Insulin transport across capillaries is rate limiting for insulin action in dogs.

Yang, Yan; Hope, Inez D.; Ader, Marilyn; Bergman, Richard N.

doi:10.1172/jci114339

Cited by 294 publications

(263 citation statements)

References 52 publications

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“…In dogs the rate of glucose utilisation correlates better with changes in lymph insulin (thought to be representative of interstitial insulin) than with changes in plasma insulin concentration [42]. In this and our previous study [43] we found a slower increase in clamp glucose requirement in cirrhotic patients.…”

Section: Discussionsupporting

confidence: 60%

Insulin sensitivity, insulin secretion and glucose effectiveness in diabetic and non-diabetic cirrhotic patients

et al. 1993

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Section: Discussionsupporting

confidence: 60%

Insulin sensitivity, insulin secretion and glucose effectiveness in diabetic and non-diabetic cirrhotic patients

et al. 1993

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“…Studies in lymph [35] as well as in interstitial fluid [10] by means of microdialysis have shown that the interstitial insulin concentration is about 50 % lower than in arterial plasma. 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].…”

Section: Discussionmentioning

confidence: 99%

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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“…The transendothelial insulin transport is an important regulator of the interstitial insulin concentration, which is normally lower than in plasma [33]. Changes in blood flow may thus affect the amount of insulin delivered to the interstitial fluid [34]. However, changes in endothelial binding capacity of insulin during haemodynamic changes may affect the plasma insulin level without altering the interstitial insulin concentration [35].…”

Section: Discussionmentioning

confidence: 99%

“…Post-treatment analyses confirmed that noradrenaline as well as adrenaline levels increased significantly with metoprolol treatment [38], whereas no changes were seen in testosterone or cortisol levels. Regarding the importance of the capillary surface area for insulin distribution [34], it may be speculated that an increase in a-adrenergic activity as a result of increased catecholamine levels during b-adrenergic blocking treatment may be an underlying mechanism for the change in insulin levels during an insulin clamp. Interestingly, it was recently demonstrated in our laboratory that an adrenaline infusion during insulin clamp in rat resulted in increased plasma concentrations of insulin, without changes in the muscle interstitial insulin concentration (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

The effect of metoprolol treatment on insulin sensitivity and diurnal plasma hormone levels in hypertensive subjects

Guðbjörnsdóttir¹,

Fowelin²,

Elam³

et al. 1997

Eur J Clin Investigation

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Abstract.To evaluate the effect of metoprolol on insulin sensitivity and diurnal plasma hormone levels, seven mildly hypertensive subjects were investigated (four men and three women, age 52 Ϯ 8, body mass index 25 . 4 Ϯ 1 . 9, mean Ϯ SD). The study had a placebo-controlled, double-blind, crossover design with 6 weeks' metoprolol treatment (100 mg b.i.d) vs. placebo. At the end of each treatment period 24-h blood samples were collected continuously for diurnal analysis of hormone levels and a hyperinsulinaemic euglycaemic clamp combined with [3-3 H]-D-glucose infusion was performed. Insulin sensitivity was evaluated by means of three different methods: diurnal plasma insulin and glucose levels; glucose consumption; and insulin sensitivity index during euglycaemic clamp conditions. Fasting blood glucose and insulin concentrations as well as mean plasma diurnal levels of insulin, growth hormone, testosterone and cortisol were similar after placebo and metoprolol treatment, whereas noradrenaline and adrenaline levels were significantly increased after metoprolol. During the clamp, plasma insulin was significantly higher after metoprolol treatment than after placebo treatment (56 Ϯ 3 vs. 64 Ϯ 2 mU L -1 , P < 0 . 05). Consequently, the insulin sensitivity index [glucose infusion rate (GIR)/ plasma insulin] was lower after metoprolol treatment (16 . 1 Ϯ 2 . 6 vs. 10 . 2 Ϯ 1 . 2, P < 0 . 05), although GIR was not significantly changed. We suggest that the insulin sensitivity index may not accurately reflect the insulin effect as the plasma level of insulin was significantly increased during insulin infusion but not at 24 h, possibly because of alteration of distribution and/or degradation rate of exogenous insulin. Thus, the likelihood of metoprolol inducing insulin resistance in hypertensive subjects may be less than previously proposed.

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Insulin transport across capillaries is rate limiting for insulin action in dogs.

Cited by 294 publications

References 52 publications

Insulin sensitivity, insulin secretion and glucose effectiveness in diabetic and non-diabetic cirrhotic patients

Insulin sensitivity, insulin secretion and glucose effectiveness in diabetic and non-diabetic cirrhotic patients

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

The effect of metoprolol treatment on insulin sensitivity and diurnal plasma hormone levels in hypertensive subjects

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