Kiyohide Nunoi

Lack of association between blood pressure and insulin in patients with insulinoma

To investigate the hypothesis that insulin affects the regulation of blood pressure, blood pressure and fasting insulin and glucose levels were measured in seven patients with insulinoma both before and after resection of the insulinoma. The diagnosis of all insulinoma cases was confirmed during surgery. Before surgery, systolic and diastolic blood pressures were 127 +/- 15 and 74 +/- 9 mmHg, respectively, and did not correlate with the fasting insulin levels. At least 3 weeks after the surgery, significant decreases in fasting insulin levels (from 568 +/- 571 to 74 +/- 43 pmol/l, P less than 0.005) and body weight (-9.8 +/- 7.1%, P less than 0.05) were observed along with a significant increase in fasting glucose levels (98.2 +/- 43.2%, P less than 0.001). However, both systolic (-4.7 +/- 9.9%) and diastolic (-0.2 +/- 6.3%) blood pressures remained unchanged. The changes in fasting insulin levels were not linearly correlated with those in systolic and diastolic blood pressures. Even after the changes in both body weight and fasting glucose levels were taken into consideration using partial correlations, the changes in fasting insulin levels did not correlate with those in systolic and diastolic blood pressures. It was concluded that blood pressure, both systolic and diastolic, was not at hypertensive levels in the patients with insulinoma and showed no decrease after resection of the insulinoma. Therefore, insulin may not affect the regulation of blood pressure in patients with insulinoma.

Reduced regional cerebral blood flow in aged noninsulin-dependent diabetic patients with no history of cerebrovascular disease: Evaluation by N-lsopropyl-123I-p-iodoamphetamine with single-photon emission computed tomography

Regional cerebral blood flow was measured using N-isopropyl-123I-iodoamphetamine with single-photon emission computed tomography (CT) in 16 aged patients with noninsulin-dependent diabetes mellitus (NIDDM, average age 72.8 years, average fasting plasma glucose 7.7 mmol/L), and 12 nondiabetic subjects (71.6 years, 5.3 mmol/L). None had any history of a cerebrovascular accident. Systolic blood pressure (SBP), total cholesterol, and triglyceride levels did not differ between groups. Areas of hypoperfusion were observed in 14 diabetic patients (12 patients had multiple lesions) and in 6 nondiabetic subjects (3 had multiple lesions). Areas where radioactivity was greater than or equal to 65% of the maximum count of the slice was defined as a region with normal cerebral blood flow (region of interest A, ROI-A), and areas where the count was greater than or equal to 45% were defined as brain tissue regions other than ventricles (ROI-B). The average ROI-A/B ratio of 16 slices was used as a semiquantitative indicator of normal cerebral blood flow throughout the entire brain. Mean ROI-A/B ratio was 49.6 +/- 1.7% in the diabetic group, significantly lower than the 57.9 +/- 1.6% at the nondiabetic group (p less than 0.005). The ratio was inversely correlated with SBP (r = -0.61, p less than 0.05), total cholesterol (r = -0.51, p less than 0.05), and atherogenic index (r = -0.64, p less than 0.01), and was positively correlated with high-density lipoprotein (HDL) cholesterol (r = 0.51, p less than 0.05) in the diabetic, but not the nondiabetic group. These observations suggest that the age-related reduction in cerebral blood flow may be accelerated by a combination of hyperglycemia plus other risk factors for atherosclerosis.

A new diabetes model induced by neonatal alloxan treatment in rats

Rats treated with streptozotocin (STZ) during the neonatal period have been used as a model of non-insulin-dependent diabetes mellitus. The present study was designed to produce another diabetes model by substituting alloxan for STZ. Male Sprague-Dawley rats of 2, 4 or 6 days of age were injected intraperitoneally with 200 mg/kg of alloxan monohydrate after 16 h fast. Control rats received vehicle alone at 6 days of age. Non-fasting plasma glucose levels in alloxan-treated rats significantly increased after 8 weeks as compared with control, as the age of alloxan treatment advanced (6.6 +/- 0.2 (S.E.M.) mM in control, 8.3 +/- 0.3 mM in 2 days, P < 0.05, 9.8 +/- 0.9 mM in 4 days, P < 0.05, 17.1 +/- 3.5 mM in 6 days, P < 0.05). For the long-term observation, alloxan-treated rats were divided into mild and severe diabetes groups. Hyperglycemia persisted in both groups until 52 weeks (6.5 +/- 0.1 mM in control, 10.3 +/- 0.7 mM in mild diabetes group, 25.3 +/- 3.6 mM in severe group), but significant albuminuria developed only in severe diabetes group. The diabetogenicity of alloxan rapidly increased during the neonatal period, and the neonatal alloxan diabetes model may be useful for studying chronic diabetic complications.

