Abnormal regulation of pancreatic glucagon secretion in obese fa/fa rats

Abstract

The results reported in the literature regarding glucagonaemia in genetically obese fa/fa rats are conflicting: normal, increased or decreased plasma glucagon levels have been reported. Due to the existence of several molecules endowed with glucagon-like immunoreactivity, it was thought that the conflicting data could be related to the degree of specificity of the different glucagon antibodies. Three antibodies that all qualified as being specific for pancreatic glucagon were used. It was found that, depending on the antibody, absolute values of basal glucagonaemia or arginine-induced glucagon output varied quantitatively and qualitatively in both lean and obese rats. When non-extracted basal or stimulated plasma samples were passed on a G-50 Sephadex column, glucagon-like immunoreactivity was present over a wide range of molecular weights, indicating the presence of non-pancreatic glucagon molecules. When an ethanol extraction was used, the fractions eluting from the G-50 Sephadex column contained only pancreatic glucagon immunoreactivity. It is concluded that ethanol extraction is necessary for the measurement of the 3500 daltons glucagon. Using this methodology it was found that: (1) basal glucagonaemia was low but identical in the two groups of rats; (2) arginine-induced glucagon secretion was greater in obese than in lean animals; (3) glucagonaemia was decreased by glucose administration in lean but not in obese rats. It is concluded that there are, in obese animals, dysfunctions of glucagon output that may play a role in their abnormal glucose tolerance.

Effects of muscarinic blockade on insulin secretion and on glucose‐induced thermogenesis in lean and obese human subjects

“…Interestingly, atropine inhibited basal glucagon concentrations in the obese patients, but not in lean controls. Similarly, an abnormal regulation of glucagon secretion was also described in Fa/Fa rats [11,30]. Increased glucagon concentration and decreased metabdic clearance rate of insulin may both contribute to the basal hyperinsulinaemia encountered in obesity, the former by increasing insulin concentrations directly, the latter through glucagon-induced insulin resistance.…”

Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide

“…The effectiveness of GLP-1 as a glucoselowering agent in NIDDM patients has been attributed to the potent suppression of glucagon secretion and inhibition of gastric emptying as well as enhanced insulin secretion. These factors, as well as increased insulin secretion, may con- tribute to the greater glucose-lowering action of DP IV inhibition in obese compared with lean rats, considering that glucagon levels are exaggerated in obese Zucker rats (29). Disadvantages of incretin therapy are the rapid metabolism of exogenously administered native peptides in the circulation and ineffectiveness of oral administration.…”

Impaired glycogen synthesis in hepatocytes from Zucker fatty fa/fa rats: the role of increased phosphorylase activity

“…Defective regulation of hepatic glucose production or hepatic glycogen synthesis by insulin in vivo could be due to changes in circulating hormones that oppose or potentiate the effects of insulin [16] or to defects (receptor or metabolic) in responsiveness of hepatocytes to hormones. The aim of the present study was to investigate the metabolic defect(s) in hepatocytes from fatty (fa/fa) rats maintained in short-term primary culture in the absence of insulin to allow recovery from the shortterm effects of hormonal perturbations in vivo.…”