The gerbil Psammomys obesus develops nutrition-dependent diabetes associated with moderate obesity. The disease is characterized by initial hyperinsulinemia, progressing to hypoinsulinemia associated with depleted pancreatic insulin stores. The contribution of changes in beta-cell turnover to insulin deficiency was investigated in vivo during transition to overt diabetes. Normo glycemic diabetes-prone P. obesus animals who were given a high-calorie diet developed hyperglycemia within 4 days, which was found to be associated with a progressive decline in pancreatic insulin content. This was accompanied by a transient increase in beta-cell proliferative activity and by a prolonged increase in the rate of beta-cell death, culminating in disruption of islet architecture. The hypothesis that "glucotoxicity" was responsible for these in vivo changes was investigated in vitro in primary islet cultures. Exposure of islets from diabetes-prone P. obesus to high glucose levels resulted in a dose-dependent increase in beta-cell DNA fragmentation. In contrast, high glucose levels did not induce DNA fragmentation in rat islets, whereas islets from a diabetes-resistant P. obesus line exhibited a reduced and delayed response. Aminoguanidine did not prevent glucose-induced beta-cell DNA fragmentation in vitro, suggesting that formation of nitric oxide and/or advanced glycation end products plays no major role. Elevated glucose concentrations stimulated beta-cell proliferation in both rat and P. obesus islets. However, unlike the marked long-lasting effect in rat islets, only a transient and reduced proliferative response was observed in P. obesus islets; furthermore, beta-cell proliferation was inhibited after prolonged exposure to elevated glucose levels. These results suggest that hyperglycemia-induced beta-cell death coupled with reduced proliferative capacity may contribute to the insulin deficiency and deterioration of glucose homeostasis in P. obesus. Similar adverse effects of hyperglycemia could play a role in the evolution of type 2 diabetes in genetically susceptible individuals.

The dose-response curve for glucose-induced insulin release obtained by infusing glucose at four to five different rates to normal subjects was sine-shaped, the insulin secretion starting at a blood glucose concentration of about 100 to 125 mg. per 100 ml. The steepest rise in plasma insulin occurred between blood glucose levels of 200 and 350 mg. per 100 ml. When blood sugar was increased further, the plasma insulin curve started to level off. There were no differences in the dose-response characteristics of the early and late insulin responses to glucose infusion. In prediabetic subjects variations in blood glucose concentration between the fasting level and about 300 mg. per 100 ml. were accompanied by only a minor insulin response. Further eleva-ation of blood glucose to 450 to 650 mg. per 100 ml. induced a normal initial insulin response in two out of the eight prediabetics, while the late response was normalized in almost all of them. Thus, the insulin-glucose dose-response curves in the prediabetics seemed to be similar to those of the normals but shifted toward higher blood glucose concentrations. In subjects with mild maturity-onset diabetes or glucose intolerance only, there seemed to exist a further shift to the right of the dose-response curves. These findings suggest that (1) the mechanisms governing the early and late insulin responses to glucose are of identical nature, and (2) the decreased insulin response to glucose in prediabetics and mild diabetics is a relative one, very high glucose concentrations being capable of eliciting normal responses. These findings are compatible with our hypothesis that the defective insulin release in prediabetes and diabetes is due to a decrease in the sensitivity of the glucose receptor of the pancreatic β cell which transmits the glucose signal for insulin release.

