Role of Islet Glucokinase, Glucose Metabolism, and Insulin Pathway in the Enhancing Effect of Islet Neogenesis-Associated Protein on Glucose-Induced Insulin Secretion

Maiztegui, Bárbara; Román, Carolina; Barbosa-Sampaio, Helena Cristina; Boschero, Antônio Carlos; Gagliardino, Juan José

doi:10.1097/mpa.0000000000000341

Cited by 15 publications

(14 citation statements)

References 40 publications

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“…Moreover, PI3K signaling appears to regulate glucokinase activity, further underscoring the contributions of the PI3K pathway to metabolic homeostasis in a variety of tissue types (64). Specifically, p110γ is integral to the appropriate β cell insulin response to glucose (65).…”

Section: Discussionmentioning

confidence: 99%

p110γ deficiency protects against pancreatic carcinogenesis yet predisposes to diet-induced hepatotoxicity

Torres

Mancinelli

Córdoba-Chacón

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Pancreatic ductal adenocarcinoma (PDAC) is notorious for its poor survival and resistance to conventional therapies. PI3K signaling is implicated in both disease initiation and progression, and specific inhibitors of selected PI3K p110 isoforms for managing solid tumors are emerging. We demonstrate that increased activation of PI3K signals cooperates with oncogenic Kras to promote aggressive PDAC in vivo. The p110γ isoform is overexpressed in tumor tissue and promotes carcinogenesis via canonical AKT signaling. Its selective blockade sensitizes tumor cells to gemcitabine in vitro, and genetic ablation of p110γ protects against Kras-induced tumorigenesis. Diet/obesity was identified as a crucial means of p110 subunit up-regulation, and in the setting of a high-fat diet, p110γ ablation failed to protect against tumor development, showing increased activation of pAKT and hepatic damage. These observations suggest that a careful and judicious approach should be considered when targeting p110γ for therapy, particularly in obese patients.

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Section: Discussionmentioning

confidence: 99%

p110γ deficiency protects against pancreatic carcinogenesis yet predisposes to diet-induced hepatotoxicity

Torres

Mancinelli

Córdoba-Chacón

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…GK promotes glucose metabolism, which can induce insulin secretion. 25 GLUT2 can induce insulin secretion by promoting the glucose transportation from blood into islet B cell and the release of insulin from islet B cell into blood. 26 Our results indicated that FMN reversed the inhibitory effect of alloxan on insulin secretion (Figure 3(a)) by up-regulating the GK and GLUT2 mRNA and proteins levels in pancreas tissue of mice with alloxan-induced type 1 diabetes (Figures 4(c) and 5(c)).…”

Section: Discussionmentioning

confidence: 99%

Formononetin exhibits anti-hyperglycemic activity in alloxan-induced type 1 diabetic mice

Qiu

Tian

Mei

et al. 2016

Exp Biol Med (Maywood)

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The aim of this study was to investigate the anti-hyperglycemic activity and mechanism of formononetin in alloxan-induced type 1 diabetic mice by determining its effect on some diabetes-related indices as described below. Body weight, fasting blood glucose, hepatic glycogen, serum insulin, and serum glucagon were determined by electronic scales, glucometer, and ELISA kits. Fas, Caspase-3, pancreatic and duodenal homeobox-1 , insulin receptor substrate 2, glucokinase and glucose transporter 2, mRNA and proteins levels in pancreas tissue, and glucokinase and glucose-6-phosphatase mRNA, and proteins levels in liver tissue were detected by fluorogenic quantitative-polymerase chain reaction and Western blot assays. The results indicated that formononetin (5, 10, and 20 mg/kg; oral administration) reversed the alloxan-induced increase of some indices (fasting blood glucose level and Fas and Caspase-3 mRNA and proteins levels in pancreas tissue) and reduction of some indices (body weight gain, oral glucose tolerance, insulin activity, hepatic glycogen level, pancreatic and duodenal homeobox-1, insulin receptor substrate 2, glucokinase and glucose transporter 2, mRNA and proteins levels in pancreas tissue, and glucokinase mRNA and protein levels in liver tissue). The glucagon level and glucose-6-phosphatase mRNA and protein levels in liver tissue were not affected by the drugs administration. In conclusion, formononetin exhibited anti-hyperglycemic activity in alloxan-induced type 1 diabetic mice by inhibiting islet B cell apoptosis and promoting islet B cell regeneration, insulin secretion, hepatic glycogen synthesis, and hepatic glycolysis.

