Shinsuke Hiramatsu

Effects of a new oral hypoglycaemic agent (CS-045) on metabolic abnormalities and insulin resistance in type 2 diabetes.

The effects of a thiazolidinedione antidiabetic agent (CS‐045) on diabetic metabolic abnormalities were studied in a double‐blind clinical trial. Fourteen patients with Type 2 diabetes were selected according to study criteria. Eight were treated with oral CS‐045 at 400 mg daily, and six were given placebo. A multi‐step, hyperinsulinaemic, euglycaemic clamp study, with simultaneous plasma free fatty acid study, and glucagon tolerance test were performed before and after administration of drug. Following 3 months of treatment with CS‐045, there were significant decreases in the mean levels of fasting plasma glucose (from 9.18 ± 0.95 to 7.78 ± 0.44 mmol l−1), postprandial plasma glucose (from 11.8 ± 1.23 to 10.36 ± 1.06 mmol l−1), and haemoglobin A1c (from 9.3 ± 0.4 to 6.8 ± 0.4%). Insulin sensitivity also improved (1st step: from 3.12 ± 0.33 to 4.70 ± 0.47 mg kg−1 min−1 (p < 0.01); 2nd step: from 5.61 ± 0.63 to 7.54 ± 0.58 mg kg−1 min−1 (p< 0.01); 3rd step: from 9.21 ± 0.67 to 11.10 ± 0.87 mg kg−1 min−1). The fasting free fatty acid level decreased significantly from 0.28 ± 0.04 to 0.22 ± 0.02 g l−1. The residual free fatty acid level (%) under insulin infusion clamp conditions decreased significantly from 63.7 ± 9.7 to 45.0 ± 9.2%. CS‐045 treatment was associated with decrease in total cholesterol, total triglycerides, and increase in HDL cholesterol. Basal C‐peptide immunoreactivity level decreased, but there was no change in the peak C‐peptide immunoreactivity value. None of these changes was observed in the placebo group. CS‐045 improved hyperglycaemia as well as insulin resistance. CS‐045 appears to have a different mode of hypoglycaemic action from that of the sulphonylureas.

Apolipoprotein E polymorphism affects the response to pravastatin on plasma apolipoproteins in diabetic patients.

In the present study, we examined the levels of plasma lipids and apolipoproteins in patients with non-insulin dependent diabetes mellitus (NIDDM) with hypercholesterolemia in different apolipoprotein E (apo E) phenotypes. We also examined the influences of apo E polymorphism on the response to pravastatin. The patients were divided into three groups, E4/E3, E3/E3, and E3/E2. There were no differences in the baseline levels of plasma lipids and apolipoproteins, except that the level of triglycerides in E3/E2 heterozygotes was significantly higher than E3/E3 homozygotes. Three months of pravastatin administration significantly reduced plasma levels of total cholesterol and low-density lipoprotein cholesterol in each group to the same degree. We observed a significant reduction of apo B both in the E4/E3 and E3/E3 groups and apo E in the E3/E3 group. Such reduction was not observed in the E3/E2 group. We conclude that pravastatin is a potent drug to correct lipid abnormalities, particularly in NIDDM patients with apo E4/E3 and E3/E3. In the E3/E2 group, its effectiveness may be diminished.

Hypersecretion of amylin from the perfused pancreas of genetically obese (fa/fa) rats and its alteration with aging

To evaluate the relationship between the development of obesity and the hypersecretion of amylin by the pancreas, we examined the effects of 16.7 mmol/L glucose and 10 mmol/L arginine on the secretion of amylin and insulin by isolated perfused pancreata from genetically obese (fa/fa) and lean (Fa/?) Zucker rats at 9, 18, and 54 weeks of age. Concentrations of amylin and insulin in the effluent were measured by radioimmunoassay (RIA). Pancreata of obese rats secreted greater amounts of amylin in response to 16.7 mmol/L glucose and 10 mmol/L arginine than did those of lean rats at all ages. The hypersecretion of amylin by obese rats was particularly marked at 18 weeks of age, when they showed the most rapid increase in body fat mass. This hypersecretion became obscure at 54 weeks of age, when obese rats showed the maximum body weight. The pattern of amylin release resembled that of insulin in all groups. However, the relative amount of amylin to insulin secreted following stimulation with 16.7 mmol/L glucose and 10 mmol/L arginine in obese rats exceeded that in lean rats at all ages. Differences in the secreted amylin to insulin molar ratios between obese and lean rats were significant when pancreata were stimulated with glucose at 18 weeks (obese, 1.23% +/- 0.05%; lean, 0.99% +/- 0.04%; P < .01), glucose at 54 weeks (P < .01), and arginine at 54 weeks (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin Treatment Improves Relative Hypersecretion of Amylin to Insulin in Rats With Non-Insulin-Dependent Diabetes Mellitus Induced by Neonatal Streptozocin Injection

