Biomedical Engineering Reference
In-Depth Information
of GLP-1, improved insulin secretion and glucose tolerance, and increased the
average islet area by 1.2-fold in obese diabetic (ob/ob) mice. Additionally, in
diabetic mice treatment with a DPP-IV inhibitor improved glycemic control and
restored the b cell mass [
43
]. The beneficial effect of GLP-1/GLP-1 analogs is also
supported by in vitro studies, where they were shown to convert pancreatic AR42 J
or ductal cells into endocrine cells including b cells [
44
,
45
]. These and many
other studies show the beneficial effect of GLP-1, GLP-1 analogs, and DPP-IV
inhibitors in the prevention of diabetes, by promoting insulin secretion and
functional b cell mass. Some of the GLP-1 agonists and DPP-IV inhibitors have
already been approved by FDA for use as antidiabetogenic agents mostly in
combination with other antidiabetic drugs [
46
].
Other gastrointestinal hormones (GIP, CCK, and gastrin) may also facilitate the
process of b cell regeneration. The role of GIP in the maintenance of b cell mass
was shown in a study where the dominant negative form of GIP receptor was
overexpressed in transgenic mice that led to the reduction of total islet and b cell
volume [
47
]. As GIP is also degraded in vivo by DPP-IV, making its half-life very
short, more stable analogs are required for its therapeutic application, e.g., in
combination with GLP-1 therapy. GIP (LysPAL16) a stable analog of GIP was
shown to enhance the differentiation of mouse embryonic stem cells (ES) into
insulin-producing cells [
48
]. Another study showed enhanced insulin production
and improved b cell volume in obese diabetic (ob/ob) mice following treatment
with three different GIP analogs [
49
].
Cholecystokinin octapeptide (CCK-8) treatment was shown to increase b cell
proliferation and reduce hyperglycemia in streptozotocin-induced diabetic rats
[
50
]. In obese (Leptin ob/ob) mice, loss of CCK resulted in reduced islet size and
b cell mass due to increased apoptosis, showing that CCK plays a role in b cell
survival [
51
]. CCK also exerted an antidiabetogenic effect when administered to
healthy individuals or type 2 diabetic patients, showing its potential as a thera-
peutic agent [
52
].
In pancreatic duct ligated rats, gastrin treatment stimulated b cell neogenesis
but not proliferation [
53
]. Overexpression of gastrin or TGF-a (transforming
growth factor-a) alone in pancreas did not show any beneficial effect on b cell
mass. However, a combined expression of gastrin and TGF-a led to increase in the
islet mass [
54
]. Increased islet mass was also observed in alloxan-treated mice and
streptozotocin-treated rats following co-administration of gastrin and EGF
(epidermal growth factor) [
55
,
56
]. In these studies, TGF a and EGF treatment
promoted metaplastic-ductule formation (through duct proliferation or transdif-
ferentiation from acinar cells), while gastrin stimulated the differentiation of
ductules to b cells.
Collectively, these studies clearly demonstrate the beneficial effect of gut
peptides, especially in the treatment of type 2 diabetes, where their insulinotropic
and b cell protective effect can be utilized.
