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Biochemische Grundlagen der gestörten Wechselbeziehungen zwischen Kohlenhydrat- und Fettstoffwechsel bei Diabetes mellitus

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Zusammenfassung

Beim Diabetes mellitus sprechen klinische und biochemische Befunde für eine Störung der Beziehungen zwischen Kohlenhydrat- und Fettstoffwechsel, die durch ein komplexes Wechselspiel lipogenetisch und lipolytisch wirksamer Hormone reguliert werden.

Als wichtigster Parameter dieser Wechselbeziehungen ist der Plasmaspiegel der freien Fettsäuren anzusehen. Er ist direkt proportional der intracellulären Acyl-CoA-Konzentration der Fettzellen. Der Acyl-CoA-Spiegel der Fettzellen ist insulinabhängig durch:

  1. 1.

    Vermehrte Glucoseeinschleusung mit Glycerin-1-£ und Acetyl-CoA-Erhöhung.

  2. 2.

    Aktivierung der Lipoproteinlipase.

  3. 3.

    Hemmung der Wirkung lipolytischer Hormone an der Adenylcyclase.

Ein Insulindefizit führt somit zur Hyperlipacidämie. Diese bewirkt:

  1. 1.

    An der Muskelzelle eine Glucoseverwertungsstörung durch Hemmung der Glykolyse an 4 Stellen: Glucosepermeation, Hexokinase, Phosphofructokinase, Pyruvatdehydrogenase. Daraus resultiert eine Hyperglykämie, die einerseits die Triglyceridablagerung im Fettgewebe fördert, andererseits durch Stimulierung derβ-Zellen zu deren Erschöpfung führt und als Promotionsphase der diabetischen Erbanlage gewertet werden kann.

  2. 2.

    An der Leberzelle eine Steigerung der Lipoproteinsynthese, die bei relativem „Nachhinken“ der Proteinsynthese zur Fettleber führt. Wird die Glycerokinasereaktion in der Leberzelle der begrenzende Schritt, erfolgt durch Endprodukthemmung der langkettigen Acyl-CoA's eine Acetyl-CoA-Anhäufung, die zur Ketogenese führt.

  3. 3.

    An der Gefäßwand durch intracelluläre Cholesterinanhäufung eine Verfettung und Zellproliferation der Endothelzellen mit Verschiebung des Verhältnisses der sauren zu den neutralen Mucopolysacchariden. Hieraus resultiert eine Filtrationsstörung der Grundsubstanz mit Retention von Lipoproteinen, Cholesterin, Triglyceriden, Phosphatiden, Ca++.

Die Fettstoffwechselstörung spielt somt eine wesentliche Rolle bei der Manifestation der diabetischen Erbanlage. Durch die Auswirkung auf Leber und Gefäßwände beeinflußt sie auch entscheidend die Prognose des Diabetes mellitus.

Summary

Clinical and chemical findings give strong evidence for a disturbance of the interaction between carbohydrate and lipid metabolism during diabetes mellitus. The interaction between carbohydrate and lipid metabolism is normally controlled by a complex balance between lipogenetic and lipolytic hormones. The plasma concentration of free fatty acids constitutes the crucial parameter of this balance and is directly related to the intracellular acyl-CoA concentration of the fat cells. The intracellular acyl-CoA concentration is insulin-dependant for the following reasons:

  1. 1.

    Insulin faciliates glucose entry into fat cells with concomitant increase of glycerol-1-phosphate and acetyl-CoA.

  2. 2.

    Insulin inhibits the effect of lipolytic hormones at the adenylcyclase system.

  3. 3.

    Insulin activates the lipoproteinlipase.

Thus the absolute or relative insulin deficiency results in a hyperlipacidemia by suppression of lipogenesis with concurrent increase in lipolysis.

The hyperlipacidemia causes:

  1. 1.

    An impedance of glucose utilization of the muscle cell by an four-fold inhibition of glycolysis at the following points: Glucose-permeation, hexokinase, phosphofructokinase, pyruvatedehydrogenase. Thus there results a hyperglycemia which on the one hand favours triglyceride deposition in adipose tissue, on the other hand leads to exhaustive stimulation of the islets of Langerhans. These stimulus for continued insulin secretion may be appreciated as a promotor of the diabetic genetic defect.

  2. 2.

    An increased lipoprotein synthesis in the hepatocyte leading to fatty liver when synthesis of the protein portion of the lipoproteins “lags behind” triglyceride synthesis. As soon as the glycerokinase-reaction becomes the rate limiting step of triglycerides synthesis in hepatocyte acetyl-CoA will accumulate as the result of long chain acyl-CoA mediated end-product inhibition. The removal of the elevated acetyl-CoA concentration by the HMG-CoA cycle leads to ketogenesis.

  3. 3.

    Fatty degeneration and cell proliferation of the endothelial cells of the blood vessel walls by an intracellular increase of cholesterol. Furthermore the ratio of the acid mucopolysaccharides to the neutral mucopolysaccharides is shifted to the former. The resultant impedance of filtration through the ground substance of blood vessels causes a retention of lipoproteins, cholesterol, triglycerides, phospholipids, Ca++.

Thus the alteration of lipid metabolism seen during diabetes mellitus contributes an equally important part to the manifestation of diabetic genetic defect and, as a consequence of its effect on the liver and blood vessel walls, as to the prognosis of diabetes mellitus.

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Abbreviations

ACTH:

Adrenocorticotropes Hormon

AMP:

Adenosinmonophosphat

ATP:

Adenosintriphosphat

CoA:

Coenzym A

DOAP:

Dihydroxyacetonphosphat

FADH2 :

Reduziertes Flavinadenindinucleotid

Glc:

Glucose

β-HMG-CoA:

β-Hydroxy-β-Methyl-Glutaryl-Coenzym A

LCAT:

Lecithin-Cholesterin-Acyl-Transferase

LPL:

Lipoproteinlipase

NADH2 :

reduziertes Niacinamidadenindinucleotid

NADPH2 :

reduziertes Niacinamidadenindinucleotidphosphat

£:

Phosphat

PDH:

Pyruvatdehydrogenase

PFK:

Phosphofructokinase

STH:

Somatotropes Hormon

TSH:

Thyreoideastimulierendes Hormon

VLDL:

Very low density lipoproteins.

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Schulze, B., Kaffarnik, H. Biochemische Grundlagen der gestörten Wechselbeziehungen zwischen Kohlenhydrat- und Fettstoffwechsel bei Diabetes mellitus. Klin Wochenschr 48, 1147–1157 (1970). https://doi.org/10.1007/BF01486632

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