Glucose Modulation of Amino Acid-Induced Glucagon and Insulin Release in the Isolated Perfused Rat Pancreas

Pagliara, Anthony S.; Stillings, Susan N; Hover, Barbara; Martin, Duane M.; Matschinsky, Franz M.

doi:10.1172/jci107822

Cited by 118 publications

(73 citation statements)

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“…This result is in good agreement with the data of Pagliara et al on the perfused rat pancreas [22]. On the other hand, during a prolonged arginine infusion, a biphasic pattern of insulin release has been demonstrated by other investigators [7,23].…”

Section: Discussionsupporting

confidence: 93%

Insulin delivery rate in response to glucose and arginine infusion in hyperthyroidism

Asano

Okumura

1982

Diabetologia

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Summary. Insulin delivery rates were estimated from the peripheral serum insulin response to a single bolus injection of glucose or arginine in eight normal subjects and eight patients with hyperthyroidism. The mean rate constant for insulin disappearance was 0.2380 _+ 0.0052 per min in the control subjects, which was not significantly different from that observed in the patients with hyperthyroidism (0.2147 _+ 0.0111 per rain). There were also no significant differences in the insulin response to glucose infusion (1.7 _+ 0.3 U during the first phase (0-I0 min) and 5.6 +_ 1.6 U during the second phase (11-60 min) in normal subjects compared with 1.2 _+ 0.5 and 3.7 _+ 1.1 U respectively in the hyperthyroid patients). The delivered insulin in response to glucose infusion was similar in the two.groups. The kg-value in the patients with hyperthyroidism was lower than that in the control subjects (1.24 _ 0.11 versus 2.11 _+ 0.22; p < 0.005). In hyperthyroidism, the low kg-value was not a result of the diminished insulin delivery to the general circulation. Insulin delivery showed a monophasic pattern following arginine infusion in both patients and control subjects. For the control subjects, the amount of insulin delivered was estimated to be 0.53 + 0.12 U during the first 10 min and 0.37 _+ 0.14 U during 11-30 min. In hyperthyroidism, the amount of insulin delivered was significantly lower than in the control subjects (0.21 _+ 0.06 U during the first 10 min and 0.07 _+ 0.03 U during 11-30 min). In the control subjects, the plasma glucose level was raised transiently following arginine infusion, but in hyperthyroidism, there was no change in plasma glucose levels. In hyperthyroidism, therefore, glucose intolerance appears to be primarily related to an antagonism of the hepatic effect of insulin by thyroxine rather than an inhibitory effect of thyroxine on insulin secretion. However, since delivery rate represents the measurement of peripheral serum insulin concentrations, these results cannot exclude an abnormality of hepatic insulin metabolism in hyperthyroidism.Key words: Insulin delivery rate, insulin secretion in hyperthyroidism, glucose, arginine, insulin disappearance rate.Glucose tolerance and insulin secretion have been examined extensively in hyperthyroidism [1][2][3][4], and a reduced glucose tolerance has been found in patients with this condition [2,3]. However, intravenous glucose infusions in hyperthyroid men or dogs have produced conflicting results concerning plasma insulin secretion [2][3][4][5].The mechanism of glucose intolerance is uncertain. It could be a consequence of a decreased capacity of insulin secretion or increased insulin catabolism [6]. In the present study, we have measured insulin delivery rates, calculated on the basis of fractional insulin disappearance rates following glucose infusion, in order to understand further B cell function in hyperthyroidism. Since the arginine-induced insulin response has been reported to be impaired in hyperthyroidism [7], the effect of arginine on the ...

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Section: Discussionsupporting

confidence: 93%

Insulin delivery rate in response to glucose and arginine infusion in hyperthyroidism

Asano

Okumura

1982

Diabetologia

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“…Blood samples were obtained just before removal of the pancreas from all diabetic and control animals which had been heparinized as described (7). The samples (2 ml) were drawn by puncturing the aorta closely above the most cranial ligature [see protocol of surgical procedure as published previously (7)].…”

Section: Introductionmentioning

confidence: 99%

“…The anesthetic and surgical preparation of the animals and composition of the perfusion media have been described in detail (7).…”

Section: Introductionmentioning

confidence: 99%

“…The total release during the period of stimulation was calculated by multiplying the concentration of the respective sample by the flow rate. The net release during the period of stimulation was calculated by deducting the average basal secretion observed during the preperfusion period (7).…”

Section: Introductionmentioning

confidence: 99%

“…Immunoreactive glucagon (7,12) and insulin (13) were measured by using double antibody systems as previously described. Glucose in rat plasma was determined with a fluorometric enzymatic assay (11).…”

Section: Introductionmentioning

confidence: 99%

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Insulin and glucose as modulators of the amino acid-induced glucagon release in the isolated pancreas of alloxan and streptozotocin diabetic rats.

