Decrease in β-Cell Mass Leads to Impaired Pulsatile Insulin Secretion, Reduced Postprandial Hepatic Insulin Clearance, and Relative Hyperglucagonemia in the Minipig

Abstract

Most insulin is secreted in discrete pulses at an interval of ϳ6 min. Increased insulin secretion after meal ingestion is achieved through the mechanism of amplification of the burst mass. Conversely, in type 2 diabetes, insulin secretion is impaired as a consequence of decreased insulin pulse mass. ␤-cell mass is reported to be deficient in type 2 diabetes. We tested the hypothesis that decreased ␤-cell mass leads to decreased insulin pulse mass. Insulin secretion was examined before and after an ϳ60% decrease in ␤-cell mass achieved by a single injection of alloxan in a porcine model. Alloxan injection resulted in stable diabetes (fasting plasma glucose 7.4 ؎ 1.1 vs. 4.4 ؎ 0.1 mmol/l; P < 0.01) with impaired insulin secretion in the fasting and fed states and during a hyperglycemic clamp (decreased by 54, 80, and 90%, respectively). Deconvolution analysis 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 the fasting state but was unable to detect stable rhythms reliably after enteric or intravenous glucose stimulation. After alloxan administration, insulin secretion and insulin pulse mass (but not insulin pulse interval) decreased in relation to ␤-cell mass. However, the decreased pulse mass (and pulse amplitude delivered to the liver) was associated with a decrease in hepatic insulin clearance, which partially offset the decreased insulin secretion. Despite hyperglycemia, postprandial glucagon concentrations were increased after alloxan administration (103.4 ؎ 6.3 vs. 92.2 ؎ 2.5 pg/ml; P < 0.01). We conclude that an alloxan-induced selective decrease in ␤-cell mass leads to deficient insulin secretion by attenuating insulin pulse mass, and that the latter is associated with decreased hepatic insulin clearance and relative hyperglucagonemia, thereby emulating the pattern of islet dysfunction observed in type 2 diabetes. Diabetes 50: [2001][2002][2003][2004][2005][2006][2007][2008][2009][2010][2011][2012] 2001 T ype 2 diabetes is characterized by impaired glucose-mediated insulin secretion (1,2). This has been documented by demonstrating reduced first-phase insulin release in response to intravenous glucose (3,4) and impaired insulin release after glucose ingestion (1,5) and during a hyperglycemic clamp (6). Further analyses indicate that most insulin secretion is derived from discrete insulin secretory bursts (7,8), the mass of which is diminished in patients with type 2 diabetes (9). In addition, it has been reported that ␤-cell mass may be decreased in patients with type 2 diabetes (10), although this remains controversial. Indeed, the role of any decrease in the ␤-cell mass in the pathogenesis of impaired insulin secretion and the pathogenesis of hyperglycemia in type 2 diabetes remains uncertain.In the present study, we addressed the hypothesis that defective insulin secretion in type 2 diabetes can be recapitulated by a selective decreas...

Loss of beta-cell mass leads to a reduction of pulse mass with normal periodicity, regularity and entrainment of pulsatile insulin secretion in G�ttingen minipigs

“…The decreased secretory burst mass after a selective loss of beta cells is in accordance with previously published data in pigs [18] and baboons [17], as is the normal regularity of basal pulsatile insulin secretion in the fasted state [18]. Loss of beta-cell mass in minipigs has been reported to result in a lack of regular oscillations in insulin concentrations in response to orally and intravenously administered glucose when evaluated by auto-correlation, whereas devoncolution of the same data showed no change in pulse frequency after a reduction of betacell mass [18]. In our study, it seemed that the responsiveness of pulsatile insulin secretion to small changes in glucose concentration was maintained after a reduction in beta-cell mass.…”

“…Thus, the data on reduced beta-cell mass in the minipig suggest an expected (and correlated) loss of pulse mass but preserved pulsatile secretion of insulin in the remaining beta-cell population. This is supported by the striking correlation between pulse mass and beta-cell mass, as has also been reported in a similar group of animals [18].…”

“…Thus, no signs of any secondary beta-cell dysfunction could be shown from the present study. Reduction of beta-cell mass in minipigs has been reported to reduce insulin decay rates in the fasted and the fed state [18]. We did not find changes in decay rates determined by deconvolution of endougenous insulin concentrations.…”

“…In our study, it seemed that the responsiveness of pulsatile insulin secretion to small changes in glucose concentration was maintained after a reduction in beta-cell mass. The lack of regularity reported in another study [18] could to some extent be attributable to the nonstationarity of insulin concentration profiles during glucose stimulation. Another important factor could be the reduced insulin secretory capacity due to a reduced beta-cell mass.…”

“…Pulsatile insulin secretion after a primary reduction of beta-cell mass has been investigated in baboons [17] and minipigs [18], and reveals a reduced amplitude but normal frequency of insulin pulses.…”