A new model of Type 2 (non-insulin-dependent) diabetes mellitus in spontaneously hypertensive rats: diabetes induced by neonatal streptozotocin treatment

SummaryThis study was designed to develop an animal model of Type 2 (non-insulin-dependent) diabetes with persistent hypertension. Male spontaneously hypertensive rats were treated with 25.0, 37.5, 50.0, 62.5 or 75.0 mg/kg of streptozotocin given intraperitoneally at 2 days of age and maintained for 12 weeks. In the rats which received 50.0 mg/kg or more streptozotocin, overt hyperglycaemia gradually and consistently developed following incomplete recovery from an initial hyperglycaemia. Compared to vehicle-treated controls, body weight gain in these animals did not differ for the first 8 weeks; thereafter, it was slightly but significantly (p < 0.05) reduced. The animals treated with 25.0 or 37.5 mg/kg streptozotocin developed mild to moderate hyperglycaemia, but their body weight gain was similar to controls. The relationships between streptozotocin dose and metabolic responses (plasma glucose, glycosylated haemoglobin, urinary glucose, food intake, etc.) were clearly demonstrated. Systolic blood pressure rose with progressing age in both controls and streptozotocin-treated rats, irrespective of dosage or metabolic response. This new rat model of Type 2 diabetes associated with persistent hypertension may be useful in studying these combined effects on small and large vessels.

Glucose tolerance and insulin secretion in conscious and unrestrained normotensive and spontaneously hypertensive rats.

We compared the glucose tolerance and insulin responses to intravenous (IV) glucose administration of a dose of 1 g/kg body weight in a conscious and unrestrained state of spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) with catheters chronically indwelled into artery and vein. Both plasma glucose levels at two minutes and ten minutes following IV glucose load as well as the incremental and total areas of plasma glucose were slightly but significantly lower in SHR than in WKY. Glucose disappearance rate (K value) was 7.7 +/- 0.3%/min in SHR, being slightly but significantly higher than that of 6.8 +/- 0.3%/min in WKY. On the other hand, insulin responses to the glucose load at ten minutes and 30 minutes as well as incremental and total insulin areas were significantly lower in SHR than in WKY. There was no significant difference in insulinogenic index between SHR and WKY. Our observations suggest that in a conscious and unrestrained state, SHR have the greater glucose tolerance associated with reduced insulin secretion than do WKY.

Diabetes induced by neonatal streptozotocin treatment in spontaneously hypertensive and normotensive rats

The development of non-insulin-dependent diabetes mellitus (NIDDM) induced by neonatal streptozotocin (STZ) treatment was compared between male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). The animals were intraperitoneally given 37.5, 50.0, 62.5, or 75.0 mg/kg of STZ at two days of age. At two days after STZ injection, plasma glucose was elevated in both groups of rats according to the dose of STZ, but the level was higher in SHR than in corresponding WKY. At ten days of age, plasma glucose in WKY returned to the similar level to that in vehicle-treated control irrespective of the doses of STZ, while in SHR it remained above control and its level was significantly higher than that in WKY. At 12 weeks of age, plasma glucose was within the control range in WKY, while in SHR it was markedly and dose-dependently elevated. The present study indicates that SHR are susceptible to NIDDM induced by neonatal STZ treatment. The difference in response to STZ between SHR and WKY was discussed.

Relationship between glycemic control and orthostatic hypotension in type 2 diabetes mellitus — a survey by the Fukuoka Diabetes Clinic Group

We examined the prevalence of orthostatic hypotension and its association with glycemic control, as assessed by hemoglobin A1 (HbA1) concentration, in type 2 diabetic patients. The prevalence of orthostatic hypotension in 886 diabetics who were referred to our study and in 587 diabetics who were not given any antihypertensive drugs was 7% and 6%, respectively. The relationship between orthostatic hypotension and HbA1 levels was evaluated only in subjects not receiving antihypertensive drugs, since antihypertensive agents might induce orthostatic hypotension. HbA1 levels were 11.0 +/- 2.1% in the diabetic patients with orthostatic hypotension, which was significantly higher than the HbA1 levels of 9.9 +/- 2.2% in the diabetic patients without orthostatic hypotension. Multivariate analysis also revealed that the association remained significant after adjustment for the treatment and duration of diabetes, age, sex and body mass index. These findings suggest that glycemic control contributes to the development of orthostatic hypotension in type 2 diabetic patients.

