Plasma insulin concentration was measured during a standardized glucose infusion test (GIT) 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.

No abstract

A B ST R A CT Splanchnic and leg exchange of glucose, lactate, pyruvate, and individual plasma amino acids was studied in diabetics 24 hr after withdrawal of insulin and in healthy controls. Measurements were made in the basal postabsorptive state and during the administration of glucose at a rate of 2 mg/kg per min for 45 min.In the basal state, net splanchnic glucose production did not differ significantly between diabetics and controls. However, splanchnic uptake of alanine and other glycogenic amino acids was 11-2 times greater in the diabetics, while lactate and pyruvate uptake was increased by 65-115%. Splanchnic uptake of these glucose precursors could account for 32% of hepatic glucose output in the diabetics, as compared to 20% in the controls. This increase in precursor uptake was a consequence of a two-to threefold increment in fractional extraction of these substrates inasmuch as arterial levels of alanine, glycine, and threonine were reduced in the diabetics, while the levels of the remaining substrates were similar in the two groups. Peripheral output of alanine and other glycogenic amino acids as reflected in arterio-femoral venous differences was similar in both groups. An elevation in arterial valine, leucine, and isoleucine was observed in the diabetics, but could not be accounted for on the basis of altera- Administration of glucose (2 mg/kg per min) for 45 min resulted in an 80% reduction in splanchnic glucose output in controls, but failed to inhibit hepatic glucose release in the diabetics despite a twofold greater increment in arterial glucose levels. In both groups no consistent changes in arterial glucagon were observed during the infusion.It is concluded that in nonketotic diabetics (a) total splanchnic output of glucose is comparable to controls, but the relative contribution of gluconeogenesis may be increased by more than 50%; (b) accelerated splanchnic uptake of glucose precursors is a consequence of increased hepatic extraction of available substrates rather than a result of augmented substrate supply; and (c) the failure of glucose infusion to inhibit hepatic glucose output suggests that the exquisite sensitivity of the liver to the infusion of glucose in normal man is a consequence of glucose-induced insulin secretion. INTRODUCTIONThe contribution of altered hepatic glucose balance to the metabolic defect in diabetes mellitus has long been the subject of inquiry and debate. Numerous investigations employing the hepatic venous catheter technique (2, 3), or isotope dilution methods (4-6), have provided data on the net rate of hepatic glucose release and on systemic glucose turnover in diabetic patients. Little is known, however, about the effect of diabetes on the hepatic uptake and peripheral release of glucose precursors. Specifically, the question of whether an augmentation in substrate availability or alterations in

With the indirect immunofluorescence technique somatostatin, a recently isolated and structurally characterized hypothalamic tetradecapeptide, which inhibits growth hormone release, has been traced in different tissues of the rat. Somatostatin or somatostatin-like immunoreactivity (SLI) was present in both neurons and endocrine-like cells. Somatostatin positive nerve cell bodies were observed in the periventricular region in the anterior parts of the hypothalamus and in probable nerve endings in the external and internal layer of the median eminence and in the pituitary stalk and in the ventromedial, arcuate and ventral premammillary nuclei and to a small extent in the periventricular region. Somatostatin positive nerve fibers were also found in the posterior pituitary, indicating the existence of a third neurosecretory hypothalamohypophysial system, and in nerves in different layers of the wall of the small and large intestine. These nerves may possibly be of sensory nature since some cell bodies of the spinal ganglia showed a weak immunofluorescence. Somatostatin or SLI was found in certain cells localized in the periphery of the pancreatic islets. In parallel studies with glucagon antibodies it could be established that the somatostatin positive cells and the glucagon positive cells were not identical but localized extremely close to each other. Furthermore, with the Hellman-Hellerström silver staining technique it could be shown that virtually all somatostatin cells are argyrophilic and vice versa. Somatostatin positive cells thus constitute the so-called A1-cells (D-cells). Glucagon positive cells, on the other hand, do in all probability not exhibit argyrophilia. The occurrence of probable somatostatin containing cells in the pancreatic islets is of special interest in view of several recent studies demonstrating an inhibitory action of this peptide on glucagon and insulin secretion. Somatostatin or SLI was found in a rather small number of cells in the thyroid gland with a parafollicular position. These cells exhibited a positive immunofluorescence also after pretreatment of the antiserum with calcitonin. Furthermore, endocrine-like cells in the stomach and in the intestine were also somatostatin positive. A large number of cells in various tissues, especially in the lamina propria of the gastro-intestinal tract, showed a strong fluorescence both after incubation with control serum and with FITC conjugated serum alone. The present results indicate that somatostatin or a somatostatin-like peptide(s), in addition to its inhibitory action on growth hormone release, may play a physiological role at many other levels of the organism.