Reversed circadian blood pressure rhythm is associated with occurrences of both fatal and nonfatal vascular events in NIDDM subjects.

To assess the significance of reversed circadian blood pressure (BP) rhythms as a predictive factor of vascular events in NIDDM, vital status after an average 4-year follow-up was determined in 325 NIDDM subjects in whom the circadian BP profile had been monitored between 1988 and 1996. Circadian BP rhythm was analyzed by the COSINOR (a compound word for cosine and vector) method, as previously described. After exclusion of 37 dropped-out subjects, 288 were recruited to the further analysis, of which 201 had a normal circadian BP rhythm (group N) and the remaining 87 had a reversed one (group R). There was no difference in sex, HbA1c, the prevalence of smokers, serum lipids, or serum electrolytes between groups N and R at baseline, whereas age, the prevalence of hypertension, serum creatinine, and diabetic complications were more pronounced in group R than in group N. During the follow-up period (which averaged 52 months in group N and 36 months in group R), fatal and nonfatal vascular (cerebrovascular, cardiovascular, peripheral vascular arteries, and retinal artery) events occurred in 20 subjects in group N and 56 in group R. Unadjusted survival times and event-free times were estimated by the Kaplan-Meier product-limit method, and there was a significant difference in both unadjusted survival and event-free survival rates between groups N and R (P < 0.001 each; log-rank test). The Cox proportional-hazards model adjusted for age, sex, circadian BP pattern, duration of diabetes, therapy for diabetes, various diabetic complications, and hypertension demonstrated that circadian BP pattern and age exhibited significant, high adjusted relative risks for fatal events, and that diabetic nephropathy, postural hypotension, and hypertension as well as circadian BP pattern exhibited significant, high adjusted relative risks with respect to the occurrence of various nonfatal vascular events. These results suggest that reversed circadian BP rhythm is associated with occurrences of both fatal and nonfatal vascular events in NIDDM subjects.

Circadian rhythm of blood pressure in normotensive NIDDM subjects. Its relationship to microvascular complications.

OBJECTIVE: To investigate the relationship between circadian rhythm of mean blood pressure (MBP) and microvascular complications in non-insulin-dependent diabetes mellitus (NIDDM) subjects. RESEARCH DESIGN AND METHODS: Seventy-six normotensive NIDDM subjects without azotemia were studied under ordinary hospital conditions with a noninvasive ambulatory blood pressure monitoring device. Time series data were analyzed by the cosinor method. RESULTS: Fifty-four subjects had a circadian MBP rhythm similar to that of 34 age-matched nondiabetic control subjects, with a peak value in the afternoon (group 1). In contrast, 22 had a reversed circadian MBP rhythm, with a peak value during the night (group 2). Obvious complications were found in 65% of group 1 and in all of group 2. The prevalence of retinopathy and somatic neuropathy and the degree of retinopathy were similar in the two groups. The prevalence and degree of autonomic neuropathy (postural hypotension and reduced beat-to-beat heart-rate variation) and nephropathy were greater in group 2 than group 1. Linear discriminant analysis revealed a correlation between the reversed circadian MBP rhythm and postural hypotension (F = 32.2, P less than 0.001) and overt nephropathy (F = 5.1, P less than 0.05) but not with beat-to-beat heart-rate variation (F = 0.17, NS). CONCLUSIONS: These results suggest that in the hospitalized normotensive NIDDM subjects, there are normal and reversed circadian MBP rhythms and that the reversal of normal circadian MBP rhythm may be related to the degree of postural hypotension and/or nephropathy.

Angiotensin II receptor and postreceptor events in adrenal glomerulosa cells from streptozotocin-induced diabetic rats with hypoaldosteronism.

