The role of GIP and pancreatic GLP-1 in the glucoregulatory effect of DPP-4 inhibition in mice

Hutch, Chelsea R.; Roelofs, Karen J.; Haller, April; Sorrell, Joyce; Leix, Kyle; D’Alessio, David; Augustin, Robert; Seeley, Randy J.; Klein, Thomas; Sandoval, Darleen A.

doi:10.1007/s00125-019-4963-5

Cited by 15 publications

(21 citation statements)

References 34 publications

(58 reference statements)

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“…Several studies have demonstrated that GLP-1 alleviated learning and memory dysfunction [30] and that a GLP-1 analogue and GIP analogue prevented memory impairments [31,32]. Additionally, it has been reported that GLP-1 and GIP inhibit microglial activation [32,33] and that linagliptin increased plasma active GLP-1 and GIP levels [12,34]. In the present study, we showed that linagliptin decreased the cell number and body area of microglia in the diabetic brain.…”

Section: Effect Of Linagliptin On Microglial Activity and Mrna Expressupporting

confidence: 66%

The dipeptidyl peptidase-4 inhibitor, linagliptin, improves cognitive impairment in streptozotocin-induced diabetic mice by inhibiting oxidative stress and microglial activation

et al. 2020

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ObjectiveAccumulating epidemiological studies have demonstrated that diabetes is an important risk factor for dementia. However, the underlying pathological and molecular mechanisms, and effective treatment, have not been fully elucidated. Herein, we investigated the effect of the dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, on diabetes-related cognitive impairment. MethodStreptozotocin (STZ)-induced diabetic mice were treated with linagliptin (3 mg/kg/24 h) for 17 weeks. The radial arm water maze test was performed, followed by evaluation of oxidative stress using DNP-MRI and the expression of NAD(P)H oxidase components and proinflammatory cytokines and of microglial activity.

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Section: Effect Of Linagliptin On Microglial Activity and Mrna Expressupporting

confidence: 66%

The dipeptidyl peptidase-4 inhibitor, linagliptin, improves cognitive impairment in streptozotocin-induced diabetic mice by inhibiting oxidative stress and microglial activation

et al. 2020

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“…We have previously shown that overexpressing CCK in mouse β-cells does not change exocrine pancreas histology, nor systemic circulation of CCK peptide, suggesting that islet-derived hormone likely does not contribute significantly to systemic levels 46 . Similarly, recent studies showed that pancreatic GLP-1 does not necessarily change systemic GLP-1 circulating levels in mice 10,50,51 . These findings enhance our understanding on the biology of incretins and may open new possibilities for therapeutic innervations, including directed therapies to activate local pathways and avoid systemic side effects.…”

Section: Discussionmentioning

confidence: 87%

Intra-islet GLP-1, but not CCK, is necessary for β-cell function in mouse and human islets

Souza

Tang

Yadev

et al. 2020

Sci Rep

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Glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK) are gut-derived peptide hormones known to play important roles in the regulation of gastrointestinal motility and secretion, appetite, and food intake. We have previously demonstrated that both GLP-1 and CCK are produced in the endocrine pancreas of obese mice. Interestingly, while GLP-1 is well known to stimulate insulin secretion by the pancreatic β-cells, direct evidence of CCK promoting insulin release in human islets remains to be determined. Here, we tested whether islet-derived GLP-1 or CCK is necessary for the full stimulation of insulin secretion. We confirm that mouse pancreatic islets secrete GLP-1 and CCK, but only GLP-1 acts locally within the islet to promote insulin release ex vivo. GLP-1 is exclusively produced in approximately 50% of α-cells in lean mouse islets and 70% of α-cells in human islets, suggesting a paracrine α to β-cell signaling through the β-cell GLP-1 receptor. Additionally, we provide evidence that islet CCK expression is regulated by glucose, but its receptor signaling is not required during glucose-stimulated insulin secretion (GSIS). We also see no increase in GSIS in response to CCK peptides. Importantly, all these findings were confirmed in islets from non-diabetic human donors. In summary, our data suggest no direct role for CCK in stimulating insulin secretion and highlight the critical role of intra-islet GLP-1 signaling in the regulation of human β-cell function.The precise control of blood glucose is dependent on the islets of Langerhans located within the pancreas. Pancreatic islets are complex structures consisting of several types of cells, including insulin-producing β-cells, glucagon-producing α-cells, and somatostatin-producing α-cells. After feeding, nutrients stimulate insulin release by the β-cell and the circulating hormone acts on peripheral tissues lowering blood glucose. The full stimulation of insulin secretion after food intake depends on the incretin effect of gut-derived peptide hormones and paracrine signaling within the islet 1 .We and others discovered that two classic gut hormones, glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK), are also produced by pancreatic islets 2-5 . GLP-1 is a peptide hormone mainly secreted by intestinal L-cells and is known to decrease blood glucose levels by enhancing β-cell insulin secretion 6 . CCK is a peptide hormone mainly secreted by intestinal I-cells and is involved in the digestion of nutrients 7 and regulation of food intake 8 . The production of both GLP-1 and CCK in the islet has been associated with β-cell expansion and survival in response to metabolic stress 5,9 . While each of these gut-derived hormones can contribute to improvements in glucose homeostasis 10,11 , it is unclear whether their local production in the islet contributes to β-cell function. Moreover, it is unknown whether CCK stimulates insulin release in human islets. Here, we describe experiments with GLP-1 and CCK receptor antagonists in isolated mouse and human islets to ass...

