Prolonged survival and improved glycemia in BioBreeding diabetic rats after early sustained exposure to glucagon-like peptide 1

Abstract

Background: Type 1 diabetes (T1D) in both humans and BioBreeding (BB) rats is an autoimmune disease that results in complete destruction of islets and insulin dependency for life. Glucagon-like peptide 1 (GLP-1) promotes beta cell proliferation and neogenesis and has a potent insulinotropic effect. We hypothesized that the expression of GLP-1 before disease onset would increase islet mass, delay diabetes and prolong survival of BB rats.

Methods: Vascular smooth muscle cells retrovirally transduced to secrete GLP-1 were seeded into TheraCyte encapsulation devices, implanted subcutaneously, and rats were monitored for diabetes.

Results: In untreated control rats, plasma GLP-1 levels were 34.5-39.5 pmol/l, whereas, in treated rats, plasma levels were elevated, in the range 90-250.4 pmol/l. Hypoglycemia was not detected and this was anticipated from the glucose-regulated action of GLP-1. Diabetes onset (mean + or - SEM) in untreated rats occurred at 56.5 + or - 0.6 days (n = 6) and, in GLP-1-treated rats, was delayed until 76.4 + or - 3.3 days (n = 5) (p < 0.001). After disease onset, untreated control rats showed a rapid weight loss and elevated blood glucose (>650 mg/dl) and did not survive beyond 11 days. At 5 days after diabetes onset, insulin-secreting islets were absent in untreated rats. By contrast, treated rats maintained weight for up to 143 days of age and showed insulin-secreting beta cells.

Conclusions: Sustained GLP-1 expression delivered by encapsulated cells before diabetes onset in BB rats showed an improved clinical outcome, suggesting the potential for treating patients using long lasting GLP-1 analogs.

Figure 1. Male and Female BB DR.^lyp/lyp rats untreated or receiving GLP-1 secreting encapsulated cells before diabetes onset

Serial weights of males and females (panel A) and blood glucose (panel B). Two female (solid blue symbols) and three male (solid red symbols) BB DR.^lyp/lyp rats were treated at 40-45 days of age, before onset of diabetes, with encapsulated VSMC transduced to secrete GLP-1. Untreated control BB DR.^lyp/lyp rats are shown as open symbols; females (blue) and males (red). All rats received 10⁷ encapsulated transduced cells.

Figure 2. Pancreas tissue from BB DR^+/+wild type, GLP-1 treated and untreated BB DR.^lyp/lyp rats

Pancreas sections were stained for insulin (a-d) and glucagon (e-h). Untreated BB DR^+/+ wild type control rat (panels a/e); untreated BB DR.^lyp/lyp rat at diabetes onset (panels b/f) and at 5 days post diabetes onset (panels c/g) and GLP-1 treated female BB DR.^lyp/lyp rat at 143 days of age (panels d/h). Untreated BB DR.^lyp/lyp control rats received daily insulin from 40 days of age to prevent hyperglycemia, severe weight loss and preserve health. Magnification 20x.