Insulin secretory dynamics after two consecutive intravenous stimulations with glucose and/or tolbutamide.

Intravenous glucose and/or tolbutamide administered in two consecutive pulses 30 and 60 min apart to the same subjects using identical doses showed that insulin secretory responses was altered during a subsequent stimulation and that this was modulated by the time factor. Insulin response was more sustained after the second glucose pulses and the insulin peak response was delayed and diminished if the second glucose dose was given 30 min after the first, but not if given 60 min later. It is suggested that the beta-cell membrane might remain partially depolarized above a certain glucose level or that a postulated signal relay mechanism might become saturated. Responses to two tolbutamide pulses did not show these characteristics; however, the second insulin response was smaller than the first. When the first pulse was glucose and the second tolbutamide, or vice versa, the second responses were altogether different from those elicited by the double doses of either tolbutamide or glucose. To explain these characteristic patterns of insulin secretory dynamics, the existence of occult glucose receptors on the beta-cell that are opened up by tolbutamide was postulated. These studies do not support the two-pool theory, or at least restrict it to glucose-stimulated insulin response. The positive correlations between the first and the second insulin responses in all tests argue strongly against the existence of an insulin feedback mechanism in man.

A model of glucose-insulin homeostasis in man that incorporates the heterogeneous fast pool theory of pancreatic insulin release.

Current physiologic knowledge about glucose-insulin homeostasis in liver, brain, pancreas, kidney, peripheral tissues, and central vascular organs has been synthesized to form a whole-system mathematical model of glucose metabolism in normal, ideal man. In addition to data of other workers, results from more than 100 intravenous glucose tolerance tests, including variable dosage, variable duration of infusion, and double pulse studies, were used to determine model structure and parameters. Model and clinical testing have focused particularly on the fast phase of insulin response to vascular glucose. The model incorporates blood circulation and equilibration of substances between vascular and interstitial spaces, and it assumes constant fractional clearance of insulin by liver and kidney. Studies using a double pulse of glucose suggest that the time derivative of glucose level is not the sole or predominant influence on fast phase insulin release, but that preinfusion glucose level and/or previous glucose exposure of the pancreas are also important. Variable dosage glucose studies suggest that the amount of insulin released during the fast phase rather than the insulin release rate is regulated by the glucose level. A two-pool, heterogeneous threshold mechanism for beta cell response to glucose is presented that is compatible with the clinical results.

Deranged insulin-secretory dynamics in offspring of two diabetic parents after double stimulation with intravenous glucose.

Nine offspring of two diabetic parents and 18 normals were studied with two intravenous glucose loads (o.5 gm./kg. body weight), 60 minutes apart. By thus stressing the beta cell, subtle defects could be identified in the prediabetics: (1) An inverse relationship between insulin peak response and insulin concentration 60 minutes postglucose was seen, a phenomenon exactly the opposite to that seen in normals. (2) Insulin peak response was delayed slightly after the first pulse and significantly after the second. (3) A less effective handling of the glucose load when compared with normals was brought out by the second stimulation. (4) There was a significant reduction in the insulin response per unit change in glucose after the first glucose pulse that was accentuated after the second pulse. This double-stimulation technique amplifies previously detected slight but significant defects in insulin secretion that might help to identify a diabetes-prone population.

Quantitative aspects of the metabolic response to pancreatic islet transplantation in rats with severe ketotic diabetes.

Injection of 100-140 mg/Kg of streptozotocin produced severe, ketotic diabetes in 12 pairs of adult rats. Transplantation of intact islets of Langerhans from syngeneic adult donors into a muscle pocket or a pouch created from pancreatic tissue of one animal from each pair eliminated ketonemia in the immediate postoperative period, while ketonemia persisted in the sham-operated controls. Mean survival of transplanted animals was 145 days, versus 70 days for controls. Mean body weight increased and blood sugar decreased in transplanted animals compared with controls; the differences were greatest in those animals which received the largest number of islets per unit body weight. In one animal, all metabolic indices returned to normal for a period of 8 wk following transplantation of 650 islets. After gaining to 300% of initial body weight, diabetes reappeared in this transplanted animal and was again reversed by a second transplantation. The metabolic data indicate that: (1) islet tissue from adult donors survives and functions in severely diabetic, ketotic hosts; and (2) metabolic response to transplantation is a function of the ratio of islet tissue to body mass, a minimum ratio of about 2-3 islets/gm body weight being required to maintain normal homeostasis.