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Patients with diabetes mellitus (DM) often suffer from various and severe infection. Patients with pancreatic DM have malnutrition due to chronic pancreatitis. Therefore it is believed that patients with pancreatic DM have a lower ability of host defence to infectious diseases than normal subjects. We examined the primpheral lymphocyte subsets (T cell, B cell, NK cell, CD3+ 56+ T) of eighteen patients (males, age = 52.8 +/- 12.7 years old, mean +/- SD) with pancreatic DM by two color flow-cytometry to evaluate the lymphocyte function. Ratios of T cell (T%, 66.9 +/- 9.3%, mean +/- SD). B cell (B%, 13.1 +/- 5.8%) and NK cell (Nk%, 19.3 +/- 8.7%) to total peripheral lymphocytes of patients with pancreatic DM were not significantly different from those (T% = 66.4 +/- 7.8%, B% = 13.5 +/- 6.7%, NK% = 19.9 +/- 9.1%) of thirteen normal subjects (males, age = 51.2 +/- 13.1). CD3+56+ T cell % (4.1 +/- 1.9%) of patients with pancreatic DM was lower than that (6.0 +/- 3.0%) of normal subjects (p < 0.05). CD3+56+ T cells have cytotoxic activity and it is likely that this activity is similar to that of NK cells. These results suggested that a decrease in peripheral CD3+56+ T cell % is a factor showing a weak host defense mechanism to infectious diseases in patients with pancreatic DM.

To investigate possible parameters for the differential diagnosis of steatorrhoea in patients with low fat intakes, faecal specimens were analysed from 15 patients with steatorrhoea due to chronic pancreatitis and seven patients with steatorrhoea due to intestinal malabsorption. The fat intakes of the patients ranged from 30.1 to 60 g, less than the average in American and European patients. The group with pancreatic steatorrhoea showed a significantly lower faecal output than the group with intestinal steatorrhoea but the two groups did not differ significantly in their total faecal fat excretion or concentration. The percentage triglycerides and the molecular ratio of triglycerides to fatty acids in the faeces were significantly higher ( P < 0.01) in the group with pancreatic steatorrhoea than in those with intestinal steatorrhoea. The molecular percentage ratio of triglycerides to fatty acids was 6.8 ± 2.2 for the chronic pancreatitis group and 2.4 ± 1.0 for the intestinal malabsorption group; while the respective faecal hydroxy fatty acid contents were 3.1 ± 3.6% and 10.1 ± 3.3% (means ± SDs). These latter two parameters appeared to be the most valuable for distinguishing the two forms of steatorrhoea.

The serum zinc, prealbumin, retinol-binding protein and carotene concentrations and the plasma fatty acid composition were determined to assess the nutritional condition of 24 patients with chronic pancreatitis compared with that of 20 healthy controls. The daily food intake and faecal fat excretion of the two groups were also measured. In the chronic pancreatitis group, the calorie and fat intakes were significantly lower than those of the controls. Serum levels of zinc, prealbumin and carotene were also significantly lower than those of the controls. Percentages of plasma linoleic and arachidonic acids were low, while percentages of palmitoleic acid, eicosapentaenoic acid and docosahexaenoic acid were high. Fish oil intake correlated negatively with plasma linoleic acid concentration ( P < 0.05). The above results indicate that the relatively high intake of fish oil and the relatively low intake of dietary fat in Japanese patients with chronic pancreatitis with a mild degree of steatorrhoea results in an abnormally low plasma level of linoleic acid.

The metabolism of cholesterol ester (CE) was studied in peritoneal macrophages taken from rats with streptozocin-induced diabetes. Levels of CE and synthesized [ 14 C]-cholesterol oleate did not differ significantly between the macrophages from diabetic and control rats incubated with low-density lipoprotein (LDL). However, when macrophages were incubated with Cu 2+ -induced oxidized LDL, CE levels were significantly higher in diabetic rats than in control rats (3.03± 0.09 μg/10 6 cells versus 2.66±0.09 μg/10 6 cells; P 14 C]-cholesterol oleate did not differ significantly between the two groups of rats. The findings suggest that CE accumulates in macrophages in the presence of diabetes mellitus and may play a role in the development of atherosclerosis in diabetes mellitus.

