Effect of phenformin on substrate metabolism of working muscle in maturity onset diabetics

Wicklmayr, M.; Dietze, Gabriele; Mehnert, Hellmut

doi:10.1007/bf00422253

Cited by 10 publications

(3 citation statements)

References 31 publications

(33 reference statements)

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“…Earlier studies indicated that phenformin, a related biguanide, increased glucose uptake into diabetic muscle undergoing work load by increasing glycogen synthesis (54). Metformin enhanced basal and insulin-stimulated glucose incorporation into glycogen in cultured rat hepatoma cells (55).…”

Section: A Klip and La Lei Termentioning

confidence: 98%

Cellular Mechanism of Action of Metformin

Klip

Leiter²

1990

Diabetes Care

215

102

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Metformin is a hypoglycemic drug effective in the treatment of non-insulin-dependent diabetes mellitus and increasingly used in Canada and Europe. Effects on intestinal glucose absorption, insulin secretion, and hepatic glucose production are insufficient to explain its hypoglycemic action, with most evidence suggesting that the major effect of the drug is on glucose utilization. In vivo and in vitro studies have demonstrated that metformin stimulates the insulin-induced component of glucose uptake into skeletal muscle and adipocytes in both diabetic individuals and animal models. This increase is more significant in diabetic than in nondiabetic animals, suggesting an enhanced action of the drug in the hyperglycemic state. The increase in glucose uptake is also reflected in an increase in the insulin-dependent portion of glucose oxidation. Potential sites of action of metformin are the insulin receptor and the glucose transporters. Although metformin increases insulin binding in various cell types, this effect is not universal and does not correlate with stimulation of glucose utilization. In contrast, direct effects of the drug on the glucose-transport system have been demonstrated. Metformin elevates the uptake of nonmetabolizable analogues of glucose in both nondiabetic rat adipocytes and diabetic mouse muscle. In the latter, the stimulatory effect of the drug is additive to that of insulin. In human and rat muscle cells in culture, metformin increases glucose-analogue transport independently of and additive to insulin, suggesting an insulin-dependent action. Most of these results suggest that the basis for the hypoglycemic effect of this biguanide is probably at the level of skeletal muscle by increasing glucose transport across the cell membrane.

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Section: A Klip and La Lei Termentioning

confidence: 98%

Cellular Mechanism of Action of Metformin

Klip

Leiter²

1990

Diabetes Care

215

102

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“…This is furthermore strengthened by the clinical experience that muscle work improves glucose metabolism in diabetes only if metabolism is well controlled by insulin [18]. That insulin is indispensable could also be shown in the isolated rat hind leg [19] and in the human muscle of juvenile diabetics [20] and maturityonset diabetics [21]. In insulin deficiency, muscle work leads to an acceleration of capillary blood flow but not of glucose uptake.…”

Section: Figurementioning

confidence: 90%

The Kallikrein-Kinin system and muscle metabolism: Biochemical aspects

et al. 1980

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Infusion of bradykinln (BK) into the brachlal artery in front of skeletal muscle of the human forearm yielding arterial concentrations of about 10 -12 mol/I caused not only acceleration of blood flow but also of glucose and branchedchain amino acid uptake into the muscle in healthy volunteers and maturlty-onset diabetics. These effects were almost entirely abolished after inhibition of prostaglandin biosynthesis.Papaverine, although causing identical acceleration of capillary blood flow, induced no metabolic action. Apart from causing enlargement of the capillary bed, bradykinin has another metabolic effect which was underlined by results obtained in the isolated perfused rat heart, indicating increased glucose uptake at constant rates of coronary blood flOW, In order to clarify whether kinins play a physiological role in muscle carbohydrate metabolism, the well-known work-induced acceleration of muscle glucose uptake was studied during the inhibition of kinin I~eration from kinlnogen by application of a protease inhibitor (Trasylol| and during additional substitution with synthetic BK. The glucose uptake under a defined work load was almost completely abolished by the protease inhibitor; application of BK restored the normal effect. Almost identical responses have been observed concerning the well-known hypoxia-indueed acceleration of muscle glucose uptake. Furthermore, insulin-lnduced acceleration of glucose uptake into the resting forearm was reduced by half when kinin liberation from kinlnogen was inhibited by Trasylol| additional application of synthetic BK restored the normal response.From the data presented, one may suggest that kinins are involved in carbohydrate and amino acid metabolism of skeletal muscle, most probably by improving the action of insulin.

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“…Subsequently, kinins were demonstrated to exert a similar effect in isolated macrophages [41]. Studies in human forearm indicated that kinins play a role in glucose uptake and metabolism in hypoxia [42,43] and in maturity-onset diabetes [44]. This action of kinins appears to be dependent on prostaglandin synthesis [45].…”

Section: Physiological Effectsmentioning

confidence: 99%

The kallikrein‐kinin system in circulatory and metabolic homeostasis

1981

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This review focuses on how the kallikrein-kinin system may influence circulatory and metabolic homeostasis through its interrelationship with the renin-angiotensin system and the prostaglandins. Biochemical and physiological aspects of each of these systems are described. Recent findings suggest that the kinins may play a role in the physiological processes of healthy individuals as well as in disease states. The major influence of kinins, both in tissue and plasma, on renal function and blood pressure homeostasis may be through their effect on prostaglandin synthesis rather than their effect on angiotensin II formation. Kinins also may play a rule in metabolism since these oligopeptides were found to influence glucose uptake in the gut and in skeletal and cardiac muscle in normal and pathological conditions. The effects of these chemical mediators on renal function are presented in terms of their anatomical location, as well as the biochemical and physiological associations between these chemical mediators.

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Effect of phenformin on substrate metabolism of working muscle in maturity onset diabetics

Cited by 10 publications

References 31 publications

Cellular Mechanism of Action of Metformin

Cellular Mechanism of Action of Metformin

The Kallikrein-Kinin system and muscle metabolism: Biochemical aspects

The kallikrein‐kinin system in circulatory and metabolic homeostasis

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