Kiyohiko Negishi

Insulin levels during fasting and the glucose tolerance test and Homa's index predict subsequent development of hypertension.

Objective To determine whether there is a longitudinal relationship between hypertension and hyperinsulinemia and to find the most useful parameter(s) for predicting the subsequent development of hypertension. Subjects and methods The oral glucose (75 g) tolerance test (OGTT) was performed in 313 patients, who were divided into three groups according to glucose tolerance based on the WHO criteria: normal, borderline and diabetes mellitus. The fasting insulin (IRI) levels, ΣIRI (the sum of the insulin levels 0, 30, 60 and 120 min after the OGTT), insulinogenic index and Homas index, a candidate for the simple assessment of insulin sensitivity, of the normotensive and hypertensive subjects in each subgroup were compared. In addition, 145 normotensive subjects were followed up for over 3 years and observed for the development of hypertension. Results Hypertensive diabetic subjects had not only higher fasting IRI levels and ΣIRI values, but they also had higher Homas indices than normotensive diabetics. Normotensive subjects with normal glucose tolerance (n = 20) did not develop hypertension. However, 16 out of 94 patients with borderline glucose tolerance and five out of 31 diabetics became hypertensive. The incidence of hypertension in the group with fasting IRI ≥ 15, ΣIRI ≥ 150 or Homas index ≥ 4 was between 5 and 9 times higher than that in the group with fasting IRI < 10, ΣIRI < 100 or Homas index < 2. This difference was still significant when multivariate analysis, including various factors such as age, body mass index (BMI) and sex, was performed. Conclusions These results suggest that higher plasma IRI levels and/or insulin resistance are closely related to the pathogenesis of hypertension in patients with diabetes mellitus. Homas index, fasting and ΣIRI may be useful predictors of the subsequent development of hypertension.

Effect of troglitazone (CS-045) and bezafibrate on glucose tolerance, Liver Glycogen synthase activity, and β-oxidation in fructose-fed rats

To clarify the relationship between lipid and glucose metabolism abnormalities in fructose-fed rats, we examined whether an improvement of insulin sensitivity by troglitazone (CS-045) or a decrease in plasma lipids by bezafibrate affects the relationship between serum levels of lipid and glucose. In addition, we also examined changes in liver glycogen metabolism and beta-oxidation in fructose-fed rats. Troglitazone ameliorated fasting hyperlipidemia, hyperglycemia, and hyperinsulinemia. In addition, it augmented glycogen synthase activity by 53%, and decreased the mitochondrial palmitic acid beta-oxidation rate and ketone body production rate by 27% and 55%, respectively. However, hyperglycemia and liver glycogen synthase activity were not improved by bezafibrate treatment despite a marked reduction of serum triglyceride (TG) levels resulting from a 1.76-fold increase in mitochondrial oxidation and a 2.04-fold increase in hepatic ketone body production. These results suggest that abnormalities in glucose and lipid metabolism in fructose-fed rats, which are ameliorated by troglitazone, may be closely linked to reduced glycogen synthase activity in the liver.

Studies of Midaglizole (DG-5128): A New Type of Oral Hypoglycemic Drug in Healthy Subjects

Midaglizole (DG-5128), 2-[2-(4,5-dihydro-1H-imidazol-2- yl)-1-phenylethyl]pyridine dihydrochloride sesquihydrate, is a novel α2-adrenoceptor antagonist. Its effects on plasma glucose, immunoreactive insulin (IRI), and immunoreactive glucagon (IRG) in healthy male volunteers were investigated. Volunteers received single oral administrations of midaglizole (150–500 mg), multiple increasing oral administrations on 3 separate days (150–300 mg 3 times daily), or successive daily oral administration for 1 wk (200 mg 3 times daily). The hypoglycemic action of midaglizole was observed within 0.5–1.0 h after its administration and thereafter for 5 h. The maximum hypoglycemic effect was found 1.0–1.5 h after administration. Midaglizole decreased postprandial hyperglycemia ina dose-dependent manner. In the fasting state, midaglizole significantly increased IRI secretion and suppressed IRG secretion. Midaglizole inhibited epinephrine-induced platelet aggregation after successive administration for 1 wk (200 mg 3 times daily). The plasma half-life of midaglizole was only 3 h, and the drug was rapidly excreted into the urine and feces, with >80% in its unchanged form, within 24 h. Midaglizole did not affect the results of any clinical or laboratory tests performed. Our data indicate that midaglizole is a possible hypoglycemic agent. Further clinical investigations are required to confirm its effects on diabetes mellitus.