The present study was performed to assess the influence of hyperlipidemia on the appearance and development of diabetic nephropathy in patients with non-insulin-dependent diabetes mellitus (NIDDM). This was done by comparing the incidence of nephropathy in 35 diabetic patients with heterozygous familial hypercholesterolemia (FH) with the incidence of nephropathy in 165 patients without FH. There was no significant difference in sex, age, body mass index, or mean duration of diabetes between the two groups. Both groups received similar treatment for diabetes. No significant difference in mean hemoglobin A 1c levels or prevalence of hypertension was noted between the two groups. Total serum cholesterol and triglyceride levels were significantly higher ( P P

This study examined the effects of a new oral hypoglycemic drug, CS-045, on glucose tolerance and serum lipids in 10 nonobese patients with non-insulin-dependent diabetes mellitus (NIDDM). Plasma glucose levels before and at 2, 3, 4, 6, 8, 10, 15, 20, and 30 minutes after administration of the intravenous glucose tolerance test (IVGTT) were significantly ( P P P P P

Thirteen patients with pancreatic diabetes caused by calcifying pancreatitis were divided into 2 groups; 5 with diabetic autonomic neuropathy [AN(+) group] and 8 without [AN(-) group]. They were subjected to an insulin-induced hypoglycemic stress test to evaluate their blood pancreatic glucagon, adrenalin, and cortisol responses. When a blood glucose level below 45 mg/100 ml was defined to be hypoglycemia, all the patients in the AN(-) group exhibited peripheral adrenalin responses, with a significant increase (mean, 19.0 times the basal level) in the blood adrenalin level. Among the AN(+) group, on the other hand, central nervous symptoms became evident rather than the peripheral adrenalin response (the blood adrenalin level hardly exceeded the basal level). With the exception of a single patient, none exhibited responses in the blood pancreatic glucagon levels. Only one patient showed a minimal cortisol response but the remaining 12 reacted normally in the cortisol release. The findings are summarized as follows: in pancreatic diabetes, insulin-induced hypoglycemia causes little change in pancreatic glucagon secretion; when the condition is complicated with autonomic neuropathy, central nervous symptoms develop while the blood adrenalin level hardly increases. These findings indicated that patients with pancreatic diabetes complicated with diabetic autonomic neuropathy have a risk of lapsing into an acute hypoglycemic coma and difficulty in recovering from the hypoglycemic state.

In this study, we evaluated the control state of body weight, blood pressure, and blood glucose during the recent 10 years in 82 patients of non-insulin-dependent diabetes mellitus (NIDDM) who had long duration of diabetes for 20-25 years without ischemic heart disease (IHD) and diabetic nephropathy (Neph). The patients without either IHD or Neph showed significantly lower incidences of obese (11 vs. 40%, p < 0.05), hypertensive (0 vs. 20%, p < 0.05) and poor glycemic control state (7 vs. 27%, p < 0.05) for 10 years than the patients with IHD alone, and showed significantly lower incidences of hypertensive (0 vs. 20%, p < 0.05) and poor glycemic control state (7 vs. 33%, p < 0.01) than the patients with Neph alone. The control state of body weight was similar between the patients without either IHD or Neph and with Neph alone. In addition, the patients without either IHD or Neph showed significantly lower incidences of obese (11 vs. 56%, p < 0.01) and hypertensive control state (0 vs. 40%, p < 0.01) for 10 years than the patients with both IHD and Neph. The control state of blood glucose was similar between the two groups. These results suggest that for long survival of NIDDM patients without development or progression of IHD and Neph, non-obese and non-hypertensive state as well as good glycemic control should be maintained for long time.

Eight non-insulin-dependent diabetes mellitus patients, in whom oral hypoglycaemic agents were not effective, were treated with an α-glucosidase inhibitor, AO-128 (0.9 mg/day) for 6 months. After 6 months of treatment there was a statistically significant decrease in the blood glucose level 1 and 2 h postprandially. The 2 h blood glucose level was also significantly reduced after 2 months' treatment. The insulin and HbAlC levels after 2 and 6 months' treatment were lower than those before administration. Faecal weight, the frequency of bowel movements, the ratio of hydroxy fatty acids to total fatty acids, and faecal short-chain carboxylic acid content were all increased significantly during treatment. The initially hard stools became normal or soft, although no actual diarrhoea developed. Both faecal bile-acid excretion and the ratio of primary bile acids to total bile acids were increased significantly after 2 months, but they showed some recovery towards the pretreatment levels after 6 months' treatment. There was no distinct change in neutral sterol and fatty acid excretion. Breath hydrogen excretion showed a slight increase after treatment. These results suggest that intestinal fermentation was promoted and the intestinal transit time was shortened by AO-128 administration.

TAMASAWA, N., YONEDA, M., MAKINO, I., TAKEBE, K., SONE, K, and KOGAWA, R. The Effect of Biliary Bile Acid Concentration and Composition on the Calcium Level in Human Gallbladder Bile. Tohoku J. Exp. Med., 1993, 171(4), 297-307 -We analyzed total and ionized calcium concentrations in gallbladder bile of 34 humans in four groups: 8 patients with no gallstone, 11 gallstone patients treated with no gallstone dissolution agents, 8 gallstone patients treated with chenodeoxycholic acid(CDCA) and 7 gallstone patients treated with ursod eoxycholic acid(UDCA). We found that total calcium level ranged from 1.40 to 8.01 mmol/liter, closely related to total bile acid concentration (r=0.759). However, ionized calcium level was maintained in a narrow range of 0.25 to 1.23mmol/liter and had no relation to total bile acid concentration. UDCA-rich bile showed relatively high level of ionized calcium. We performed ultrafiltration of bile with cut-off molecular weight 1, 000 to investigate the interaction between biliary calcium and bile acid aggregates. The proportion of ultrafiltrated bile acid level to that in original bile in the UDCA group was statistically higher than the other groups. Relatively large percentage of smaller bile acid aggregates in UDCA-rich bile may impair its calcium solubility.

