Hiroshi Kajinuma

Risk factors for worsening to diabetes in subjects with impaired glucose tolerance

SummaryIn a 5–12 year follow-up study of 288 subjects with impaired glucose tolerance after a 100-g glucose load, 48 worsened to overt Type 2 (non-insulin-dependent) diabetes with the elevation of fasting blood glucose. The initial level of blood glucose was a major predictor of subsequent worsening to diabetes. In addition, subjects with a lower insulin response to glucose showed a higher incidence of worsening to the disease, irrespective of blood glucose levels. Multivariate analysis indicated that a diminished insulin response and a high maximal body weight index, as well as a high level of fasting and 2-h glucose values at the initial 100-g oral glucose tolerance test were significant independent risk factors for the development of diabetes in Japanese subjects.

Characteristics of cranial nerve palsies in diabetic patients.

The incidence of palsy in the third, sixth and seventh cranial nerves was studied with regard to central nervous system involvement in diabetic patients. Among 1961 diabetic patients, 19 (0.97%) demonstrated cranial nerve palsies. Nine out of these 19 patients showed facial palsy; 6 palsy of the oculomotor nerve; 2 palsy of the abducent nerve; and 3 both oculomotor and abducent nerve palsies. In contrast, only 5 out of 3841 non-diabetic patients (0.13%) had any cranial nerve palsies; all 5 were cases of facial palsy. The incidence of cranial palsies in diabetic patients was significantly higher than that in non-diabetic patients (P less than 0.01). Concerning age, sex, the state of glycemic control, diabetic complications and method of treatment, there were no differences disclosed in the diabetic patients with cranial nerve palsy. The incidences of diabetic complications were compared between the patients with facial palsy and those with ophthalmoplegia. Only one out of 9 patients with facial palsy (11%) had diabetic complications, whereas 7 out of 10 patients with ophthalmoplegia (70%) demonstrated diabetic complications and the difference was significant. Thus ophthalmoplegia appears to be more closely related to diabetic metabolism while facial palsy is less strongly correlated with diabetes.

A pilot clinical trial of a new oral hypoglycemic agent, CS-045, in patients with non-insulin dependent diabetes mellitus

CS-045, (+/-)-5-[4-(6-hydroxy-2,5,7,8-tetramkethylchroman-2- ylmethoxy)benzyl]-2,4-thiazolidinedione, lowers plasma glucose in several animal models of non-insulin dependent diabetes mellitus (NIDDM) presumably by increasing insulin sensitivity. Little adverse effect was found in a phase 1 study on healthy male subjects. In order to test its efficacy in lowering plasma glucose in NIDDM in man, a pilot multi-center clinical trial of CS-045 was carried out in 146 patients with NIDDM whose glycemic control was inadequate (FPG greater than 140 mg/dl) on diet and/or other oral hypoglycemic agents. CS-045 was given orally in a daily dose of 200 mg or 400 mg for 12 weeks in addition to the previous treatment. The mean fasting plasma glucose (FPG) and fructosamine began to decrease within 2 weeks and the mean HbA1c within 8 weeks. After 12 weeks, the FPG fell from 192 +/- 41 to 155 +/- 45 mg/dl (P less than 0.01), fructosamine from 3.7 +/- 0.6 to 3.3 +/- 0.6 (P less than 0.01), and HbA1c from 8.9 +/- 1.5 to 8.1 +/- 1.5% (P less than 0.01). The drug was effective in 39% of patients in that FPG fell by more than 20% of the initial value. This rate of efficacy was the same when CS-045 was given alone or together with other oral hypoglycemic agents. The drug was more effective in a dosage of 400 mg than with 200 mg (the rate of efficacy 46% vs 25%) and more effective in obese patients than in lean patients (46% vs 25%).(ABSTRACT TRUNCATED AT 250 WORDS)

Chlorpropamide-induced Hyponatremia: Incidence and Risk Factors

The incidence and risk factors of chlorpropamide-induced hyponatremia were assessed in diabetic outpatients. In 176 chlorpropamide-treated patients, 11 (6.3%) exhibited hyponatremia (serum sodium ≤ 129 meq/L) during the mean follow-up period of 7.4 yr. In contrast, only one (0.6%) developed hyponatremia in 162 tolbutamide or glibenclamide-treated patients (P < 0.005). Moreover, administration to elderly patients and combination with thiazide diuretics were regarded as significantly potent risk factors for the development of hyponatremia in patients receiving chlorpropamide.

