Takahumi Tsuchiya

Troglitazone Reduces Plasma Leptin Concentration but Increases Hunger in NIDDM Patients

OBJECTIVE Troglitazone, which improves peripheral insulin resistance of experimental diabetic animals and diabetic patients, affects ob gene expression in the adipose tissue of rodents. The present study was undertaken to examine a hypothesis that clinical administration of troglitazone may reduce circulating leptin levels and affect eating behavior in NIDDM patients. RESEARCH DESIGN AND METHODS Troglitazone was administered at a dosage of 200 mg twice daily for 12 weeks in 20 poorly controlled NIDDM patients. Chronological changes in glycemic control, serum lipids, immunoreactive leptin (IRL) levels, and BMI were measured. Body fat weight was also assessed by bioelectric impedance. RESULTS Troglitazone significantly decreased fasting plasma glucose, serum immunoreactive insulin, and HbA1c levels. Serum levels of IRL and triglyceride were significantly reduced by troglitazone administered for 4, 8, and 12 weeks. Troglitazone administration significantly increased the BMI in NIDDM patients, and two-thirds of the patients complained of increased hunger after the start of troglitazone administration. CONCLUSIONS Troglitazone significantly reduces circulating leptin levels at clinical doses. It may affect the eating behavior of poorly controlled NIDDM patients through the improvement of glycemic control and/or the reduction of circulating leptin.

Pioglitazone increases circulating adiponectin levels and subsequently reduces TNF‐α levels in Type 2 diabetic patients: a randomized study

Background   Adipocytokines are involved in the development of insulin resistance and endothelial dysfunction in diabetic patients. However, the relationship between these factors remains unclear. We observed a chronological change in circulating adipocytokines and blood pressure levels with administration of oral hypoglycaemic agents in Type 2 diabetic (T2DM) subjects.

LEPTIN STIMULATES INSULIN SECRETION AND SYNTHESIS IN HIT-T 15 CELLS

Leptin, an ob gene product, corrects hyperinsulinemia in ob/ob mice. The leptin receptor may exist in pancreatic islets. The present studies were undertaken to determine the direct effect of 1-100 ng/ml recombinant leptin on insulin secretion and synthesis in HIT-T 15 cells by using static culture system. The addition of recombinant leptin significantly increased insulin secretion for 20 min at the highest concentration (100 ng/ml). The addition of recombinant leptin dose-dependently increased insulin secretion for 24 h in the 7 mM glucose-containing F-12 K medium. The incubation with recombinant leptin for 24 h increased preproinsulin mRNA expression, assessed with reverse transcription-polymerase chain reaction (RT-PCR) method. It was furthermore demonstrated that HIT-T 15 cells possessed the specific binding site for [125I]-labeled leptin. The present study demonstrated the existence of the leptin-specific binding sites that mediate its stimulatory effect on insulin secretion and synthesis in HIT-T 15 cells.

An increase of circulating leptin in patients with liver cirrhosis.

OBJECTIVE: Leptin, the ob gene product, is an anorexigenic peptide secreted from adipose tissue. However, the mechanism of leptin clearance/degradation has not been well determined in humans. The present study was undertaken to examine a possible involvement of liver in determining circulating leptin concentrations in humans.SUBJECTS: In the present study 58 healthy control subjects and 68 patients with liver cirrhosis (LC) without any renal dysfunction were randomly included.METHOD: The serum immunoreactive leptin (IRL) concentrations relative to the body mass index (BMI) were determined. Serum IRL and estradiol (E2) concentrations were assayed by radioimmunoassay (RIA).RESULTS: The correlations between the BMI and circulating IRL concentrations were all significant in male healthy controls (M-C), male patients with LC (M-LC), female healthy controls (F-C) and female patients with LC (F-LC). Circulating IRL concentrations were significantly higher than control in F-LC but not M-LC groups. The ratio of circulating IRL concentrations to the BMI was significantly higher in the M-LC group than in the M-C group and also significantly higher in the F-LC group than in the F-C group. The correlation between the IRL/BMI ratio and serum total bilirubin concentrations was significant (r=0.417, P<0.05) in the M-LC group, but not in the F-LC group. There was no significant correlation of the IRL/BMI ratio to serum E2 or albumin concentrations in either M-LC or F-LC groups.CONCLUSION: The present data demonstrated that the rate of increase in circulating IRL concentrations with the BMI was higher in LC patients of both genders. Liver may play a role in determining circulating leptin levels.