Dieticians computed the fat and cholesterol contents of 11 foods that were commercially produced as ready-to-eat food from food component lists and obtained the P/S ratio (polysaturated/saturated fatty acids) from the fatty acid component list. Meanwhile the same foods were diluted and homogenized. The internal standard was combined with hepatadecanoic acid and tricaprin. The samples that had been extracted by the Folch method were analyzed for their lipid content (GC analysis using a HS-SS-10 columns for fatty acids and an OV-1 column for lipid and cholesterol). A significant positive correlation was noted between the results of dieticians' analysis and those obtained from a gas chromatographic analysis of lipid and cholesterol contents and the P/S ratio, proving that lipid analysis of food by dieticians is highly reliable. Therefore for diseases (such as hyperlipemia, arteriosclerosis, obesity, diabetes mellitus, fatty liver, and pancreatitis) in which dietary factors have a significant effect on their clinical course, dietary instructions on dietary fats based on an analysis by dieticians are considered to be effective.

The effectiveness and safety of MCI-028, a synthetic human corticotropin-releasing hormone (hCRH), as a diagnostic drug were examined in 65 healthy male and 24 healthy female adult volunteers. Mean maximum concentrations of plasma ACTH and cortisol after intraveneous administration of 100 μg of MCI-028 were 3.0 and 2.0 times their basal concentrations, respectively, and there were no significant age or sex differences in the responses. Good reproducibility was observed in the responses in 59 male subjects who received a second administration after 1 to 2 weeks. Although slight adverse reactions such as mild and transient hot flushing were observed, these were not serious.

Faecal lipid excretion was determined in 16 females on an unrestricted diet and on a fat-restricted diet using a chromatographic method for the simultaneous analysis of faecal lipids. The fat-restricted diet reduced the total quantity of faeces and the amounts of fatty acids, neutral sterols and bile acids excreted were almost halved compared with when on an unrestricted diet. This indicates that dietary fat, fibre and cholesterol affect the amount of faecal bile acid, neutral sterol and fatty acid excretion. The amount of cholesterol/animal sterols excreted and the percentage of primary bile acids were, however, similar for both the fat-restricted and unrestricted diets.

A double blind study was conducted to objectively evaluate the usefulness of Cefuzonam (CZON) in the treatment of bacterial pneumonia and lung abscess. Cefotiam (CTM) was used as a control drug. Each drug was administered by intravenous drip infusion at 1 g at a time, twice daily, for 14 days as a rule. The results are as follows: 1. Enrolled in this study were 145 cases in total, comprising 72 of CZON group and 73 of CTM group. Of the total cases, 109 (53 of CZON group and 56 CTM group) were evaluated for clinical efficacy by the evaluation committee. Exclusion rate and background of patients were not significantly different between the two groups. 2. Clinical effectiveness assessed by the committee showed the efficacy rates of 84.9% (45 cases out of 53) for the CZON group and 83.3% (47 cases out of 56) for the CTM group, with no significant difference between the two groups. 3. The bacteriological eradication rates were 89.5% (17 strains out of 19) for the CZON group and 78.3% (18 strains out of 23) for the CTM group, with no significant difference between the two groups. 4. The incidence of side effects was 5 cases (7.5%) for the CZON group and 3 cases (4.2%) for the CTM group. The incidence rate of laboratory test abnormality was 28.4% (19 cases out of 67) for the CZON group and 31.3% (12 cases out of 67) for the CTM group. There was no significant difference between the two groups. 5. Usefulness rates calculated by the committee were 79.2% (42 cases out of 53) for the CZON group and 76.8% (43 cases out of 56) for the CTM group. There was no significant difference between the two groups. These results show that CZON is a useful drug in the treatment of bacterial pneumonia and lung abscess.

Renal effects of 4-week fixed maintenance doses of bunazosin three times daily (2.0 mg t.i.d., n = 8) and propranolol (40 mg t.i.d., n = 8) were evaluated in patients with mild-to-moderate essential hypertension [World Health Organization (WHO) stages I and II]. Both bunazosin and propranolol decreased blood pressure (BP) significantly (p less than 0.05), but the magnitude of reduction in diastolic BP (DBP) was greater with bunazosin (p less than 0.05) than with propranolol. Bunazosin produced a nonsignificant increase in renal blood flow (RBF) by 14%, a significant increase in glomerular filtration rate (GFR) 11% (p less than 0.05), and a decrease in total renal vascular resistance (TRR) by 15% (p less than 0.05), whereas propranolol caused no significant changes in these parameters. Urinary sodium excretion rate and the fractional excretion of sodium were unchanged by either of the drugs. The results of this short-term study suggest that bunazosin may be a drug that will increase RBF and GFR and decrease TRR with a concomitant hypotensive action in patients with mild-to-moderate essential hypertension. Whether these renal functional effects of the drug would benefit such patients must be determined in long-term studies.

