John W. Rosevear

Model studies of blood-glucose regulation

A simplified, linearized model of the system regulating blood-glucose concentrations is reviewed. This model, which predicts a damped sine wave response to an oral glucose load, lumps the large number of kinetic parameters into a much smaller number which can, at least in part, characterize the human glucose regulatory system. The predictions based on the model are compared with measurements of blood-glucose and blood-insulin concentrations during the oral glucose-tolerance test. Various other conditions are simulated and their implications are discussed in terms of the mathematical model used.

A Mathematical Model of the Glucose-tolerance test

A complete description of the response of man to large doses of glucose involves the use of more than sixteen rate constants, each varying from one person to the next. It is demonstrated here that the response of blood-glucose concentration (G) as a function of time (t) can be represented adequately by an equation involving only four constants in the equation: G=G0+A e−αt sin ωt. The values of these four constants are defined by the four measurements usually made in an ordinary glucose-tolerance test. The natural frequency ω0=r(ω2 + α2) is shown to represent the product of the rate constants for insulin production due to added glucose and for glucose utilization due to insulin action. On the basis of measurements on over 750 persons, it is suggested that the value of ω0 can be used to distinguish normal from diabetic persons more closely than any other parameter.

Effect of Thiazide Diuretics on Plasma Volume, Body Electrolytes, and Excretion of Aldosterone in Hypertension

A study has been made at the Mayo Clinic of the results of treatment in 28 hypertensive patients receiving thiazide diuretics. The use of these agents produced a significant but very temporary reduction in plasma volume in most patients. The plasma volume reverted to or toward normal after the first week of treatment; therefore, hypovolemia could not explain the prolonged hypotensive effect of these drugs. Administration of thiazide diuretics did not deplete the body of its sodium stores, as measured by isotope studies in five patients on an unrestricted diet. Therapy with thiazides did not produce a persistent increase in urinary aldosterone excretion in the nine patients studied for this possibility.

Tests of a mathematical model of the blood-glucose regulatory system

Abstract A simplified model of the blood-glucose regulatory system has been conformed to data from glucose-tolerance tests in nondiabetics measured by continuous sampling after oral ingestion and by intermittent determinations after different routes of administration. Despite the numerous approximations inherent in the model, all the data were conformed within the limits of experimental error. This extended the applicability of the simplified model used and indicated that the assumption of a single regulatory hormone such as insulin was adequate to fit most normal responses. Small deviations between some of the simulated curves and the actual data suggested modifications that would improve the model. Such changes would sacrifice simplicity for greater accuracy in predicting the detailed response.

Studies of diabetic instability. II. Tests of insulinogenic reserve with infusions of arginine, glucagon, epinephrine, and saline☆

Abstract Insulinogenic reserve was tested with arginine, glucagon, and epinephrine in eight unstable and four stable diabetics and in five normal subjects. All subjects were fasted and resting during the tests. Blood glucose regulatory stability was measured during near-normal (ambulatory-fed) conditions in the same subjects. Evaluation of insulinogenic reserve was based on changes in plasma immunoreactive insulin (IRI) concentration. The validity of assessing changes in IRI concentration in the presence of insulin-binding antibodies was supported with simultaneous measurements of indirect indications of the biologic effects of insulin. The changes, from base-line values, in IRI concentrations were consistent with and appropriate for the changes in blood glucose and serum free fatty acid and ketone body concentrations. No significant blood glucose fluctuations occurred under unstimulated fasting-resting conditions in any subject (saline test), in contrast to the distinct differences between groups in the amplitude of glycemic excursions during ambulatory-fed conditions. Blood glucose and ketone body concentrations increased steadily during the saline test in unstable diabetics in contrast to stable diabetics and normals. A correlation was evident between insulin secretory ability under resting-fasting conditions and blood glucose regulatory stability during ambulatory-fed conditions. Unstable diabetics had no demonstrable insulinogenic reserve, except for one maturity-onset diabetic with biochemical and clinical characteristics of unstable diabetes. Stable diabetics had demonstrable insulinogenic reserve but less than that of normals.