The relationship between early diabetic nephropathy and control of plasma glucose in non-insulin-dependent diabetes mellitus: The effect of glycemic control on the development and progression of diabetic nephropathy in an 8-year follow-up study

To clarify the relationship between early diabetic nephropathy and the glycemic control in non-insulin-dependent diabetes mellitus (NIDDM) without hypertension, excretion of urinary albumin was studied retrospectively for 8 years. The patients with early diabetic nephropathy were divided into two groups according to the initial urinary albumin index (UAI: mg/g.creatinine), namely, a normoalbuminuric (less than 15 mg/g.creatinine) and a microalbuminuric group (15 < or = UAI < 200 mg/g.creatinine). Comparisons of changes in UAI were made between good (HbA1 < 9.0% and fasting plasma glucose (FPG) < 140 mg/100 mL throughout the observation period) and poor glycemic control groups after 4 and 8 years. In the patients with normoalbuminuria at the initial determination, five of 11 patients (45.5%) with good glycemic control and 14 of 22 patients (63.6%) with poor glycemic control became microalbuminuric after 8 years, respectively (p < 0.05). In the microalbuminuric patients, five of ten patients (50%) with poor glycemic control became macroalbuminuric (UAI > or = 200 mg/g.creatinine), although only one case worsened of five patients with good glycemic control (p < 0.05). In conclusion, the development or progression of early diabetic nephropathy in NIDDM was significantly inhibited by good glycemic control (FPG < 140 mg/100 mL and HbA1 < 9.0%), independent of hypertension, and probably irrespective of the mode of therapeutic intervention.

Evidence for Association Between the Class I Subset of the Insulin Gene Minisatellite (IDDM2 Locus) and IDDM in the Japanese Population

Although the shortest (class I) minisatellite (i.e., variable number of tandem repeats [VNTR]) alleles in the 5′ region of the insulin gene are positively associated with IDDM in Caucasians, the majority of Japanese are homozygous for class I alleles. Here, we determined the exact length, in number of repeat units (RUs), of class I alleles in Japanese subjects. The distribution of class I alleles in Japanese was trimodal, with peaks located at 32/33, 41, and 44 RUs. The shortest component (i.e., 1S [25-38 RUs]) alleles were significantly increased in the IDDM group compared with the control group (54 vs. 46%; P = 0.040). The 1S/1S genotype was significantly increased in the IDDM patients (34 vs. 20%; P = 0.005; relative risk 2.1). Furthermore, the transmission disequilibrium test of Japanese families with 1S/1M or 1S/1L heterozygous parents confirmed the association of 1S alleles: 17 alleles of 1S and 6 alleles of 1M (39-41 RUs) or 1L (42-44 RUs) were transmitted to affected offspring (P = 0.022). In addition, we found tight linkage of 1S with allele 9 of the tyrosine hydroxylase gene microsatellite and allele (-) of the IGF-II gene Apa I polymorphism, but neither 9 nor (-) alleles were significantly associated with IDDM. The present study suggests that a class I subset may have a role in IDDM susceptibility in Japan. It was revealed that the difference between 1S alleles and 1M or 1L alleles is almost consistently characterized by a sequence variation generated by deletion of two copies of an ACAGGGGTCC CGGGG repeat element, implying that sequence variation of class I alleles may influence disease susceptibility.

Acarbose controls postprandial hyperproinsulinemia in non-insulin dependent diabetes mellitus

We investigated how fasting or postprandial insulin levels were altered by treatment with acarbose or sulfonylureas. Plasma glucose and serum insulin, C-peptide, and proinsulin levels were measured before as well as 1 and 2 h after breakfast in 23 patients with non-insulin-dependent diabetes mellitus and 17 patients with impaired glucose tolerance. In the diabetic patients, 12 weeks of acarbose therapy decreased the postprandial levels of glucose (1 h: -60.0%; 2 h: -67.6%), insulin (1 h: -67.5%; 2 h: -72.2%) and proinsulin (1 h: -55.2%; 2 h: -46.7%), and proinsulin (1 h: -20.9%; 2 h: -57.5%). In contrast, sulfonylurea treatment increased postprandial insulin and proinsulin levels. Since increased in the serum insulin or proinsulin levels are associated with a higher risk of cardiovascular disease, the present findings suggest that the acarbose-induced reduction of the postprandial serum insulin or proinsulin responses to food intake might be useful for preventing vascular complications in patients with diabetes.

Improvement of glucose tolerance by bezafibrate in non-obese patients with hyperlipidemia and impaired glucose tolerance

Glucose intolerance or diabetes mellitus, hyperlipidemia, obesity and hypertension may have a close interrelation based on insulin resistance. We selected 28 impaired glucose tolerance (IGT) patients with hyperlipidemia. The IGT patients demonstrated hypertriglyceridemia associated with hyperinsulinemia, a typical manifestation of insulin resistance. Administration of bezafibrate at 400 mg/day for 4 weeks to the IGT patients with hypertriglyceridemia resulted in an improvement of the plasma glucose level and insulin response to 75 g oral glucose loading associated with a concomitant decrease in non-esterified fatty acids. The ratio of the level of serum C-peptide to that of insulin after a 75 g oral glucose tolerance test (OGTT) was augmented after 4 weeks of bezafibrate administration. However, reduction of the cholesterol level with pravastatin did not alter these parameters. These results suggest that treatment to reduce the level of serum triglycerides, but not that of cholesterol, may have a beneficial effect for improving insulin resistance even in the non-obese subjects with IGT and decreasing the risk of coronary heart disease.

