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Erol Cerasi

ABSTRACT

The effect of repeating a 60 min glucose infusion at a 40 to 70 min interval was investigated after an overnight fast in 14 healthy, non-obese subjects with normal glucose tolerance and normal insulin response to glucose administration. When a hyperglycaemic plateau of around 300 mg/100 ml was induced by the first glucose infusion, the insulin response to a second challenge was enhanced over the range of stimulations used. Both the early and late phase insulin responses were amplified, the enhancement being more marked with higher stimulatory levels of glucose. The blood glucose-insulin dose-response curve became steeper after pretreatment with glucose, the stimulatory threshold level not being altered. These findings suggest that the synergism between the glucose pretreatment, and the insulin releasing effect of glucose, is of multiplicative type, resulting in increase of the maximum effect of the glucose.

The dose-dependency of this potentiation was investigated by keeping the second glucose challenge at a constant level and altering the dose of the first infusion. It was necessary to reach hyperglycaemias around and above 300 mg/100 ml during the first infusion in order to obtain enhancement of the insulin response to the second stimulus. The dose-response curve of the potentiating effect of glucose is thus displayed towards the right when compared with that describing the insulin releasing effect of glucose, which has its threshold around 100 mg/100 ml.

It is suggested that glucose exerts a dual effect on the pancreatic islets: an immediate one which initiates the release of insulin, and a time-bound one which modulates the first action.

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Erol Cerasi

ABSTRACT

If two consecutive glucose infusions are administered with 40 min of rest between, the insulin response to the second challenge is markedly potentiated. When the insulin response to the first glucose infusion was suppressed by 65 % with the aid of adrenaline, potentiation of the insulin response to the second infusion was not modified. This suggests that the generation of a state of enhancement in the islet does not necessitate that glucose exerts its insulin releasing action. It is postulated that islet glucose metabolism may be involved in producing the potentiation.

Pretreatment of the subjects with a glucose infusion enhanced also the insulin responses to glucagon and to tolbutamide, given intravenously 50 min later. Thus, the potentiation generated by glucose is not restricted to the insulinogenic signal induced by glucose. The eventual role that the beta-cell adenylate cyclase may play in this respect is discussed.

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Erol Cerasi

ABSTRACT

Glucose-induced potentiation of glucose-induced insulin release was quantitatively evaluated in 14 non-obese subjects with normal glucose tolerance but decreased insulin response, and in six non-obese patients with mild, adult-onset diabetes, by measuring the insulin responses to two consecutive glucose infusion tests, administered with 40 or 70 min interval. Enhancement of the second insulin response occurred in both groups. In low insulin responders, the dose-response relationship between blood glucose and plasma insulin was flatter and shifted to the right when compared to the control. Pretreatment with glucose increased strikingly the slope of this relationship, the responses now being within the normal range. The enhancement induced by glucose seems to be of multiplicative type. In mildly diabetic subjects, insulin response to glucose infusion was low and sluggish, only a minor initial response being observed. Pretreatment with glucose modified the profile of the insulin response, a clear-cut initial response of greater magnitude being obtained at least in some of the patients. The sensitivity of the islet to the potentiating action of glucose was higher in low insulin responders than in controls, the minimal glucose concentration needed to induce potentiation of the forthcoming response being much lower. The dose-response curve for the relationship between the blood glucose level of the preinfusion period and the percentual enhancement of the insulin response obtained at the second stimulation was, in low insulin responders, higher than and shifted to the left of the curve of the control subjects. In the group of diabetics, sensitivity for potentiation by glucose seemed not different from the controls.

These studies indicate that the ability of glucose to initiate insulin release and its ability to generate time-bound potentiation in the islet correspond to two distinct functions. In the early stages of the diabetic syndrome, only the recognition of glucose as the initiator of an insulinogenic signal is impaired. The pancreatic beta-cell in these subjects seems to recognize normally glucose as the promotor of the potentiation.

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Ulf Adamson and Erol Cerasi

ABSTRACT

The acute effects of human growth hormone (GH) on the basal levels of glucose and insulin in blood were investigated in 11 healthy men. GH doses of 5, 10, 20, and 40 μg/kg body weight were given iv as a constantrate infusion over 30 min, and resulted in peak hormone levels (30 min) of 20.5 ± 1.0, 48.5 ± 2.2, 108.2 ± 4.5, and 229.2 ± 14.6 ng/ml, respectively. There was a small (max 9.8 ± 2.6 %) but significant decrease in the blood glucose level, observed already at 15 min after the beginning of the GH infusion and persisting up to 90 min. The highest dose of GH induced the most marked changes, but there was otherwise no clear correlation between dose and effect. The basal plasma insulin levels showed a more marked (max 16.0 ± 4.7 %) decrease which was not correlated, in time or in magnitude, with the changes in blood glucose. In some subjects, in whom no significant decrease in blood glucose was observed, plasma insulin still demonstrated a similar fall (max 20.2 ± 7.6 %). Neither were these changes in plasma insulin correlated to the dose of GH within the range used in this study. The findings suggest that the early, insulin-like effect of GH on blood glucose is distinct from its effect on the pancreas. The latter is a suppressive one, consistent with earlier findings on glucose-induced insulin release.

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Ulf Adamson and Erol Cerasi

ABSTRACT

The time and dose dependency of the effects of a 30-min long iv infusion of human growth hormone (GH) on glucose tolerance and glucose-stimulated insulin release was investigated in 19 healthy subjects. Glucose tolerance deteriorated immediately following GH, and the k-value continued to decrease up to 300 min later. A small but significant reduction of glucose tolerance persisted 24 h after GH administration. Significant deterioration of glucose tolerance was observed with the smallest GH dose used (5 μg per kg body weight), increasing the amount of the hormone having no further major influence.

