The interaction between the adenylate cyclase system and insulin-stimulated glucose transport. Evidence for the importance of both cyclic-AMP-dependent and -independent mechanisms

Lönnroth, Peter; Davies, J. Islwyn; Lönnroth, Ivar; Smith, Ulf

doi:10.1042/bj2430789

Cited by 35 publications

(12 citation statements)

References 29 publications

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“…Changes in the receptor-kinase activity detected by that method may not reflect the situation in the intact cell. Our data on the effect of isoprenaline on glucose transport are consistent with previous reports [12,[29][30][31].…”

Section: Discussionsupporting

confidence: 93%

The relationship between insulin binding, insulin activation of insulin-receptor tyrosine kinase, and insulin stimulation of glucose uptake in isolated rat adipocytes. Effects of isoprenaline

Klein

Matthaei

Drenkhan

et al. 1991

Biochemical Journal

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We have studied the relationship between insulin activation of insulin-receptor kinase and insulin stimulation of glucose uptake in isolated rat adipocytes. Glucose uptake was half-maximally or maximally stimulated, respectively, when only 4 % or 14 % of the maximal kinase activity had been reached. To investigate this relationship also under conditions where the insulin effect on activation of receptor kinase was decreased, the adipocytes were expos'ed to 10 ,uM-isoprenaline alone or with 5 jug of adenosine deaminase/ml. An approx. 30 % (isoprenaline) or approx. 50 % (isoprenaline + adenosine deaminase) decrease in the insulin effect on receptor kinase activity was found at insulin concentrations between 0.4 and 20 ng/ml, and this could not be explained by decreased insulin binding. The decreased insulin-effect on kinase activity was closely correlated with a loss of insulin-sensitivity of glucose uptake. Moreover, our data indicate that the relation between receptor kinase activity and glucose uptake (expressed as percentage of maximal uptake) remained unchanged. The following conclusions were drawn. (1) If activation of receptor kinase stimulates glucose uptake, only 14 % of the maximal kinase activity is sufficient for maximal stimulation. (2) Isoprenaline decreases the coupling efficiency between insulin binding and receptor-kinase activation, this being accompanied by a corresponding decrease in sensitivity of glucose uptake. (3) Our data indicate that the signalling for glucose uptake is closely related to receptor-kinase activity, even when the coupling efficiency between insulin binding and kinase activation is altered. They thus support the hypothesis that receptor-kinase activity reflects the signal which originates from the receptor and which is transduced to the glucosetransport system. INTRODUCTIONThe insulin receptor is a transmembrane glycoprotein composed of two a-subunits of 135 kDa and two f-subunits of 95 kDa [1,2]. Insulin binding to the a-subunits causes rapid phosphorylation of tyrosine residues on the fl-subunits [1,3]. The phosphorylation of tyrosine-containing sites on the receptor in turn activates the insulin-receptor kinase toward tyrosine residues of other protein substrates [4][5][6]. Several lines of evidence indicate that autophosphorylation and activation of the insulin receptor as a tyrosine kinase is an important early step necessary for the transduction of many, if not all, of the biological effects of insulin [1,7,8]. A decreased ability of insulin receptors to autophosphorylate or to activate their kinase in response to insulin could therefore cause or contribute to insulin resistance. In fact, a decreased kinase activity of insulin receptors has been found in a variety of situations where the effects of insulin on biological actions are decreased [9][10][11][12][13][14], including type-II diabetes [15][16][17]. For technical reasons it has, however, so far been difficult to relate directly alterations in the coupling between insulin binding and insulin-induced activation o...

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Section: Discussionsupporting

confidence: 93%

The relationship between insulin binding, insulin activation of insulin-receptor tyrosine kinase, and insulin stimulation of glucose uptake in isolated rat adipocytes. Effects of isoprenaline

Klein

Matthaei

Drenkhan

et al. 1991

Biochemical Journal

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“…In rat muscle, however, a clear difference between interstitial muscle insulin and plasma insulin is evident only at concentrations in the upper physiological range, that is beyond approximately 1.5 nmol/l, which in our clamp model equals the EC 50 for the effect of insulin on glucose infusion rate [36]. The present data confirm that the interstitial insulin concentration is similar to plasma insulin in the lower concentration range.…”

Section: Discussionsupporting

confidence: 71%

Induction of rat muscle insulin resistance by epinephrine is accompanied by increased interstitial glucose and lactate concentrations

