Table 3.

Effects of GLP-1R agonists and native GLP-1 in rodent models of diabetes, where changes in β cell mass were assessed.

Rodent Model	GLP-1R Agonist	Key Findings	Reference
90–95% Partial pancreatectomy in rats	Ex-4, ip, 1 nmol/kg daily for 10 days starting immediately post surgery	Improved glucose tolerance 25 days post surgery in Ex-4 group Increase in β cell area in partial pancreatectomy receiving Ex-4 relative to sham controls receiving Ex-4. No increase in β cell BrdU index in partial pancreatectomy receiving Ex-4 relative to surgery alone Conclusion: increase in β cell neogenesis and increased β cell function and insulin content resulted in larger β cell area	(Xu et al., 1999)
db/db mice GLP-1R −/− mice	Ex-4, ip, 1 nmol/kg daily for 2 weeks	Improved glucose tolerance and lower HbA1c 1.76-fold increase in β cell mass Increase in PDX-1 levels in whole pancreatic extracts and increase in number of PDX-1 expressing cells in the ductular network. Conclusion: neogenesis in the ducts initiated by PDX-1 expression, no such effects seen in GLP-1R −/− mice	(Stoffers et al., 2000)
22 month old glucose intolerant Wistar rats	GLP-1, continuous sc infusion, 1.5 pM/kg·min, 5 days	Restoration of glucose tolerance Increase in PDX-1mRNA and protein levels in whole pancreatic extracts. Initial increase in proliferation of acinar cells at 3 days – gone by 5 days of treatment. Increase in insulin-positive cells in the ducts. Number of insulin-positive cells in any one duct appeared to decrease with the increasing size of the duct. Conclusion: differentiation involved an initial increase in proliferation of exocrine tissue followed by differentiation from the ductular network.	(Perfetti et al., 2000)
STZ Wistar neonate rats	Ex-4, ip, 3 μg/kg body weight GLP-1, ip, 400 μg/kg body weight 5 days Once a day Rats observed on day 7 and at 2 months of age.	Basal hyperglycemia lowered Glucose tolerance not improved β cell mass increased β cell proliferation not different between STZ saline controls and STZ receiving GLP-1R agonists. Significant increase in number of individual or clusters or insulin-positive cells in ducts Conclusion: pancreatic regeneration due to increased β cell neogenesis with no evidence of increased proliferation or decreased apoptosis	(Tourrel et al., 2001)
db/db mice	Ex-4, ip, 1 nmol/kg daily for 2 weeks	Improved glucose tolerance,delay in the onset of diabetes 1.35-fold increase in β cell mass and 2.3-fold increase in insulin/BrdU positive cells 3.2-fold decrease in β cell apoptosis Number of small islets and single β cells increased Increased protein levels of PKB and ERK1 (but not ERK2) and decrease in Caspase 3 in whole pancreatic extracts Conclusion: PKB and MAPK pathways involved in increasing β cell proliferation and survival following chronic elevation of GLP-1R signaling	(Wang and Brubaker, 2002)
ZDF/GmiTM-fa/fa	GLP-1, continuous sc infusion, 30 pmol/kg·min, 2 days	Improved glucose tolerance 1.6-fold increase in β cell mass 1.4-fold increase in Ki-67/insulin positive cells 3.6-fold decrease in the number of apoptotic β cell nuclei Conclusion: beneficial effects of GLP-1R signaling in ZDF rats are mediated by increased β cell proliferation and decreased apoptosis	(Farilla et al., 2002)
db/db mice ob/ob mice	Liraglutide/NN2211, sc, 100 μg/kg body weight twice a day ob/ob for 2 weeks 200 μg/kg db/db body weight twice a day for 2 weeks	Non-significant increases in β cell proliferation and β cell mass seen with the 100 μg/kg dose in the ob/ob mice Significant increase in β cell proliferation (approximately 3-fold) and β cell mass in the 200 μg/kg db/db study Conclusion: Longer pharmacokinetic half-life of NN2211 was reflected in a longer duration of effect than seen with Ex-4 100 μg/kg	(Rolin et al., 2002)
Non-diabetic Sprague Dawley rats	Liraglutide/NN2211, sc, 200 μg/kg body weight, twice a day for 1 or 6 weeks	Fasting blood glucose comparable to vehicle treated controls Sustained lower body weight Transient increase by 19% in β cell mass after 1 week β cell mass normalized by 6 weeks No change in α cell mass Volume weighted mean islet volume also unchanged Conclusion: In normal rats there is a temporary increase in β cell mass but a sustained decrease in total body weight	(Bock et al., 2003)
70% Partial pancreatectomy BALB/c mice & GLP-1R −/− mice	Endogenous GLP-1 suppressed by Ex (9-39), sc, 50 pmol/kg·min, for 2 weeks beginning one day prior to surgery	Ex (9-39) did not impair β cell mass regeneration after partial pancreatectomy in BALB/c mice. Regeneration was impaired in the GLP-1R −/− mice	(De Leon et al., 2003)
ZDF fa/fa rats 60% Partially pancreatectomized Sprague Dawley rats	Liraglutide/NN2211, sc, 150 or 30 μg/kg body weight, twice a day for 2 or 6 weeks Liraglutide/N2211 sc, 150 μg/kg body weight twice a day for 4 days	6-weeks Significant reduction in HbA1c and improved glucose tolerance in the high dose group β cell volume increased in both high and low dose groups –only statistically significant for the low dose group Non-significant increases in β cell proliferation with both doses No apparent changes in non-β cell islet mass as measured by a cocktail of antibodies against glucagon, somatostatin, and pancreatic polypeptide No significant increases in β cell volume or proliferation	(Sturis et al., 2003)
Zucker fa/fa 9 weeks old nondiabetic	Ex-4, 3 μg/kg body weight twice a day for 6 weeks	Decreased HbA1c in Ex-4 treated mice and par fed controls Hyperinsulinemic euglycemic clamp revealed improved insulin sensitivity in Ex-4 treated animals than in the par fed or the controls Animals treated with Ex-4 showed a decrease in β cell mass Conclusion: Pancreatic β cell mass increased hyperbolically with decreasing insulin sensitivity in the controls and par fed animals The decreased β cell mass in Ex-4 treated animals was due increased insulin sensitivity.	(Gedulin et al., 2005)
Sprague Dawley rats STZ treatment (one injection 65 mg/kg)	Ex-4 ip 1 nmol/kg daily, begun 1 week following STZ treatment and terminated 10 days later	Improved glucose tolerance in OGTT performed 3 weeks after the start of Ex-4 treatment 2.6-fold increase in β cell mass relative to untreated STZ animals No decrease in apoptosis Conclusion: Pancreatic endocrine regeneration due entirely to neogenesis and proliferation	(Xu et al., 2006)
4 week old db/db mice	Plasmid encoding GLP-1 fused to mouse IgG1 heavy chain constant region to form a bivalent peptide	Plasmid injected intramuscularly in concert with electroporation at 4 weeks of age and at 6 weeks of age. Fasting blood glucose levels were lower and fasting insulin levels were higher relative to controls 12 weeks after the first injection. Conclusion: Administration of GLP-1 via this method did have long lasting anti-diabetogenic effect on these animals.	(Kumar et al., 2006)