Sitagliptin Reduces Hyperglycemia and Increases Satiety Hormone Secretion More Effectively When Used with a Novel Polysaccharide in Obese Zucker Rats3

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.

Gut microorganisms as promising targets for the management of type 2 diabetes

“…As mentioned earlier, GLP-1 secretion can also be stimulated by metabolites produced by the gut microbiota [25]. Reimer et al demonstrated that co-administration of sitagliptin and a viscous fermentable fibre, which is broken down into SCFA, more effectively reduced fasting glycaemia in obese Zucker rats than either treatment alone [53]. Similar results were obtained in the same model when this fibre was combined with metformin or with metformin and sitagliptin [54].…”

Combining sitagliptin/metformin with a functional fiber delays diabetes progression in Zucker rats

“…PolyGlycopleX (a-D-glucurono-a-D-manno-b-D-manno-b-D-gluco), (a-L-gulurono-b-D mannurono), b-D-gluco-b-D-mannan (PGX) is a highly viscous and fermentable functional fiber that has been shown to reduce hyperglycemia and increase GLP1 secretion in obese Zucker rats (Grover et al 2011b). We have recently demonstrated that the individual glycemialowering potential of sitagliptin and PGX can be augmented when they are co-administered in obese Zucker rats (Reimer et al 2012a). Whether the effectiveness of MET and sitagliptin/metformin (S/MET) can likewise be improved with co-administration with PGX is not known.…”

“…The drugs were administered for 6 weeks. The dose of PGX has been shown to reduce HbA1c and serum cholesterol and increase b-cell mass previously (Grover et al 2011b, Reimer et al 2012a. Doses of MET and sitagliptin were selected from the low end of the ranges used in the literature (Chen et al 2011, Maiztegui et al 2011, Pyra et al 2012 in order that potential synergistic effects with PGX could be detected.…”

“…Administration of MET or S/MET was via oral gavage given on a daily basis in the morning. The composition of the diets which were formulated on a background diet of 24% fat (wt/wt) and containing the test fiber, PGX, or the insoluble reference fiber, cellulose (Anderson et al 1994), has been previously published (Reimer et al 2012a). MET and S/MET hydrochloride (as Janumet) were obtained by prescription at a pharmacy in Dayton, NJ and prepared in water for the daily gavage.…”

“…Following the cardiac blood draw, one kidney, one lobe of the liver, and a section of the distal ileum were snapfrozen for later DPP4 analysis (DPP4 activity in kidney and Dpp4 mRNA levels according to our previous work (Reimer et al 2012a)). The pancreas was fixed in 10% neutral buffered formalin and transferred to 70% ethanol after 24 h. The pancreas was serial sectioned twice at approximately five microns and either stained with hematoxylin and eosin or immunohistochemically stained with a mouse antibody against rat insulin according to our previous work (Grover et al 2011a).…”