Regulation of muscle malonyl-CoA levels in the nutritionally insulin-resistant desert gerbil, Psammomys obesus.
BACKGROUND
Malonyl-CoA, an allosteric inhibitor of carnitine palmitoyl transferase, controls the oxidation of fatty acids in muscle and other tissues by regulating their entrance into mitochondria. The level of malonyl-CoA in muscle is influenced by the uptake of energy substrates such as glucose, the precursor of its synthesis. The desert gerbil, Psammomys obesus, develops a severe insulin resistance with hyperinsulinemia and hyperglycemia when transferred from its native nutrition to a relative high-energy (HE) rodent chow. In keeping with this it shows a low rate of glucose transport and a failure of insulin to suppress hepatic glucose production during a hyperinsulinemic-euglycemic clamp.


METHODS
The concentration of malonyl-CoA has been determined by radio-enzymatic assay together with the levels of citrate and malate in the gastrocnemius muscle of diabetes-prone (DP) and diabetes-resistant (DR) P. obesus during the administration of exogenous insulin, during an hyperinsulinemic-euglycemic clamp and following a 48-h fast.


RESULTS
Muscle GLUT4 protein was reduced by 44% in DP Psammomys on a HE diet, compared with normoglycemic-normoinsulinemic animals on a low-energy (LE) diet. Muscle levels of malonyl-CoA, its precursor citrate and the citrate counter-ion malate were not elevated in DP Psammomys on the HE diet despite the hyperinsulinemia. Likewise, the administration of external insulin in subcutaneous (sc) implants to DP Psammomys did not evoke hypoglycemia, decrease glucose production or increase the concentration of malonyl-CoA and citrate in muscle, as it did in both albino rats and a selected line of DR Psammomys. In contrast, fasting significantly reduced muscle malonyl-CoA and citrate levels in the DP and DR Psammomys and promoted the fat oxidative pathway.


CONCLUSIONS
Since non-diabetic Psammomys on a LE diet already show insulin resistance in the fed state, the sustained low malonyl-CoA levels in these animals imply a readiness for the oxidation of fatty acids. In a desert gerbil, adjusted to a food-scarce environment, such a continuing utilization of fatty acids as energy substrate by muscle would preserve the available glucose for glucose-dependent tissues and would diminish the need for gluconeogenesis.
Department of Biochemistry and Diabetes Research Unit, Hadassah University Hospital, Jerusalem 91120, Israel. shafrir@md.huji.ac.il
Eleazar
E
Shafrir
Ehud
E
Ziv
Asish K
AK
Saha
Neil B
NB
Ruderman
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors; D003889:Desert Climate; D004032:Diet; D004343:Drug Implants; D004734:Energy Metabolism; D005260:Female; D005849:Gerbillinae / Q000502:physiology*; D015309:Glucose Clamp Technique; D006946:Hyperinsulinism / Q000097:blood; D007262:Infusions, Intravenous; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D007557:Israel; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*
D001786:Blood Glucose; D004343:Drug Implants; D007328:Insulin; D008316:Malonyl Coenzyme A; D002334:Carnitine O-Palmitoyltransferase