ONUMA, T., TSUTSUI, M., OCHIAI, S., BOKU, A., YANADA, A., HIRAI, Y., NAKAHATA, H. and TAKEBE, K. Acid Cholesteryl Ester Hydrolase Activity of Mononuclear Leukocyte in Type 2 (Non-Insulin-Dependent) Diabetic Patients. Tohoku J. Exp. Med., 1990, 160 (4), 375-381-Acid cholesteryl ester hydrolase activity of mononuclear leukocytes was measured in 52 Type 2 (non-insulin-dependent) diabetic patients. Enzyme activity was significantly lower in the diabetic patients than in 14 age-matched control subjects (0.89±0.08 (mean±S.E.) vs. 2.20±0.17nmol/mg protein/hr, p

To examine the effects of growth hormone-releasing factor (GRF) on islet hormone release, rat pancreas was perfused. rhGRF at the concentration of 10(-7) M or more enhanced insulin secretion stimulated by 16.7 mM glucose, hpGRF slightly enhanced insulin secretion as well. The insulin secretion induced by 10(-6) M rhGRF was completely inhibited by 10(-6) M propranolol. rhGRF at the concentration of 10(-8) M or more stimulated glucagon secretion even in the presence of 16.7 mM glucose. The glucagon secretion stimulated by 10(-6) M rhGRF was inhibited in the early period but increased thereafter by 10(-6) M propranolol. 10(-6) M rhGRF slightly stimulated glucagon secretion in the presence of 16.7 mM glucose when STZ diabetic rat pancreas was perfused. rhGRF at the concentration of 10(-6) M enhanced somatostatin secretion stimulated with 16.7 mM glucose. We concluded that rhGRF stimulated insulin, glucagon and somatostatin secretion and the insulin secretion was inhibited by beta-blocker. hpGRF stimulated insulin and glucagon secretion as well.

We describe a case with unilateral chorea associated with thyrotoxicosis. A 23-year-old female with no family history of neurological diseases acutely developed choreic movements of the left extremities during gross thyrotoxicosis. CT scan and MRI study demonstrated no abnormality. Single-photon emission CT with technetium Tc 99m-labeled hexamethylpropyleneamine oxime revealed normal cerebral perfusion. Although the choreic movements were partially improved by dopamine antagonist, they persisted for two months until successful treatment of the thyrotoxicosis finally abolished these movements. Increased sensitivity of dopamine receptors may be responsible for persistent choreic movements in thyrotoxicosis.

It is well known that interleukin (IL)-1 is a potent activator of the hypothalamo-pituitary-adrenal axis in the rat. Many studies have reported that prostaglandins (PGs), especially PGE2, in the brain may mediate the IL-1 stimulation of corticotropin-releasing hormone release, which then leads to adrenocorticotropin (ACTH) secretion. However, a general consensus has yet to emerge regarding whether PGE2 is the only or the most important PG in the brain mediating IL-1-induced ACTH secretion in the rat. To address this question, we examined the effect of intracerebroventricular (icv) administration of antisera against PGE1, PGE2 or PGF2 alpha, or normal rabbit serum on the ACTH response induced by an icv injection of IL-1 beta in the rat. Each antibody or normal rabbit serum (as the control) was given icv 15 min before an icv administration of human recombinant IL-1 beta (50 ng). IL-1 beta produced a significant rise in plasma ACTH levels, and this response was significantly suppressed by either of the three PG antibodies. Interestingly, the inhibitory effect of anti-PGE2 antibody seemed to be somewhat weaker than those of the other two antibodies. We conclude that not only PGE2 but also PGE1 and PGF2 alpha in the brain may mediate the IL-1 beta stimulation of ACTH secretion in the rat.

Forty-five patients with pancreatic steatorrhoea (27 with calcified pancreatitis, 13 with non-calcified pancreatitis, two with pancreaticoduodenectomy, one with total pancreatectomy, and two with pancreatic cancer) were divided into four groups and given the following medication for 2 to 4 weeks: 4 to 6 g/day of sodium bicarbonate (group I); 9 g/day of high-lipase pancreatin (lipase, 56 600 U/g, Fédération Internationale Pharmaceutique (FIP); group II); 12 to 24 tablets or 9.0 g of commercial pancreatic enzyme preparations (group III); or 50 mg of omeprazole (group IV). Faecal fat excretion was evaluated before and after drug administration. Faecal fat excretion was reduced by 2.9 g (range, 1.7 to 5.0 g) in group I; 8.8 g (range, 2.9 to 39.9 g) in group II; 10.8 g (range, 2.3 to 21.8 g) in group III; and 4.3 g (range, 3.6 to 5.6 g) in group IV. The pancreatic digestive enzyme preparation was more effective than sodium bicarbonate and agents that raise the pH of the upper small intestine (such as proton-pump inhibitors) in reducing faecal fat excretion. The results indicate that all of the preparations used are effective against mild pancreatic steatorrhoea. If the condition is more advanced, however, a massive dosage of pancreatic digestive enzyme and possibly the combined use of an agent to raise the pH of the upper small intestine are likely to be effective.

