Effects on Insulin Output and on Pancreatic Blood Flow of Exogenous Insulin Infusion into an in Situ Isolated Portion of the Pancreas4

Rappaport, A. M.; Ohira, Seiichi; Coddling, Judith A.; G, Empey; Kalniņš, Artis; Lin, Boniface J.; Haist, R. E.

doi:10.1210/endo-91-1-168

Cited by 34 publications

(12 citation statements)

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“…The glucose-clamp technique, by maintaining euglycemia, minimizes factors known to affect insulin secretioneither directly through changes in blood glucose concentration, or indirectly, through the activation of counterregulatory mechanisms. Studies of direct feedback inhibition of insulin release by insulin have yielded conflicting data (32)(33)(34)(35)(36). Unfortunately, the insulin radioimmunoassay could not distinguish between the porcine and endogenous insulin.…”

Section: Resultsmentioning

confidence: 99%

A Model of the Kinetics of Insulin in Man

Sherwin¹,

Kramer²,

Tobin³

et al. 1974

J. Clin. Invest.

471

282

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A B S T R A C T The design of the present study of the kinetics of insulin in man combines experimental features which obviate two of the major problems in previous insulin studies. (a) The use of radioiodinated insulin as a tracer has been shown to be inappropriate since its metabolism differs markedly from that of the native hormone. Therefore porcine insulin was administered by procedures which raised insulin levels in arterial plasma into the upper physiologic range. Hypoglycemia was prevented by adjusting the rate of an intravenous infusion of glucose in order to control the blood glucose concentration (the glucose-clamp technique). (b) Estimation of a single biological half-time of insulin after pulse injection of the hormone has been shown to be inappropriate since plasma insulin disappearance curves are multiexponential. Therefore the SAAM 25 computer program was used in order to define the parameters of a three compartment insulin model.The combined insulin mass of the three compartments (expressed as plasma equivalent volume) is equal to inulin space (15.7% body wt). Compartment 1 is apparently the plasma space (4.5%). The other two compartments are extra-vascular; compartment 2 is small (1.7%) and equilibrates rapidly with plasma, and compartment 3 is large (9.5%) and equilibrates slowly with plasma.The SAAM 25 program can simulate the buildup and decay of insulin in compartments 2 and 3 which cannot be assayed directly. Insulin in compartment 3 was found to correlate remarkably with the time-course of the servo-controlled glucose infusion. Under conditions of a steady-state arterial glucose level, glucose infusion is a measure of glucose utilization. We conclude that compartment 3 insulin (rather than plasma insulin) is a more direct determinant of glucose utilization. We suggest that the combined use of glucose-clamp and kinetic-modeling techniques should aid in the delineation of pathophysiologic states affecting glucose and insulin metabolism.

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Section: Resultsmentioning

confidence: 99%

A Model of the Kinetics of Insulin in Man

Sherwin¹,

Kramer²,

Tobin³

et al. 1974

J. Clin. Invest.

471

282

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show abstract

“…Because there is constitutive secretion of insulin, a tonic level of insulin signaling in these cells may influence acute stimulatory responses and thus obscure any effect of exogenously added insulin. These three issues, in addition to the use of different species and disparate methodological approaches, may account in part for the discrepancies regarding the impact of insulin on its own secretion (11,12,14,20,21). To circumvent the first problem, and to establish the effect of exogenously added insulin on its own secretion, we have measured connecting (C)-peptide secretion rates in response to a variety of agonists from isolated perifused rat islets.…”

mentioning

confidence: 99%

Effects of Glucose, Exogenous Insulin, and Carbachol on C-peptide and Insulin Secretion from Isolated Perifused Rat Islets

