Kazuhiro Hosokawa

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.

Diabetes Associated With a Novel 3264 Mitochondrial tRNALeu(UUR) mutation

OBJECTIVE To present a novel mitochondrial DNA mutation in a diabetic family RESEARCH DESIGN AND METHODS The proband was a 64-year-old man. In the family, diabetes was maternally inherited. He had diabetes, cerebellar ataxia, cervical lipoma, hearing loss, olfactory dysfunction, ophthalmoplegia, and facial nerve bilateral palsy. On examination, early insulin secretion was blunted, and the M value on glucose clamp test was low. In muscle, ragged red fibers were not found. T-to-C mutation at position 3264 was detected in the proband (0.5% mutant DNAs in leukocyte and 30% in muscle), but was not detected in 201 normal individuals. RESULTS Heteroplasmy of mutation, maternal inheritance of diabetes, and symptoms related to mitochondrial dysfunction suggest the pathogenecity of this 3264 mutation. As for diabetes etiology, both impaired insulin secretion and decreased insulin sensitivity seem to be important. In phenotypic characteristics, the combination of cerebellar ataxia and lipoma is a symptom sometimes found in myoclonic epilepsy and ragged red fibers (MERRFs). Ophthamoplegia is a symptom of chronic progressive external ophthalmoplegia (CPEO). These suggest that our proband had phenotypic overlap with MERRF and CPEO. Conversely, facial nerve bilateral palsy is a rare finding. The pictures that focused on his cranial nerves were thus unique, suggesting the heterogeneity of mitochondrial DNA (mtDNA)-related diabetes. CONCLUSIONS A novel 3264 mitochondrial DNA mutation in diabetes gives new insight to the etiology of mitochondrial diabetes. Its pathogenecity supports the belief that the tRNA(Leu)(UUR) gene is an etiological hot spot of mitochondrial diseases.

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.

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.

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 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

Incidence of peripheral arteriosclerotic complications of the lower extremities in diabetic patients with chronic renal failure.

Abstract:  Patients with diabetes mellitus are at high risk of arteriosclerotic complications. The same is true for those with chronic renal failure (CRF). The present study evaluated clinical factors on the occurrence of peripheral arterial diseases. The severity of peripheral arterial disease was defined as mild (plaque, calcifications) or severe (70% stenosis, obstructions) based upon ultrasonographical examination. Overall in diabetic patients, mild ultrasonographical findings such as plaque and calcification were observed in 25% (17/69) of predialysis patients and in 18% (7/38) of those on hemodialysis (HD). Severe arteriosclerotic findings such as stenosis and obstruction were seen in 42% (29/69) of predialysis patients and in 50% (19/38) of those on HD. The incidence is identical between predialysis patients and patients on HD, regardless of the severity of peripheral arterial diseases. In an attempt to compare diabetics with non‐diabetics, the incidence of mild abnormal findings was found in 22% (24/107) of diabetics and in 30% (11/37) of non‐diabetics. Similarly, the percentage of patients with severe arteriosclerotic findings was found in 45% (48/107) in diabetics and 11% (4/37) in non‐diabetics. The incidence of the severe type findings in the diabetics is significantly more frequent than that in the non‐diabetics (P < 0.01, by the χ2 test). In non‐diabetic predialysis patients, the incidence of mild arteriosclerotic findings was observed in 30% (7/23), and 29% (4/14) of non‐diabetic patients on HD. Similarly, the percentage of severe type was 9% (2/23) in non‐diabetic predialysis patients, and 14% (2/14) in non‐diabetic patients on HD. These data are not only supportive of previous data that diabetes is a risk factor for arteriosclerosis, but also suggestive that, even before the initiation of dialysis, patients with CRF are already susceptible to arteriosclerotic assault of peripheral arterial complications.