A somatostatin analogue (SMS-201-995, hereinafter "octreotide") was s.c. administered to 5 healthy subjects under consecutive dripping of CCK-PZ (cholecystokinin-pancreozymin) and secretin (0.01 CHR U/kg/minutes), after inserting a Dreiling double tube into Treitz's ligament. Bile acid concentration, and bicarbonate and lipase excretions in duodenal juice were determined every 10 minutes up to 120 minutes and compared with controls. Moreover, octreotide (100 μg) was s.c. administered to 5 healthy subjects 30 minutes before meals for 7 days. Fecal fat and bile acid excretions before and after administration were determined. Bile acid concentration, and bicarbonate and lipase excretions in the octreotide group decreased to 1/3 -1/4 that of controls. Bile acid concentration became 0 mM for 60 minutes. Fecal fat excretion increased; obvious Steatorrhea occurred in 2 cases. Fecal bile acid excretion decreased to about 1/4. These results suggest that decreases in bile acid secretion should be considered, as well as pancreatic lipase and bicarbonate secretions, when fatty stool occurs after octreotide administration.(Internal Medicine 33: 593-596, 1994)

This study analyzed the prevalence, aggravating factors (including duration of diabetes, glycemic control, body mass index, hypertension, serum total cholesterol, changes of ST on ECG and diabetic therapies) and characteristics of diabetic retinopathy in 75 patients with pancreatic diabetes resulting from calcifying pancreatitis. The patients were divided into three Groups: Group I (27 patients in whom diabetes was detected earlier than pancreatic stones), Group II (36 patients in whom diabetes and pancreatic stones were simultaneously detected) and Group III (12 patients in whom pancreatic stones were detected earlier than diabetes). The prevalence of retinopathy was dependent on the duration of diabetes as well as poor glycemic control. It was significantly (p < 0.01) higher among the patient with the duration of diabetes that was more than 5 years than that of the patients whose duration was less than 5 years. The prevalence of retinopathy in Group I (63%) was significantly (p < 0.05) higher than that in Group II (30.6%) and Group III (12.5%). Proliferative retinopathy was not found in any patients with a duration of diabetes less than 5 years, while it was found in 5 patients with a duration of more than 5 years (5 cases out of 31 patients). Diabetic retinopathy was correlated with the duration of diabetes and glycemic control, and was not linked to frequency of hypoglycemia and family history of diabetes. From the results above, we concluded that diabetic retinopathy in patients with pancreatic diabetes due to calcifying pancreatitis might be taken as evidence that such complications are primarily due to chronic hyperglycemia and the duration of diabetes mellitus rather than to genetic factors and other factors (body mass index, hypertension, serum total cholesterol and diabetic therapies).

NAKAMURA, T., TAKEBE, K., KUDOH, K., ISHII, M., IMAMURA, K., KIKUCHI, H., KASAI, F., TANDOH, Y., YAMADA, N., ARAI, Y., TERADA, A. and MACHIDA, K. Increased Plasma Gluconeogenic and System A Amino Acids in Patients with Pancreatic Diabetes due to Chronic Pancreatitis in Comparison with Primary Diabetes. Tohoku J. Exp. Med., 1994, 173 (4), 413-420-We examined the plasma amino acid profiles of 17 patients with pancreatic diabetes in comparison with those of 14 healthy subjects and 16 patients with primary diabetes of similarly poor glycemic control. We also measured fasting plasma glucagon and free insulin levels in patients with pancreatic diabetes and in those with primary diabetes. The fasting plasma amino acid level was highest in patients with pancreatic diabetes. Furthermore, the plasma glucagon level in patients with pancreatic diabetes was significantly low, and negative correlations were found between glucagon and glucagon-related System A and gluconeogenic amino acids. On the other hand, the levels of branched-chain amino acids (BCAA) and System L amino acids, which are subjected to change in the state of diabetes mellitus, increased in patients with pancreatic diabetes. From the above results, we determined that the amino acid profile in patients with pancreatic diabetes resembled that in patients with total pancreatectomy. It is our opinion that the increases of amino acid levels (gluconeogenic and System A amino acids) in patients with pancreatic diabetes is not dependent on maldigestion/malabsorption under treatment, but is mainly dependent on glucagon deficiency.