Early development of nephropathy in a new model of spontaneously hypertensive rat with non-insulin-dependent diabetes mellitus

SummaryWe designed the present study to clarify whether the development of nephropathy was accelerated by a combination of hypertension and non-insulin-dependent diabetes. Spontaneously hypertensive rats with non-insulin-dependent diabetes induced by neonatal streptozotocin treatment (25.0–75.0 mg/kg) were separated into severely or mildly diabetic groups according to their non-fasting plasma glucose levels at 12 weeks of age and the findings were compared with the data on a control group treated with citrate buffer alone. The natural courses of urinary excretion rate of total protein, the molecular composition by sodium dodecyl sulfate polyacrylamide gel electrophoresis with laser desitometer and N-acetyl-β-D-glucosaminidase were measured in the three groups from 12 weeks until 36 weeks of age. Total urinary protein in the control group decreased with age (p<0.05), while in the mildly diabetic group changes were nil; in the severely diabetic group, however, the excretion rates of total urinary protein and high molecular weight protein consistently and progressively increased with age (p<0.05). The low molecular weight protein continuously decreased with age in the mildly diabetic and control groups (p<0.05), while in the severely diabetic group there was no decrease after 28 weeks of age. The urinary N-acetyl-β-D-glucosaminidase markedly increased (p<0.05) in the severely diabetic group throughout the period compared with findings in the control group, but drastically decreased (p<0.05) in the mildly diabetic group with age. There were significant correlations between the mean glycosylated haemoglobin levels and all the urinary parameters measured (p<0.05). These observations suggest that development of nephropathy is accelerated by the glycaemic level in hypertensive rats. This new model should be appropriate for studying the combined effects of hypertension and diabetes mellitus on the kidney.

Comparison of reliability of plasma fructosamine and glycosylated hemoglobin assays for assessing glycemic control in diabetic patients on hemodialysis

To search for a reliable marker of medium-term integrated blood glucose level in diabetics on maintenance hemodialysis (HD), plasma fructosamine and glycosylated hemoglobin (Hb) levels were determined every week and blood glucose levels were determined four times every day over 3 weeks. The mean values of fructosamine (mol/L per 40 g of albumin) and of glycosylated Hb of other the study period correlated (r = .746, P less than .001) for combined materials of diabetic and nondiabetic subjects. However, plasma fructosamine values at the end of the study period did not correlate with the overall mean blood glucose values during the preceding 8 to 21 days (r = .372, NS). In contrast, glycosylated Hb values correlated closely with the same mean blood glucose values (r = .703, P less than .001). Fructosamine values significantly decreased during a HD, irrespective of the increases in albumin and total protein. In conclusion, glycosylated Hb was a reliable marker of long-term integrated blood glucose even in diabetics on HD. However, fructosamine was not a reliable marker of medium-term integrated blood glucose in these patients.

Blood Pressure Changes in Spontaneously Hypertensive and Normotensive Rats with Neonatal Streptozotocin Induced Type 2 Diabetes

We examined the blood pressure changes in hypertensive and normotensive rats with Type 2 diabetes induced by neonatal streptozotocin (STZ) treatment. STZ was intraperitoneally injected at 2 days of age with the dose of 25, 50 and 75 mg/kg for male spontaneously hypertensive rats (SHR) and with 75, 100, 125 and 150 mg/kg for male normotensive Wistar Kyoto rats (WKY). Blood pressure was measured by indirect tail-cuff method until 12 weeks of age. STZ-treated SHR, of which plasma glucose and glycosylated hemoglobin increased and body weight decreased with the dose of STZ, developed and maintained hypertension, same as did the vehicle-treated control SHR. On the other hand, STZ-treated WKY which developed only mild hyperglycemia lost body weight with the dose of STZ but the blood pressures rose slightly, these changes being correlated with the glycemic levels. The explanation for these differences between SHR and WKY remained to be elucidated.