The Physiology of Proinsulin C-Peptide: Unanswered Questions and a Proposed Model

Yosten, Gina L. C.; Kolar, Grant R.

doi:10.1152/physiol.00008.2015

Cited by 25 publications

(17 citation statements)

References 53 publications

(75 reference statements)

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“…C-peptide indicates insulin production since it is a by-product of the conversion of proinsulin to functional insulin. 23 Along with endocrine function, expression of transcription factor PDX1 could be seen. This transcription factor is central in β-cell function and survival.…”

Section: Discussionmentioning

confidence: 99%

Cold-perfusion decellularization of whole-organ porcine pancreas supports human fetal pancreatic cell attachment and expression of endocrine and exocrine markers

et al. 2017

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Despite progress in the field of decellularization and recellularization, the outcome for pancreas has not been adequate. This might be due to the challenging dual nature of pancreas with both endocrine and exocrine tissues. We aimed to develop a novel and efficient cold-perfusion method for decellularization of porcine pancreas and recellularize acellular scaffolds with human fetal pancreatic stem cells. Decellularization of whole porcine pancreas at 4°C with sodium deoxycholate, Triton X-100 and DNase efficiently removed cellular material, while preserving the extracellular matrix structure. Furthermore, recellularization of acellular pieces with human fetal pancreatic stem cells for 14 days showed attached and proliferating cells. Both endocrine (C-peptide and PDX1) and exocrine (glucagon and α-amylase) markers were expressed in recellularized tissues. Thus, cold-perfusion can successfully decellularize porcine pancreas, which when recellularized with human fetal pancreatic stem cells shows relevant endocrine and exocrine phenotypes. Decellularized pancreas is a promising biomaterial and might translate to clinical relevance for treatment of diabetes.

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Section: Discussionmentioning

confidence: 99%

Cold-perfusion decellularization of whole-organ porcine pancreas supports human fetal pancreatic cell attachment and expression of endocrine and exocrine markers

et al. 2017

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“…Over the course of the last two decades, proinsulin C‐peptide has gained recognition as a potential therapeutic target for the treatment of diabetes‐associated microvascular dysfunction . Although originally thought to be merely a byproduct of insulin prohormone processing, C‐peptide is now known to possess biological activities, particularly in the microvessels, and has been shown to exert anti‐inflammatory, anti‐oxidant and metabolic actions . Additionally, C‐peptide may act synergistically with insulin to maintain the vascular endothelium, although the mechanisms underlying this potential interaction have not been fully elucidated .…”

Section: C‐peptide and The Deductive Ligand–receptor Matching Strategymentioning

confidence: 99%

“…C‐peptide receptor ‘null’ cells) could complicate the isolation of the C‐peptide receptor(s). Likewise, because the actions of C‐peptide appear to be intimately linked with those of insulin , C‐peptide may exhibit cooperative binding with insulin, and thus, the efficient binding and purification of a C‐peptide receptor would require the presence of insulin. Therefore, isolation of the C‐peptide receptor based on its biochemical and binding properties may not be feasible.…”

Section: C‐peptide and The Deductive Ligand–receptor Matching Strategymentioning

confidence: 99%

“…First, using this strategy assumes that the receptor is a GPCR. Whilst multiple lines of evidence suggest C‐peptide interacts with a GPCR to exert its cellular effects , other types of membrane receptors, particularly integrins, which have been shown to activate G proteins in some instances , could mimic the effects of GPCRs. Secondly, our system excludes GPCRs with known ligands and focuses only on orphan GPCRs as potential candidates.…”

Section: C‐peptide and The Deductive Ligand–receptor Matching Strategymentioning

confidence: 99%

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Targeting orphan G protein‐coupled receptors for the treatment of diabetes and its complications: C‐peptide and GPR146

2016

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G protein-coupled receptors (GPCRs) are the most abundant receptor family encoded by the human genome and are the targets of a high percentage of drugs currently in use or in clinical trials for the treatment of diseases such as diabetes and its associated complications. Thus orphan GPCRs, for which the ligand is unknown, represent an important untapped source of therapeutic potential for the treatment of many diseases. We have identified the previously orphan GPCR, GPR146, as the putative receptor of proinsulin C-peptide, which may prove to be an effective treatment for diabetes-associated complications. For example, we have found a potential role of C-peptide and GPR146 in regulating the function of the retinal pigment epithelium, a monolayer of cells in the retina that serves as part of the blood–retinal barrier and is disrupted in diabetic macular edema. However, C-peptide signaling in this cell type appears to depend at least in part on extracellular glucose concentration and its interaction with insulin. In this review, we discuss the therapeutic potential of orphan GPCRs with a special focus on C-peptide and GPR146, including past and current strategies used to ‘deorphanize’ this diverse family of receptors, past successes, and the inherent difficulties of this process.

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“…C-peptide levels in the peripheral blood are widely accepted as the most appropriate evaluation of insulin secretion, and are not eliminated in the first-pass metabolism through the liver [ 4 , 5 ]. Previously considered to be an inactive by-product of insulin synthesis, C-peptide is a hormonally active peptide [ 5 , 6 ]. In type 1 diabetes, an Italian study with a large clinical cohort demonstrated a significant association between C-peptide and microvascular complications, including neuropathy [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

C-peptide is independent associated with diabetic peripheral neuropathy: a community-based study

Qiao

Zheng

Zhang

et al. 2017

Diabetol Metab Syndr

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BackgroundBecause the relationship between C-peptide and diabetic peripheral neuropathy (DPN) is controversial, the aim of our study was to evaluate the relationship between C-peptide and DPN in community-based Chinese patients with type 2 diabetes.MethodsIn total, 220 consecutive type 2 diabetic patients treated by our regional medical consortium were enrolled. DPN was assessed by clinical symptoms, signs, and electromyography.ResultsFasting C-peptide, 2-h postprandial C-peptide and ΔC-peptide (i.e., 2-h postprandial C-peptide minus the fasting C-peptide) serum concentrations in the non-DPN group were significantly higher than those in the clinical DPN group (all P ≤ 0.040) and the confirmed DPN group (all P < 0.002). The three C-peptide parameters were independently associated with DPN (all P < 0.05) after adjusting for age, sex, diabetes duration, smoking status, systolic pressure, body mass index, angiotensin-converting enzyme inhibitors/angiotensin receptor blocker use, fasting plasma glucose, HbA1c, triglyceride and estimated glomerular filtration rate. Compared with the ΔC-peptide quartile 1 (reference), patients in quartile 3 (odds ratio [OR], 0.110; 95% confidence interval [CI] 0.026–0.466; P = 0.003) and quartile 4 (OR, 0.012; 95% CI 0.026–0.559; P = 0.007) had a lower risk of DPN after adjusting for the confounders.ConclusionsC-peptide was negatively associated with DPN in community-based Chinese type 2 diabetic patients in China.

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The Physiology of Proinsulin C-Peptide: Unanswered Questions and a Proposed Model

Cited by 25 publications

References 53 publications

Cold-perfusion decellularization of whole-organ porcine pancreas supports human fetal pancreatic cell attachment and expression of endocrine and exocrine markers

Cold-perfusion decellularization of whole-organ porcine pancreas supports human fetal pancreatic cell attachment and expression of endocrine and exocrine markers

Targeting orphan G protein‐coupled receptors for the treatment of diabetes and its complications: C‐peptide and GPR146

C-peptide is independent associated with diabetic peripheral neuropathy: a community-based study

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