| 1. |
- Bravo, Carolina, et al.
(författare)
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Leptin/Adiponectin Ratios Using Either Total Or High-Molecular-Weight Adiponectin as Biomarkers of Systemic Insulin Sensitivity in Normoglycemic Women
- 2017
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Ingår i: Journal of Diabetes Research. - : Hindawi Limited. - 2314-6753 .- 2314-6745. ; , s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- Plasma leptin/adiponectin ratio (LAR) is negatively associated with insulin sensitivity indexes. High-molecular-weight adiponectin (HMWA) was proposed as the most biologically active form of this insulin-sensitizing adipokine. There are no studies assessing the relative merits of leptin/HMWA ratio over LAR as a biomarker of systemic insulin sensitivity. A standard 2-hour oral glucose tolerance test (OGTT; 75 g of glucose) and a short minimal-model intravenous glucose tolerance test (IVGTT; 0.3 g/kg body weight) were performed in 58 Chilean normoglycemic women (age: 27 ± 6.3 years, BMI 23.6 ± 3.2 kg/m2). LAR was negatively associated with HOMA-S (; ), Matsuda-ISICOMP (; ), and the calculated sensitivity index (CSi) derived from IVGTT (; ). In comparison to LAR, leptin/HMWA ratio did not increase neither the linear fit () nor the magnitude of association with insulin sensitivity indexes (slope of multiple linear regression). The discriminatory capacity of both ratios to classify insulin-resistant versus insulin-sensitive subjects was similar for HOMA-S (), Matsuda-ISICOMP (), or CSi (). In conclusion, LAR showed consistent negative associations with different systemic insulin sensitivity indexes. The use of HMWA to generate leptin/HMWA ratio did not show any advantage over LAR as a biomarker of systemic insulin sensitivity in normoglycemic women
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| 2. |
- Bacos, Karl, et al.
(författare)
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Type 2 diabetes candidate genes, including PAX5, cause impaired insulin secretion in human pancreatic islets
- 2023
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Ingår i: The Journal of clinical investigation. - 0021-9738 .- 1558-8238. ; 133:4
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes (T2D) is caused by insufficient insulin secretion from pancreatic β-cells. To identify candidates contributing to T2D pathophysiology, we studied human pancreatic islets from ~300 individuals. We found 395 differentially expressed genes (DEGs) in islets from individuals with T2D, including, to our knowledge, novel (OPRD1, PAX5, TET1) and previously identified (CHL1, GLRA1, IAPP) candidates. A third of the identified islet expression changes may predispose to diabetes, as they associated with HbA1c in individuals not previously diagnosed with T2D. Most DEGs were expressed in human β-cells based on single-cell RNA-sequencing data. Additionally, DEGs displayed alterations in open chromatin and associated with T2D-SNPs. Mouse knock-out strains demonstrated that T2D-associated candidates regulate glucose homeostasis and body composition in vivo. Functional validation showed that mimicking T2D-associated changes for OPRD1, PAX5, and SLC2A2 impaired insulin secretion. Impairments in Pax5-overexpressing β-cells were due to severe mitochondrial dysfunction. Finally, we discovered PAX5 as a potential transcriptional regulator of many T2D-associated DEGs in human islets. Overall, we identified molecular alterations in human pancreatic islets contributing to β-cell dysfunction in T2D pathophysiology.
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| 3. |
- Cataldo Bascuñan, Luis Rodrigo, et al.
(författare)
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Serotonergic Regulation of Insulin Secretion
- 2019
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Ingår i: Acta Physiologica. - : Wiley. - 1748-1716 .- 1748-1708. ; 225:1
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Forskningsöversikt (refereegranskat)abstract
- The exact physiological role for the monoamine serotonin (5-HT) in modulation of insulin secretion is yet to be fully understood. Although the presence of this monoamine in islets of Langerhans is well established, it is only with recent advances that the complex signaling network in islets involving 5-HT is being unraveled. With more than fourteen different 5-HT receptors expressed in human islets, and receptor independent mechanisms in insulin producing β-cells, our understanding of 5-HT's regulation of insulin secretion is increasing. It is now widely accepted that failure of the pancreatic β-cell to release sufficient amounts of insulin is the main cause of Type 2 Diabetes (T2D), an ongoing global epidemic. In this context, 5-HT signaling may be of importance. In fact, 5-HT may serve an essential role in regulating the release of insulin and glucagon, the two main hormones that control glucose and lipid homeostasis. In the present review, we will discuss past and current understanding of 5-HT's role in the endocrine pancreas. This article is protected by copyright. All rights reserved.
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| 4. |
- Cataldo, Luis Rodrigo, et al.