In 4 studies on 3 acromegalic patients, who had normal iv glucose tolerance and high insulin response to infused glucose (Al), the oxidation to 14CO2 of [2-14C] pyruvate (injected intravenously in trace amount after overnight fast) was not different from that in 9 studies of 9 nonacromegalic [00BB]high insulin responders[00AB](Ni). In 4 studies on 3 other acromegalic patients, who had low glucose tolerance and less insulin response to glucose (A2), the formation of 14CO2 was reduced to \ m=1/ 2\ \ p=n-\ \ m=2/ 3\ that of Al or N1 and was about proportionate to the reduction in glucose tolerance. In A2 the 14CO2 formation was slightly lower than the mean for 10 studies with 7 non-acromegalic subjects, who were [00BB]l ow insulin responders[00AB] with normal or low glucose tolerance (N2). Among non-acromegalics expiration of 14CO2 was significantly lower in N2 than in N1. Among 4 non-acromegalic subjects treated with human growth hormone for 3\p=n-\4days one had a marked reduction in pyruvate oxidation, while all had a decrease in glucose tolerance. Analysis of 14C in blood glucose at 60 minutes after injection of [2-14C]-pyruvate suggested that slightly more total 14C-glucose was present in A2 than N1 without any differences between A2 and N2 or N1 and N2. Two out of 4 studies in A1 showed lower than normal amounts of 14C-glucose. No change in 14C-glucose occurred after administration of HGH.The findings suggest that impairment of pyruvate oxidation accompanies a lowered glucose tolerance in acromegalics with a diabetic tendency. Changes in gluconeogenesis from pyruvate appear to be minimal.Whereas 25 % or more of acromegalie patients manifest diabetes mellitus Aron et al. 1966) and the administration of growth hormone to

Non-insulin-dependent diabetic (NIDDM) patients show a high incidence of cardiovascular disease, with greater risk of recurrent myocardial infarction and a less favourable clinical outcome than non-diabetic patients. The majority of NIDDM patients are treated with sulphonylurea (SU) derivatives. In the 1970's the University Group Diabetes Program concluded that tolbutamide treatment caused increased cardiovascular mortality; the study, which led to curtailment of oral antidiabetic treatment in the USA, was received with scepticism in Europe. Later criticism of its methodology reduced the impact of the study; however, the question of the safety of SU in NIDDM patients with cardiovascular disease has been re-opened in the face of new experimental data. The heart and vascular tissues do have prerequisites for SU action, i.e. SU receptors and ATP-dependent K+ (K+ATP) channels. These channels play an important role in the protection of the myocardium against ischaemia-reperfusion damage, and their closure by SU could lead to amplified ischaemic damage. Here we review evidence from animal and human studies for deleterious SU effects on ischaemia-induced myocardial damage, either by direct action or through diminished cardioprotective preconditioning. Closure of K+ATP channels by SU can lead to reduction of post-infarct arrhythmias; the drug has also been claimed to improve various atherosclerosis risk factors. The evidence for these beneficial effects of SU is also reviewed. We look at the major difficulties that hamper transfer of information from experimental studies to clinical decision-making: a) The affinity of SU for heart K+ATP channels is orders of magnitude lower than for beta-cell channels; is it reasonable to expect in vivo cardiac effects with therapeutic 'pancreatic' SU doses? b) Most studies utilized high doses of acutely administered SU; are effects similar in the chronic steady-state of the SU-treated diabetic patient? c) Convincing SU effects have been demonstrated in acutely induced ischaemia by acutely administering the drug; do such effects persist in the clinical situation of gradually progressive ischaemia? d) Ischaemia and modification of K+ATP channel activity induce complex events, some with opposing effects; what is the net result of SU action, and do different SU derivatives lead to different outcomes? e) In the chronic (and hence clinically relevant) situation, how can direct (deleterious or beneficial) SU effects be separated from beneficial effects mediated by the metabolic action of the drug? Only large prospective clinical studies, making use of advanced technology for assessment of cardiovascular function, can answer these questions. Millions of NIDDM patients are treated with SU derivatives; many are in the age group where cardiovascular risks are extremely high. The question of whether SU derivatives are beneficial or deleterious for these patients must finally be settle unequivocally.

The double antibody technique of Hales & Randle (1963) for determination of insulin in plasma was developed for the assay of HGH in plasma. The precision and reproducibility of the method as well as the recovery of HGH added to plasma were highly satisfactory. Increased HGH values were obtained in acromegaly and during insulin hypoglycaemia, while decreased values were observed during glucose infusion. Successful treatment of acromegaly was accompanied by the return of plasma HGH levels toward normal. The plasma HGH values obtained with the present method cannot be considered as reflecting the absolute amounts of HGH, since several factors in the assay procedure, mainly the incubation time and the concentration of HGH antibodies used, markedly influenced the values obtained. It is questioned whether the radioimmunological assay methods for HGH per se give an absolute measure of this hormone in plasma.