Summary
Interactions between the metabolism of glucose and lipids provide the basis for a number of metabolic disturbances which have been observed in clinical and experimental diabetes. Particular examples are abnormalities which may be seen in the storage and mobilisation of lipid and in the relative contribution of glucose and fatty acid to energy needs. The concept of a Glucose Fatty Acid Cycle is reviewed and forms the basis for recent studies which are outlined. An essential feature of the Cycle is the proposal that the normal relationship between glucose and fatty acid metabolism is reciprocal and not dependent; and that the augmented release of fatty acids for oxidation in muscle and other tissues in diabetes is not primarily due to defective glucose metabolism. The release and oxidation of fatty acids may depend upon lipolysis which may be directly regulated by hormone action and not dependent upon glucose metabolism. It can also depend upon esterification of fatty acids which may involve the metabolism of glucose to glycerol phosphate. Evidence is presented that lipid mobilization in the alloxan-diabetic rat which may be insensitive to inhibition by insulin action is primarily dependent upon activation of lipolysis. Although the concentration of glycerol phosphate is diminished in muscle in this form of diabetes this is not a consequence of diminished glucose uptake and it is moreover associated with an increased rate of esterification of fatty acids. In adipose tissue the concentration of glycerol phosphate is not reduced, even though glucose uptake is diminished, and the rate of esterification of fatty acid is accelerated. The concentration of triglyceride in muscle is increased in alloxan-diabetes in the rat and this may be attributed to increased mobilisation of fatty acids from adipose tissue associated with increased esterification to triglyceride in muscle. An increased rate of glucose uptake may be an important factor leading to triglyceride storage in adipose tissue and possibly in muscle when insulin acts on these tissues in the normal animal. The evidence for the possibility that lipid mobilisation may have consequential effects on carbohydrate metabolism and insulin sensitivity in alloxan-diabetes has been briefly reviewed and suggestions made for future studies. It is suggested that our understanding of the mechanisms which may control insulin sensitivity is incomplete, and as a consequence the quantitative importance of the contributions which fatty acid oxidation may make to insulin insensitivity in diabetes remains to be established.
Résumé
Les interactions entre le métabolisme du glucose et des lipides fournissent la base d'un certain nombre de troubles métaboliques qui ont été observés dans le diabète clinique et expérimental. Des exemples particuliers sont des anomalies qui peuvent être observées dans le stockage et la mobilisation de la graisse et dans la contribution relative du glucose et de l'acide gras aux besoins énergétiques. Le concept d'un Cycle Glucose Acide Gras est passé en revue et forme la base des études récentes dont on donne la description générale. Un trait essentiel du Cycle est l'hypothèse que la relation normale entre le métabolisme du glucose et le métabolisme des acides gras est réciproque et non dépendante; et que la libération accrue des acides gras pour l'oxydation dans le muscle et les autres tissus, observée dans le diabète n'est pas due primitivement à un métabolisme défectueux du glucose. La libération et l'oxydation des acides gras peuvent dépendre de la lipolyse qui peut être régulée directement par l'action hormonale et ne pas dépendre du métabolisme du glucose. Elles peuvent aussi dépendre de l'estérification des acides gras, qui peut impliquer le métabolisme du glucose jusqu'au glycérol phosphate. La preuve est présentée que la mobilisation des lipides chez le rat diabétique alloxanique qui peut se montrer insensible à l'action inhibitrice de l'insuline, dépend primitivement de l'activation de la lipolyse. Bien que la concentration du glycérol phosphate soit diminuée dans le muscle dans cette forme de diabéte, ceci n'est pas la conséquence de la diminution de la captation du glucose; elle est d'ailleurs associée à un accroissement de la vitesse d'estérification des acides gras. Dans le tissu adipeux la concentration en glycérol phosphate n'est pas réduite, bien que la captation de glucose soit diminuée, et la vitesse d'estérification des acides gras est accélérée. La concentration de triglycéride dans le muscle est accrue dans le diabète alloxanique du rat et ceci peut être attribué à un accroissement de la mobilisation des acides gras à partir du tissu adipeux, associé à un accroissement de l'estérification en triglycéride dans le muscle. Une augmentation de la vitesse de captation du glucose peut être un facteur important conduisant au stockage du triglycéride dans le tissu adipeux et peut-être dans le muscle lorsque l'insuline agit sur ces tissus chez l'animal normal. On a brièvement passé en revue les arguments établissant la possibilité que la mobilisation des lipides entraîne des effets sur le métabolisme des hydrates de carbone et sur la sensibilité àl'insuline dans le diabète post-alloxanique; des suggestions sont faites pour des études ultérieures. II est suggéré que notre compréhension des mécanismes qui peuvent contrôler la sensibilité à l'insuline est incomplète et en conséquence, l'importance quantitative des contributions que l'oxydation des acides gras peut apporter à l'insensibilité à l'insuline dans le diabète demeure à établir.
