Abstract
The incidence of type 2 diabetes mellitus (T2DM) is rapidly increasing worldwide with
significant consequences on individual quality of life as well as economic burden
on states’ healthcare costs. While origins of the pathogenesis of T2DM are poorly
understood, an early defect in glucose-stimulated insulin secretion (GSIS) from pancreatic
β-cells is considered a hallmark of T2DM [1].
Upon a glucose stimulus, insulin is secreted in a biphasic manner with an early first-phase
burst of insulin, which is followed by a second, more sustained phase of insulin output
[2]. First phase insulin secretion is diminished early in T2DM as well is in subjects
who are at risk of developing T2DM [3]
[4]
[5]
[6].
An effective treatment of T2DM with incretin hormone glucagon-like peptide-1 (GLP-1)
or its long acting peptide analogue exendin-4 (E4), restores first-phase and augments
second-phase glucose stimulated insulin secretion. This effect of incretin action
occurs within minutes of GLP-1/E4 infusion in T2DM humans. An additional important
consideration is that incretin hormones augment GSIS only above a certain glucose
threshold, which is slightly above the normal glucose range. This ensures that incretin
hormones stimulate GSIS only when glucose levels are high, while they are ineffective
when insulin levels are below a certain threshold [7]
[8].
Activation of the GLP-1 receptor, which is highly expressed on pancreatic β-cells,
stimulates 2 distinct intracellular signaling pathways: a) the cAMP-protein kinase
A branch and b) the cAMP-EPAC2 (EPAC=exchange protein activated by cAMP) branch. While
the EPAC2 branch is considered to mediate GLP-1 effects on first-phase GSIS, the PKA
branch is necessary for the former branch to be active [9]
[10]. However, how these 2 branches interplay and converge and how their effects on insulin
secretion and insulin vesicle exocytosis are coordinated is poorly understood.
Thus, at the outset of our studies we have a poorly understood intracellular interplay
of cAMP-dependent signaling pathways, which – when stimulated – restore glucose-dependent
first phase and augment second phase insulin secretion in the ailing β-cells of T2DM.
Key words
type 2 diabetes - Prkar1a - insulin secretion
