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Pharmacological potential of novel agonists for FFAR4 on islet and enteroendocrine cell function and glucose

A G McCloskey¹, M G Miskelly¹, P R Flatt¹

¹School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland.

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences

|November 1, 2019

Abstract

Background:

To investigate the metabolic effects of FFAR4-selective agonists on islet and enteroendocrine cell hormone release and the combined therapeutic effectiveness with DPP-IV inhibitors.

Methods:

Insulinotropic activity and specificity of FFAR4 agonists were determined in clonal pancreatic BRIN-BD11 cells. Expression of FFAR4 was assessed by qPCR and western blotting following agonist treatment in BRIN-BD11 cells and by immunohistochemistry in mouse islets. Acute in-vivo effects of agonists was investigated after intraperitoneal (i.p.) or oral administration in lean and HFF-obese diabetic mice.

Results:

GSK137647 (10^-¹¹-10^-⁴ M) and Compound-A (10^-¹⁰-10^-⁴ M) stimulated insulin secretion at 5.6 mM (p < 0.05-p < 0.001) and 16.7 mM (p < 0.05-p < 0.001) glucose in BRIN-BD11 cells, with no cytotoxicity effects as assessed by MTT. FFAR4 antagonist (AH-7614) abolished the insulintropic effect of GSK137647 (p < 0.05-p < 0.001), whilst FFAR1 antagonist (GW1100) had no effect. Incubation of BRIN-BD11 cells with GSK137647 and Compound-A increased FFAR4 (p < 0.01) gene expression at 16.7 mM glucose, with a corresponding increase in FFAR4 (p < 0.01) protein concentrations. FFAR4 upregulation was attenuated under normoglycaemic conditions. Immunohistochemistry demonstrated co-localisation of FFAR4 and insulin in mouse islets. Orally administered GSK137647 or Compound-A (0.1 µmol/kgBW) improved glucose tolerance (p < 0.001), increased plasma insulin (p < 0.001), GLP-1 (p < 0.05), GIP (p < 0.05) and induced satiety (p < 0.001) in HFF mice, with glucose-lowering effects enhanced in combination with DPP-IV inhibitor (Sitagliptin) (p < 0.05).

Conclusions:

Specific FFAR4 agonism improves glucose tolerance through insulin and incretin secretion, with enhanced DPP-IV inhibition in combination with Sitagliptin.

General Significance:

These findings have for the first time demonstrated that selective FFAR4 activation regulates both islet and enteroendocrine hormone function with agonist combinational therapy, presenting a promising strategy for the treatment of type-2-diabetes.

Insights

Selective FFAR4 agonists enhance insulin and incretin secretion, improving glucose tolerance. Combining FFAR4 agonists with DPP-IV inhibitors like Sitagliptin offers a promising therapeutic strategy for type-2-diabetes.

Area of Science:

Metabolic research
Endocrinology
Pharmacology

Background:

Investigating the metabolic effects of FFAR4-selective agonists on hormone release from islet and enteroendocrine cells.
Assessing the combined therapeutic effectiveness of FFAR4 agonists with DPP-IV inhibitors.

Purpose of the Study:

To determine the insulinotropic activity and specificity of FFAR4 agonists.
To evaluate the in-vivo effects of FFAR4 agonists on glucose tolerance and hormone secretion.
To explore the synergistic effects of FFAR4 agonists and DPP-IV inhibitors in a diabetic mouse model.

Main Methods:

Utilized clonal pancreatic BRIN-BD11 cells to assess insulin secretion and FFAR4 expression (qPCR, Western blotting).
Determined FFAR4 specificity using FFAR4 and FFAR1 antagonists.
Administered FFAR4 agonists orally to HFF-obese diabetic mice to assess in-vivo effects on glucose tolerance, insulin, GLP-1, and GIP levels.
Evaluated the combined effects with DPP-IV inhibitor (Sitagliptin).

Main Results:

GSK137647 and Compound-A stimulated insulin secretion in BRIN-BD11 cells without cytotoxicity.
FFAR4 agonists increased FFAR4 gene and protein expression in a glucose-dependent manner.
Oral administration of FFAR4 agonists improved glucose tolerance, increased insulin and incretin (GLP-1, GIP) levels, and induced satiety in obese diabetic mice.
Combination therapy with Sitagliptin enhanced glucose-lowering effects.

Conclusions:

Selective FFAR4 agonism effectively regulates both islet and enteroendocrine hormone function.
FFAR4 agonists improve glucose tolerance via enhanced insulin and incretin secretion.
Combination therapy with FFAR4 agonists and DPP-IV inhibitors presents a promising strategy for type-2-diabetes treatment.

Read full analysis

Keywords:

Combinational Therapy DPP-IV Inhibition FAR4 Incretin Insulin Specificity

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