1998

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Epinephrine and b-adrenergic stimulation rapidly inhibit insulin-mediated glucose uptake by induction of insulin resistance mainly in the skeletal muscle [1,2]. The insulin signalling pathway may be altered by b-adrenergic stimulation both by cAMP and cAMP independent mechanisms [3]. An inhibitory action at multiple sites is suggested since the insulin signal is disturbed at the receptor level [4] as well as in the tyrosine kinase [5], the glucose transporter protein [6] and the glycolytic pathway [7]. Moreover, induction of lipolysis by b-adrenergic stimuli leads to decreased oxidation of glucose through the action of the Randle cycle [8].The glucose transporter protein is considered to be rate-limiting for insulin-stimulated glucose uptake in the muscle. Moreover, recent research has emphasized the importance of the capillary wall as a major determinant of the transendothelial delivery of glucose [9] and insulin [10] in skeletal muscle since the interstitial concentrations of glucose and insulin are lower than those in the arterial plasma [9,10]. This is further supported by the findings that the insulin-[11] and glucose-[12] stimulated increase in muscle blood flow correlates with glucose uptake in normal as well as in insulin resistant muscles [13].The importance of blood flow for the rate of delivery of glucose and insulin to the muscles is, however, Diabetologia (1998) Summary Muscle glucose uptake and lactate release during b-adrenergic stimulation by epinephrine (epi) and b-adrenergic blockade by propranolol (prop) were investigated during an euglycaemic hyperinsulinaemic (30 pmol × kg ±1 × min ±1 ) with or without added somatostatin (0.1 mg/min; pancreatic) clamp in female rats. To assess the interstitial insulin, glucose and lactate concentrations, microdialysis was done in the medial femoral muscle in both legs. The influence of muscle skeletal blood flow on interstitial insulin, glucose and lactate was examined with the microsphere technique, using 57 Co-microspheres. Epinephrine decreased glucose infusion rate by about 75 % (p < 0.0001) and increased concentrations of interstitial glucose by about 35 % (p < 0.001) and lactate by about 65 % (p < 0.01). Plasma insulin concentration increased during b-adrenergic stimulation by about 25 % (p < 0.05) whereas the interstitial insulin concentration was unchanged. Muscle blood flow in the hindlimb was considerably enhanced by about 130 %, (p < 0.001) by epinephrine. Infusion of propranolol totally abolished all the above effects induced by epinephrine. The data show that insulin resistance and vasodilation induced by b-adrenergic stimulation with epinephrine is accompanied by increased interstitial glucose as well as lactate concentrations in muscle. The increased interstitial glucose concentration is the result of a decreased cellular uptake of glucose together with an increased capillary delivery of glucose by vasodilation. It is concluded that the severe cellular resistance to insulin induced by epinephrine could not be overcome either by the increased...

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“…Two remaining possibilities are that PACAP stimulates the glucose output from the liver, which has been demonstrated in vitro (56,57), and that PACAP indirectly stimulates hepatic glucose output through stimulation of epinephrine release from the adrenals. This latter explanation is supported by the finding that PACAP increases plasma epinephrine levels in mice (79); epinephrine is known to antagonize insulin action (88). This hypothesis is also supported by a recent study showing that after adrenalectomy in mice, which prevents any influence through epinephrine, PACAP potentiates glucose elimination (89).…”

Section: Islet Physiology Of Pacapmentioning

confidence: 72%

The Neuropeptide Pituitary Adenylate Cyclase–Activating Polypeptide and Islet Function

2001

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The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is ubiquitously distributed in both the central and peripheral nervous systems and exerts a variety of effects. PACAP is a neuropeptide in pancreatic islets, where it has been suggested as a parasympathetic and sensory neurotransmitter. PACAP stimulates insulin secretion in a glucose-dependent manner, by an effect executed mainly through augmenting the formation of cAMP and stimulating the uptake of calcium. Accumulating evidence in animal studies points to a physiological importance of PACAP in the regulation of the insulin response to feeding. This review summarizes the current knowledge of islet actions and mechanisms and the function of PACAP. Diabetes 50: 1959

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The interaction between the adenylate cyclase system and insulin-stimulated glucose transport. Evidence for the importance of both cyclic-AMP-dependent and -independent mechanisms

Cited by 35 publications

References 29 publications

The relationship between insulin binding, insulin activation of insulin-receptor tyrosine kinase, and insulin stimulation of glucose uptake in isolated rat adipocytes. Effects of isoprenaline

The relationship between insulin binding, insulin activation of insulin-receptor tyrosine kinase, and insulin stimulation of glucose uptake in isolated rat adipocytes. Effects of isoprenaline

Induction of rat muscle insulin resistance by epinephrine is accompanied by increased interstitial glucose and lactate concentrations

The Neuropeptide Pituitary Adenylate Cyclase–Activating Polypeptide and Islet Function

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