SHIMURA, M., ONUMA, T., TSUTSUI, M., KIKUCHI, T., MATSUI, J., BOKU, A. and TAKEBE, K. Three Types of “Mid-Band” Lipoproteins in Non-Insulin-Dependent Diabetes Mellitus: Relation to Metabolic Abnormalities and Vascular Complications. Tohoku J. Exp. Med., 1994, 173 (2), 247-257-A number of fine bands which occur in positions between the β- and pre-β-lipoproteins in polyacrylamide gell electrophresis are called mid-bands (MB). In this study, the relationship between the occurrence of these MB and metabolic abnormalities or vascular complications was evaluated in 181 patients with non-insulin-dependent diabetes mellitus (NIDDM). The incidence of MB in diabetic patients was significantly higher than that in 149 healthy control subjects (35 vs. 20%, p

Relationship of the lipoprotein(a) [Lp(a)] concentration as a risk factor independent of other factors with the severity of diabetic retinopathy were evaluated by multiple regression analysis. The subjects were 158 patients with non-insulin-dependent diabetes mellitus (NIDDM). Multiple regression analysis was carried with the severity of diabetic retinopathy as the dependent variable and 13 independent variables, namely the Lp(a) concentration, sex, age, body mass index, duration of diabetes, ischemic heart disease, fasting plasma glucose, glycosylated hemoglobin A1c, total cholesterol, triglyceride, high-density lipoprotein cholesterol, anti-diabetic treatments, and diabetic nephropathy. The analysis was performed separately in all subjects, males only, and females only. The standard partial regression coefficient of Lp(a) was significant (0.293, p < 0.01), and the multiple correlation coefficient was 0.611 in the males. However, the standard partial correlation coefficient of Lp(a) was not significant in all patients and in females only. The rank of contribution of Lp(a) to retinopathy was the third in males, following triglyceride and nephropathy and followed by anti-diabetic treatments. These results suggest that Lp(a) might be an independent risk factor for diabetic retinopathy in male patients with NIDDM.

NAKAMURA, T., TAKEBE, K., IMAMURA, K., MIYAZAWA, T., ISHII, M., KUDOH, K., TERADA, A., MACHIDA, K., KIKUCHI, H., KASAI, F., TANDOH, Y., ARAI, Y. and YAMADA, N. Decreased Gastric Secretory Functions in Diabetic Patients with Autonomic Neuropathy. Tohoku J. Exp. Med., 1994, 173 (2), 199-208-A total of 37 subjects consisted of 10 healthy subjects (Group III), 15 diabetic patients without autonomic neuropathy (Group II), and 12 diabetic patients with autnomic neuropathy including gastroparesis in 6 cases (Group I). All three groups were comparable in age. In order to clarify the gastric function in diabetic patients with autonomic neuropathy, secretion of serum gastrin, gastric secretory function, endoscopic Congo red test of fundic glands, and coefciency of variance of electrocardiographic beat-to-beat intervals (C.V.R-R) were examined. In Group I, 5 patients had hypergastrinemia, but its elevation was inhibited when an acid solution was injected into the stomach. Gastric secretion and C.V.R-R were markedly lower in Group I, compared with Groups II and III. In Group I, the area of fundic glands (parietal cells) was reduced considerably. The C.V.R-R was significantly correlated with fasting serum gastrin concentration and with maximal acid output. From these results, in diabetic patients with autonomic neuropathy (vagal neuropathy), gastric acid secretion in response to tetragastrin stimulation was lowered with a reduction in area of fundic gland distribution. Hypergastrinemia may reflect a negative feedback mechanism responding to decreased acidity of gastric content in the antrum.

To assess the diagnostic usefulness of a synthetic human corticotropin-releasing hormone (CRH) formulation (Code No. MCI-028), we administered 100 micrograms of the peptide intravenously to 183 patients with hypothalamo-pituitary-adrenocortical (HPA) disorders, and obtained the following findings. Among the 183 patients, data from 125 patients were suitable for analyzing the effects of the test. In patients with Cushing's disease, high plasma adrenocorticotropic hormone (ACTH) and cortisol levels increased further in response to MCI-028, while in patients with adrenal Cushing's syndrome, low ACTH and high cortisol values remained unchanged. In patients with pituitary-type hypopituitarism or isolated ACTH deficiency, low ACTH and cortisol levels responded poorly or insignificantly to MCI-028, whereas those with hypothalamic hypopituitarism showed delayed and considerable degree of responses of plasma ACTH and little increase in plasma cortisol levels. In Addison's disease, high plasma ACTH increased further in response to MCI-028, but low cortisol levels did not change. In patients with Cushing's syndrome soon after successful surgical treatment, plasma ACTH responsiveness was low or different depending on the clinical course of the patient. Patients treated with high doses of glucocorticoids for non-endocrine diseases tended to show impaired ACTH and cortisol responsiveness to MCI-028. Side effects, including the transient flushing which was observed most frequently in this study, did not cause any clinical problems.