C-peptide Immunoreactivity (CPR) in Urine

Human urinary C-peptide immunoreactivity (CPR) was measured by a double-antibody radioimmunoassay using synthetic human C-peptide. Urine CPR was stable as long as one year, if stored frozen. Urine CPR was eluted by gel filtration as a single peak in the region that corresponded to 125I-labeled C-peptide. Even in a patient with insulin antibody whose serum contained a CPR fraction with higher molecular weight, urine CPR was eluted in its expected region. Normal subjects excreted 81 ± 36 μg. CPR per day. Urine CPR excretion was very low in juvenile-onset diabetics, variable in adult-onset diabetics and liver disease patients, and increased in patients on corticosteroid treatment. Diurnal changes and a 50-gm. glucose tolerance test revealed that urine CPR excretion rate increased in parallel with plasma CPR levels. The responses of diabetic patients were smaller and more sluggish. Urine CPR excretion tended to be decreased in patients with renal diseases and extremely low in those on regular hemodialysis. CPR was positively correlated with serum creatinine. Urine CPR was not increased in patients with marked β2-microglobulin excretion. Highly significant correlations were observed between 24-hour urine CPR values and fasting plasma CPR or summed CPR after glucose load. Thus, urine CPR seems to provide a good means to assess B-cell function, and it is particularly suitable to monitor B-cell function continuously or when multiple blood samplings are not practical. Continuous measurement of daily urine CPR in diabetic patients on glibenclamide treatment revealed that improvement of blood sugar control could occur without preceding increases in total daily B-cell secretion.

Initial Phase II Clinical Studies on Midaglizole (DG-5128): A New Hypoglycemic Agent

Midaglizole (DG-5128), 2-[2-(4,5-dihydro-1H-imidazol-2-yl)-1-phenylethyl]pyridine dihydrochloride sesquihydrate, is a new type of oral antidiabetic agent that has an α2-adrenoceptor-antagonizing effect. As previously reported, midaglizole reduces plasma glucose, mainly by stimulation of insulin secretion, and inhibits epinephrine-induced platelet aggregation in normal human subjects. In this study, the clinical safety and efficacy of shortterm administration of midaglizole were evaluated in 47 patients with non-insulin-dependent diabetes mellitus (NIDDM). After an observation period on diet or sulfonylurea treatment (1 patient was on insulin), patients received 150–250 mg 3 times a day of midaglizole for 2–4 wk, (some patients continued treatment for >4 wk). In 20 of the patients first treated with diet and then switched to midaglizole treatment, fasting plasma glucose (FPG) decreased significantly from 187 ± 10 mg/ dl (mean ± SE) to 147 ± 13 mg/dl (P < .05) and 120 ± 6 mg/dl (P < .01) 2 and 4 wk, respectively, after administration of midaglizole. Glycosylated hemoglobin (HbA1 also decreased from 12.0 ± 0.7 to 11.3 ± 1.1 and 10.7 ± 0.6% after 2 and 4 wk, respectively. In 23 of the patients whose treatment was changed from sulfonylureas to midaglizole, FPG, and HbA1 levels were maintained at the same values obtained before administration of midaglizole. In patients treated with midaglizole for >12 wk, FPG and HbA1 were kept at the lowered levels. Moreover, midaglizole treatment showed a clear inhibitory effect on postprandial hyperglycemia and onFPG, reflecting the general improvement in the daily plasma glucose curve with significantly reduced fluctuation. In the oral glucose tolerance test, midaglizole significantly improved glucose tolerance, potentiated insulin secretion, and tended to depress glucagon secretion. No abnormal findings attributable to midaglizole were noted in clinical and laboratory examinations, except for diarrhea and soft stools in 4 cases (8.5%) out of 47. No hypoglycemic symptoms were observed in this trial. Thus, midaglizole is clinically effective for NIDDM because it improves the daily plasma gluocse curve, with decreased fasting and postprandial hyperglycemia, in addition to amelioration of oral glucose tolerance accompanied by accelerated insulin secretion.

