Mitsutaka Kitazawa

Effect of 24 weeks of treatment with epalrestat, an aldose reductase inhibitor, on peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus

The effects of treatment with epalrestat, an aldose reductase inhibitor, on peripheral neuropathy were studied in 45 patients with non-insulin-dependent diabetes mellitus (NIDDM). Epalrestat 150 mg three times daily was given for 24 weeks. Subjective symptoms, such as spontaneous pain in the lower extremities and numbness and hypoesthesia of the extremities or trunk, were significantly (P < 0.001) relieved after 12 and 24 weeks of epalrestat treatment. Vibratory perception thresholds, as measured by using a tuning fork (C-128) and a vibrometer, were improved after 24 weeks of treatment. Furthermore, there were no adverse effects on glucose or lipid metabolism during treatment. These results suggest that long-term (24-week) epalrestat therapy can be used effectively to treat peripheral neuropathy in NIDDM patients without affecting glucose or lipid metabolism.

Reversed circadian blood pressure rhythm independently predicts endstage renal failure in non-insulin-dependent diabetes mellitus subjects.

To investigate the significance of reversed circadian blood pressure (BP) rhythm as a predictor for diabetic endstage renal failure, introduction of hemodialysis (HD) was determined as an end point in 325 noninsulin-dependent diabetes mellitus (NIDDM) subjects, in whom 24-h BPs had been monitored during their first admissions between 1988 and 1996. Circadian BP rhythm was analyzed by the COSINOR method, as previously reported. After exclusion of 68 dropout subjects, 257 were recruited for further analyses, in which 194 had normal circadian BP rhythms (N), and the remaining 63 had reversed rhythms (R). During this follow-up period, the numbers of HD-introduced subjects in N and R were 6 and 16, respectively, showing a higher prevalence in the latter (p < 0.001, chi2 test). Follow-up periods were significantly shorter in HD-introduced diabetic subjects of N and R than those in HD-free subjects of each group. In baseline characteristics, there were no differences in age, gender, or serum creatinine between HD-free and HD-introduced subjects of N or R. With regard to microvascular complications, the degree of retinopathy and nephropathy in N and R tended to be more pronounced in HD-introduced subjects than in HD-free subjects. Further, mean levels of circadian mean BP rhythms in HD-introduced subjects of N or R were similarly high, compared with those in HD-free subjects of each group, irrespective of circadian BP pattern. Unadjusted HD-free times were estimated by the Kaplan-Meier method, with a significant difference noted between N and R (p < 0.001; log-rank test). The Cox proportional-hazards model adjusted for circadian BP pattern, age, gender, blood pressure level, glycemic control, duration of diabetes, serum total protein, and serum creatinine demonstrated that circadian BP pattern, age, gender (female), blood pressure level (hypertension), and serum creatinine exhibited significant high relative risks. Thus, our data suggest that reversed circadian BP rhythm is an independent predictor of endstage renal failure in NIDDM subjects.

Mitochondrial DNA Mutations Are Associated with Both Decreased Insulin Secretion and Advanced Microvascular Complications in Japanese Diabetic Subjects

To assess the roles of various mitochondrial (Mt) DNA mutations in diabetic and nondiabetic subjects, we screened Mt DNAs at the 3243 base pair (bp) and its adjacent portion in unrelated Japanese diabetic and nondiabetic subjects. Furthermore, to clarify the clinical features of diabetic subjects harboring a Mt DNA mutation, we evaluated the ability of insulin secretion and microvascular complications in diabetic subjects. Five hundred thirty-seven diabetic patients and 612 unrelated nondiabetic subjects were recruited into this study. In Mt DNA analyses, Mt DNA was isolated from peripheral leukocytes of the subjects, and then an Mt DNA fragment surrounding the tRNA(Leu(UUR)) site was amplified by the polymerase chain reaction (PCR) using two sets of primers. These fragments were further digested with three kinds of restriction endonucleases and were subjected to agarose gel electrophoresis. When a mutation was present, Mt DNA fragments were directly sequenced with an autosequencer. Baseline characteristics in all subjects were examined, and microvascular complications and insulin secretory capacity in diabetic subjects were newly evaluated. Eight kinds of Mt DNA mutations, which were point mutations, were found in 74 subjects. Each affected subject had only one mutation in the Mt DNA examined. Among them, the mutations at np 3316, 3394, 3593, and 3391 were accompanied by amino acid replacement. Thirty-eight diabetic patients were affected (7.1%), including two subjects with a point mutation at np 3243, and 26 nondiabetic subjects were affected (4.2%). Thus, there was a higher prevalence in diabetic subjects than in nondiabetic subjects. There was no significant difference in the prevalence of maternally inherited diabetes between these two groups. The mean level of urinary C-peptide excretion was lower in diabetic subjects with an Mt DNA mutation (DM+) than in those without it (DM-). Although the prevalence of hypertension in DM+ was higher than that in DM-, diabetic retinopathy and nephropathy in DM+ were problematic, in comparison with those in DM-, when statistical corrections were performed for the effect of hypertension. Furthermore, a strategy based on logistic regression analysis revealed that advanced retinopathy and decreased urinary C-peptide excretion in all diabetic subjects studied were strongly related to the presence of Mt DNA mutation. Our results suggest that Mt DNA mutations in Japanese diabetic subjects are related to the development of diabetes, and also that these mutations are associated with not only a decrease in insulin secretion but also advanced diabetic microvascular complications.