Zusammenfassung
Die Zusammenhänge zwischen Glucose- und Fettstoffwechsel sind die Basis für eine Reihe von Stoffwechselstörungen, die beim klinischen und experimentellen Diabetes beobachtet wurden. Die Störungen, die man in der Fettspeicherung und Fettmobilisation und in dem relativen Anteil der Glucose und der Fettsäuren am Energiestoffwechsel sieht, sind spezielle Beispiele. Die Annahme eines Glucose-Fettsäure-Cyclus (Glucose Fatty Acid Cycle) wird dargestellt. Diese bildet den Ausgangspunkt für neuere Untersuchungen, die beschrieben werden. Ein wesentlicher Zug dieses Cyclus ist die Annahme, daß die normalen Beziehungen zwischen Glucose- und Fettsäurestoffwechsel umkehrbar und unabhängig sind und daß beim Diabetes die vermehrte Freisetzung von Fettsäuren für die Oxydation im Muskel und anderen Geweben primär nicht auf eine Störung des Glucosestoffwechsels zurückzuführen ist. Vielmehr kann die Freisetzung und Oxydation der Fettsäuren von einer Lipolyse abhängig sein, die direkt durch hormonelle Wirkung gesteuert wird und vom Glucosestoffwechsel nicht abhängig ist. Sie kann auch von der Veresterung der Fettsäuren abhängig sein, die mit dem Abbau von Glucose zu Glycerinphosphat in Zusammenhang steht. Es werden Hinweise vorgelegt, die zeigen, daß die Fettmobilisation bei der alloxandiabetischen Ratte, die durch Insulinwirkung nicht gehemmt werden kann, primär von einer Aktivierung der Lipolyse abhängt. Obwohl die Konzentration von Glycerinphosphat bei dieser Form des Diabetes im Muskel vermindert ist, ist das nicht eine Folge der verminderten Glucoseaufnahme, sondern ist vielmehr mit einer gesteigerten Veresterungsrate der Fettsäuren verbunden. Obwohl die Glucoseaufnahme vermindert ist, ist die Konzentration des Glycerinphosphates im Fettgewebe nicht verringert und die Veresterungsrate der Fettsäuren sogar vermehrt. Die Konzentration der Triglyceride ist beim Alloxandiabetes der Ratte im Muskel vermehrt. Das kann auf die gesteigerte Mobilisation von Fettsäuren aus dem Fettgewebe verbunden mit einer vermehrten Veresterung zu Triglyceriden im Muskel zurückgeführt werden. Eine gesteigerte Glucoseaufnahme kann ein wichtiger Faktor für eine Triglyceridspeicherung im Fettgewebe und möglicherweise auch im Muskel sein, wenn beim Normaltier Insulin auf diese Gewebe einwirkt. Die Hinweise dafür, daß möglicherweise die Fettmobilisation nachfolgende Wirkungen auf den Kohlenhydratstoffwechsel und die Insulinempfindlichkeit beim Alloxandiabetes hat, werden kurz geschildert und Vermutungen für weitere Untersuchungen geäußert. Es wird angenommen, daß unsere Einsicht in den Steuerungsmechanismus der Insulinempfindlichkeit unvollständig ist und daß deshalb die quantitative Bedeutung der Fettsäureoxydation auf die Insulinunempfindlichkeit beim Diabetes noch aufzuklären bleibt.
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Some of this material also formed the basis for parts of the Banting Memorial Lecture of the British Diabetic Association delivered at the Medical School of the University of Bristol, England, in October, 1965. The studies reported have been supported by grants from the British Diabetic Association, the British Insulin Manufacturers, The Medical Research Council, the Science Research Council and the Royal Society.
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Randle, P.J. Carbohydrate metabolism and lipid storage and breakdown in diabetes. Diabetologia 2, 237–247 (1966). https://doi.org/10.1007/BF01268180
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DOI: https://doi.org/10.1007/BF01268180