Role of early insulin secretion in postglucose-loading hyperglycaemia and postfat-loading hyperlipidaemia: comparing nateglinide and glibenclamide for acute effects on insulin secretion in OLETF rats

AIM: The aim of this study was to clarify the role of an early insulin secretion in postprandial hyperglycaemia and hyperlipidaemia; a study using spontaneously type 2 diabetic Otsuka Long-Evans Tokushima Fatty rats with visceral obesity was performed to investigate the acute effect of nateglinide (NAT) vs. glibenclamide (GB) on increases in glucose after glucose loading and on increases in triglyceride (TG) after fat loading. METHODS: Fasting rats were given 50 mg/kg of NAT, 1 mg/kg of GB or 5% methyl cellulose (vehicle) as control and then immediately given oral glucose 1 g/kg. RESULTS: An acute increase in insulin levels in portal blood peaked at 15 min in the NAT group, while insulin levels in the GB group continued to increase significantly after 60 min. Glucose levels in peripheral blood were significantly lower in the NAT group at 30 and 60 min and in the GB group at 120, 180 and 270 min after glucose loading, compared with those in the vehicle group. Subsequently, fasting rats were given NAT, GB or vehicle and then immediately given oral fat emulsion (soy oil 2 g/kg). An acute increase in insulin secretion was seen with NAT, peaking at 30 min, while TG, chylomicron and very low-density lipoprotein levels after fat loading were shown to be significantly lower with NAT than with vehicle. However, the continued insulin secretion observed with GB led to no significant decrease in TG levels after fat loading. In addition, lipoprotein lipase mRNA expression in adipose tissue increased significantly 120 min after NAT administration in comparison with baseline. This increase was not noted with GB administration. CONCLUSION: Abnormalities in early insulin secretion are closely associated with the pathogenesis of various disease conditions that combine to characterize type 2 diabetes, suggesting that normalizing early insulin response in portal blood represents an important treatment not only for postprandial hyperglycaemia but also for postprandial hyperlipidaemia.