Sitagliptin reduces hyperglycemia and increases satiety hormone secretion more effectively when used with a novel polysaccharide in obese Zucker rats

Abstract

The novel polysaccharide (NPS) PolyGlycopleX (PGX) has been shown to reduce glycemia. Pharmacological treatment with sitagliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor, also reduces glycemia by increasing glucagon-like peptide-1 (GLP-1). Our objective was to determine if using NPS in combination with sitagliptin reduces hyperglycemia in Zucker diabetic fatty (ZDF) rats more so than either treatment alone. Male ZDF rats were randomized to: 1) cellulose/vehicle [control (C)]; 2) NPS (5% wt:wt)/vehicle (NPS); 3) cellulose/sitagliptin [10 mg/(kg · d) (S)]; or 4) NPS (5%) + S [10 mg/(kg · d) (NPS+S)]. Glucose tolerance, adiposity, satiety hormones, and mechanisms related to DPP4 activity and hepatic and pancreatic histology were examined. A clinically relevant reduction in hyperglycemia occurred in the rats treated with NPS+S (P = 0.001) compared with NPS and S alone. Blood glucose, measured weekly in fed and feed-deprived rats and during an oral glucose tolerance test, was lower in the NPS+S group compared with all other groups (all P = 0.001). At wk 6, glycated hemoglobin was lower in the NPS+S group than in the C and S (P = 0.001) and NPS (P = 0.06) groups. PGX (P = 0.001) and S (P = 0.014) contributed to increased lean mass. Active GLP-1 was increased by S (P = 0.001) and GIP was increased by NPS (P = 0.001). Plasma DPP4 activity was lower in the NPS+S and S groups than in the NPS and C groups (P = 0.007). Insulin secretion and β-cell mass was increased with NPS (P < 0.05). NPS alone reduced LDL cholesterol and hepatic steatosis (P < 0.01). Independently, NPS and S improve several metabolic outcomes in ZDF rats, but combined, their ability to markedly reduce glycemia suggests they may be a promising dietary/pharmacological co-therapy for type 2 diabetes management.

FIGURE 1

HbA1c (C) and blood glucose concentrations in feed-deprived (A) and fed (B) obese ZDF rats treated with NPS, S, both, or neither for 6 wk. Values are mean ± SEM, n = 8–11. Labeled means at a time without a common letter differ, P < 0.05. C, control; HbA1c, glycated hemoglobin; NPS, novel polysaccharide; NPS+S; novel polysaccharide and sitagliptin; S, sitagliptin; ZDF, Zucker diabetic fatty.

FIGURE 2

Plasma insulin (A), GIP (B), GLP-1 (C), leptin (D), amylin (E), and blood glucose (F) of obese ZDF rats during an OGTT. Values are mean ± SEM, n = 8–11. Labeled means at a time without a common letter differ, P < 0.05. C, control; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide 1; NPS, novel polysaccharide; NPS+S; novel polysaccharide and sitagliptin; OGTT, oral glucose tolerance test; S, sitagliptin; ZDF, Zucker diabetic fatty.

FIGURE 3

Plasma and liver DPP4 activity in obese ZDF rats treated with NPS, S, both, or neither for 6 wk. Values are mean ± SEM, n = 8–11. Labeled means without a common letter differ, P < 0.05. C, control; DPP4, dipeptidyl peptidase 4; NPS, novel polysaccharide; NPS+S; novel polysaccharide and sitagliptin; S, sitagliptin; ZDF, Zucker diabetic fatty.

FIGURE 4

Photomicrographs of pancreas of obese ZDF rats treated with NPS, S, both, or neither for 6 wk. The bars are 200 μm. The brown-stained tissue is positive for insulin-containing cells within the pancreas. Photographs were selected as representative of the respective treatments. C, control; NPS, novel polysaccharide; NPS+S; novel polysaccharide and sitagliptin; S, sitagliptin; ZDF, Zucker diabetic fatty.