Streptozotocin-induced chronic diabetic rats develop hyporeninemic hypoaldosteronism. The hypoaldosteronism is associated with selective unresponsiveness of aldosterone to angiotensin II (AII) and an atrophy of the zona glomerulosa. To assess the nature of the adrenal unresponsiveness to AII, we examined the [125I]monoiodoAII binding and the responses of pregnenolone formation and aldosterone production to AII using adrenal glomerulosa cells from diabetic rats 6 weeks after an injection of streptozotocin. Comparisons were made using the cells from control rats treated with vehicle. Diabetic rats had low levels of plasma renin activity, plasma 18-hydroxycorticosterone, and plasma aldosterone, and normal levels of plasma corticosterone and plasma potassium. The zona glomerulosa width was narrower in diabetic than in control rats. Scatchard analysis of the AII binding data demonstrated that the number and affinity of the receptors were similar in the cells from control and diabetic rats. When corrected to an uniform number of cells per group, baseline levels of pregnenolone formation and aldosterone production were similar in the cells from control and diabetic rats. However, cells from diabetic rats had a less sensitive and lower response of both pregnenolone formation and aldosterone production to AII. In contrast, the effect of ACTH on pregnenolone formation and aldosterone production was similar in the cells from control and diabetic rats. These results indicate that the main defect responsible for the hypoaldosteronism may be located on some step(s) mediating between AII receptors and conversion of cholesterol to pregnenolone, presumably on the calcium messenger system, with a disturbance downstream from AII binding.

Effects of angiotensin II, adrenocorticotropin, and potassium on aldosterone production in adrenal zona glomerulosa cells from streptozotocin-induced diabetic rats.

Hyporeninemic hypoaldosteronism has been shown to occur in streptozotocin-induced chronic diabetic rats with normokalemia. To test the nature of the aldosterone deficiency, we investigated the responses of aldosterone production to angiotensin II (AII), ACTH, and potassium in adrenal zona glomerulosa cells from diabetic rats at 6 weeks after an injection of streptozotocin compared with those in the cells from control rats. In diabetic rats, plasma glucose was high and plasma immunoreactive insulin was low. Diabetic rats also had low levels of PRA and plasma AII, low levels of plasma aldosterone, and normal levels of plasma corticosterone and plasma potassium. The zona glomerulosa width was narrower in diabetic rats than in control rats. Basal aldosterone production, when corrected to an uniform number of cells per group, was similar in the cells from control and diabetic rats. Cells from diabetic rats showed a less sensitive and lower response of aldosterone production to AII, increases in the threshold and the ED50, and a decrease in the maximal AII-stimulated aldosterone level. ACTH, however, caused a similar effect on aldosterone production in the cells from control and diabetic rats. Cells from diabetic rats exhibited a less sensitive response of aldosterone production to potassium and a tendency to be low in the maximal potassium-stimulated aldosterone level, presumably attributable to the impairment of adrenal zona glomerulosa cells to AII. We conclude that the hypoaldosteronism observed in our diabetic rats may be secondary to the deficiency of AII.

Role of the renin-angiotensin system in enhancing the aldosterone response to adenocorticotropin during acute sodium depletion in normal subjects.

The role of the renin-angiotensin system in enhancing aldosterone responsiveness to ACTH during acute sodium depletion was studied in 14 healthy medical students. Acute sodium depletion was achieved by oral treatment with 80 mg furosemide and 200 mg SQ 14,225 for 1 day. The im administration of 250 micrograms alpha ACTH-(1-24) or vehicle was performed at 0800-0900 h both on the day after ad libitum diet (control) and 1 h after the oral administration of 50 mg SQ 14,225 on the day after acute sodium depletion. Treatments with furosemide and SQ 14,225 before both ACTH and vehicle administration induced a reproducible sodium depletion, accompanied by a marked increase in PRA and no significant increase in plasma aldosterone. The administration of ACTH, but not of vehicle, produced significant increases in plasma aldosterone in both control and acute sodium-depleted subjects. However, the ACTH-induced increases in plasma aldosterone and their maximal net and percent increments during acute sodium depletion were significantly greater than control values. It is concluded that angiotensin II does not play an important role in enhancing the aldosterone-stimulating activity of ACTH during acute sodium depletion and that sodium depletion per se may be responsible for this enhancement.

Lack of enhanced responsiveness of plasma 18-hydroxycorticosterone and aldosterone to adrenocorticotropin as well as to angiotensin-II during moderate sodium depletion in type II diabetic subjects with normoreninemia.