Insulin Resistant State in Type 2 Diabetes Is Related to Advanced Autonomic Neuropathy

To elucidate the relationships between obesity, glycemic control, dyslipidemia, hypertension, microvascular complications, and insulin resistance assessed using an euglycemic hyperinsulinemic clamp technique, we studied 54 hospitalized type 2 diabetic subjects (DM) and 10 age‐ and sex‐matched normotensive, nonobese control subjects (C). Glucose infusion rate (GIR) derived from the clamp study was used as an index of insulin resistance. Body mass index (BMI), the prevalence of hypertension, HbA1c and serum nonesterified fatty acids (NEFA) were significantly higher, and serum high‐density‐lipoprotein (HDL)‐cholesterol was significantly lower in DM than in C (p < 0.05 or less). The median GIR level was significantly lower in DM than in C (p = 0.038). The difference in GIR between the two groups was still statistically significant even after adjustment for BMI, mean BP, HbA1c, NEFA, and HDL‐cholesterol. However, after simultaneous adjustment for these factors, there was no difference in GIR between the two groups. Body mass index, mean BP, HbA1c, and NEFA showed negative correlations, and serum HDL‐cholesterol showed a positive correlation with GIR, but neither age nor duration of diabetes correlated with GIR. When GIR values in DM were divided according to the degree of neuropathy, retinopathy, and nephropathy, and compared to those in C, GIR levels tended to be decreased with increasing severity of each microvascular complication, but there was no difference in median GIR levels among the diabetic subgroups. Relationships between the GIR levels and confounding factors such as age, sex, BMI, mean BP, HbA1c, serum NEFA, and serum HDL‐cholesterol, were examined simultaneously with a multiple regression analysis. This analysis revealed that HbA1c and serum NEFA may affect the GIR level. Furthermore, together with these two factors, the relationships between the GIR levels and the severity of each microvascular complication were explored with the same analysis. This model clearly demonstrated that both the decreased CVR‐R and pronounced orthostatic fall in systolic BP were independent factors for the decreased GIR. These findings suggest that marked autonomic dysfunction, rather than other confounding factors, is related to increased insulin resistance in DM.

Insulin resistance is associated with reduced nocturnal falls of blood pressure in normotensive, nonobese type 2 diabetic subjects.

To assess the relationship between insulin resistance and ambulatory blood pressure (BP) pattern, we determined glucose infusion rate (GIR) as a marker of insulin resistance using a glucose clamp method, and measured 24-h BPs in 25 normotensive, nonobese type 2 diabetic subjects. They were divided into two groups: 11 dippers and 14 nondippers. Clinical characteristics were similar in the two groups except for orthostatic fall in systolic BP. The median GIR level was significantly lower in nondippers than in dippers (P < 0.05). Spearmans rank correlation revealed that the GIRs were negatively correlated with the systolic, diastolic and mean BPs during nighttime (P < 0.05 or less), but not with daytime or whole day BPs. Moreover, based on a logistic regression analysis, the GIR as well as orthostatic fall in systolic BP discriminated independently between dippers and nondippers. Thus, our results suggest that insulin resistance is associated with decreased nocturnal BP fall in type 2 diabetic subjects.

Effects of posture on the plasma hormonal and renal water-electrolyte excretory responses to acute water loading in diabetic subjects with hypoadrenergic orthostatic hypotension.

The effects of posture on the plasma hormonal and renal water-electrolyte excretory responses to acute water loading (20 mL/kg BW, orally) were studied in six non-insulin-dependent diabetes mellitus (NIDDM) subjects with hypoadrenergic orthostatic hypotension (HOH), eight NIDDM subjects without HOH, and seven nondiabetic subjects. The three groups were similar with respect to basal levels of mean blood pressure (MBP), serum sodium and osmolality, plasma renin activity (PRA), the plasma volume regulatory hormones alpha-atrial natriuretic peptide (ANP), arginine vasopressin (AVP) and aldosterone, and urinary water and sodium excretion. In the supine state, while allowing the subjects to stand only to void, water loading resulted in no changes in MBP and similar responses of these plasma and urinary parameters in the three groups. In the standing state, water loading produced responses of MBP, and plasma and urinary parameters comparable to those in the supine state in the diabetic group without HOH and the nondiabetic group. In the diabetic group with HOH, however, MBP and hourly urinary water and sodium excretion rates were low compared to those in the other two groups. During water loading, plasma ANP decreased, and, despite the fall of MBP, plasma AVP remained unchanged, and PRA and plasma aldosterone increased normally in the diabetic group with HOH. These results demonstrate that, in NIDDM subjects with HOH, changing from lying to standing induces deranged renal water and sodium handling after water loading, accompained by a decrease in plasma ANP, and inadequate responses of plasma AVP, PRA, and plasma aldosterone to hypotension.

Effects of long-term cilazapril treatment on glucose and lipid metabolism in hypertensive patients with non-insulin-dependent diabetes mellitus.

The effects of long-term cilazapril treatment on glucose and lipid metabolism were assessed in 25 hypertensive patients with non-insulin-dependent diabetes mellitus (NIDDM). Patients were treated with 0.5 to 1 mg of cilazapril once daily or a combination of cilazapril and other antihypertensive drugs once daily for 48 weeks. Both systolic and diastolic blood pressures were significantly reduced (P < 0.001) throughout the study with no significant changes in heart rate and no adverse effects such as cough. There were no significant changes in body mass index or serum levels of glycated hemoglobin A1c, fructosamine, total cholesterol, triglycerides, lipoproteins (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and very-low-density lipoprotein cholesterol), or apolipoproteins (apo A-I, apo C-II, apo C-III, apo B, and apo E). Cilazapril caused a significant increase (P < 0.05) in levels of apo A-II and a significant decrease (P < 0.05) in the apo B:apo A-I ratio, an index of arteriosclerosis. These results suggest that cilazapril has favorable effects on glucose and lipid metabolism and that it may be useful as the first or second choice of antihypertensive drugs in hypertensive patients with NIDDM.