Zawalich

2002

Journal of Biological Chemistry

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Isolated perifused rat islets were stimulated with glucose, exogenous insulin, or carbachol. C-peptide and, where possible, insulin secretory rates were measured. Glucose (8 -10 mM) induced dose-dependent and kinetically similar patterns of C-peptide and insulin secretion. The addition of 100 nM bovine insulin had no effect on C-peptide release in response to 8 -10 mM glucose stimulation. The addition of 100 nM bovine insulin or 500 nM human insulin together with 3 mM glucose had no stimulatory effect on C-peptide secretion rates from perifused rat islets. Stimulation with carbachol plus 7 mM glucose enhanced both C-peptide and insulin secretion, and the further addition of 100 nM bovine insulin had no inhibitory effect on C-peptide secretory rates under this condition. Perifusion studies using pharmacologic inhibitors (genistein and wortmannin) of the kinases thought to be involved in insulin signaling potentiated 10 mM glucose-induced secretion. The results support the following conclusions. 1) C-peptide release rates accurately reflect insulin secretion rates from collagenase-isolated, perifused rat islets. 2) Exogenously added bovine insulin exerts no inhibitory effect on release to several agonists including glucose. 3) In the presence of 3 mM glucose, exogenously added bovine or human insulin do not stimulate endogenous insulin secretion.Insulin secretion from the pancreatic ␤-cell is tightly regulated by stimulatory signals generated during the intracellular metabolism of glucose and by neurohumoral agonists operative at the cell membrane (1-5). Most recently an additional layer of complexity has been added by reports suggesting that insulin exerts an autocrine stimulatory effect on insulin secretion from the ␤-cell (6, 7). This concept was based primarily on amperometric measurements using ␤-cells preincubated in 5-hydroxytryptamine (5HT).1 Because 5HT exposure exerts inhibitory effects on insulin release (8 -10), the precise physiologic significance of findings made with 5HT-preloaded ␤-cells is unclear. Moreover, previous studies exploring the potential role of insulin on stimulated secretion showed no effect (11) or supported the concept that insulin exerts a negative, not positive, feedback on its own secretion (12-15).There are at least three major issues that must be addressed in attempting to establish the impact of exogenously added insulin on endogenous insulin secretory rates. The first is technical; it is difficult to accurately measure endogenous insulin release rates in the presence of exogenous insulin. The second relates to concentration of insulin necessary to establish an effect of exogenously added hormone on the ␤-cell. Considering that the ␤-cell continually releases insulin into a small volume of interstitial fluid, the level of insulin bathing the ␤-cell may be quite high. For example, calculations based on islet cell volume, the insulin diffusion constant and insulin secretory rates, suggest that these levels may exceed 100 nM during glucose stimulation (16). Even at rest, levels o...

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“…The negative-feedback interaction between plasma insulin and (3-cell insulin release has been the subject of much debate (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). In vitro studies of insulin's effect on its own secretion have yielded conflicting results, although the most recent study negates the presence of a direct negative-feedback loop (1,(9)(10)(11)(12). Similarly, in vivo studies both support (2)(3)(4)(5) and refute (6)(7)(8) the existence of a negative-insulin-feedback interaction.…”

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confidence: 99%

Insulin Suppresses Its Own Secretion In Vivo

1987

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This study addressed the controversial question of whether a negative-insulin-feedback loop exists in vivo. We utilized prehepatic insulin production, calculated by computerized deconvolution analysis of peripheral C-peptide concentration, as a measure of endogenous insulin secretion. Prehepatic insulin production was determined in 10 normal men who randomly underwent a control study and two additional studies involving different insulin infusion rates that achieved circulating insulin concentrations within the physiologic range during euglycemic clamps. The results demonstrate a dose-dependent suppression of prehepatic insulin production from 5.8 +/- 1.4 mU/min during the control study to 4.0 +/- 1.2 and 3.2 +/- 0.9 mU/min during plasma insulin levels of 34 +/- 4 and 61 +/- 6 microU/ml, respectively (P less than .05). Therefore, in contrast to recently reported results in vitro, insulin inhibits its own secretion in humans.

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Effects on Insulin Output and on Pancreatic Blood Flow of Exogenous Insulin Infusion into an in Situ Isolated Portion of the Pancreas4

Cited by 34 publications

References 0 publications

A Model of the Kinetics of Insulin in Man

A Model of the Kinetics of Insulin in Man

Effects of Glucose, Exogenous Insulin, and Carbachol on C-peptide and Insulin Secretion from Isolated Perifused Rat Islets

Insulin Suppresses Its Own Secretion In Vivo

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