A newly synthesized inhibitor of pancreatic lipase and micelle formation, FL-386, was administered at a dose of 400 mg (in the diet, for seven consecutive days) to nine healthy adult volunteers, and changes in faecal mass, frequency of defaecation, and properties of the stools were observed. High performance liquid chromatography and gas-liquid chromatography were used to analyse the faeces for short-chain carboxylic acids, neutral sterols, bile acids, fats and hydroxyfatty acids. FL-386 had little effect on the amounts and composition of short-chain carboxylic acids, neutral sterols, and bile acids excreted, nor did it produce changes in the composition of fatty acids, or the percentages of hydroxyfatty acids in the stool. However, in those patients treated with FL-386, the faecal mass was increased, and stools were softer and contained increased amounts of fatty acids. The compound did not produce particularly fatty stools. It was concluded that FL-386 induces slight disturbance in the digestion and absorption of dietary lipids.

TAMASAWA, N. and TAKEBE, K. Analytical Examination of Oxidized Free and Esterified 7-Ketocholesterol and Related Oxysterols in Human Plasma Incubated with Copper. Tohoku J. Exp. Med., 1992, 168 (1), 37-45-Oxygenated derivatives of cholesterol (oxysterols) have been demonstrated to possess a wide variety of biological properties and evaluated for their abilities to inhibit cholesterol biosynthesis. We investigated a method to analyze copper-catalyzed oxidation products of human plasma cholesterol. Free and esterified oxysterols produced were mainly 7-ketocholesterol, and small amounts of 7β-hydroxy- cholesterol and 5, 6α-epoxy-cholesterol were also identified. Quantitatively, the sterol nucleus of ester was less susceptible to oxidation than that of the free form. This finding suggested that the cholesterol nucleus of ester form was more resistant against oxidative stress than free form. Additionally we demonstrated that the addition of probucol, a powerful antioxidant used clinically to lower blood cholesterol, inhibited this copper-catalyzed oxdiation of cholesterol.-7- ketocholesterol; free oxysterol; esterified oxysterol; cholesterol oxdiation; probucol

BABA, T., KODAMA, T., TOMIYAMA, T., FUJITA, N. and TAKEBE, K. Hyperinsulinemia and Blood Pressure in Non-obese Middle-aged Subjects with Normal Glucose Tolerance. Tohoku J. Exp. Med., 1991, 165 (3), 229-235-A possible link between hyperinsulinemia and blood pressure was studied in non-obese subjects with normal glucose tolerance. First, the responses in plasma glucose and serum insulin to an oral glucose load (75-g oral glucose tolerance test) were compared between 42 patients with essential hypertension and 93 normotensive control subjects. Second, of the 93 normotensive subjects, the relations of serum insulin levels to blood pressure, serum cholesterol, and triglycerides concentrations were assessed in 8 hyperinsulinemic (serum insulin level [during fasting, or after glucose loading, or both]>2 S.D. higher than the mean) and 8 pair-matched normoinsulinemic subjects (serum insulin level within 1 S.D, of the mean), individually matched for age, sex, and body mass index. Plasma glucose and serum insulin responses to the glucose load in hypertensive subjects were identical to the respective responses in normotensive subjects, while the mean total serum cholesterol level was slightly higher (p

The superoxide anion (O2-) production in polymorphonuclear leukocytes stimulated by phorbol myristate acetate in IDDM and non-insulin dependent diabetes mellitus (NIDDM) was determined by the method of Johnston et al, compared with that of each age matched controls. And the correlation between O2- production and hemoglobin (Hb) A1 and A1c value was investigated. The O2- production in IDDM was 24.4 +/- 7.4 (mean +/- SD, n mol per 4 X 10(5) cells) at 10 min. and 51.4 +/- 8.7 at 30 min., in NIDDM each 31.6 +/- 9.3, 60.2 +/- 14.4, and in controls each 40.5 +/- 4.2, 72.4 +/- 3.1. O2- production in IDDM was significantly lower than that in NIDDM (p less than 0.001 at 10 min. and p less than 0.01 30 min.) and controls (p less than 0.001 at 10 and 30 min.). O2- production at 10 and 30 min. possessed a negative correlation with Hba1 and A1c value (HbA1: p less than 0.01 at 10 min. p less than 0.05 at 30 min., HbA1c: p less than 0.01 at 10 and 30 min.). These findings suggest that impaired O2- production might be one of the factors accounting for depressed bactericidal activity of polymorphonuclear leukocytes in IDDM, and that a protracted hyperglycemia might shed some effect on O2- production.

