were identified in children <15 years of age. The ascertainment rate using the capture-recapture methodology was 92.6% for the primary source, 48.1% for the secondary source, and 96.3% for both sources combined. The average incidence rate was extremely low, 1.15/100,000 (95% CI 0.75-1.70). The highest incidence was seen in 1988 (3.4/100,000 [1.12-8.07]) and the lowest incidence rate was in 1982, with no cases found. The incidence rates for IDDM by sex and age-group are presented in Table 1. The mean age at diagnosis was 9.45 ± 3.47 years (peak age at onset: 13 years) for boys and 9.6 ± 2.69 years (peak age at onset: 9 years) for girls. Based on the information available in the medical records, 66% were Mestizos, and 34% were Caucasians. Unfortunately, the census data do not provide information by ethnic breakdown, so it is not possible to calculate ethnicity-specific incidence rates. However, data for all of Mexico (6) indicate that 60% of the population is Mestizo, 30% American Indian, 9% Caucasian, and 1% of other origin. Applying these data to the population of Veracruz-Boca del Rio, an estimate of ethnicity-specific incidence rates would be 1.15/100,000 in Mestizos versus 4.15/100,000 in Caucasians. This study provides the first evidence using standardized methodology that the risk for IDDM in children in Mexico, is among the lowest in the Iberian heritage populations and in the world. It is important to note that even if the number of cases identified was small, the ascertainment rate for the registry was high, making it highly unlikely that cases were missed. This study suggests that the gradient across Spanish heritage populations may be as high as 40-fold.

No association of ALDH2 genotype in MELAS.

Dear Sir Mitochondrial DNA encodes only for a limited number of mitochondrial proteins whereas the majority of the proteins which constitute the mitochondrion are of nuclear origin. Therefore, alterations in both mitochondrial and nuclear DNA have the potential to affect mitochondrial function [1]. Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) and mitochondrial diabetes mellitus associated with 3243 tRNALeu(UUR) mutation (MDM3243) are both related to the same 3243 mutation [2]. The mechanism for the different association of the same mutation with the two diseases has not been clarified. We previously reported the importance of inactive aldehyde dehydrogenase 2 (ALDH2) genotype, a nuclear DNA mutation, for inheritance of non-insulin-dependent diabetes mellitus (NIDDM) and its high prevalence in patients with MDM-3243 [3, 4]. This time, we investigated the genotype further in MELAS associated with the 3243 tRNALeu(UUR) mutation (MELAS-3243). We recruited 34 MELAS subjects from four different institutes (National Institute of Neuroscience, Tohoku University, Saiseikai Central Hospital, and Showa University [16 male, 18 female, age from 4 to 50 years, mean ± SD: 23.4 ± 13.4 years, onset of MELAS from 3 to 44 years, 18.2 ± 12.2 years]). They were unrelated. They had hallmarks of MELAS, such as stroke, epilepsy, headache or convulsion. The 3243 mtDNA mutations and ALDH2 genotype were determined in peripheral leukocytes and/or in muscle. The details for the mitochondrial DNA and ALDH2 genotype examination have been described elsewhere [4–6]. The non-diabetic control group for ALDH2 genotype consisted of 461 Japanese who were the same as we previously reported elsewhere. We found 11 (33%) patients with MELAS-3243 had the inactive ALDH2 genotype (Table 1). The frequency of the ALDH2 genotype in MELAS-3243 and normal control subjects were not different. This suggests that the inactive ALDH2 genotype is not associated with MELAS-3243 in contrast to the association of ALDH2 with MDM-3243 as we previously reported [4]. Odawara et al. [7] postulated that, because many MELAS families with 3243 mutation have diabetes and families with diabetes rarely complicate MELAS, factors other than the 3243 mutation are required to account for the phenotypes of MELAS. However, in general, MELAS-3243 patients have an high amount of 3243 mutation in tissues, while MDM-3243 patients show a very low percentage of the mutation even in tissues such as muscles [6]. Since the genetic contribution to pathogenesis in mitochondrial disease is supposed to be greater in those carrying large amounts of deleterious mutation MELAS-3243 may have a greater genetic contribution of 3243 mutation to the initiation of the disease than MDM3243. In contrast, in MDM-3243, other factors like easy acetadehyde accumulation due to inactive ALDH2 genotype or other unknown environmental factors may make a contribution in altering mitochondrial function [3, 4]. Thus, our results suggest the different association of ALDH2 genotype with MELAS-3243 and MDM-3243. This difference may give an hint as to the different aetiologies between the two diseases.