Abstract:
:Glucose metabolism affects most major signal pathways in pancreatic beta-cells. Multiple protein kinases, including protein kinase C (PKC) isoenzymes, are involved in these effects; however, their role is poorly defined. Moreover, the dynamics of kinase isoenzyme activation in reference to the biphasic insulin secretion is unknown. In perfused pancreas of Wistar rats, PKCalpha staining was strongly associated with insulin staining, jointly accumulating in the vicinity of the plasma membrane during early first-phase insulin response. The signal declined before the onset of second phase and reappeared during second-phase insulin release as foci, only weekly associated with insulin staining; this signal persisted for at least 15 min after glucose stimulation. In the GK rat, glucose had minimal effect on beta-cell PKCalpha. In control beta-cells, PKCdelta stained as granulated foci with partial association with insulin staining; however, no glucose-dependent translocation was observed. In the GK rat, only minimal staining for PKCdelta was observed, increasing exclusively during early first-phase secretion. In Wistar beta-cells, PKCepsilon concentrated near the nucleus, strongly associated with insulin staining, with dynamics resembling that of biphasic insulin response, but persisting for 15 min after cessation of stimulation. In GK rats, PKCepsilon staining lacked glucose-dependent changes or association with insulin. PKCzeta exhibited bimodal dynamics in control beta-cells: during early first phase, accumulation near the cell membrane was observed, dispersing thereafter. This was followed by a gradual accumulation near the nucleus; 15 min after glucose stimulus, clear PKCzeta staining was observed within the nucleus. In the GK rat, a similar response was only occasionally observed. In control beta-cells, glucose stimulation led to a transient recruitment of PKCtheta, associated with first-phase insulin release, not seen in GK beta-cell. Data from this and related studies support a role for PKCalpha in glucose-induced insulin granule recruitment for exocytosis; a role for PKCepsilon in activation of insulin granules for exocytosis and/or in the glucose-generated time-dependent potentiation signal for insulin release; and a dual function for PKCzeta in initiating insulin release and in a regulatory role in the transcriptional machinery. Furthermore, diminished levels and/or activation of PKCalpha, PKCepsilon, PKCtheta, and PKCzeta could be part of the defective signals downstream to glucose metabolism responsible for the deranged insulin secretion in the GK rat.
journal_name
Diabetesjournal_title
Diabetesauthors
Warwar N,Efendic S,Ostenson CG,Haber EP,Cerasi E,Nesher Rdoi
10.2337/diabetes.55.03.06.db05-0001subject
Has Abstractpub_date
2006-03-01 00:00:00pages
590-9issue
3eissn
0012-1797issn
1939-327Xpii
55/3/590journal_volume
55pub_type
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