scholarly journals Requirement for TRanslocon-Associated Protein (TRAP) α in insulin biogenesis

2019 ◽  
Author(s):  
Xin Li ◽  
Omar A. Itani ◽  
Leena Haataja ◽  
Kathleen J. Dumas ◽  
Jing Yang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Beta Cells ◽  
Signal Sequence ◽  
Pancreatic Beta Cell ◽  
Critical Role ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
C Elegans ◽  
Mechanistic Basis

The mechanistic basis for the biogenesis of peptide hormones and growth factors is poorly understood. Here we show that the conserved endoplasmic reticulum (ER) membrane translocon-associated protein (TRAP) α, also known as signal sequence receptor 1 (SSR1)1, plays a critical role in the biosynthesis of insulin. A genetic screen in the nematode Caenorhabditis elegans revealed trap-1, which encodes the C. elegans TRAPα ortholog, as a modifier of DAF-2 insulin receptor (InsR) signaling. Genetic analysis indicates that TRAP-1 acts upstream of DAF-2/InsR to control C. elegans development. Endogenous C. elegans TRAP-1 and mammalian TRAPα both localized to the ER. In pancreatic beta cells, TRAPα deletion impaired preproinsulin translocation but did not affect the synthesis of α1-antitrypsin, indicating that TRAPα selectively influences the translocation of a subset of secreted proteins. Surprisingly, loss of TRAPα function also resulted in disruption of distal steps in insulin biogenesis including proinsulin processing and secretion. These results show that TRAPα assists in the ER translocation of preproinsulin and unveil unanticipated additional consequences of TRAPα loss-of-function on the intracellular trafficking and maturation of proinsulin. The association of common intronic single nucleotide variants in the human TRAPα gene with susceptibility to Type 2 diabetes and pancreatic beta cell dysfunction2 suggests that impairment of preproinsulin translocation and proinsulin trafficking may contribute to the pathogenesis of Type 2 diabetes.

scholarly journals Requirement for translocon-associated protein (TRAP) α in insulin biogenesis

2019 ◽  
Vol 5 (12) ◽  
pp. eaax0292 ◽  
Author(s):  
Xin Li ◽  
Omar A. Itani ◽  
Leena Haataja ◽  
Kathleen J. Dumas ◽  
Jing Yang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Signal Sequence ◽  
Critical Role ◽  
Endoplasmic Reticulum Membrane ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Cell Dysfunction ◽  
Proinsulin Processing ◽  
Mechanistic Basis

The mechanistic basis for the biogenesis of peptide hormones and growth factors is poorly understood. Here, we show that the conserved endoplasmic reticulum membrane translocon-associated protein α (TRAPα), also known as signal sequence receptor 1, plays a critical role in the biosynthesis of insulin. Genetic analysis in the nematode Caenorhabditis elegans and biochemical studies in pancreatic β cells reveal that TRAPα deletion impairs preproinsulin translocation while unexpectedly disrupting distal steps in insulin biogenesis including proinsulin processing and secretion. The association of common intronic single-nucleotide variants in the human TRAPα gene with susceptibility to type 2 diabetes and pancreatic β cell dysfunction suggests that impairment of preproinsulin translocation and proinsulin trafficking may contribute to the pathogenesis of type 2 diabetes.

scholarly journals Syzygium aqueum (Burm.f.) Alston Prevents Streptozotocin-Induced Pancreatic Beta Cells Damage via the TLR-4 Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Mona F. Mahmoud ◽  
Shimaa Abdelaal ◽  
Heba Osama Mohammed ◽  
Assem M. El-Shazly ◽  
Rachid Daoud ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Signaling Pathway ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Pancreatic Beta Cell ◽  
Herbal Remedies ◽  
Standard Drug

Although several treatments are available for the treatment of type 2 diabetes mellitus, adverse effects and cost burden impose the search for safe, efficient, and cost-effective alternative herbal remedies. Syzygium aqueum (Burm.f.) Alston, a natural anti-inflammatory, antioxidant herb, may suppress diabetes-associated inflammation and pancreatic beta-cell death. Here, we tested the ability of the bioactive leaf extract (SA) to prevent streptozotocin (STZ)-induced oxidative stress and inflammation in pancreatic beta cells in rats and the involvement of the TLR-4 signaling pathway. Non-fasted rats pretreated with 100 or 200 mg kg−1 SA 2 days prior to the STZ challenge and for 14 days later had up to 52 and 39% reduction in the glucose levels, respectively, while glibenclamide, the reference standard drug (0.5 mg kg−1), results in 70% reduction. Treatment with SA extract was accompanied by increased insulin secretion, restoration of Langerhans islets morphology, and decreased collagen deposition as demonstrated from ELISA measurement, H and E, and Mallory staining. Both glibenclamide and SA extract significantly decreased levels of TLR-4, MYD88, pro-inflammatory cytokines TNF-α, and TRAF-6 in pancreatic tissue homogenates, which correlated well with minimal pancreatic inflammatory cell infiltration. Pre-treatment with SA or glibenclamide decreased malondialdehyde, a sensitive biomarker of ROS-induced lipid peroxidation, and restored depleted reduced glutathione in the pancreas. Altogether, these data indicate that S. aqueum is effective in improving STZ-induced pancreatic damage, which could be beneficial in treating type 2 diabetes mellitus.