Responses of plasma aldosterone (PA) and its precursor steroids to alpha ACTH-(1-24) (85.2 nmol, iv) injection and graded angiotensin-II (AII) infusions (3.90 and 7.80 pmol/kg.min for 30 min at each dose) on both 170 and 100 mmol sodium intakes were assessed in 25 type II diabetic subjects with normoreninemia and 11 age-matched normal subjects. The diabetic subjects and the normal subjects did not differ in mean blood pressure, serum electrolytes, and creatinine clearance, except for an increase in fasting plasma glucose (P less than 0.001) in the diabetic subjects. A 100-mmol sodium intake for 4 days produced an increase in basal plasma renin activity (P less than 0.01), plasma 18-hydroxycorticosterone (18-OHB; P less than 0.05), and PA (P less than 0.05), and a decrease in urinary sodium excretion (P less than 0.001) in the two groups. These parameters were similar in the two groups. ACTH injection produced significant increases in plasma cortisol, plasma corticosterone, plasma 18-OHB, and PA (P less than 0.005 or P less than 0.001), and graded AII infusions produced significant increases in plasma 18-OHB and PA (P less than 0.05 or P less than 0.01) during both 170- and 100-mmol sodium intakes in the two groups. In the diabetic subjects, however, the responses of plasma 18-OHB and PA to both ACTH injection and graded AII infusions on a 100-mmol, but not on a 170-mmol, sodium intake were subnormal (P less than 0.05 or P less than 0.01) and were similar to those on a 170-mmol sodium intake. These results indicate a lack of enhanced responsiveness of plasma 18-OHB and PA to both ACTH and AII during moderate sodium restriction in nonazotemic type II diabetic subjects with normoreninemia. It appears that these subjects have selective unresponsiveness of adrenal zona glomerulosa to sodium depletion per se, but not to ACTH or AII.

Association of a nocturnal rise in plasma alpha-atrial natriuretic peptide and reversed diurnal blood pressure rhythm in hospitalized normotensive subjects with non-insulin dependent diabetes mellitus.

Diurnal changes in plasma atrial natriuretic peptide (ANP), plasma renin activity (PRA) and plasma aldosterone as related to those in blood pressure (BP) were studied under hospital conditions in 18 diabetic subjects without proteinuria and 8 age-matched control subjects. Of 18 diabetic subjects, 10 had a normal diurnal BP rhythm with the peak value in the afternoon (group 1) and 8 had a reversed BP rhythm with the peak value during the night (group 2). Autonomic dysfunction estimated by measuring orthostatic BP and heart-rate changes and beat-to-beat heart-rate variations was more pronounced in group 2 than in group 1. Fasting plasma glucose and HbA1c were similarly high in both diabetic groups. Group 1 showed modestly elevated mean 24-h MBP and plasma ANP levels, modestly low mean 24-h PRA and plasma aldosterone levels, and a lack of diurnal ANP changes similar to that in controls. Group 2 showed markedly elevated mean 24-h BP and plasma ANP levels, markedly low mean 24-h PRA and plasma aldosterone levels, and nocturnal rises in plasma ANP and BP. PRA and plasma aldosterone exhibited circadian rhythms with their peak values found in the early morning in all three groups. The daytime/overnight excretion ratios of sodium and water were normal in group 1 and low in group 2. These results indicate that diurnal changes in plasma ANP, PRA and plasma aldosterone are altered in diabetic subjects with normal and reversed diurnal BP rhythms, predominantly in the latter.

Plasma aldosterone response to angiotensin II in sodium-restricted elderly subjects with essential hypertension.

The plasma aldosterone (PA) response to sodium restriction (25 mEq daily for 4 days) and to graded infusions of angiotensin II (AII, 2, 4 and 8 ng/kg/min each for 30 min) during a low-sodium intake were studied in 15 elderly subjects with mild essential hypertension versus 10 elderly normotensive subjects. The PA response to sodium restriction relative to changes in plasma renin activity (PRA) was estimated by the ratio of PA increment to PRA increment after sodium restriction (delta PA/delta PRA). THe PA response to graded AII infusions was determined by the increment of PA above the basal level after each dose of AII. In 10 of the 15 elderly hypertensive subjects whose PRAs responded normally to sodium restriction, the delta PA/delta PRA ratios and PA increments during the graded AII infusions were similar to those in the elderly normotensive subjects. However, in the remaining 5 elderly hypertensive subjects whose PRAs responded subnormally to sodium restriction, the delta PA/delta PRA ratios were high and the PA increments greater during the graded AII infusions. THe increments of mean blood pressure during the graded AII infusions were similar in the foregoing 10 of 15 hypertensive subjects, and significantly greater during the AII infusion rates of 4 and 8 ng/kg/min in the remaining 5 hypertensive subjects when compared with those in the normotensive subjects. Apparently some subjects with essential hypertension, whose PRAs response subnormally to sodium restriction, have an abnormally enhanced adrenal responsiveness to AII under the conditions of low-sodium intake.