Glucose-stimulated insulin release was significantly inhibited 1 h after administration of a relatively high GH dose (40 μg per kg), both if expressed as mean plasma insulin levels, or as insulin release per magnitude of glucose stimulation (insulinogenic index). In the majority of subjects, insulin release was inhibited also by lower GH doses (5–20 μg GH per kg). However, the mean change with these doses was not statistically significant. The inhibitory effect of GH on insulin secretion seemed to have a duration of several hours. Five hours, but not 24 h, after GH administration (10 μg GH per kg) insulin release was still significantly suppressed.

It is suggested that the initial effect of GH on pancreatic beta cells may be inhibition of insulin release, in contrast with the enhancement of insulin secretion observed during chronic administration of GH.

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Ulf Adamson and Erol Cerasi

ABSTRACT

The acute effect of growth hormone (GH) administration on the dose-kinetics of glucose-stimulated insulin release was investigated in eight healthy, non-obese male subjects. The glucose-insulin dose-response relationship in these subjects was established by performing glucose infusions at three different dose levels. In a second series of experiments, the glucose infusions were preceded by a 30 min infusion of GH (40 μg/kg body weight), terminated 60 min before administration of glucose. GH induced small but significant reductions in the basal levels of blood glucose and plasma insulin. The glucose tolerance (k-value) was diminished after GH at all glucose doses. Both the initial late phases of insulin response to glucose were impaired following GH treatment. This effect was most pronounced when the intermediary glucose dose (eliciting a blood glucose level around 300 mg/100 ml) was used. Thus, the insulinogenic index (whole period of stimulation) was reduced by GH to 88.9 ± 7.6, 60.4 ± 7.1 and 74.3 ± 11.0% of the respective controls when the smallest, the intermediate, and the largest glucose loads, respectively, were given.

The blood glucose-plasma insulin dose-response curves were shifted to the right of the control ones when glucose infusion was preceded by GH. These findings suggest that GH diminishes the sensitivity of the islet for the insulin releasing action of glucose.

Some possible mechanisms by which GH may modify insulin release are discussed.

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Erol Cerasi and Bertil Andersson

ABSTRACT

An analogue computer model has been constructed for the analysis of the interrelationship between blood glucose and plasma insulin concentrations during glucose infusion. The model presented gives quantitative information on the effect of plasma insulin on glucose uptake, the total amount of glucose taken up by the tissues at a given time, the effect of blood glucose on the release of stored and newly formed insulin, and the rapidity by which plasma insulin is increased in response to hyperglycaemia.

Such an analogue computer model might be a useful tool in the investigation of the various dynamic factors involved in the glucose – insulin interrelationship.

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Erol Cerasi and Rolf Luft

ABSTRACT

Plasma insulin concentration was measured during a standardized glucose infusion test (GIT) in 85 healthy subjects with a normal glucose tolerance and in 28 patients with manifest diabetes mellitus or decreased glucose tolerance. Each test was evaluated with the aid of an analogue computer model, and parameters characterizing different parts of the insulin curve during GIT were obtained. Large variations existed in all parameter values both in the normal and diabetic groups, and the overlapping between the two groups was considerable.

In 15 out of 85 healthy subjects the plasma insulin response during GIT was of the diabetic type as judged from the frequency distribution of the computer parameters (low values). The similarity was still more striking when the characteristics of the insulin curves in these 15 subjects were compared with those in patients with mild diabetes or with a decreased glucose tolerance only.

It is postulated that this type of low insulin response reflects a derangement of the release of insulin into the circulation, and that it marks an alteration which probably is a prerequisite for the development of diabetes mellitus. In this sense, these subjects may be considered to be potential diabetics.

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Erol Cerasi and Rolf Luft

ABSTRACT

In a previous paper it was shown that 15 out of 85 healthy subjects with a normal intravenous glucose tolerance demonstrated a low plasma insulin response to glucose infusion which was similar to that obtained in diabetic subjects. In the present paper it has been shown that the type of insulin response to glucose infusion was the same when the test was repeated.

Low insulin responders to glucose infusion, as a group, also showed low insulin response to intravenous tolbutamide and oral glucose. This indicates that the type of insulin response is characteristic for a given subject irrespective of the stimulation used.

There seemed to be no difference in the occurrence of diabetes in the family history of the groups of low and high insulin responders.

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Erol Cerasi and Rolf Luft

ABSTRACT

The insulin response during a standardized glucose infusion (GIT) was studied in a group of 13 monozygotic twin pairs previously registered as consisting of one diabetic/one non-diabetic member. At the time of the study three of the non-diabetic subjects had developed overt diabetes and three decreased glucose tolerance only.

Of the non-diabetic members all but one (with diabetes due possibly to chronic pancreatitis in the sibling) showed an insulin response similar to that seen in diabetic subjects, and in healthy subjects previously assumed to be potential diabetics. The present study therefore supports our earlier suggestion that a low insulin response characterizes potential diabetes.

There was a striking similarity between the insulin curves in the twin pairs, irrespective whether diabetes occurred in one, in both or in none of the members.

It is suggested as a working hypothesis that the type of insulin response to glucose infusion is genetically determined, and that a low insulin response is a prerequisite for the development of diabetes mellitus.