Table 2. Recent findings (2016-2021) on synthetic and natural compounds that induce incretin secretion from enteroendocrine L-cells.

Synthetic/Natura l Compounds	Target Sites	Study Models/Subjects	Outcomes	References
Synthetic Compounds
AgoPAMs	Activates GPR40/FFAR1	Diabetic Goto-Kakizaki rats GLP-1R-/- mice and wild type mice	Increased GLP-1, GIP, PYY and insulin secretion; reduced glucose level, food intake and body weight Reduced glucose level in both mice types; induced higher insulin secretion in wild type than GLP-1R-/- mice	[138]
SCO-267	Activates GPR40/FFAR1	GLUTag cells Wild-type mice and GPR40-knockout (Ffar1−/−) mice Normal rats Neonatal streptozotocin-treated rats Diet-induced obese rats	Induced GLP-1 secretion Increased GLP-1 secretion; reduced food intake and body weight reduction in wild-type mice, but not Ffar1-/- mice Increased GLP-1, GIP, PYY, insulin and glucagon secretions Increased insulin and GLP-1 level; improved glucose tolerance; no changes in food intake and body weight Increased GLP-1 and PYY plasma levels; reduced food intake, cholesterol, fat mass and body weight; no changes in lean mass and glucose and triglycerides plasma level	[139]
GSK137647 and Compound-A	Activate GPR120/FFAR 4	High-fat-fed Swiss TO mice Lean Swiss TO mice	Both agents increased GLP-1 and insulin level; improved glucose tolerance; synergistically increased glucose lowering effect is observed when given together with sitagliptin (DPP4-i); GSK137647 increased GIP level, but not Compound-A; AH-7614 (FFAR4 antagonist) impaired both agents’ insulinotropic and glucose lowering properties Both agents improved glucose excursion; satiation effect was observed when agents given alone, but sitagliptin (DPP4-i) impaired the satiation effect of Compound A at 60 min and GSK137647 from 60 min to 180 min	[140]
AZ13581837 and Metabolex-36	Activate GPR120/FFAR 4	STC-1 Lean wild-type mice GPR120 null mice	Both agents increased GLP-1 secretion Both increased GLP-1 and insulin secretion; reduced glucose level; exendin 9–39 (GLP-1 receptor antagonist) abolished insulin secretion and glucose lowering effect of both agents Glucose tolerance effect of Metabolex-36 was not observed; AZ13581837 did not induce acute insulin secretion and it impaired glucose elimination	[141]
AS1269574	Activates GPR119 and Transient Receptor Potential Ankyrin 1 (TRPA1) channel	STC-1 GLUTag	Stimulated GLP-1 release and increased [Ca2+]i Stimulated proglucagon gene promoter activity	[142]
DS-8500a	Activates GPR119	Zucker fatty rats Fasted Sprague-Dawley rats Neonatal streptozotocin-treated rats	Increased plasma GLP-1 concentration and reduced glucose level Did not change plasma glucose concentration; stimulated insulin secretion in the presence of glucose Induced glucose-stimulated insulin secretion; reduced glucose level	[143]
ZB-16	Activates GPR119	Streptozotocin–nicotinamide-treated rats	Increased GLP-1, insulin, insulin-positive pancreatic endocrine cells and glucose utilisation.	[144]
YH18421	Activates GPR119	GLUTag Normal C57BL/6J male mices Diet induced obese mice model	Increased GLP-1 secretion Single YH18421 oral administration improved glucose tolerance and GLP-1 level; synergistically increased glucose lowering effect and GLP-1 levels are observed when YH18421 given together with Linagliptin (DPP4-i) Four weeks repeated YH18421 administration lower blood glucose level and showed dose-dependently inhibited weight gain; synergistically increased glucose lowering effect is observed when YH18421 given together with sitagliptin (DPP4-i)	[145]
HBK001	Activates GPR119 and inhibits DPP4	ICR mice Diabetic KKAy mice db/db (BKS.Cg-m+/+ Leprdb/J) mice	Increased GLP-1 and GIP level; inhibited DPP4 activity; reduced blood glucose level Reduced plasma glucose level and food intake; increased insulin secretion; no effect on body weight Reduced plasma glucose level	[146]
L3740	Activates GPBAR1/TGR5	Mouse intestinal organoids Human intestinal organoids GLU-Venus mice in vivo model	Increased L-cell density and GLP-1 secretory capacity; elevated expression of Gcg and Cck and transcription factors Ngn3 and NeuroD1; no increment effect on L-cells and no GLP-1 secretion was observed from organoids lacking GPBAR1 Increased L-cell density; elevated expression of Gcg and transcription factors NeuroD1 Increased basal GLP-1 plasma level, L-cell density and expression of Gcg and Ngn3 and GLP-1 levels; improved glucose tolerance; no differences in food intake and body weight	[147]
