GIP mediates the incretin effect and glucose tolerance by dual actions on α cells and β cells

El, Kimberley; Gray, Sarah M.; Capozzi, Megan E.; Knuth, Emily; Jin, Erli; Svendsen, Berit; Clifford, Alexander M.; Brown, Jennifer; Encisco, Sara E.; Chazotte, Bryanna M.; Sloop, Kyle W.; Nunez, Derek J.; Merrins, Matthew J.; D’Alessio, David A.; Campbell, Jonathan E.

doi:10.1126/sciadv.abf1948

Cited by 89 publications

(103 citation statements)

References 42 publications

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“…Glucagon secretion was also stimulated by SCO-267 in humans. Considering the recent studies showing that glucagon functions as a physiological insulinotropic hormone, SCO-267-mediated glucagon stimulation may further promote insulin secretion as well as that of other insulinotropic hormones (20)(21)(22)(23)(24)(25). However, glucagon is counterregulatory to insulin and elevates plasma glucose levels through its action mediated in the liver (26).…”

Section: Discussionmentioning

confidence: 99%

SCO-267, a GPR40 Full Agonist, Stimulates Islet and Gut Hormone Secretion and Improves Glycemic Control in Humans

Nishizaki¹,

Matsuoka²,

Kagawa³

et al. 2021

Diabetes

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SCO-267 is a full agonist of the free fatty acid receptor 1 (GPR40), which regulates the secretion of islet and gut hormones. In this phase 1 study, we aimed to evaluate the clinical profile of single and multiple once-daily oral administration of SCO-267 in healthy adults and patients with diabetes. Plasma SCO-267 concentration was seen to increase in a dose-dependent manner after administration, and its plasma exposure was maintained for 24 h. Repeated dose did not alter the pharmacokinetic profile of SCO-267 in healthy adults. SCO-267 was generally safe and well tolerated at all evaluated single and multiple doses. Single and repeated doses of SCO-267 stimulated the secretion of insulin, glucagon, glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, and peptide YY in healthy adults. Furthermore, a single dose of SCO-267 stimulated the secretion of these hormones, decreased fasting hyperglycemia, and improved glycemic control during an oral glucose tolerance test in patients with diabetes, without inducing hypoglycemia. This study is the first to demonstrate the clinical effects of a GPR40 full agonist. SCO-267 is safe and well tolerated and exhibits once-daily oral dosing potential. Its robust therapeutic effects on hormonal secretion and glycemic control make SCO-267 an attractive drug candidate for the treatment of diabetes.

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Section: Discussionmentioning

confidence: 99%

SCO-267, a GPR40 Full Agonist, Stimulates Islet and Gut Hormone Secretion and Improves Glycemic Control in Humans

Nishizaki¹,

Matsuoka²,

Kagawa³

et al. 2021

Diabetes

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“…Similar results were observed from islets of pSENP1-KO mice following HFD (data not shown). Although GIP-dependent α-to-β-cell communication primarily impacts the incretin response to a mixed meal, rather than to oral glucose ( 31 ), an overall reduction in intra-islet glucagon could reduce insulin secretion by lowering β-cell cAMP tone ( 26 ). We wanted to focus on the role for β-cell SENP1 and so generated βSENP1-KO mice ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Recent work suggested an important interaction among incretin responses, glucagon secretion, and insulin release ( 39 ). GIP-induced glucagon secretion supports insulin secretion following a mixed meal ( 26 , 40 – 42 ) but does not likely contribute in the response to oral glucose alone ( 31 ). Thus, the reduced glucagon response to GIP + alanine in the pSENP1-KO islets used here as a strong stimulus of α-cell function likely does not contribute to worsened oral glucose intolerance.…”

Section: Discussionmentioning

confidence: 99%

β-Cell Knockout of SENP1 Reduces Responses to Incretins and Worsens Oral Glucose Tolerance in High-Fat Diet–Fed Mice