Troglitazone inhibits isolated cell proliferation, and induces apoptosis in isolated rat mesangial cells

Background/Aims: Troglitazone is one of thiazolidinedione derivatives as a high affinity ligand for peroxisome proliferator-activated receptor-gamma (PPAR-γ). The in vivo studies demonstrated that troglitazone ameliorated microalbuminuria. There have been few reports about direct effect of thiazolidinedione derivatives on mesangial cell function. We determined the effect of troglitazone on isolated rat mesangial cell proliferation. Methods: We determined PPAR-γ mRNA expression in isolated rat mesangial cells. Chronic effects of 10–6 to 10–4 mol/l troglitazone on mesangial cell proliferation and mitogen-activated protein (MAP) kinase activity were also determined. The effects of troglitazone on apoptosis were investigated in rat mesangial cells. Results: Rat PPAR-γ mRNA was detected in isolated rat mesangial cells. Living cell number, assessed by colorimetric [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT) assay, was significantly decreased with 10–4 mol/l troglitazone. The addition of 10–6 to 10–4 mol/l troglitazone dose-dependently inhibited 5-bromo-2′-deoxyuridine (BrdU) uptake into isolated rat mesangial cells. The addition of 10–4 and 10–5 mol/l troglitazone significantly reduced MAP kinase activity. Troglitazone at the concentrations of 10–6 to 10–4 mol/l dose-dependently increased DNA fragmentation rates, indicating that troglitazone may cause apoptosis in rat mesangial cells. Bax and Bcl-xL proteins were not changed, although Bcl-2 proteins increased with troglitazone. Conclusions: The present data demonstrated that troglitazone inhibits cell proliferation, and induces apoptosis in rat mesangial cells, raising a possibility that it directly affects renal function.

Orchiectomy and response to testosterone in the development of obesity in young Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats.

OBJECTIVE: Withdrawal of testosterone prevents the development of hyperglycaemia in male Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats, a model of non-insulin-dependent diabetes mellitus (NIDDM), but the exact mechanism has not been established. The present studies were undertaken to examine a possible role of testosterone in the development of obesity in young OLETF rats who have not shown marked hyperphagia.METHODS: Body weight, food intake and circulating concentrations of metabolic factors including immunoreactive leptin (IRL) were measured at five weeks of age in young male OLETF rats and their lean controls, Long-Evans-Tokushima-Otsuka (LETO) rats. At six weeks of age, both LETO and OLETF rats were bilaterally orchiectomized (Orchx) and half of each group implanted with a silastic tube containing testosterone. After a three week observation period, all animals were killed and circulating concentrations of metabolic factors and the ob gene expression in retroperitoneal white adipose tissues were measured.RESULTS: Body weight and 24 h food intake were already increased in OLETF rats at five weeks of age. Serum testosterone concentrations were significantly lower in OLETF rats than in LETO rats. Expression of the ob gene was significantly decreased in the retroperitoneal white adipose tissue of OLETF rats, and their serum IRL concentrations were lower. Food intake and body weight gain for three weeks after the operation were significantly lower in the Orchx group of OLETF rats than in the sham-operated group. Hyperglycaemia, accompanied by hyperinsulinaemia, was attenuated by orchiectomy in OLETF rats. Circulating IRL concentrations were significantly higher in OLETF rats than in LETO rats and decreased by orchiectomy. Testosterone supplement reversed all of the changes caused by orchiectomy in OLETF rats. In contrast, the changes, which were observed after orchiectomy in OLETF rats, were not obvious in LETO rats.CONCLUSION: The present data indicate that testosterone plays a role in the development of obesity and NIDDM in young OLETF rats, but that changes of leptin production in white adipose tissue may not be important in the development of obesity in young OLETF rats.

Relationship between Hypothalamic-Pituitary-Adrenal Axis Function and Leptin Release.

The activation of sympathetic activity which is related to hypothalamic corticotropin-releasing hormone (CRH) release may modulate ob gene expression in vivo. In the present studies, we determined changes in circulating leptin concentrations by modulating sympathetic activity by adrenalectomy, corticosterone supplement, hypothalamic CRH infusion and starvation in male Wistar rats. Bilateral adrenalectomy significantly inhibited serum leptin concentrations and the continuous supplement of corticosterone by silastic tube restored the reduction of serum leptin concentrations in adrenalectomized rats. Intracerebro-ventricular infusion of 2μg recombinant rat CRH significantly decreased serum leptin concentrations at 2 hours after the infusion. In addition, 24-hour starvation significantly decreased retroperitoneal adipose tissue ob gene expression, measured by the reverse transcription-polymerase chain reaction (RT-PCR) method, and serum leptin concentrations. The data obtained herein indicated that the activation of CRH-ACTH axis by adrenalectomy, intracerebro-ventricular CRH infusion and starvation inhibits leptin production from adipose tissues and the reduced production of the anorexigenic message from adipose tissues may play a role in maintaining homeostasis in vivo by the disinhibition of hypothalamic feeding centers which is inhibited by hypothalamic CRH-containing neurons.

Possible liver damage by biosynthetic human insulin

To the Editor We have experienced two non-insulin-dependent diabetic patients with liver damage after the start of biosynthetic human insulin in yeast (Pen®ll, Insulin human regular, Novo Nordisc, Tokyo, Japan) administration, for whom change of insulin to another type of biosynthetic human insulin in Escherichia coli improved liver dysfunction. These patients raised the possibility that remaining bacterial polypeptide might cause liver damage in diabetic patients treated with biosynthetic human insulin.