Diabetic ketoacidosis in a case of pheochromocytoma

A 31-year-old woman was admitted to our hospital because of diabetic ketoacidosis (DKA). Ultrasound sonography revealed the existence of the left adrenal tumor and endocrinological examinations established a diagnosis of pheochromocytoma. She had been healthy and there was no evidence for gestational diabetes in her personal history. Characteristic features were not found in her tumor size and the catecholamine levels as compared with typical cases of pheochromocytoma. An overwhelming secretion of catecholamine might suppress insulin secretion, as evidenced by the improvement after the resection of the tumor. However, a significant insulin resistance continued after tumor resection. Obesity and the heterozygosity of beta3-adrenergic receptor gene (Try64Arg) might play a role in insulin resistance, which resulted in DKA at least in part. Literature survey revealed four cases of DKA in the patients with pheochromocytoma including ours, three of which were Japanese. Pancreatic capacity to secrete insulin has been reported to be less than Caucasians, which might be another reason for DKA. Thus, we speculate that both suppressed insulin secretion and insulin resistance deteriorated by obesity or other factor(s) such as abnormality in beta3 adrenergic receptor probably depress beta-cell function resulting in abnormal metabolic imbalance such as DKA.

A Higher Proinsulin Response to Glucose Loading Predicts Deteriorating Fasting Plasma Glucose and Worsening to Diabetes in Subjects with Impaired Glucose Tolerance

To evaluate the clinical significance of proinsulin determination, we measured glucose, insulin, C‐peptide and proinsulin during 75‐g oral glucose loading in 59 patients. In a 2.5‐year follow‐up study of 37 subjects with impaired glucose tolerance (IGT) at the initial test, 11 patients changed from IGT to a normal state and 5 patients showed worsening to overt Type 2 diabetes with elevation of fasting plasma glucose; 21 patients remained unchanged. Although our data showed that both fasting (IGT: p = 0.4523) and 120‐min plasma glucose (IGT: p = 0.8168) values at the initial test were not significantly correlated with increased fasting plasma glucose levels in a 2.5‐year follow‐up study, subjects with a higher 120‐min proinsulin response to glucose during the initial OGTT showed a significant correlation (IGT: p <0.0001) with increased fasting plasma glucose levels after follow‐up period and developed Type 2 diabetes. The present findings suggest that the proinsulin response to glucose loading might be a useful indicator for predicting worsening to diabetes in subjects with impaired glucose tolerance.

TROGLITAZONE AND METFORMIN, BUT NOT GLIBENCLAMIDE, DECREASE BLOOD PRESSURE IN OTSUKA LONG EVANS TOKUSHIMA FATTY RATS

To determine whether hypoglycemic agents such as sulfonylureas, biguanides and the newly developed insulin sensitizers such as troglitazone, have hypotensive effects in an animal model of non-insulin-dependent diabetes mellitus associated with insulin resistance, male Otsuka Long Evans Tokushima Fatty (OLETF) rats aged 12 weeks were administered following hypoglycemic agents or vehicle by gavage for 26 weeks; glibenclamide (5 mg/kg/day), metformin (100 mg/kg/day) and troglitazone (70 mg/kg/day). The gain in body weight was similar in the different groups. At 36 weeks of age, troglitazone significantly decreased fasting plasma glucose levels when compared to controls. The area under the curve (AUC) for insulin during glucose loading (2 g/kg, i.p.) was 50% lower in the group treated with troglitazone. Serum triglyceride levels in troglitazone-treated rats were also significantly lower than in the glibenclamide-treated group. Plasma membrane GLUT4 protein content was significantly augmented by a factor of 1.48-fold (p<0.02) in the glibenclamide-treated group and tended to be increased 1.32 times by administration of metformin (p=0.06). The systolic blood pressure increased with age in controls and the glibenclamide-treated group. In contrast, treatment with either metformin or troglitazone significantly decreased systolic blood pressure after the age of 29 weeks. Plasma norepinephrine and epinephrine concentrations did not show a significant decrease in the treated group when compared with the control group. These results suggest that metformin and troglitazone, but not glibenclamide, lower blood pressure in an animal model of insulin resistance, providing further evidence of the beneficial effect of insulin sensitizing hypoglycemic agents on blood pressure.