In NIDDM, B-cells are insensitive to glucose. We studied the specificity and evolution of this abnormality in 6-10-wk-old neonatally streptozocin-diabetic (STZ) and in dexamethasone-treated (DMT) rats. Not only the effect of ambient but also that of previous glucose (priming effect) was characterized in the perfused pancreas. In fed STZ, blood glucose was elevated to 9.2 +/- 0.8 versus 5.3 +/- 0.2 mM in control (C) rats. Ambient glucose (27 mM) in the perfusate induced a significant but reduced total response (11% of C) that was predominantly monophasic. Secretion was promptly induced (in less than 20 s) both in STZ and C. Other nutrients, i.e., glyceraldehyde (10 mM) and alpha-ketoisocaproic acid (KIC) (5 mM) also induced reduced and monophasic responses, whereas, in contrast, 3-isobutyl-1-methylxanthine (IBMX) induced an enhanced response that was 3.8-fold larger than in C. In DMT, blood glucose was normal (5.4 +/- 0.3 mM). Ambient glucose (27 mM) in the perfusate induced a normal first phase and a moderately reduced second phase (52% of untreated rats). DMT rats were hyperresponsive to IBMX, this agent inducing 2.5-fold higher release than in untreated rats. Previous perfusion with 27 mM glucose enhanced twofold the effect of a second stimulation period with glucose in C. This induction of priming by glucose could not be demonstrated in fed STZ or in DMT. However, when STZ were fasted or insulin treated for 36 h, induction of priming reappeared, i.e., the second pulse of glucose evoked 2-3-fold more insulin release than the first pulse.(ABSTRACT TRUNCATED AT 250 WORDS)

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Previous exposure to glucose enhances insulin and depresses glucagon secretion by the pancreas. We have investigated whether secretion of somatostatin is also influenced by a glucose priming effect. In perfused rat pancreas from 36 h fasted rats a 5 min pulse of arginine (8 mmol/l) rapidly elicited a peak of somatostatin release. A similar somatostatin response was evoked by a second, identical, pulse of arginine after perfusion with "basal" glucose (3.9 mmol/l) for 45 min. On the other hand when 27.7 mmol/l D-glucose, was administered for 20 min between arginine pulses, there was significant stimulation of somatostatin secretion. When arginine was re-introduced 15 min after the cessation of the pulse of elevated glucose the magnitude of the arginine-induced peak (min 0-2 of stimulation) was increased from 16.2 +/- 4.1 to 33.1 +/- 4.7 pg/2 min, p less than 0.01, relative to the first stimulation with arginine. None of these effects of glucose could be reproduced by D-galactose. The somatostatin response to arginine was higher in pancreata from fed than from 36 h fasted animals as was also basal release (22.8 +/- 5.0 vs 9.0 +/- 2.0 pg/min). In the fed state the response to the second pulse of arginine was however reduced by 50% after perfusion with "basal" glucose. This decrease in responsiveness was counteracted by perfusion with 27.7 mmol/l glucose for 20 min between the arginine pulses. It is concluded that previous exposure to an elevated concentration of glucose enhanced D-cell responsiveness to arginine in the fasted as well as the fed state.

A B S T R A C T The influence of previous exposure to glucose on the subsequent B-and A2-cell secretory responses to arginine was investigated in the perfused pancreas of the rat. Arginine (8 mM) was administered in two brief (9 min) pulses separated by a period of 66 min. In pancreata from 18-h-fasted animals the two pulses of arginine elicited biphasic glucagon secretory responses, while stimulation of insulin release was barely detectable. When 27.7 mM glucose was administered for 30 min during the intervening period up to 20 min before the second pulse of arginine, the glucagon response to arginine was diminished by 55% while the insulin release was markedly increased in comparison with the first pulse. 8.3 mM glucose, when administered before the second pulse of arginine, exerted effects that were smaller but otherwise similar to those of 27.7 mM glucose.The inclusion of 3.9 mM glucose during the stimulation periods with arginine decreased the glucagon and greatly increased the insulin secretory response. Under these conditions, previous exposure to 27.7 mM glucose inhibited the glucagon and enhanced the insulin response to the second stimulatory pulse of arginine to the same relative degree as when arginine was administered alone.Diazoxide (2 mM), when administered together with 27.7 mM glucose, almost completely inhibited insulin release induced by the presence of glucose, yet did not influence the modulation exerted by glucose on the subsequent insulin and glucagon secretory response to arginine. Conversely, these effects of the glucose pulse could not be reproduced by 1 ,ug/ml of porcine

The effects of prior exposure to glucose or an inhibitor of glycolysis (iodoacetate) on A-cell sensitivity to