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“…4c,d) but unaffected by blockage of Y2R (by JNJ-31020028) (Fig. 4e,f), Y1R (BIBO3304) [27] or GLP1R (antagonistic antibody, GLP1R0017) ( Fig. 4g-j).…”

Section: Resultsmentioning

confidence: 95%

Selective stimulation of colonic L cells improves metabolic outcomes in mice

et al. 2020

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Aims/hypothesis Insulin-like peptide-5 (INSL5) is found only in distal colonic L cells, which co-express glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). GLP-1 is a well-known insulin secretagogue, and GLP-1 and PYY are anorexigenic, whereas INSL5 is considered orexigenic. We aimed to clarify the metabolic impact of selective stimulation of distal colonic L cells in mice. Methods Insl5 promoter-driven expression of Gq-coupled Designer Receptor Exclusively Activated by Designer Drugs (DREADD) was employed to activate distal colonic L cells (L distalDq). IPGTT and food intake were assessed with and without DREADD activation. Results L distalDq cell stimulation with clozapine N-oxide (CNO; 0.3 mg/kg i.p.) increased plasma GLP-1 and PYY (2.67-and 3.31-fold, respectively); INSL5 was not measurable in plasma but was co-secreted with GLP-1 and PYY in vitro. IPGTT (2 g/kg body weight) revealed significantly improved glucose tolerance following CNO injection. CNO-treated mice also exhibited reduced food intake and body weight after 24 h, and increased defecation, the latter being sensitive to 5-hydroxytryptamine (5-HT) receptor 3 inhibition. Pre-treatment with a GLP1 receptor-blocking antibody neutralised the CNO-dependent improvement in glucose tolerance but did not affect the reduction in food intake, and an independent group of animals pair-fed to the CNOtreatment group demonstrated attenuated weight loss. Pre-treatment with JNJ-31020028, a neuropeptide Y receptor type 2 antagonist, abolished the CNO-dependent effect on food intake. Assessment of whole body physiology in metabolic cages revealed L distalDq cell stimulation increased energy expenditure and increased activity. Acute CNO-induced food intake and glucose homeostasis outcomes were maintained after 2 weeks on a high-fat diet. Conclusions/interpretation This proof-of-concept study demonstrates that selective distal colonic L cell stimulation has beneficial metabolic outcomes.

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The role of GIP and pancreatic GLP-1 in the glucoregulatory effect of DPP-4 inhibition in mice

Cited by 15 publications

References 34 publications

The dipeptidyl peptidase-4 inhibitor, linagliptin, improves cognitive impairment in streptozotocin-induced diabetic mice by inhibiting oxidative stress and microglial activation

The dipeptidyl peptidase-4 inhibitor, linagliptin, improves cognitive impairment in streptozotocin-induced diabetic mice by inhibiting oxidative stress and microglial activation

Intra-islet GLP-1, but not CCK, is necessary for β-cell function in mouse and human islets

Selective stimulation of colonic L cells improves metabolic outcomes in mice

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