Effect of bombesin infused intrapancreatically on glucagon and insulin secretion

Synthetic bombesin was infused at a dose of 20 pmoles/kg/min for 10 min into the cranial pancreaticoduodenal artery of anesthetized dogs. Plasma immunoreactive glucagon concentrations in the cranial pancreaticoduodenal vein as well as in the femoral artery were concurrently and slowly elevated. However, the net release of glucagon from the pancreas did not increase significantly during infusion of bombesin. Plasma immunoreactive insulin concentrations in the pancreatic vein were transiently raised, and a delayed rise was noted in arterial plasma IRI. Net release of insulin was significantly augmented during infusion of the tetradecapeptide. Plasma glucose levels did not change after bombesin. These results indicate that the gastrointestinal tetradecapeptide may stimulate secretion of both insulin and gut glucagonlike immunoreactivity in the dog.

Serum gliclazide concentration in diabetic patients: Relationship between gliclazide dose and serum concentration

Serum levels of gliclazide were determined by radioimmunoassay in seven healthy controls and in 18 diabetic in-patients receiving single oral dosing and consecutive dosing over 5 days. Following a single oral dose of 40 mg in the seven controls and eight diabetic patients, and 120 mg in ten diabetic patients, the serum levels of gliclazide peaked on average at 2 h, followed by a slow decline, the t1/2 being 16.5 h in the volunteers, 12.3 h in the diabetic patients receiving 40 mg, and 10.5 h in those receiving 120 mg. During consecutive administration, the serum levels both at fasting and at the peak reached a plateau in 2 days and no further accumulations were observed. The steady-state peak levels of gliclazide in the diabetic patients revealed a strongly positive correlation with the dose per m2 body surface area (r = 0.78, P less than 0.001), and their steady-state fasting levels correlated positively but weakly with the dose per m2 body surface area (r = 0.48, P less than 0.05). Thus, measuring either the fasting or the peak concentration of gliclazide will be useful for monitoring drug concentration in the serum. Pharmacokinetics of gliclazide will contribute to the elucidation of the relationship of serum level and clinical effectiveness in diabetic subjects.

Effect of Intrapancreatic Injection of Potassium and Calcium on Insulin and Glucagon Secretion in Dogs

Acute changes in plasma immunoreactive insulin (IRI) and immunoreactive glucagon (IRG) levels in the pancreatic vein of dogs were studied following rapid pulse injections of CaCl2, KCl and glucose into the pancreatic artery. Blood from the pancreatic vein was taken continuously by changing the collection tubes every five seconds. IRI secretion was stimulated by all three agents within thirty seconds, while IRG secretion was stimulated by the injection of KCl but not by CaCl2 or glucose. Detailed comparisons of IRI responses revealed that IRI release occurred most rapidly after the injection of KCl and most slowly after the injection of glucose. Stimulation of IRI and IRG release occurred simultaneously after KCl injection. The data suggest that potassium stimulates α and β cells directly, without increasing calcium influx. The slower insulin-releasing effect of glucose, as compared with the cations, supports the theory that glucose acts by increasing calcium uptake.

Effect of vasoactive intestinal polypeptide infused intrapancreatically on glucagon and insulin secretion

Synthetic vasoactive intestinal polypeptide (VIP) was infused at a dose of 50 ng/kg/min for 10 min into the cranial pancreaticoduodenal artery in anesthetized dogs. Both mean blood flow and plasma glucagon concentration in the cranial pancreaticoduodenal vein were significantly enhanced during the infusion, indicating a great augmentation in glucagon output. The pancreatic venous plasma concentration of insulin was not significantly raised, but its output increased during the infusion, again due to the increase in plasma flow. Plasma concentration of glucagon in the femoral artery was not significantly augmented, whereas that of insulin was enhanced during VIP infusion. Mean arterial plasma glucose levels rose gradually during the infusion. Intrapancreatic pretreatment with propranolol failed to exert any significant inhibiting effect upon the VIP-induced enhancement in plasma glucose, pancreatic venous blood flow, or bihormonal output. These results suggest that the vasoactive polypeptide of intestinal origin may regulate the function of the endocrine pancreas and that this effect may not be mediated mainly via the beta-adrenergic receptor system.