(författare)
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The human batokine EPDR1 regulates β-cell metabolism and function
- 2022
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Ingår i: Molecular Metabolism. - : Elsevier BV. - 2212-8778. ; 66
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Ependymin-Related Protein 1 (EPDR1) was recently identified as a secreted human batokine regulating mitochondrial respiration linked to thermogenesis in brown fat. Despite that EPDR1 is expressed in human pancreatic β-cells and that glucose-stimulated mitochondrial metabolism is critical for stimulus-secretion coupling in β-cells, the role of EPDR1 in β-cell metabolism and function has not been investigated. Methods: EPDR1 mRNA levels in human pancreatic islets from non-diabetic (ND) and type 2 diabetes (T2D) subjects were assessed. Human islets, EndoC-βH1 and INS1 832/13 cells were transfected with scramble (control) and EPDR1 siRNAs (EPDR1-KD) or treated with human EPDR1 protein, and glucose-stimulated insulin secretion (GSIS) assessed by ELISA. Mitochondrial metabolism was investigated by extracellular flux analyzer, confocal microscopy and mass spectrometry-based metabolomics analysis. Results: EPDR1 mRNA expression was upregulated in human islets from T2D and obese donors and positively correlated to BMI of donors. In T2D donors, EPDR1 mRNA levels negatively correlated with HbA1c and positively correlated with GSIS. EPDR1 silencing in human islets and β-cell lines reduced GSIS whereas treatment with human EPDR1 protein increased GSIS. Epdr1 silencing in INS1 832/13 cells reduced glucose- and pyruvate- but not K+-stimulated insulin secretion. Metabolomics analysis in Epdr1-KD INS1 832/13 cells suggests diversion of glucose-derived pyruvate to lactate production and decreased malate-aspartate shuttle and the tricarboxylic acid (TCA) cycle activity. The glucose-stimulated rise in mitochondrial respiration and ATP/ADP-ratio was impaired in Epdr1-deficient cells. Conclusion: These results suggests that to maintain glucose homeostasis in obese people, upregulation of EPDR1 may improve β-cell function via channelling glycolysis-derived pyruvate to the mitochondrial TCA cycle.
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| 5. |
- Cataldo, Luis Rodrigo, et al.
(författare)
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The MafA-target gene PPP1R1A regulates GLP1R-mediated amplification of glucose-stimulated insulin secretion in β-cells
- 2021
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Ingår i: Metabolism: Clinical and Experimental. - : Elsevier BV. - 1532-8600.
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Tidskriftsartikel (refereegranskat)abstract
- The amplification of glucose-stimulated insulin secretion (GSIS) through incretin signaling is critical for maintaining physiological glucose levels. Incretins, like glucagon-like peptide 1 (GLP1), are a target of type 2 diabetes drugs aiming to enhance insulin secretion. Here we show that the protein phosphatase 1 inhibitor protein 1A (PPP1R1A), is expressed in β-cells and that its expression is reduced in dysfunctional β-cells lacking MafA and upon acute MafA knock down. MafA is a central regulator of GSIS and β-cell function. We observed a strong correlation of MAFA and PPP1R1A mRNA levels in human islets, moreover, PPP1R1A mRNA levels were reduced in type 2 diabetic islets and positively correlated with GLP1-mediated GSIS amplification. PPP1R1A silencing in β-cell lines impaired GSIS amplification, PKA-target protein phosphorylation, mitochondrial coupling efficiency and also the expression of critical β-cell marker genes like MafA, Pdx1, NeuroD1 and Pax6. Our results demonstrate that the β-cell transcription factor MafA is required for PPP1R1A expression and that reduced β-cell PPP1R1A levels impaired β-cell function and contributed to β-cell dedifferentiation during type 2 diabetes. Loss of PPP1R1A in type 2 diabetic β-cells may explains the unresponsiveness of type 2 diabetic patients to GLP1R-based treatments.
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| 6. |
- Gheibi, Sevda, et al.
(författare)
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Reduced Expression Level of Protein Phosphatase PPM1E Serves to Maintain Insulin Secretion in Type 2 Diabetes
- 2023
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797. ; 72:4, s. 455-466
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Tidskriftsartikel (refereegranskat)abstract
- Reversible phosphorylation is an important regulatory mechanism. Regulation of protein phosphorylation in β-cells has been extensively investigated, but less is known about protein dephosphorylation. To understand the role of protein dephosphorylation in β-cells and type 2 diabetes (T2D), we first examined mRNA expression of the type 2C family (PP2C) of protein phosphatases in islets from T2D donors. Phosphatase expression overall was changed in T2D, and that of PPM1E was the most markedly downregulated. PPM1E expression correlated inversely with HbA1c. Silencing of PPM1E increased glucose-stimulated insulin secretion (GSIS) in INS-1 832/13 cells and/or islets from patients with T2D, whereas PPM1E overexpression decreased GSIS. Increased GSIS after PPM1E silencing was associated with decreased oxidative stress, elevated cytosolic Ca2+ levels and ATP to ADP ratio, increased hyperpo-larization of the inner mitochondrial membrane, and phosphorylation of CaMKII, AMPK, and acetyl-CoA car-boxylase. Silencing of PPM1E, however, did not change insulin content. Increased GSIS, cell viability, and activation of AMPK upon metformin treatment in β-cells were observed upon PPM1E silencing. Thus, protein de-phosphorylation via PPM1E abrogates GSIS. Conse-quently, reduced PPM1E expression in T2D may be a compensatory response of β-cells to uphold insulin secretion under metabolic duress. Targeting PPM1E in β-cells may thus represent a novel therapeutic strategy for treatment of T2D.