et al. 2021

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Lin et al. Supplementary FiguresSupplementary Figure 1. Additional in vivo glucose homeostasis assessment of male and female pSENP1-KO mice on CD. (A) Fasting insulin; (B) fasting glucose, (C) body weight, and (D) IP insulin tolerance of pSENP1-WT, -HET and -KO male mice on CD (n=6-22 mice). (E) Fasting insulin, (F) fasting glucose, (G) body weight, and (H) IP insulin tolerance of pSENP1-WT, -HET and -KO female mice on CD (n=7-17 mice). AUC -area under the curve. Data are mean ± SEM and were compared with student t test, one-way or two-way ANOVA followed by Bonferroni post-test. Unless stated otherwise, *-p<0.05, indicated comparison between pSENP1-WT and -KO. Supplementary Figure 2. In vivo glucose homeostasis assessment of female pSENP1-KO mice following HFD. (A) OGTT and (B) associated plasma insulin responses, (C) IP insulin tolerance, (D) body weight, (E) fasting glucose, and (F) fasting insulin of pSENP1-WT, -HET and -KO female mice following HFD (n=9-14 mice). Supplementary Figure 3. Islet morphometry analysis of female pSENP1-KO mice after HFD. (A) Representative immunostaining, -cell mass, islet number, and islet size distribution of female pSENP1-WT (n = 5 mice, 15 sections and 189 islets) and pSENP1-KO (n = 6 mice, 18 sections and 197 islets) following HFD. Insulin (green), glucagon (red), and nuclei (blue). Scale bar=100 µm. Data are presented as mean ± SEM. Lin et al. -cell SENP1 limits oral glucose intolerance 2 Supplementary Figure 4. Additional in vivo glucose homeostasis assessment of βSENP1-KO male mice. (A) IP insulin tolerance of male SENP1-WT, -HET, and -KO mice following HFD (n=15, 8, 8 mice). (B) Delta area under the curve (AUC) of IP insulin tolerance tests of male SENP1-WT, -HET, and -KO mice on CD and following HFD (n=6, 6, 6, 15, 8, 8 mice). (C) Fasting insulin of male SENP1-WT, -HET, and -KO mice on CD and following HFD (n=6, 4, 5, 13, 17, 14). (D) fasting glucose (n=15-22 mice) levels and (E) Body weight (n=18-23 mice) in male SENP1-WT and -KO mice on CD and following HFD. Data are presented as mean ± SEM. AUC -area under the curve. Data are mean ± SEM and were compared with student t test, one-way or two-way ANOVA followed by Bonferroni post-test. Unless stated otherwise, *-p<0.05, indicated comparison between βSENP1-WT and -KO. Supplementary Figure 5. In vivo glucose homeostasis assessment of βSENP1-KO female mice. (A) Fasting insulin (n=6, 8, 4, 13, 16, 14 mice), (B) fasting glucose (n=21, 22, 20, 21, 21, 22), and (C) body weights (n=30, 23, 25, 20, 22, 22) of female SENP1-WT, -HET, and -KO mice on CD and following HFD. (D) OGTT (n=11, 12, 12 mice), (E) IPGTT (n=10, 11, 9 mice), and (F) IP insulin tolerance (n=6, 9, 8) of female βSENP1-WT, -HET and -KO mice on CD. (G) OGTT (n=11, 13, 11 mice) and (H) associated plasma insulin response (n=7, 7, 8 mice) of female SENP1-WT, -HET, and -KO mice following HFD. (I) IPGTT (n=8, 9, 10 mice), and (J) associated plasma insulin response (n=6, 9, 6 mice) of female SENP1-WT, -HET, and -KO mice following HFD. (K) IP insulin tolerance (n...

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“…However, GLP1R-dependent cross-talk between alpha and beta cells might be higher in situations when alpha cells are simultaneously activated, such as in the postprandial state when they are directly stimulated by amino acids and/or gut-derived GIP, as also suggested by a recent study. 43 …”

Section: Discussionmentioning

confidence: 99%

The Human and Mouse Islet Peptidome: Effects of Obesity and Type 2 Diabetes, and Assessment of Intraislet Production of Glucagon-like Peptide-1

et al. 2021

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To characterize the impact of metabolic disease on the peptidome of human and mouse pancreatic islets, LC-MS was used to analyze extracts of human and mouse islets, purified mouse alpha, beta, and delta cells, supernatants from mouse islet incubations, and plasma from patients with type 2 diabetes. Islets were obtained from healthy and type 2 diabetic human donors, and mice on chow or high fat diet. All major islet hormones were detected in lysed islets as well as numerous peptides from vesicular proteins including granins and processing enzymes. Glucose-dependent insulinotropic peptide (GIP) was not detectable. High fat diet modestly increased islet content of proinsulin-derived peptides in mice. Human diabetic islets contained increased content of proglucagon-derived peptides at the expense of insulin, but no evident prohormone processing defects. Diabetic plasma, however, contained increased ratios of proinsulin and des-31,32-proinsulin to insulin. Active GLP-1 was detectable in human and mouse islets but 100–1000-fold less abundant than glucagon. LC-MS offers advantages over antibody-based approaches for identifying exact peptide sequences, and revealed a shift toward islet insulin production in high fat fed mice, and toward proglucagon production in type 2 diabetes, with no evidence of systematic defective prohormone processing.

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GIP mediates the incretin effect and glucose tolerance by dual actions on α cells and β cells

Cited by 89 publications

References 42 publications

SCO-267, a GPR40 Full Agonist, Stimulates Islet and Gut Hormone Secretion and Improves Glycemic Control in Humans

SCO-267, a GPR40 Full Agonist, Stimulates Islet and Gut Hormone Secretion and Improves Glycemic Control in Humans

β-Cell Knockout of SENP1 Reduces Responses to Incretins and Worsens Oral Glucose Tolerance in High-Fat Diet–Fed Mice

The Human and Mouse Islet Peptidome: Effects of Obesity and Type 2 Diabetes, and Assessment of Intraislet Production of Glucagon-like Peptide-1

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