George D. Molnar

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.

Abnormalities of Endogenous Glucagon and Insulin in Unstable Diabetes

The responses of glucagon, growth hormone, and insulin secretion to the oral administration of glucose and to the intravenous infusion of saline, arginine, and insulin were measured in seven patients who had stable diabetes, eight who had unstable diabetes, and seven healthy volunteers. Hyperglycemia suppressed secretion of glucagon in normal subjects but not in diabetics. The oral glucose and arginine infusion tests demonstrated partial preservation of insulin-secretory ability in stable diabetics and its virtual absence in unstable diabetics. Glucagon responses to arginine infusion were similar in all three groups. In response to hypoglycemia induced by insulin infusion, the concentrations of plasma glucagon increased in normal subjects and, to a lesser extent, in stable diabetics but increased in only two of the unstable diabetics. The impairment in glucagon response during hypoglycemia in diabetics correlated positively with the degree of diabetic instability and insulin deficiency during glucose and arginine testing. The severity of the insulin deficiency also correlated with the degree of diabetic instability. These findings support the hypothesis that inherent abnormalities of insulin and glucagon secretion may account for many of the clinical characteristics of unstable and stable diabetic patients.

On measuring the adequacy of diabetes regulation: Comparison of continuously monitored blood glucose patterns with values at selected time points

SummaryIndividual blood glucose (BG) measurements at selected time points were compared with continuously recorded BG data as criteria of the adequacy of diabetes regulation. Indices reflecting the adequacy of diabetes regulation have previously been developed from continuously monitored BG measurements during studies under standardized near-normal living conditions. These indices are: (1) mean amplitude of glycemic excursions (MAGE), (2) diurnal mean blood glucose (MBG), (3) mean of daily differences of paired BG values (MODD). Because of the intensive studies necessary to obtain these indices, approximations based on individual BG measurements which might easily be obtained in practice were sought. The BG value 80 min after breakfast correlated best with the MAGE. The average of the fasting BG value and the value at 80 min after breakfast correlated well with the MBG. These individual BG measurements distinguished the groups of subjects. The difference between fasting BG values on successive days (AFBG) correlated well with the MODD. However, unlike MODD itself, AFBG did not distinguish the groups of subjects. Some other selected BG values with different timing were nearly equally highly correlated with these three criteria of BG behavior. Thus, relatively few but critically timed BG measurements on successive days, with suitable urinary glucose measurements, during standardized therapeutic programs may serve as an index of the efficacy of the therapy. By these same means, the characteristics of the patients diabetes might also be assessed.

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.

Effects on Metabolism and Cardiac Output of Glucose-Potassium Solution, With and Without Insulin

Abstract In the first 48 hours following open-heart operation, 33 patients in rotation had an infusion of (1) 2 liters of 10% glucose in water, 80 units of regular insulin, and 160 mEq of potassium (GIK), (2) the same solution without insulin (GK), or (3) 5% glucose in water (a control group). The three groups were matched: in each, 8 patients had Functional Class III or IV disease by New York Heart Association criteria, and 8 had valves replaced. Anesthesia and perfusion techniques and supportive care before and after operation were identical in all groups. During infusion, mean arterial levels of the following were significantly lower in the GIK group than in the two other groups: osmolality, sodium, glucose, lactate, fatty acids, and total ketone bodies. Arterial oxygenation, acid-base balance, and pyruvate, growth hormone, calcium, and insulin levels did not differ among groups. Mean plasma potassium levels were the same during infusion in all groups, but 1 patient in the GIK group, 4 in the GK group, and 4 in the control group had ventricular arrhythmias requiring treatment. The only death was in the GK group. For patients with Functional Class III or IV disease, cardiac output (left atrial-to-thoracic aorta dye curve) was significantly higher both days in the GIK group than in the other groups. The GIK solution promoted aerobic carbohydrate metabolism over lipid metabolism, more hemodilution, and better cardiac output than did GK. The GIK solution may be effective in controlling ventricular hyperirritability.

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.

Disappearance of bovine insulin from plasma in diabetic and normal subjects

Abstract Disappearance curves for radioiodinated and immunoreactive bovine insulins were determined and analyzed in 30 subjects (5 normal volunteers and 25 diabetic patients). Simultaneous determinations were made of blood glucose and of insulin binding by insulin antibodies. There was significant negative association between the disappearance of bovine insulin from plasma and the insulin-binding level of circulating insulin antibodies. The presence of diabetes, the clinical character of the diabetes (whether stable or unstable), and the presence of chronic diabetic complications, of themselves, had no apparent significant influence that could be separated from the effect of circulating levels of insulin-binding antibodies on the disappearance of bovine insulin from plasma.

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.

Myocardial and Body Metabolism in Fatal Cardiogenic Shock after Valvular Replacement

Cellular energy substrates and metabolites, electrolytes, oxygenation, and acid-base balance, in arterial and coronary sinus blood of seven adult patients who died after valvular replacements, were studied and compared with these measurements from five patients having aortic replacement who survived. Six of the patients were in New York Heart Association class IV. All but one died within 24 hr of acute circulatory failure, with excessive bleeding being a contributing factor. Plasma potassium and osmolality remained higher in the first postoperative hours in nonsurvivors. Ketone bodies, growth hormone, and lactate levels rose precipitously as shock became severe. Increased arterial blood osmolality and potassium, plus a still-rising lactate concentration, were evident 2 hr after operation in patients who died in the next 24 hr. Low cardiac output, hyperosmolality, and the degree of lactic acidosis were the only early changes predicting the fatal outcome.