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| 7. |
- Muñoz, Felipe, et al.
(författare)
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Unique features of β-cell metabolism are lost in type 2 diabetes
- 2024
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Ingår i: Acta Physiologica. - 1748-1708.
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Forskningsöversikt (refereegranskat)abstract
- Pancreatic β cells play an essential role in the control of systemic glucose homeostasis as they sense blood glucose levels and respond by secreting insulin. Upon stimulating glucose uptake in insulin-sensitive tissues post-prandially, this anabolic hormone restores blood glucose levels to pre-prandial levels. Maintaining physiological glucose levels thus relies on proper β-cell function. To fulfill this highly specialized nutrient sensor role, β cells have evolved a unique genetic program that shapes its distinct cellular metabolism. In this review, the unique genetic and metabolic features of β cells will be outlined, including their alterations in type 2 diabetes (T2D). β cells selectively express a set of genes in a cell type-specific manner; for instance, the glucose activating hexokinase IV enzyme or Glucokinase (GCK), whereas other genes are selectively “disallowed”, including lactate dehydrogenase A (LDHA) and monocarboxylate transporter 1 (MCT1). This selective gene program equips β cells with a unique metabolic apparatus to ensure that nutrient metabolism is coupled to appropriate insulin secretion, thereby avoiding hyperglycemia, as well as life-threatening hypoglycemia. Unlike most cell types, β cells exhibit specialized bioenergetic features, including supply-driven rather than demand-driven metabolism and a high basal mitochondrial proton leak respiration. The understanding of these unique genetically programmed metabolic features and their alterations that lead to β-cell dysfunction is crucial for a comprehensive understanding of T2D pathophysiology and the development of innovative therapeutic approaches for T2D patients.
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| 8. |
- Roberts, Fiona Louise, et al.
(författare)
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Monoamines' role in islet cell function and type 2 diabetes risk
- 2023
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Ingår i: Trends in Molecular Medicine. - 1471-4914. ; 29:12, s. 1045-1058
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Forskningsöversikt (refereegranskat)abstract
- The two monoamines serotonin and melatonin have recently been highlighted as potent regulators of islet hormone secretion and overall glucose homeostasis in the body. In fact, dysregulated signaling of both amines are implicated in β-cell dysfunction and development of type 2 diabetes mellitus (T2DM). Serotonin is a key player in β-cell physiology and plays a role in expansion of β-cell mass. Melatonin regulates circadian rhythm and nutrient metabolism and reduces insulin release in human and rodent islets in vitro. Herein, we focus on the role of serotonin and melatonin in islet physiology and the pathophysiology of T2DM. This includes effects on hormone secretion, receptor expression, genetic variants influencing β-cell function, melatonin treatment, and compounds that alter serotonin availability and signaling.
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| 9. |
- Verma, Gaurav, et al.
(författare)
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Ribosomal biogenesis regulator DIMT1 controls β-cell protein synthesis, mitochondrial function, and insulin secretion
- 2022
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Ingår i: The Journal of biological chemistry. - : Elsevier BV. - 1083-351X .- 0021-9258. ; 298:3
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Tidskriftsartikel (refereegranskat)abstract
- We previously reported that loss of mitochondrial transcription factor B1 (TFB1M) leads to mitochondrial dysfunction and is involved in the pathogenesis of type 2 diabetes (T2D). Whether defects in ribosomal processing impact mitochondrial function and could play a pathogenetic role in β-cells and T2D is not known. To this end, we explored expression and the functional role of dimethyladenosine transferase 1 homolog (DIMT1), a homolog of TFB1M and a ribosomal RNA (rRNA) methyltransferase implicated in the control of rRNA. Expression of DIMT1 was increased in human islets from T2D donors and correlated positively with expression of insulin mRNA, but negatively with insulin secretion. We show that silencing of DIMT1 in insulin-secreting cells impacted mitochondrial function, leading to lower expression of mitochondrial OXPHOS proteins, reduced oxygen consumption rate, dissipated mitochondrial membrane potential, and a slower rate of ATP production. In addition, the rate of protein synthesis was retarded upon DIMT1-deficiency. Consequently, we found that DIMT1 deficiency led to perturbed insulin secretion in rodent cell lines and islets, as well as in a human β-cell line. We observed defects in rRNA processing and reduced interactions between NIN1 (RPN12) binding protein 1 homolog (NOB-1) and Pescadillo ribosomal biogenesis factor 1 (PES-1), critical ribosomal subunit RNA proteins, the dysfunction of which may play a part in disturbing protein synthesis in β-cells. In conclusion, DIMT1 deficiency perturbs protein synthesis, resulting in mitochondrial dysfunction and disrupted insulin secretion, both potential pathogenetic processes in T2D.
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