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“…Previous reports have shown that treating rat pancreatic islets with INGAP-PP in vitro induces the expression of genes directly related to the secretory function of b-cells (11)(12)(13)(14)(15). This treatment enhances insulin secretion in response to glucose, amino acids, KCl, and tolbutamide and increases calcium intracellular concentrations (15,16), which may be due to the activation of the PI3-K/AKT pathway (17). INGAP-PP treatment also leads to increased b-cell replication and neogenesis while decreasing its rate of apoptosis (11).…”

Section: Introductionmentioning

confidence: 94%

Transcriptional signature of islet neogenesis-associated protein peptide-treated rat pancreatic islets reveals induction of novel long non-coding RNAs

Romero,

Heidenreich,

Román

et al. 2023

Front. Endocrinol.

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BackgroundDiabetes mellitus is characterized by chronic hyperglycemia with loss of β-cell function and mass. An attractive therapeutic approach to treat patients with diabetes in a non-invasive way is to harness the innate regenerative potential of the pancreas. The Islet Neogenesis-Associated Protein pentadecapeptide (INGAP-PP) has been shown to induce β-cell regeneration and improve their function in rodents. To investigate its possible mechanism of action, we report here the global transcriptional effects induced by the short-term INGAP-PP in vitro treatment of adult rat pancreatic islets.Methods and findingsRat pancreatic islets were cultured in vitro in the presence of INGAP-PP for 4 days, and RNA-seq was generated from triplicate treated and control islet samples. We performed a de novo rat gene annotation based on the alignment of RNA-seq reads. The list of INGAP-PP-regulated genes was integrated with epigenomic data. Using the new gene annotation generated in this work, we quantified RNA-seq data profiled in INS-1 cells treated with IL1β, IL1β+Calcipotriol (a vitamin D agonist) or vehicle, and single-cell RNA-seq data profiled in rat pancreatic islets. We found 1,669 differentially expressed genes by INGAP-PP treatment, including dozens of previously unannotated rat transcripts. Genes differentially expressed by the INGAP-PP treatment included a subset of upregulated transcripts that are associated with vitamin D receptor activation. Supported by epigenomic and single-cell RNA-seq data, we identified 9 previously unannotated long noncoding RNAs (lncRNAs) upregulated by INGAP-PP, some of which are also differentially regulated by IL1β and vitamin D in β-cells. These include Ri-lnc1, which is enriched in mature β-cells.ConclusionsOur results reveal the transcriptional program that could explain the enhancement of INGAP-PP-mediated physiological effects on β-cell mass and function. We identified novel lncRNAs that are induced by INGAP-PP in rat islets, some of which are selectively expressed in pancreatic β-cells and downregulated by IL1β treatment of INS-1 cells. Our results suggest a relevant function for Ri-lnc1 in β-cells. These findings are expected to provide the basis for a deeper understanding of islet translational results from rodents to humans, with the ultimate goal of designing new therapies for people with diabetes.

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Role of Islet Glucokinase, Glucose Metabolism, and Insulin Pathway in the Enhancing Effect of Islet Neogenesis-Associated Protein on Glucose-Induced Insulin Secretion

Cited by 15 publications

References 40 publications

p110γ deficiency protects against pancreatic carcinogenesis yet predisposes to diet-induced hepatotoxicity

p110γ deficiency protects against pancreatic carcinogenesis yet predisposes to diet-induced hepatotoxicity

Formononetin exhibits anti-hyperglycemic activity in alloxan-induced type 1 diabetic mice

Transcriptional signature of islet neogenesis-associated protein peptide-treated rat pancreatic islets reveals induction of novel long non-coding RNAs

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