Compound 24 (BDM72881)	Activates GPBAR1/TGR5	Diet-induced obesity and insulin resistance C57Bl6 mice	Increased GLP-1 secretion and improved glucose homeostasis	[148]
LX2761	Inhibits SGLT-1 and SGLT-2	Healthy mice Healthy rats Streptozotocin-treated mice	Reduced glucose level; increased plasma GLP-1 when administered alone and synergistic increased GLP-1 level is observed when given together with sitagliptin (DPP4-i); no significant changes in food intake and body weights Reduced glucose excursions; increased plasma GLP-1; no significant changes in food intake and body weights Early-onset diabetes: Reduced fasting and postprandial glucose level; slowing of the rise in HbA1c levels; no effect on food intake, body weight and GLP-1 level on the final study day Late-onset diabetes: Reduced fasting and postprandial glucose level and HbA1c; increased GLP-1 level, survival rate, food intake and body weight	[149]
CPU025	Activates GPR40/FFAR1 and peroxisome proliferator-activated receptor δ (PPARδ)	FLIPR assay (Chinese hamster ovary (CHO, RRID:CVCL_0213) cells) AutoDock vina1.1.2 Male ICR mice Diabetic ob/ob mice and C57BL/6 mice	EC50 value of 38.7 nM for GPR40/FFAR1 Molecular docking simulations showed multiple hydrogen bonding formed between carboxylic acid of CPU025 and key binding residues of GPR40/FFAR1 (Arg2258, Tyr2240, Arg183 and Tyr91) Could not induce GLP-1 secretion Exhibited better reduction in blood glucose, HbA1c, triglyceride and consumption of food and water than TAK-875, GPR40/FFAR1 partial agonist; no body weight changes; improved β-cell function; displayed relatively dense arrangement of insulin-positive cells; alleviated fatty liver	[150]
ZLY032	Activates GPR40/FFAR1 and PPARδ	Male ob/ob mice and male C57BL/6 mice	Improved fasting glucose level, HbA1c, glucose tolerance and pancreatic β-cell function; decreased plasma total cholesterol, triglyceride, LDL, adipocytes area, liver steatosis and ballooning; showed stronger insulin sensitive and lipid improvement compared to TAK-875; no changes in body weight	[151]
DKS26	Unidentified/ unreported receptors	NCI-H716 cells Streptozotocin-treated and db/db diabetic mice	Echanced GLP-1 release and expression Increased plasma insulin level; enhanced GLP-1 release and expression; reduced glucose level, plasma glycosylated serum protein; no significant changes in body weight A reduction of food intake was observed in Streptozotocin-treated mice, but no effect on db/db diabetic mice	[152]
Natural Compounds
Polygonatum cyrtonema polysaccharide	Activates sweet taste receptor T1R2/T1R3	NCI-H716 and male Sprague-Dawley rats	Increased GLP-1 secretion	[47]
Matrine	Activates CaSR	STC-1 cells Type 2 diabetic C57BL/6	Increased GLP-1 secretion mice Improved glucose metabolism; reduced fasting serum insulin level; increased GLP-1 level and oral-induce insulin level; high-dose Matrine increase body weight in the third week of study	[153]
Curcumin	Activates GPR 40/120	GLUTag Male Sprague-Dawley rats	Increased GLP-1 secretion; reduced GLP-1 secretion when pre-treated with GW1100 (GPR40/120 antagonist) and neomycin (PLC inhibitor - a downstream molecule of GPR40/120 pathway) Increased GLP-1 and insulin secretion; improved glucose tolerance; reduced glucose-lowering effect when pre-treated with GW1100 (GPR40/120 antagonist)	[154]
Phytosphingosine	Activates GPR120/FFAR 4	Transforming Growth Factor α-shedding assay	IC50 value of 33.4 μM; the activation is significantly inhibited by AH7614 (GPR120/FFAR 4 antagonist)	[155]
Angelica dahurica extract (phellopterin)	Activates GPR119	GLUTag Normal C57BL6 mice Diabetic db/db mice	Increased GLP-1 secretion Increased insulin and reduced glucose level Reduced glucose level	[156]
Costus pictus D. Don	Unidentified/ unreported receptors	GLUTag	Increased acute GLP-1 secretion; improved GLUTag viable cells when given in low concentration (1.56, 3.125 and 6.25 μg/ml); no changes on prohormone convertase 1 and 2 protein expression; reduced proglucagon and prohormone convertase 1 gene expression	[157]
Delphinidin 3-rutinoside-rich blackcurrant extract	Unidentified/ unreported receptors	Male Sprague-Dawley rats	Increased GLP-1 and insulin secretion, and reduced glucose level	[158]