Studies of diabetic instability. I. Immunoassay of human insulin in plasma containing antibodies to pork and beef insulin

Abstract The feasibility of assaying human immunoreactive insulin (IRI) in plasma containing antibodies to pork and beef insulins was evaluated. The binding of both pork and beef insulins by endogenous antibodies was positively and highly correlated with the IRI concentration in the same fasting plasma specimens. Endogenous antibodies with low degrees of binding for tracer amounts of radioactive pork insulin showed little or no change in B F ratio (an index of their insulin binding) when human insulin, up to 1000 μU/ml, was added in vitro. However, with antibodies with higher degrees of binding of pork insulin, the addition of human insulin, 20–50 μU/ml, produced measurable changes in B F ratio. By immunoprecipitation assay, human insulin added in vitro was nearly completely recoverable in plasma containing endogenous antibodies with a low degree of binding for pork and beef insulins. In plasma containing antibodies with higher degrees of binding of pork and beef insulin, apparent recoveries of human insulin in vitro were excessive. The apparent increments measured and the amounts added in vitro were linearly related. Endogenous antibodies distort IRI concentration in vitro during radioimmunoprecipitation assay in proportion to their ability to bind tracer amounts of radioactive insulin. With endogenous antibodies of low degrees of insulin binding, relatively accurate IRI assays are feasible.

Treatment of Wilson's disease (hepatolenticular degeneration) with DL‐penicillamine

SINCE IT HAS BEEN THOUGHT that the abnormal accumulation of copper in the liver, brain, and kidneys might account for the symptoms and clinical findings in Wilson’s disease, it was only logical that treatment was designed with the aim of increasing the excretion of copper from the body. McCance and Widdowson,’ in 1946, and Mandelbrote and associates,” in 1948, had demonstrated that the administration of dimercaprol (BAL) could produce an increased urinary excretion of copper. This led Cumings? to report the use of BAL in the treatment of Wilson’s disease. Denny-Brown and Porter‘ also reported their experience with the use of BAL in the treatment of this condition. Because of several disadvantages of BAL, a search has been made for other preparations that might increase the urinary excretion of copper and have the advantages of oral administration and little or no toxicity. In 1956, Walshes reported the use of p, p-dimethylcysteine ( penicillamine) in hepatolenticular degeneration, demonstrating that it appeared to be superior to BAL in promoting the urinary excretion of copper. In 1958, Fister, Boulding, and Bakers reported the results of treatment with penicillamine over a period of nine months. Seven, Kliman, and Peterson,’ in 1959, recorded their experience in the treatment of 2 patients with penicillamine for ten months. Osbom and Walshea compared the effect of penicillamine and BAL on the turnover of copper in hepatolenticular degeneration. Walshe# recently reviewed the experience of 16 medical centers involving the treatment of 22 patients with penicillamine over periods ranging from four weeks to three years. In most of these patients, penicillamine proved better than BAL in promoting the urinary excretion of copper and in producing clinical improvement. However, 3 patients showed either no improvement or actual worsening of the clinical state despite a satisfactory increase in the urinary excretion of copper. Lange and Hagerlo reported on the treatment of 3 patients, plus 1 patient in whom the condition was “preclinical,” but their patients

Myocardial Metabolism in Patients Having Aortic-valve Replacement

Concentrations of metabolites and electrolytes in arterial and coronary sinus blood were studied in ten patients undergoing whole-body perfusion for aortic valve replacement. The study continued through three postoperative days. A comparison was made between five patients whose hearts were beating d

Simulation studies of blood-glucose regulation: effect of intestinal glucose absorption.

Abstract Preliminary studies had indicated the usefulness of a simplified model of the blood-glucose regulatory system in predicting the response to an oral load. Analog simulations have been performed to test inherent approximations and to determine the relative importance of some of the biological mechanisms involved in this regulation. The effect of the form used for intestinal glucose absorption was examined in this report. Three levels of approximation were simulated and evaluated in terms of physiological similarity and control system response. For some simulated conditions, absorptive parameters could be shown to mask intrinsic characteristics of the glucose-hormonal control system that might be reflected in the response to an oral glucose-tolerance test. However, for parameters in the normal range and appropriately sized glucose loads, a small (four to seven) number of measurements sufficiently characterized the glucose response.

