Loss of beta-cell mass leads to a reduction of pulse mass with normal periodicity, regularity and entrainment of pulsatile insulin secretion in Göttingen minipigs.
OBJECTIVE
Type 2 diabetes is associated with impaired insulin action and secretion, including disturbed pulsatile release. Impaired pulsatility has been related to impaired insulin action, thus providing a possible link between release and action of insulin. Furthermore, progressive loss of beta-cell mass has been implicated in the pathogenesis of Type 2 diabetes. The aim of this study was to evaluate a possible link between loss of beta-cell mass and impaired pulsatile insulin secretion with special focus on glucose responsiveness of insulin secretion.


METHODS
The kinetic and dynamic profiles of insulin in Göttingen minipigs are favourable for studies on pulsatility and a model of diabetes with reduced beta-cell mass has recently been established. Pigs were studied before (n=14) and after (n=10) reduction of beta-cell mass by nicotinamide (67 mg/kg) and streptozotocin (125 mg/kg) from 17.7+/-4.7 (normal animals, n=5) to 6.1+/-2.0 mg/kg. Pulsatile insulin secretion was examined during basal (n=8 normal, n=6 beta-cell reduced) and glucose entrained (n=6 normal, n=4 beta-cell reduced) conditions. Insulin concentration time series were analysed by autocorrelation and spectral analyses for periodicities and regularity, and by deconvolution for pulse frequency, mass and amplitude.


RESULTS
Reduction of beta-cell mass and secondary hyperglycaemia resulted in correspondingly (r=0.7421, p=0.0275) reduced pulse mass (42% of normal during basal and 31% during entrained conditions) with normal periodicity (6.6+/-2.2 vs 5.8+/-2.4 min, p=0.50), regularity and entrainability of insulin secretion.


CONCLUSIONS
Neither beta-cell loss, nor 2 weeks of slight hyperglycaemia, as seen in the beta-cell-reduced minipig, probably accounts for the disturbed insulin pulsatility observed in human Type 2 diabetes.
Larsen
M O
MO
Department of Pharmacological Research I, Pharmacology, Research and Development, Novo Allé 6A1.005, 2880 Bagsvaerd, Denmark. mmla@novonordisk.com
Gotfredsen
C F
CF
Wilken
M
M
Carr
R D
RD
Pørksen
N
N
Rolin
B
B
D000818:Animals; D016923:Cell Death; D004338:Drug Combinations; D006943:Hyperglycemia / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D009536:Niacinamide / Q000494:pharmacology; D010507:Periodicity; D011673:Pulsatile Flow; D013311:Streptozocin / Q000494:pharmacology; D013552:Swine; D013556:Swine, Miniature
D004338:Drug Combinations; D007328:Insulin; D009536:Niacinamide; D013311:Streptozocin