Long‐chain fatty acyl‐coenzyme A‐induced inhibition of glucokinase in pancreatic islets from rats depleted in long‐chain polyunsaturated ω3 fatty acids

Abstract

The metabolism of D-glucose was recently reported to be impaired in pancreatic islets from second generation rats depleted in long-chain polyunsaturated omega3 fatty acids. Considering the increased clearance of circulating non-esterified fatty acids prevailing in these rats, a possible inhibition of glucokinase in insulin-producing cells by endogenous long-chain fatty acyl-CoA was considered. The present study was mainly aimed at assessing the validity of the latter proposal. The activity of glucokinase in islet homogenates, as judged from the increase in D-glucose phosphorylation rate in response to a rise in the concentration of the hexose represented, in the omega3-depleted rats, was only 81.8 +/- 4.8% (n = 11; p < 0.005) of the paired value recorded in control animals. This coincided with the fact that the inclusion of D-glucose 6-phosphate (3.0 mM) and D-fructose 1-phosphate (1.0 mM) in the assay medium resulted in a lesser fractional decrease of D-glucose phosphorylation in omega3-depleted rats than in control animals. Moreover, whereas palmitoyl-CoA (50 microM) decreased the activity of glucokinase by 38.0 +/- 6.0% (n = 4; p < 0.01) in islet homogenates from normal rats, the CoA ester failed to affect significantly the activity of glucokinase in islet homogenates from omega3-depleted rats. These findings afford direct support for the view that glucokinase is indeed inhibited by endogenous long-chain fatty acyl-CoA in islets from omega3-depleted rats, such an inhibition probably participating to the alteration of D-glucose catabolism prevailing in these islets.

The metabolic syndrome of fructose-fed rats: Effects of long-chain polyunsaturated ω3 and ω6 fatty acids. V. Post-mortem findings

“…The results of such measurements, as given in Table III, document a higher activity of glucokinase in the liver of the Fsal rats than in the other 3 groups of rats (P<0.05 or less). The higher liver glucokinase activity in the Fsal rats, as compared with either the Fsun or Fsaf rats, is reminiscent of the higher glucokinase activity found in the pancreatic islet homogenates of control rats, as compared with second generation rats depleted in long-chain polyunsaturated ω3 fatty acids, a difference tentatively ascribed to inhibition of the enzyme by endogenous long-chain fatty acyl-coenzyme A in the ω3-depleted rats (7). Indeed, in the present study, the Fsal rats were the sole fructose-fed animals exposed to a diet containing sizeable amounts of long-chain polyunsaturated ω3 fatty acids (1), this coinciding with a lower liver triglyceride content (P<0.001) in the Fsal rats than in the Fsun or Fsaf rats.…”

“…The methods used for the measurement of the plasma concentration of albumin (2), blood concentration of glycated hemoglobin (2), liver protein content (6) and hepatic glucokinase activity (7) have been described previously. The kits used for the measurement of the plasma concentration of urea and creatinine (Biocon, Vöhl-Marienhagen, Germany), calcium (Spinreact S.A., Girona, Spain), iron (Randox Laboratories Ltd., Crumlin, UK), plasma and liver triglycerides and phospholipids (Spinreact S.A.) plasma and liver cholesterol (Biolabo, Maizy, France), plasma HDL-cholesterol (Biocon) were obtained from the sources cited in parentheses.…”

The metabolic syndrome of fructose-fed rats: Effects of long-chain polyunsaturated ω3 and ω6 fatty acids. IV. D-glucose metabolism by isolated pancreatic islets

“…These findings are in good agreement with the observation that in islet homogenates from second-generation ω3-depleted rats, the phosphorylation of D-glucose by glucokinase is impaired relative to that found in control animals (7). The latter situation was previously proposed to be attributable to the accumulation of long-chain fatty-acyl CoA in the islets of ω3-depleted rats (7).…”

Direct effects of eicosapentaenoic and docosahexaenoic acids on phospholipid and triglyceride fatty acid pattern, glucose metabolism, 86rubidium net uptake and insulin release in BRIN-BD11 cells

“…In the latter case, the two major anomalies found in the latter rats consisted in a lesser increase in the generation of glucose metabolites in response to a given rise in hexose concentration and a lower ratio between D-[U-14 C]glucose oxidation and D-[5-3 H]glucose utilization [2]. These two anomalies were tentatively attributed to inhibition of glucokinase by endogenous long-chain fatty acyl-coenzyme A [1]. In these experiments, however, the increase in either D-[5-3 H]glucose utilization and D-[U-14 C]glucose oxidation in response to a rise in D-glucose concentration from 1.1 to 11.1 mM was less pronounced in the x3-enriched cells than in the control cells.…”

“…The long-term effects of a dietary deprivation of longchain polyunsaturated x3 fatty acids on enzymatic [1], metabolic [2,3], ionic [4][5][6], and secretory [2,[4][5][6] variables in isolated pancreatic islets were recently investigated in second-generation x3-depleted rats. Extrapancreatic events including insulin resistance [2,7], liver steatosis [8,9], and visceral obesity [10] were also documented in these second-generation x3-depleted rats, and confirmed in normal rats exposed seven weeks after birth for 3-7 months to an x3-depleted diet [11].…”