Enhancement of potassium-, and angiotensin II-stimulated aldosterone production by the calcium chelator EGTA in bovine adrenal glomerulosa cells in vitro.

The present study was designed to assess the effect of the calcium chelator EGTA (ethylenglycolbis-(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid; 1.0 mM) on potassium (8 mM)- and angiotensin II (AII; 10 nM)-stimulated aldosterone production in bovine adrenal glomerulosa cells in vitro. The combined administration of EGTA and potassium, or of EGTA and AII, yielded a significant increase in the levels of aldosterone production. The net increment in aldosterone production after the combined administration of EGTA and potassium, or that after the combined administration of EGTA and AII was also significantly higher than the sum of that evoked by EGTA and potassium alone, or the sum of that evoked by EGTA and AII alone, respectively. At similar concentrations of extracellular ionized calcium ([Ca2+]out) or magnesium, the levels of agonist-stimulated aldosterone production were markedly elevated by the administration of EGTA. These results indicate that lowering [Ca2+]out concentrations with EGTA enhances potassium- and AII-stimulated aldosterone production in bovine adrenal glomerulosa cells in vitro. This enhancement may be predominantly due to another effect of EGTA, in addition to the stimulation of calcium entry into the cells.

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.

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.

Effects of perindopril on glucose and lipid metabolism in patients with mild-to-moderate essential hypertension and glucose intolerance.

The effect of perindopril, an angiotensin-converting enzyme inhibitor, on glucose and lipid metabolism was evaluated in 12 patients with mild-to-moderate essential hypertension and glucose intolerance. Perindopril was administered at a dosage of 2 to 8 mg once daily for 12 weeks. Both the systolic and diastolic blood pressures were significantly reduced throughout the treatment period. There were no significant changes in the insulinogenic index (delta plasma immunoreactive insulin/delta plasma glucose) calculated from the results of 75-g oral glucose tolerance tests performed before and after perindopril treatment. Serum levels of glycosylated hemoglobin, fructosamine, lipids, lipoproteins, and apolipoproteins were also not affected. These results suggest that perindopril can be used effectively to treat hypertension in patients with glucose intolerance without affecting glucose and lipid metabolism.

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.

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.

Increased basal levels of plasma nitric oxide in Type 2 diabetic subjects. Relationship to microvascular complications.

To assess the underlying mechanisms of decreased endothelial function and advanced vascular complications in patients with Type 2 diabetes, we determined basal levels of plasma nitric oxide (NO(x): NO(2)(-) and NO(3)(-)) using a newly developed high-performance liquid chromatography (HPLC)-Griess method in hospitalized 129 diabetic and 76 nondiabetic subjects, and examined their clinical characteristics. Serum lipid peroxide and advanced glycation end products (AGEs) as markers of oxidative stress were also measured, and intima-media thickness (IMT) of the carotid artery was evaluated as a marker of atherosclerosis. In diabetic subjects, microvascular complications were newly evaluated during their admission. There were no differences in age or sex between the diabetic and nondiabetic subjects. Although there was no difference in basal plasma NO(2)(-) levels between the two groups, the basal levels of plasma NO(3)(-) in diabetic subjects were significantly higher than those in nondiabetic subjects. Plasma NO(x) levels in neither diabetic nor nondiabetic subjects correlated with serum lipids, HbA1c, or IMT. In diabetic subjects, plasma NO(3)(-) levels were related not only to the presence of hypertension but also to advanced microvascular complications. Moreover, plasma NO(3)(-) levels were positively correlated with both serum lipid peroxide and AGEs. Multiple regression analysis revealed that serum AGEs level was strongly associated with plasma NO(3)(-) level. Thus, the findings are consistent with the hypothesis that decreased endothelium-dependent vasodilation in diabetic subjects is associated with the impaired action of NO secondary to its inactivation resulting from increased oxidative stress, rather than decreased NO production from vascular endothelium, and that abnormal NO metabolism is related to advanced diabetic microvascular complications.

