Role of AMPD2 in impaired glucose tolerance induced by high fructose diet

Abstract

A high intake of products containing fructose is known to mediate insulin resistance. In the liver, AMPD2, an isoform of AMPD, has important glucose metabolic homeostasis functions including maintenance of AMP-activated protein kinase (AMPK). We speculated that AMPD2 induces impaired glucose tolerance in individuals who consume a high-fructose diet. We gave either a normal-chow (NCD) or high-fructose (HFrD) diet for 40 days to 8-week-old male wild-type (WT) and Ampd2 −/− homozygote (A2 −/−) C57BL/6 mice. A glucose tolerance test (GTT) and pyruvate tolerance test (PTT) were used to evaluate glucose metabolism. In addition, gluconeogenesis and glycolysis enzymes, and AMPK phosphorylation in the liver were investigated. With consumption of the HFrD, A2 −/− mice showed enhanced glucose tolerance in GTT and PTT results as compared to the WT mice, which were independent of changes in body weight. Also, the levels of phosphoenolpyruvate carboxy kinase and glucose-6-phosphatase (hepatic gluconeogenic enzymes) were significantly reduced in A2 −/− as compared to WT mice. The hepatic glycolytic enzymes glucokinase, phosphofructokinase, and pyruvate kinase were also examined, though there were no significant differences between genotypes in regard to both mRNA expression and protein expression under HFrD. Surprisingly, hepatic AMPK phosphorylation resulted in no changes in the A2 −/− as compared to WT mice under these conditions. Our results indicated that Ampd2–deficient mice are protected from high fructose diet-induced glycemic dysregulation, mainly because of gluconeogenesis inhibition, and indicate a novel therapeutic target for type 2 diabetes mellitus.

Spaceflight Activates Autophagy Programs and the Proteasome in Mouse Liver

“…Adenosine monophosphate deaminase 2 ( Ampd2 , Table 3 ), an enzyme that converts AMP to inosine monophosphate (IMP) and maintains cellular guanine nucleotide pools [ 43 ], was downregulated, potentially attenuating protein synthesis. This protein also mediates gluconeogenesis in the rodent liver [ 44 ] and, together with Pde4d upregulation ( Table 3 ), suggests pathways impacting cellular quiescence may be altered by spaceflight.…”

Interplay between adenylate metabolizing enzymes and AMP‐activated protein kinase

“…Indeed, it has been reported that AMPD2 knock‐out mice are protected from the glycaemic dysregulation caused by a high fructose diet. An accumulation of AMP would be expected in these mice, but, apparently, the protection exerted by enzyme ablation was not mediated by AMPK activation . Finally, Lanaspa et al .…”

“…Indeed, it has been reported that AMPD2 knock-out mice are protected from the glycaemic dysregulation caused by a high fructose diet. An accumulation of AMP would be expected in these mice, but, apparently, the protection exerted by enzyme ablation was not mediated by AMPK activation [75]. Finally, Lanaspa et al [76] demonstrated that a decrease in AMPD2 activity in hibernating ground squirrel during the winter determines the switch of the metabolic arrangement of the liver from lipogenic during the summer to fat oxidizing during hibernation.…”

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“…The relation between insulin resistance, fasting hyperglycemia and glucose intolerance has been said to be mediated by increased synthesis of nonesterified fatty acid (NEFA) and subsequently triacylglycerol (triglyceride) production in the liver from fructose metabolism 44 . Ectopic lipid deposition in liver and skeletal muscles and consequently intramyocellular lipid accumulation result in the production of toxic lipid-derived metabolites which cause serine/threonine phosphorylation of insulin substrate, and this has been shown to reduce insulin signaling, 45,46 thus causing insulin resistance. The insulin resistance and obesity induced by fructose feeding in experimental animals induce compensatory hyperinsulinemia 47 which may cause beta cell exhaustion, thus impairing beta cell function.…”