Efficacy and safety of a new injectable cephem antibiotic, cefpirome sulfate (hereafter, CPR), against respiratory tract infections were examined and compared with those of a control drug, ceftazidime (hereafter, CAZ). As a rule, CPR 0.5 g twice a day, 1.0 g twice a day, or CAZ 1.0 g twice a day (hereafter CPR 0.5 g group, CPR 1.0 g group, and CAZ group) was administered for 14 days and the following results were obtained. 1. The total number of cases was 470 (155 cases in the CPR 0.5 g group, 160 cases in the CPR 1.0 g group, and 155 cases in the CAZ group). Among them 390 cases were subjected to analyses of clinical efficacy by the efficacy evaluation committee (131 cases in the CPR 0.5 g group, 131 cases in the CPR 1.0 g group and 128 cases in the CAZ group). 2. Efficacy rates determined by the efficacy evaluation committee were 82.4% (108/131) for the CPR 0.5 g group, 81.7% (107/131) for the CPR 1.0 g group, and 83.6% (107/128) for the CAZ group. Efficacy rates determined by the physician in charge were 82.0% (105/128) for the CPR 0.5 g group, 80.5% (99/123) for the CPR 1.0 g group, and 88.5% (108/122) for the CAZ group. No statistically significant difference was observed among the 3 groups. In evaluation of equivalency, clinical efficacy for the CPR 0.5 g group and the CPR 1.0 g group determined by the clinical efficacy evaluation committee was proved to be statistically equivalent to that for the CAZ group. 3. In patients with pneumonia, efficacy rates determined by the efficacy evaluation committee were 87.1% (61/70) for the CPR 0.5 g group, 80.7% (71/88) for the CPR 1.0 g group, and 78.9% (56/71) for the CAZ group. Efficacy rates determined by the physician in charge were 85.3% (58/68) for the CPR 0.5 g group, 80.7% (67/83) for the CPR 1.0 g group, and 86.2% (56/65) for the CAZ group and no statistically significant difference was observed among the 3 groups. In patients with chronic respiratory tract infection, efficacy rates determined by the efficacy evaluation committee were 77.0% (47/61) for the CPR 0.5 g group, 83.7% (36/43) for the CPR 1.0 g group, and 89.5% (51/57) for the CAZ group. Efficacy rates determined by the physician in charge were 78.3% (47/60) for the CPR 0.5 g group, 80.0% (32/40) for the CPR 1.0 g group, and 91.2% (52/57) for the CAZ group. No statistically significant difference was observed among the 3 groups.(ABSTRACT TRUNCATED AT 400 WORDS)

BABA, T., MURABAYASHI, S., TOMIYAMA, T. and TAKEBE, K. Uncontrolled Hypertension is Associated with a Rapid Progression of Nephropathy in Type 2 Diabetic Patients with Proteinuria and Preserved Renal Function. Tohoku J. Exp. Med., 1990, 161 (4), 311-318-The relationship between blood pressure and progression of nephropathy was studied the mean follow-up period of 32.6± 17.9 (S.D.) months in 20 Type 2 (non-insulin-dependent) diabetic patients with clinical nephropathy (proteinuria >0.5g/day) and preserved renal function (serum creatinine level

The possibility of an impaired hepatic de-esterification of enalapril to enalaprilat due to hepatic dysfunction was assessed in seven patients with compensated liver cirrhosis and 10 normal control subjects. The peak serum concentration and time to the peak serum concentration of enalaprilat, as well as the suppression of serum angiotensin converting enzyme activity, following a single oral dose of enalapril maleate (10 mg) were not different in the two groups. The elimination half-life of enalaprilat was related to renal function. The results suggest that hepatic biotransformation of the drug may not be disturbed in a clinically significant manner in patients with moderate hepatic dysfunction due to compensated liver cirrhosis.

The time course of hypothalamic corticotropin-releasing factor (CRF) activity after the administration of ether stress was different from that after immobilization stress. The maximal response CRF activity was observed 2 min after ether stress, followed by a precipitous decrease 5 min after the stress. A gradual increase of CRF activity was subsequently observed for several minutes with fluctuated changes. Thus, response pattern was vibratory. But under immobilization stress, markedly fluctuant changes of CRF activity seen in the case of ether stress did not appear after the maximal response observed at 2 min, indicating that the response pattern was not vibratory. On the other hand, the concentration of plasma corticosterone increased significantly 5 min after the ether or immobilization stress with the peak value around 17 min.

Dynamics of insulin and glucagon secretion were investigated by using a new model of spontaneous diabetes rats produced by the repetition of selective breeding in our laboratories. The perfusion experiments of the pancreas showed that the early phase of insulin secretion to continuous stimulation with glucose was specifically impaired, although the response of the early phase to arginine was preserved. The glucose-induced insulin secretion in the nineth generation (F8) which had a more remarkably impaired glucose tolerance was more reduced than in the sixth generation (F5). No significant difference of glucagon secretion in response to arginine or norepinephrine was noted between the diabetes rats and control ones. The present data indicate that the defective insulin secretion is a primary derangement in a diabetic state of the spontaneous diabetes rat. This defect in the early phase of glucose-induced insulin secretion suggests the specific impairment of the recognition of glucose by the pancreatic beta-cells. The spontaneous diabetes rats are very useful as a model of disease for investigating pathophysiology of non-insulin dependent diabetes mellitus.