The dissociated release of insulin and amylin in the hyperglycemic state has been reported. This relative hypersecretion of amylin is thought to provide an important insight into how amylin aggregates to form islet amyloid deposits in non-insulin-dependent diabetes mellitus (NIDDM). The aim of the present study was to characterize the alterations of amylin hypersecretion in NIDDM with exacerbation or amelioration of diabetic control. For this purpose, neonatally streptozocin (nSTZ) diabetic rats were treated with dexamethasone (0.25 mg/kg) or Lente insulin (3 to 5 U/kg) daily for 14 days, and responses of amylin and insulin to 16.7 mmol/L glucose or 10 mmol/L arginine were evaluated in vitro using an isolated perfused pancreas system. nSTZ rats exhibited moderate elevations of plasma glucose compared with normal rats. In the isolated perfused pancreas, the molar ratio of secreted amylin to insulin in response to 16.7 mmol/L glucose by nSTZ pancreas (1.8% +/- 0.2%) was significantly greater than that of normal rat pancreas (1.2% +/- 0.1%). Plasma glucose levels in nSTZ rats (7.3 +/- 0.4 mmol/L) increased with dexamethasone treatment (17.8 +/- 1.1 mmol/L, P < .005) and decreased with insulin treatment (5.8 +/- 0.4 mmol/L, P < .05). The secreted amylin to insulin ratio in dexamethasone-treated nSTZ rats was significantly greater than that of the controls (P < .05). Moreover, insulin-treated nSTZ rats exhibited decreased amylin to insulin molar ratios compared with saline-treated nSTZ rats (P < .05), which had the same levels as normal rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Short Term Intensive Insulin Therapy Improves Insulin Secretion Significantly in Type 2 Diabetic Patients

To investigate the effects of short-term (1 week) intensive insulin therapy, on glycemic control, insulin secretion, and insulin sensitivity in type 2 diabetic patients, an open prospective study was conducted in sixteen type 2 diabetic patients receiving diet therapy alone or treatment with oral hypoglycemic agents. Of the study subjects, 8 patients were treated with insulin, the remaining 8 patients served as the control group. The metabolic parameters were evaluated once before treatment and once during one of the following treatments : glycemic control as measured by 1,5-anhydro-D-glucitol (1,5-AG) and area under curve of glucose (AUCglucose), insulin secretion as measured by area under curve of daily serum insulin (AUCinsulin), and insulin sensitivity as measured by the K index of the insulin tolerance test (K(ITT)). Post-treatment plasma glucose (AUCglucose) and 1,5-AG levels in patients who had received intensive insulin therapy were comparable to those of the control group. A statistically significant increase in AUCinsulin occurred after intensive insulin therapy for just 1 week, while no change occurred in the control group. Insulin sensitivity (K(ITT)) did not improve significantly in patients treated with insulin or patients from the control group. These results indicate that intensive insulin therapy for 1 week improves insulin secretion remarkably but has little effect on insulin sensitivity in type 2 diabetic patients. Clinically, this suggests that intensive insulin therapy for one week might be one of the initial treatments of choice for such patients.

Recombinant human growth hormone replacement in a Japanese man with a novel PROP1 gene mutation (R112X).

Congenital combined pituitary hormone deficiency (CPHD) is associated with deficiencies of anterior pituitary hormones. PROP1 gene mutations are often responsible for CPHD, but few such cases have been reported in Japan. This study describes a 37-year-old Japanese man with CPHD, treated with hydrocortisone, testosterone, and L-thyroxine, who was evaluated for adult growth hormone deficiency (GHD). Gene analysis revealed a previously unknown PROP1 mutation (R112X). After 10 months of recombinant human growth hormone (rhGH) administration, cortisol and urinary free cortisol levels were significantly lower than before therapy. This case underscores the importance of reassessing hypothalamic-pituitary-adrenal axis function in GHD patients, especially those with a PROP1 mutation, during rhGH therapy.