970-P: Comparative Assessment of the Effect of Vildagliptin and Metformin on Pancreatic Beta-Cell Function and Insulin Sensitivity in Newly Diagnosed Asian Indians with Type 2 Diabetes

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 970-P
Author(s):  
KRISHNAMOORTHY SATHEESH ◽  
CHAMUKUTTAN SNEHALATHA ◽  
ARUN NANDITHA ◽  
ARUN RAGHAVAN ◽  
RAMACHANDRAN VINITHA ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Beta Cell Function ◽  
Asian Indians ◽  
Cell Function ◽  
Pancreatic Beta Cell ◽  
Comparative Assessment ◽  
Newly Diagnosed ◽  
Pancreatic Beta Cell Function

Hyperglycemia causes oxidative stress in pancreatic beta-cells of GK rats, a model of type 2 diabetes

Diabetes ◽  
1999 ◽  
Vol 48 (4) ◽  
pp. 927-932 ◽  
Author(s):  
Y. Ihara ◽  
S. Toyokuni ◽  
K. Uchida ◽  
H. Odaka ◽  
T. Tanaka ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Gk Rats

scholarly journals MicroRNAs and Oxidative Stress: An Intriguing Crosstalk to Be Exploited in the Management of Type 2 Diabetes

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 802
Author(s):  
Teresa Vezza ◽  
Aranzazu M. de Marañón ◽  
Francisco Canet ◽  
Pedro Díaz-Pozo ◽  
Miguel Marti ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Signaling Pathways ◽  
Current Knowledge ◽  
Critical Role ◽  
Cell Dysfunction ◽  
Non Coding Rnas ◽  
And Oxidative Stress ◽  
Molecular Crosstalk

Type 2 diabetes is a chronic disease widespread throughout the world, with significant human, social, and economic costs. Its multifactorial etiology leads to persistent hyperglycemia, impaired carbohydrate and fat metabolism, chronic inflammation, and defects in insulin secretion or insulin action, or both. Emerging evidence reveals that oxidative stress has a critical role in the development of type 2 diabetes. Overproduction of reactive oxygen species can promote an imbalance between the production and neutralization of antioxidant defence systems, thus favoring lipid accumulation, cellular stress, and the activation of cytosolic signaling pathways, and inducing β-cell dysfunction, insulin resistance, and tissue inflammation. Over the last few years, microRNAs (miRNAs) have attracted growing attention as important mediators of diverse aspects of oxidative stress. These small endogenous non-coding RNAs of 19–24 nucleotides act as negative regulators of gene expression, including the modulation of redox signaling pathways. The present review aims to provide an overview of the current knowledge concerning the molecular crosstalk that takes place between oxidative stress and microRNAs in the physiopathology of type 2 diabetes, with a special emphasis on its potential as a therapeutic target.

scholarly journals A Common Functional Regulatory Variant at a Type 2 Diabetes Locus Upregulates ARAP1 Expression in the Pancreatic Beta Cell

2014 ◽  
Vol 94 (2) ◽  
pp. 186-197 ◽  
Author(s):  
Jennifer R. Kulzer ◽  
Michael L. Stitzel ◽  
Mario A. Morken ◽  
Jeroen R. Huyghe ◽  
Christian Fuchsberger ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Pancreatic Beta Cell ◽  
Regulatory Variant

scholarly journals A role for pancreatic beta-cell secretory hyperresponsiveness in catch-up growth hyperinsulinemia: Relevance to thrifty catch-up fat phenotype and risks for type 2 diabetes

2011 ◽  
Vol 8 (1) ◽  
pp. 2 ◽  
Author(s):  
Marina Casimir ◽  
Paula B de Andrade ◽  
Asllan Gjinovci ◽  
Jean-Pierre Montani ◽  
Pierre Maechler ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Pancreatic Beta Cell ◽  
Catch Up

scholarly journals Pancreatic beta-cell granule peptides form heteromolecular complexes which inhibit islet amyloid polypeptide fibril formation

2004 ◽  
Vol 377 (3) ◽  
pp. 709-716 ◽  
Author(s):  
Emma T. A. S. JAIKARAN ◽  
Melanie R. NILSSON ◽  
Anne CLARK
Keyword(s):  
Type 2 Diabetes ◽  
Amyloid Fibrils ◽  
Secretory Granules ◽  
Pancreatic Beta Cell ◽  
Islet Amyloid Polypeptide ◽  
Fibril Formation ◽  
Islet Amyloid ◽  
Β Sheet

Islet amyloid polypeptide (IAPP), or ‘amylin’, is co-stored with insulin in secretory granules of pancreatic islet β-cells. In Type 2 diabetes, IAPP converts into a β-sheet conformation and oligomerizes to form amyloid fibrils and islet deposits. Granule components, including insulin, inhibit spontaneous IAPP fibril formation in vitro. To determine the mechanism of this inhibition, molecular interactions of insulin with human IAPP (hIAPP), rat IAPP (rIAPP) and other peptides were examined using surface plasmon resonance (BIAcore), CD and transmission electron microscopy (EM). hIAPP and rIAPP complexed with insulin, and this reaction was concentration-dependent. rIAPP and insulin, but not pro-insulin, bound to hIAPP. Insulin with a truncated B-chain, to prevent dimerization, also bound hIAPP. In the presence of insulin, hIAPP did not spontaneously develop β-sheet secondary structure or form fibrils. Insulin interacted with pre-formed IAPP fibrils in a regular repeating pattern, as demonstrated by immunoEM, suggesting that the binding sites for insulin remain exposed in hIAPP fibrils. Since rIAPP and hIAPP form complexes with insulin (and each other), this could explain the lack of amyloid fibrils in transgenic mice expressing hIAPP. It is likely that IAPP fibrillogenesis is inhibited in secretory granules (where the hIAPP concentration is in the millimolar range) by heteromolecular complex formation with insulin. Alterations in the proportions of insulin and IAPP in granules could disrupt the stability of the peptide. The increase in the proportion of unprocessed pro-insulin produced in Type 2 diabetes could be a major factor in destabilization of hIAPP and induction of fibril formation.

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