Yoshihito Atsumi

Stratified analyses for selecting appropriate target patients with diabetic peripheral neuropathy for long-term treatment with an aldose reductase inhibitor, epalrestat

Aimsu2003 The long‐term efficacy of epalrestat, an aldose reductase inhibitor, in improving subjective symptoms and nerve function was comprehensively assessed to identify patients with diabetic peripheral neuropathy who responded to epalrestat treatment.

Insulin edema in diabetes mellitus associated with the 3243 mitochondrial tRNALeU(UUR) mutation; Case reports

We encountered a patient with diabetes mellitus due to the 3243 mitochondrial tRNA mutation(DM-Mt3243), who developed insulin edema and hepatic dysfunction after starting insulin. Such a rare phenomenon was unlikely to be a fortuitous coincidence in mitochondrial diabetes, as none in 197 non-mutant NIDDM patients had same episode. Moreover, similar leg edema was noticed in another DM-Mt3243 patient, and other two DM-Mt3243 patients had leg edema which responded to coenzyme Q10. These observations suggest further a role of mitochondrial function on leg edema. The mechanism of his insulin edema may involve vasomotor changes induced by the rapidly glycemic control, because our case of insulin edema had a prominent increase of strong succinate dehydrogenase reactive vessels. Alternatively, myocardial dysfunction might have produced leg edema and hepatic dysfunction, because he had subclinical myocardial dysfunction, judged by imaging with beta-methyl-p-(123I)-iodophenyl-pentadecanoic acid. The third explanation is that a rapid improvement of glycemic control might have induced hepatic reoxygenation and the production of reactive oxygen species in the liver that contributed to cell damage. Thus, although we cannot draw definite conclusion, our experiences here suggest that mitochondrial dysfunction is important in the etiology of insulin edema.

ALDH2/ADH2 Polymorphism Associated with Vasculopathy and Neuropathy in Type 2 Diabetes

In the history of diabetes, chlorpropamide alcohol flushing test (CPAF) was a big topic in the 1970s to 1980s. Alcohol tolerance after chlorpropamide has prognostic significance, with the intolerant group (CPAF-positive group) being less prone to develop vascular complication than the tolerant group (CPAF-negative group). A mechanism of CPAF has been regarded as the inhibition of aldehyde dehydrogenase 2 (ALDH2) by an N-alkyl-substituted derivative of chlorpropamide, and the expression of these mutations of ALDH2 and alcohol dehydrogenase 2 (ADH2) could determine the alcohol tolerance among the Japanese population. Therefore, we hypothesized that expression of different ALDH2 and ADH2 polymorphisms may induce differences in vascular complications in diabetes and conducted two studies. The first study (study 1) was to determine the association of ALDH2/AHD2 polymorphism with diabetic complications. To know the association of ALDH2/AHD2 polymorphism with diabetic vasculopathy and neuropathy, a total of 158 patients with type 2 diabetes were divided into four groups on the basis of ALDH2 activity and ADH2 superactivity. The frequency of proteinuria and the percentage of proliferative retinopathy among the patients with retinopathy was higher in those with active ALDH2 and superactive ADH2. We speculated that protein kinase C isoforms up-regulated by 4-hydroxynonenal that was detoxified by ALDH2 and ADH2 may account for the long-term development of diabetic nephropathy and severe retinopathy. As for neuropathy, the frequency of symptomatic neuropathy was higher in patients with inactive ALDH2 and usual ADH2. We speculate that increased tissue levels of toxic aldehyde could result from inactive ALDH2 and usual ADH2 expression, which results in the increased level of reactive aldehyde in sensory neuron pathway, thereby causing symptomatic polyneuropathy.

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.

Mitochondrial aldehyde dehydrogenase in diabetes associated with mitochondrial tRNA (Leu(UUR)) mutation at position 3243

OBJECTIVE To ascertain why alcohol is prone to manifest unpleasant effects in diabetes associated with mitochondrial tRNALeu(UUR) mutation at position 3243 (DM-Mt3243), we investigated the genotype of aldehyde dehydrogenase (ALDH) 2 and alcohol dehydrogenase 2 (ADH2) in DM-Mt3243. RESEARCH DESIGN AND METHODS Nineteen unrelated patients with DM-Mt3243 were included in the study (12 men and 7 women). They were recruited from ∼700 diabetic patients at three different institutes, without prior information of alcohol habit. ALDH2, ADH2, and 3243 mutation were genotyped by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) methods. There were 461 unrelated Japanese individuals and 170 non-3243 mutant NIDDM patients enrolled as control subjects. RESULTS In the DM-Mt3243 group, 15 (79%) patients had inactive ALDH2 and 18 (95%) had atypical ADH2. The frequency of the inactive ALDH2 genotype was higher than that in the normal control subjects (P < 0.002) and that in the NIDDM control subjects (P < 0.003). However, the frequencies of ADH2 genotype in the DM-Mt3243 group, the normal control subjects, and the NIDDM control subjects were not different. CONCLUSIONS Inactive ALDH2 genotype was frequently observed in DM-Mt3243. It suggests that DM-Mt3243 is associated with ALDH2 inactivity. We speculate the trait of acetaldehyde accumulation on ALDH2 inactivity may favor mitochondrial DNA abnormalities, thereby worsening ATP production and impairing insulin secretion. In addition, the interaction of ALDH1 and ALDH2 may alter the retinoid metabolism in the pancreas, thereby influencing insulin secretion and precipitating diabetes. Thus, this association of ALDH2 genotype with DM-Mt3243 provides insight into the etiology of diabetes in the mitochondrial diseases.