Growth hormone release in unstable diabetes: Tests with saline, arginine, glucagon, and epinephrine

RiassuntoGli AA. hanno confrontato, in 8 soggetti con diabete instabile, 4 con diabete stabile e 5 normali, le modificazioni dei livelli plasmatici di HGH durante somministrazione di arginina, glucagone, adrenalina e soluzione fisiologica. Questi stessi soggetti erano stati precedentemente sottoposti al test dell’ipoglicemia insulinica e la variabilità della loro glicemia era stata quantificata in condizioni di vita simili a quelle normali (attività fisica ed alimentazione). Rispetto alla infusione di soluzione fisiologica, l’arginina ha determinato incrementi significativamente maggiori dell’HGH; tale effetto non è stato invece osservabile con il glucagone o l’adrenalina. In confronto con i valori pre-infusione, l’adrenalina ha dato luogo a riduzione delle concentrazioni di HGH. Le caratteristiche degli aumenti e delle diminuzioni medî dei livelli di HGH indotti dalla somministrazione di arginina sono risultate simili nei 3 gruppi di soggetti. Solo durante l’infusione di soluzione fisiologica, nei pazienti affetti da diabete instabile sono state osservate concentrazioni dell’ormone significativamente più alte che non in quelli con diabete stabile o nei soggetti normali. In tali pazienti, gli incrementi maggiori o simili dell’HGH erano sempre accompagnati da valori di glucosio ematico — e spesso anche di NEFA e di corpi chetonici — più elevati di quelli riscontrati nei soggetti con diabete stabile e negli individui normali. Nel diabete instabile, la liberazione di HGH è anormale in quanto non viene inibita dall’iperglicemia. Tale anomalia è associata ad una difettosa modulazione della glicemia e di altre variabili, mediata dalla incapacità di secernere insulina endogena.RésuméSur 8 sujets avec diabète instable, 4 avec diabète stable et 5 sujets normaux, les auteurs ont comparé les modifications des niveaux plasmatiques de HGH pendant l’administration d’arginine, de glucagon, d’adrénaline et de sérum physiologique. Les mêmes sujets avaient été soumis précédemment au test de l’hypoglycémie insulinique, et la variabilité de leur glycémie avait été quantifiée en conditions de vie semblables aux normales (relativement à l’activité physique et à l’alimentation). Par rapport à l’infusion de sérum physiologique, l’arginine a provoqué une augmentation remarquablement plus élevée de HGH; le glucagon et l’adrénaline, au contraire, n’ont pas provoqué cet effet. Relativement aux niveaux antérieurs à l’infusion, l’adrénaline a provoqué une réduction des concentrations de HGH. Les caractéristiques des augmentations et des diminutions moyennes des niveaux de HGH provoquées par l’arginine, sont résultées semblables dans les trois groupes de sujets. Seulement pendant l’infusion de sérum physiologique, les concentrations de l’hormone étaient remarquablement plus élevées chez les patients avec diabète instable que chez les patients avec diabète stable ou chez les sujets normaux. Chez ces patients, les accroissements plus forts de HGH étaient toujours accompagnés par des valeurs du glucose hématique — et souvent aussi des NEFA et des corps cétoniques — plus élevées que celles trouvées dans les sujets avec diabète stable et chez les individus normaux. Dans le diabète instable, la libération de HGH est anormale, puisqu’elle n’est pas inhibée par l’hyperglycémie. Cette anomalie est associée à une défectueuse modulation soit de la glycémie, soit d’autres variables, due à l’absence de sécrétion insulinique endogène.ResumenSe han comparado los cambios en las concentraciones plasmáticas de hormona de crecimiento (HGH) durante la administración de arginina, glucagón, epinefrina y solución salina en 8 diabéticos inestables, 4 diabéticos estables y 5 sujetos normales. Previamente, todos estos sujetos habían sido estudiados mediante la inducción de hipoglicemia insulínica y la variabilidad de sus glicemias había sido cuantificada en condiciones parecidas a las de la vida ordinaria (ambulatorias