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 <20 s) both in STZ and C. Other nutrients, i.e., glyceraldehyde (10 mM) and α-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.
We conclude that partial B-cell insensitivity to glucose in STZ alters time dynamics of the insulin response, includes loss of a priming effect, is influenced by hyperglycemia, and is nutrient but not glucose specific. Results in DMT indicate that increased demands on B-cell secretion can lead to hyperresponsiveness to nonmetabolic secretagogues as well as loss of induction of priming by glucose without concomitant loss of sensitivity to ambient glucose.