Double-gene ablation of SSTR1 and SSTR5 results in hyperinsulinemia and improved glucose tolerance in mice.
BACKGROUND
Previous studies conducted in our laboratory showed that single-gene ablation of somatostatin receptor (SSTR)1 or 5 results in diabetes in mice. The objective of this study was to determine the effect of double-gene ablation of SSTR1 and SSTR5 on insulin secretion and glucose homeostasis in mice.


METHODS
SSTR1/5 -/- mice and wild-type (WT) control mice were generated and their genotype verified via polymerase chain reaction. Insulin secretion and glucose levels in these mice were examined with the use of an intraperitoneal glucose tolerance test (1.2-2.0 g/kg body weight). In vitro glucose-stimulated insulin secretion was studied with the use of the isolated perfused mouse pancreas model and islet culture techniques. Pancreata morphologic alterations were determined, and an immunohistochemistry analysis was performed.


RESULTS
In vitro incubation of isolated islets from WT mice with somatostatin peptides resulted in significant reduction in insulin secretion, whereas SSTR1/5 -/- mouse islets had no response to somatostatin peptides confirming SSTR1/5 gene ablation. SSTR1/5 -/- mice also had significant increase of both basal and glucose-stimulated insulin levels in vitro. During the intraperitoneal glucose tolerance test, SSTR1/5 -/- mice had significantly improved glucose tolerance and sustained an increase in late-phase insulin secretion in vivo. Histological analysis demonstrated significant islet hyperplasia in the SSTR 1/5 -/- mouse pancreas. Immunostaining revealed an overall increase of glucagon and pancreatic polypeptide-producing cells in the islets of SSTR1/5 -/- mice.


CONCLUSIONS
Double-gene ablation of SSTR1 and SSTR5 in mice resulted in a distinct phenotype with islet cell hyperplasia, hyperinsulinemia, and improved glucose tolerance. This form of diabetes differs from that seen in mice in which only the SSTR1 or SSTR5 gene was ablated. These results demonstrate that SSTR1 and SSTR5 are important regulators of insulin secretion and glucose regulation, and suggest that SSTR1 and SSTR5 are coordinately regulated.
Wang
X P
XP
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Tex, USA.
Norman
M A
MA
Yang
J
J
Cheung
A
A
Moldovan
S
S
Demayo
F J
FJ
Brunicardi
F C
FC
D000818:Animals; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000235:genetics*; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D006946:Hyperinsulinism / Q000235:genetics*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D017481:Receptors, Somatostatin / Q000235:genetics* / Q000502:physiology
D007328:Insulin; D017481:Receptors, Somatostatin; C101130:somatostatin receptor type 1; C094573:somatostatin receptor 5; D005947:Glucose