Altered circadian blood pressure rhythm and progression of diabetic nephropathy in non-insulin dependent diabetes mellitus subjects: an average three year follow-up study.

BACKGROUND: In addition to autonomic dysfunction, diabetic nephropathy has been identified as another factor inducing a reversed circadian blood pressure (BP) rhythm in diabetic subjects. This study was carried out to assess the relationship between alterations in circadian BP rhythm and progression of diabetic nephropathy in subjects with non-insulin dependent diabetes mellitus (NIDDM). METHODS: Ambulatory 24-hour BP, 24-hour urinary albumin excretion rate (UAE), and plasma hormonal factors were measured during an average 3-year follow-up in 16 hospitalized subjects with NIDDM. Twelve age-matched control subjects were also studied. RESULTS: During an average 3-year follow-up, diabetic subjects had no significant progression of severe nephropathy and/or somatic neuropathy and showed no transition from a normal to a reversed mean blood pressure (mBP) pattern. However, mBP during whole day or nighttime, but not daytime, at baseline in diabetic subjects was high as compared with control subjects exhibiting an increased night/day mBP ratio and a decreased night/day mBP difference. The mBPs during various time periods (whole day, daytime, and nighttime) at follow-up in diabetic subjects were more elevated than those at baseline, showing a more increased night/day mBP ratio and a more decreased night/day mBP difference. In diabetic subjects, UAE during follow-up was increased, and UAE increments were well correlated with changes in mBP during whole day and nighttime. Plasma renin activity (PRA) and plasma aldosterone (PA) were decreased, while plasma alpha-atrial natriuretic peptide (ANP) was increased at follow-up, compared with at baseline. The mBP increments during various time periods were well correlated with changes in these hormonal factors, and UAE increments were well correlated with changes in PA and plasma ANP. CONCLUSIONS: The altered circadian BP rhythm observed in diabetic subjects may occur at the early stage of diabetic nephropathy with opposite changes in plasma renin-aldosterone and plasma ANP.

Treatment of renovascular hypertension using stent implantation in an elderly patient with NIDDM.

A 70-year-old man with NIDDM was diagnosed as having renovascular hypertension (RVH), based on a stenosis of the ostial portion of the left renal artery with markedly elevated plasma renin activity (PRA) in both the left renal vein and the peripheral blood, and positive captopril tests. After percutaneous transluminal renal angioplasty (PTRA), his blood pressure (BP) and PRA normalized. However, since restenosis occurred three months later, stent therapy was applied, and consequently BP and PRA normalized immediately after this procedure. During the one-year follow-up, side effects have not been noted. We propose that stent therapy may be feasible for ostial renal artery stenosis in elderly diabetic patients.

Pentasomy X mosaic in two adult sisters with diabetes mellitus.

Pentasomy X mosaic in two adult sisters with non-insulin dependent diabetes mellitus is described. The younger sister had schizophrenia, and both were mentally retarded, but no apparent somatic abnormalities were found. Chromosome analyses revealed karyotype 45,X/46,XX/47,XXX/48,XXXX/49,XXXXX mosaic with a low frequency of aneuploidy on cultured peripheral lymphocytes and 46,XX on cultured skin fibroblasts in both sisters. The low frequency of X chromosome aberration may be responsible for the lack of somatic abnormalities and the long life in both sisters. The association of pentasomy X mosaicism and diabetes mellitus however appears to be coincidental.

Non-obese Cushing's syndrome in an aged woman with non-insulin-dependent diabetes mellitus.

A 76-year-old diabetic woman with non-obese Cushing's syndrome developed poor glycemic control with glibenclamide. She presented with a slight weight loss while bedridden due to a fall. Cushing's syndrome in this patient was suspected because of hypercortisolemia with eosinopenia, and adrenal Cushing's syndrome was diagnosed by endocrine and radiological examinations. A right adrenal adenoma was confirmed by autopsy. In this patient, progressive obesity and other common features of Cushing's syndrome may have been concealed by aging itself and coexisting diabetes mellitus.