Pagliara¹,

Stillings²,

Haymond³

et al. 1975

J. Clin. Invest.

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A B S T R A C T The hyperglucagonemia that occurs in vivo in animals made diabetic with alloxan or streptozotocin is not suppressed by high glucose but is suppressed by exogenous insulin. These observations together with other studies suggested that insulin-dependent glucose transport and metabolism by the a-cells serves as the primary mechanism controlling glucagon secretion. This hypothesis was tested in the present investigation. The possible interactions between glucose, insulin, and a mixture of 20 amino acids at physiological proportions were examined in the isolated-perfused pancreas of normal, alloxan diabetic, and streptozotocin diabetic rats. Release of insulin and glucagon were used as indicators of A-cell and a-cell function. According to rigid criteria the diabetic animals entering the study were severely diabetic. It was found that in vitro: (a) basal glucagon release (measured in the absence of an a-cell stimulus or inhibitor) was extremely low, even lower (i.e. 10%) than the basal rates seen in controls; (b) the a-cells of alloxanized-and streptozotocin-treated rats responded with a biphasic glucagon release to stimulation by an amino acid mixture; (c) this a-cell response was reduced after both streptozotocin and alloxan; (d) glucose at 5 mM was a potent inhibitor of amino acid-induced glucagon secretion in both types of experimental diabetes; (e) in alloxan diabetes a-cell stimulation by amino acids can be curbed by exogenous This work was presented in part at the meetings

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Substrate Control of Insulin Release

Newgard

Matschinsky

2001

Comprehensive Physiology

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Outlook Potassium ChannelIslet Cells and Hepatocytes p Cells LEVELS OF CIRCULATING NUTRIENTS such as glucose, fatty acids, and amino acids, are precisely controlled in mammals during fasting and feeding alike. Insulin and the pancreatic p cells, which secrete this hormone, play a pivotal role in the control of fuel homeostasis. To serve this critical regulatory function, the p cells are analogous to the thermostat of heating or cooling systems. They measure the nutrient levels of the blood on a moment-tomoment basis and secrete insulin at rates exactly appropriate for maintenance of optimal fuel levels.The concept of the thermostat incorporates the principles of set-point and threshold. Set-point is the desired level of a regulated parameter, that is, the temperature in a heating or cooling system or the fuel levels in the blood.The most prominent role of the p cell is to maintain glucose levels at a set-point of around 5 mM. The threshold of 5 AM stimulate insulin Secretion from islet p cells of essentially all mammals, and this is critical for maintaining glucose levels at or near the set-point. The glucose threshold is the most important niodulator of p-cell function since most other p-cell secretagogues act by potentiating the stimulatory effect of the sugar.The amount of insulin secreted by p cells is also regulated by the insulin responsiveness of the major target tissues of the hormone: muscle, adipocytes, and liver. In insulin-resistant states, such as obesity or in the early stages of non-insulin-dependent diabetes mellitus (NIDDM), a compensatory increase in insulin secretion is required to maintain blood nutrient homeostasis. This compensatory response can involve both an increase in islet p-cell volume and a lowering of the threshold for GSIS. These changes may result in higher rates of insulin secretion at glucose concentrations lower than the normal stimulatory threshold and a consequent increase in the basal level of insulin in the blood. The purpose of this chapter is to expand upon the foregoing simplified description of p-cell function and to present the current understanding of the biochemical and molecular mechanisms involved in nutrient-stimulated insulin secretion. A great deal of research has been carried out in this area since the last edition of this Handbook (99), and it is not the purpose of this chapter to provide a comprehensive review of all of this work. Rather, we highlight major new findings, particularly those that integrate the tools of molecular biology with biochemical and physiological constructs developed earlier or evolving currently. CELLULAR ARCHITECTURE OF PANCREATIC ISLETSis defined as the 1e;el of a regulated parameter that triggers a regulatory function, that is, activation of cooling or heating functions by a specific temperature in the case of a thermostat or activation of insulin secretion by a specific fuel level in the case of the p cell. The threshold for glucose-stimulated insulin secretion (GSIS) coincides with Any discussion of pancreatic P-cell function must...

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Glucose Modulation of Amino Acid-Induced Glucagon and Insulin Release in the Isolated Perfused Rat Pancreas

Cited by 118 publications

References 26 publications

Insulin delivery rate in response to glucose and arginine infusion in hyperthyroidism

Insulin delivery rate in response to glucose and arginine infusion in hyperthyroidism

Insulin and glucose as modulators of the amino acid-induced glucagon release in the isolated pancreas of alloxan and streptozotocin diabetic rats.

Substrate Control of Insulin Release

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