y con alimentación). En comparación con la infusión salina, la arginina indujó elevaciones significativamente mayores de HGH, efecto que no fué observado con el glucagón o la epinefrina. En comparación con los niveles previos al comienzo de la infusión, la epinefrina disminuyó las concentraciones de HGH. Las características de las elevaciones y disminuciones promedio de HGH luego de la administración de arginina fueron similares en los 3 grupos de sujetos. Únicamente durante la infusión salina los diabéticos inestables tuvieron concentraciones de HGH significativamente más altas que los diabéticos estables y los sujetos normales. Los mayores o similares incrementos de HGH en los diabéticos inestables se presentaron siempre con glicemias, y frecuentemente niveles de ácidos grasos no esterificados y cuerpos cetónicos más elevados que en los diabéticos estables y los normales. La liberación de HGH es anormal en la diabetes inestable, no siendo inhibida por la hiperglicemia. Esta anormalidad está asociada a una modulación defectuosa de la glicemia y otras variables, mediada por la incapacidad para segregar insulina endógena.ZusammenfassungBei 8 labilen und 4 stabilen Diabetikern und 5 Normalpersonen verglichen die Verfasser die Änderungen der Plasmaspiegel von HGH unter Verabreichung von Arginin, Glukagon, Adrenalin und physiologischer Kochsalzlösung. Vorher war bei den gleichen Probanden die Probe der Insulin-Hypoglykämie durchgeführt und die Variabilität des Blutzuckerspiegels unter normalen Lebensbedingungen ähnlichen Verhältnissen (körperliche Tätigkeit und Ernährung) quantifiziert worden. Im Vergleich mit der Infusion physiologischer Kochsalzlösung rief Arginin eine signifikant grössere Zunahme des HGH hervor. Diese Wirkung konnte mit Glukagon und Adrenalin nicht beobachtet werden. Im Vergleich zu den vor der Infusion gemessenen Werten führte Adrenalin zu einem Abfall der HGH-Konzentration. Die Art der mittleren Zu-und Abnahme des HGH-Spiegels infolge der Argininverabreichung war bei den drei Gruppen ähnlich. Nur während der Infusion von physiologischer Kochsalzlösung wurden bei labilen Diabetikern signifikant höhere Hormonkonzentrationen beobachter als bei stabilen Diabetikern und Normalpersonen. Bei diesen Patienten gingen ähnliche oder grössere Anstiege des HGH immer mit höheren Blutzuckerspiegeln und häufig auch mit höheren NEFA- und Ketonkörperwerten einher als bei stabilen Diabetikern und Normalpersonen. Beim labilen Diabetes ist die HGH-Freisetzung insofern abnorm, als ein erhöhter Blutzuckerspiegel sie nicht hemmt. Diese Anomalie ist infolge der mangelnden Sekretion endogenen Insulins mit einer defekten Modulation des Blutzuckers und anderer Variablen verbunden.SummaryChanges in plasma growth hormone (HGH) concentrations during tests with arginine, glucagon, epinephrine and saline were compared in 8 unstable and 4 stable diabetics, and 5 normal subjects. These same subjects had previously also been tested with insulin-induced hypoglycemia and their blood glucose variability had been quantified during near-normal (ambulatory-fed) living conditions. Compared with saline infusion, arginine induced higher HGH increases but glucagon and epinephrine did not. Compared to preinfusion levels, epinephrine decreased HGH concentrations. Patterns of mean HGH increase and decrease after arginine were similar in the 3 groups of subjects. Only during saline infusion did unstable diabetics have higher peak levels than did stable diabetics and normal subjects. The higher or similar increases of HGH in unstable diabetics always occurred at higher concentrations of blood glucose and frequently, but not invariably, at higher concentrations of serum free fatty acids and ketone bodies than in stable diabetics and in normals. HGH release is abnormal in unstable diabetics in that hyperglycemia does not inhibit the release of HGH. The abnormality is associated with impaired modulation of blood glucose and other variables through inability to secrete endogenous insulin.