Diabetes mellitus associated with the 3243 mitochondrial tRNALeu(UUR) mutation: Insulin secretion and sensitivity

To investigate the pathophysiology of diabetes mellitus associated with the 3243 mitochondrial tRNA(Leu)(UUR) mutation (DM-Mt3243), insulin secretion and sensitivity were studied using the 75-g oral glucose tolerance test (oGTT), 1-mg intravenous glucagon test, and euglycemic glucose clamp test. Twelve DM-Mt3243 patients were investigated (seven men and five women). Their ages ranged from 36 to 74 years, and the onset of diabetes occurred at 44.5 +/- 9.5 years (mean +/- SD). In the glucose tolerance test, nine patients (75.0%) showed lower C-peptide reactivity (CPR) than normal at 30 minutes, suggesting blunted insulin secretion. Three patients showed an impaired glucose tolerance (IGT) pattern, although they had absolute hyperglycemia at the onset of diabetes. In the glucagon test, 10 patients (76.3%) had CPR within the normal range at 6 minutes, indicating an adequate response. In the glucose clamp test, the M value was 8.70 +/- 2.35 mg/kg/min and was within normal limits in all patients. The glucose metabolized (M value) was negatively correlated with 24-hour urinary C-peptide excretion (r = .696, P < .05). Thus, plasma CPR to glucose loading was blunted in many DM-Mt3243 patients, but CPR to glucagon was relatively well preserved. This difference in the intrinsic insulin response to the two stimuli may be characteristic of DM-Mt3243. Although M values were normal in all subjects, the correlation with 24-hour urinary C-peptide excretion suggests a relationship between insulin sensitivity and insulin secretion. These two mechanisms may cooperate to maintain homeostasis in this disease. Since three patients did not progress with aging, this mutation may not always cause gradual beta-cell destruction.

Muscle histopathology in diabetes mellitus associated with mitochondrial tRNALeu(UUR) mutation at position 3243

Diabetes mellitus associated with 3243 mitochondrial tRNA(Leu(UUR)) mutation (DM-Mt3243) is a subtype of the mitochondrial multisystem syndromes, usually lacking myopathy. Muscle biopsies were obtained from 5 patients with diabetes and one patient with impaired glucose tolerance, all possessing the 3243 mutation without hallmarks of MELAS. The specimens were subjected to histochemical, biochemical, and genetic analysis. Ragged-red fibers were seen in 4 of the 6 patients (67%), and focal cytochrome c oxidase deficiency in 3 (50%). Strongly succinate dehydrogenase-reactive blood vessels was found in 5 patients (83%). The histochemical signs were present even when the mutant percentage was very low. The percentage of mutant DNA was almost always higher in muscles than in leukocytes. The combination of allele specific PCR amplification and PCR-RFLP method was useful to evaluate the mutant proportion. The mutant percentage in muscle was under 50% in 5 (83%) patients. Mitochondrial enzyme activity was deficient only in one patient. This study presents the detailed muscle histopathology in the DM-Mt3243 group. Abnormal histopathologic findings seemed similar to those noted in MELAS. However, mutant percentage in muscles was lower than that of MELAS, and respiratory chain enzyme activity was well preserved.

Clinical Picture of a Case of Diabetes With Mitochondrial tRNA Mutation at Position 3271

M: itochondrial DNA mutation with a |T-to-C transition at position 3271 is the second most common mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) in Japan (1). We recently encountered a diabetic patient with the mutation but without neuromuscular pictures of MELAS. This is the first report of the presence of the 3271 mutation in a family with diabetes and without MELAS. The proband was a 39-year-old man who was 174 cm tall and weighed 66 kg. He had no hearing loss, history of obesity, or clinical features of MELAS. Diabetes congregated in the maternal line, and he, his sister, and his mother were found, on analysis of hair follicles, to have the 3271 mutation ( ) (1). In the proband, the amount of mutant DNA seemed higher in muscle than in leukocytes or in hair follicles (Fig. 2A). None of 170 bp • 140 bp •

Posttreatment Neuropathy in Diabetic Subjects With Mitochondrial tRNA (Leu) Mutation

in type 1 diabetic patients (Abstract). Diabetes 42:(Suppl 1): 126A, 1993 5. Veneman T, Mitrakou A, Mokan M, Cryer P, GerichJ: Induction of hypoglycemia unawareness by asymptomatic nocturnal hypoglycemea. Diabetes 42:1233-1237,1993 6. Lingenfelser T, Renn W, Sommerwerck U, Jung MF, Buettner UW, Zaiser-Kashel H, Kashchel R, Eggstein M, Jakober B: Compromised hormonal counterrugulation, symptom awareness, and neurophysiological function after recurrent short-term episodes of insulin-induced hypoglycemia in 1DDM patients. Diabetes 42:610-618, 1993

Exercise regimen for patients with diabetic nephropathy

To elucidate the relationship between physical activity and the progress of diabetic nephropathy, patients were divided into two groups with physical activity maintained (G) or restricted (R). The period between the onset of 1+ and 3+ proteinuria was 56 +/- 25 months in G and 68 +/- 25 months in R. But the period between 3+ proteinuria and the serum creatinine exceeding 2.0 mg/dl was 29 +/- 19 and 23 +/- 22 months, respectively. Duration of the nephrotic stage before the entry to dialysis was about 27 months in each group. After initiation of hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), postural hypotension tended to be less in G and Karnofsky score for fitness in daily physical activity was significantly better in G. Even after macroalbuminuria emerged, it was concluded that a strict restriction of exercise is of little benefit.