Decrease in beta-cell mass leads to impaired pulsatile insulin secretion, reduced postprandial hepatic insulin clearance, and relative hyperglucagonemia in the minipig

Most insulin is secreted in discrete pulses at an interval of similar to6 m in. Increased insulin secretion after meal ingestion is achieved through th e mechanism of amplification of the burst mass. Conversely, in type 2 diabe tes, insulin secretion is impaired as a consequence of decreased insulin pu lse mass. beta -cell mass is reported to be deficient in type 2 diabetes. W e tested the hypothesis that decreased beta -cell mass leads to decreased i nsulin pulse mass. Insulin secretion was examined before and after an simil ar to 60% decrease in beta -cell mass achieved by a single injection of all oxan in a porcine model. Alloxan injection resulted in stable diabetes (fas ting plasma glucose 7.4 +/- 1.1 vs. 4.4 +/- 0.1 mmol/l; P < 0.01) with impa ired insulin secretion in the fasting and fed states and during a hyperglyc emic clamp (decreased by 54, 80, and 90%, respectively). Deconvolution anal ysis revealed a selective decrease in insulin pulse mass (by 54, 60, and 90 %) with no change in pulse frequency. Rhythm analysis revealed no change in the periodicity of regular oscillations after alloxan administration in th e fasting state but was unable to detect stable rhythms reliably after ente ric or intravenous glucose stimulation. After alloxan administration, insul in secretion and insulin pulse mass (but not insulin pulse interval) decrea sed in relation to beta -cell mass. However, the decreased pulse mass (and pulse amplitude delivered to the liver) was associated with a decrease in h epatic insulin clearance, which partially offset the decreased insulin secr etion. Despite hyperglycemia, postprandial glucagon concentrations were inc reased after alloxan administration (103.4 +/- 6.3 vs. 92.2 +/- 2.5 pgtml; P < 0.01). We conclude that an alloxan-induced selective decrease in beta - cell mass leads to deficient insulin secretion by attenuating insulin pulse mass, and that the latter is associated with decreased hepatic insulin cle arance and relative hyperglucagonemia, thereby emulating the pattern of isl et dysfunction observed in type 2 diabetes.