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Pharmacological and Surgical Interventions to Improve Brain Insulin Resistance
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Linus Haberbosch, Lukas Maurer, Reiner Jumpertz-von Schwartzenberg
Especially, the successful application of GLP-1-RA to modulate peripheral insulin secretion and action in patients with type 2 diabetes has attracted great attention within this context (3). GLP-1-RA increases glucose-dependent insulin secretion (incretin effect) of the beta cells. This effect is dependent on adenylate cyclase (ADCY) turn-over of ATP to cAMP which can activate exchange protein activated by cAMP (EPAC) leading to increased insulin granule exocytosis. Besides EPAC activation, insulin secretion can also be mediated by a protein kinase A-dependent pathway (Figure 13.1). However, GLP-1 agonism not only triggers insulin secretion but also induces insulin gene transcription and biosynthesis to replenish insulin stores of the beta cells. Insulin gene transcription and its biosynthesis are mediated by protein kinase A (PKA) dependent and independent signaling cascades, both stimulating the insulin transcription factor PDX-1 (Figure 13.1). The PKA-independent pathway of PDX-1 activation is mediated via phosphoinositide 3-kinase (PI-3K) and insulin receptor substrate 2 (IRS-2) activation (Figure 13.1).
Islet Transplantation in Type 1 Diabetes: Stem Cell Research and Therapy
Published in Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Medicinal Chemistry with Pharmaceutical Product Development, 2019
DE then forms a primitive gut tube (GT) along which various endoderm organ domains are specified and directed [32]. Pancreas develops from the posterior foregut, emerging as buds from dorsal and ventral sides of the gut tube. At this early stage pancreatic development depends on retinoid signaling and inhibition of hedgehog signaling [33, 34]. The developing pancreas at this stage consists of epithelial progenitors that express Pdx1 (IPF1) and give rise to endocrine, exocrine and ductal cells of the pancreas. Moreover, this epithelium also expresses transcription factor genes such as Hlxb9, Hnf6, Ptf1a, and Nkx6-1. These transcription factors together with Pdx1 encode proteins that contribute to pancreatic development [35]. After initial bud formation, the epithelium grows, proliferates and differentiates in response to signals emanating from adjacent mesenchyme such as mesenchymal Fgf10 [36]. In addition to transcription factors, several growth factors regulate the process of gastrulation. For example, in mice Nodal, a member of transforming growth factor (TGF)-β super family, which, in turn, regulates the Wnt, fibroblast growth factor (FGF) and bone morphogenetic protein-4 (BMP-4) pathways that is important for development of anterior and posterior axes during gastrulation [31, 37].
Congenital Anomalies of the Pancreas
Published in John F. Pohl, Christopher Jolley, Daniel Gelfond, Pediatric Gastroenterology, 2014
Kathy D. Chen, Sohail Z. Husain
Both pancreatic agenesis and hypoplasia (OMIM #260370) are rare findings which are described in case reports and have been described alone or in association with other congenital abnormalities. The syndrome results from a more global defect in pancreatic development. Some cases are linked to homozygous or compound heterozygous mutations in the pancreatic and duodenal homeobox (PDX1) gene, also known as insulin promoter factor-1. Patients have both exocrine and endocrine deficiencies. Infants present with neonatal insulin-dependent diabetes mellitus, intrauterine growth retardation, subsequent failure to thrive from pancreatic insufficiency, and they require pancreatic enzyme replacement therapy. Imaging with ultrasound or CT scan can reveal absence of pancreatic tissue.
Islet hypoplasia of adult offspring rats caused by intrauterine chronic hypoxia is compensated by up-regulation of INS and PDX-1
Published in Islets, 2023
Tianfeng Chen, Yang Xiao, Shaodan Xu, Helin Ke, Shilin Li
However, increased expression of INS and PDX-1 genes was also observed in the ICH group, suggesting that there may be a “negative feedback” process as a compensatory mechanism for β-cell dysfunction in the body due to the changes in the metabolic environment. PDX-1 is one of the most important regulatory factors related to β-cell development, regeneration, differentiation, and other functions.18 In mature β-cells, PDX-1 can activate INS genes and positively promote the secretion of related factors involved in glucose metabolism, such as GLUT2 protein.29 They can promote insulin secretion together. Besides, in vitro experiments revealed that PDX-1 allows adipose-derived mesenchymal stem cells to differentiate into insulin-secreting cells, with great potential for islet β-cell secretion and regenerative capacity.30
Jiedutongluotiaogan formula restores pancreatic function by suppressing excessive autophagy and endoplasmic reticulum stress
Published in Pharmaceutical Biology, 2022
Jinli Luo, Wenqi Jin, Meiying Jin, Weiwei Pan, Shengnan Gao, Xiaohua Zhao, Xingrong Lai, Liwei Sun, Chunli Piao
Then, we investigated the effects of JTTF on insulin secretion by injured INS-1 cells by using an ELISA kit. LPS exposure reduced INS-1 cell insulin content, while JTTF treatment exerted a potent insulinotropic effect on INS-1 cells (Figure 6(a)). The level of insulin secretion by INS-1 cells after treatment with JTTF at all tested concentrations was increased as compared to that of the LPS-only group, with the greatest effect observed for 200 µg/mL JTTF (Figure 6(b)). PDX1, a homeodomain transcription factor, is required for early embryonic development of the pancreas (Stoffers et al. 1997). In mature beta-cells, depletion and reduction of PDX1 induces glucose intolerance as evidence for a critical role of PDX1 for maintaining beta-cell function (Holland et al. 2002). Our preliminary results showed that JTTF treatment could restore PDX1 expression levels (Figure 6(c)). The expression of mRNA of PDX1, MafA, INS1 and INS2 were upregulated in all four groups (Figure 6(d–g)).
Cross talk between exosomes and pancreatic β-cells in diabetes
Published in Archives of Physiology and Biochemistry, 2022
The main function of the β-cells is the regulation of glucose metabolism, which is essential for coupling glucose sensing to insulin release, and glucose-stimulated insulin secretion (GSIS) is the best functional characteristic of mature β-cells (Salinno et al.2019) (Figure 2). After glucose enters β-cells through glucose transporters, it is quickly phosphorylated into glucose-6-phosphate (G6P) by glucokinase (GK) (Christensen and Gannon 2019). G6P is then metabolised through glycolysis to generate pyruvate, nicotinamide adenine dinucleotide, and adenosine triphosphate (ATP). Pyruvate, which subsequently enters the mitochondria, goes through the citric acid cycle and the electron transport chain to produce ATP with reactive oxygen species (ROS) as byproducts (Maechler 2013). The increase in the ATP/ADP ratio in the cell induces the closure of the KATP channels, leading to membrane depolarisation, and triggers the action potential that opens the voltage-gated Ca2+ channels. Finally, the influx of Ca2+ induces insulin secretion (Prentki and Nolan 2006). It should be noted that the expression of GK and the glucose transporter 2 (GLUT2) is strongly and positively related to the state of differentiation of β-cells, and both are under regulatory control of duodenal homeobox protein 1 (PDX1) (Lebrun et al.2005). Accordingly, PDX1 plays a key role both in promoting β-cell growth and enhancing β-cell function (Prentki and Nolan 2006).