Publications by authors named "Malin Fex"

Article Synopsis
  • The study examines the effectiveness of a new automated multiplex Antibody Detection by Agglutination-PCR (ADAP) method for diagnosing type 1 diabetes compared to traditional single-plex radiobinding assays (RBA).
  • It analyzed various autoantibodies in nearly 10,000 participants, aiming to establish diagnostic thresholds for identifying different stages of type 1 diabetes.
  • Results showed ADAP had higher sensitivity and comparable specificity to RBA, suggesting it may be a more effective diagnostic tool for detecting multiple autoantibodies in type 1 diabetes.
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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.

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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.

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Article Synopsis
  • - **Access to Human Beta Cells**: The study presents EndoC-βH5 cells as an advanced model for understanding human pancreatic beta cell functions and potential diabetes treatments, closely mimicking primary adult cells.
  • - **Cell Generation and Features**: These cells were created by integrating specific genes into human fetal pancreas, with successful removal of unwanted transgenes, resulting in cells that are easy to use and assess for insulin secretion and other functions.
  • - **Findings and Applications**: EndoC-βH5 cells demonstrate strong glucose-dependent insulin secretion and are suitable for drug testing and studying beta cell behavior, indicating their utility in diabetes research and therapy.
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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.

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Article Synopsis
  • Type 2 diabetes (T2D) is linked to insufficient insulin secretion from pancreatic β cells, prompting a study of human pancreatic islets from around 300 individuals to find candidate genes involved in T2D.
  • The research identified 395 differentially expressed genes (DEGs) related to T2D, including several novel genes and previous candidates, with a notable fraction possibly predisposing individuals to diabetes.
  • Functional experiments on mouse models indicated that specific DEGs, particularly OPRD1, PAX5, and SLC2A2, are crucial for regulating glucose levels and body composition, with PAX5 potentially acting as a major transcriptional regulator of T2D-related gene expression in pancreatic islets.
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Article Synopsis
  • EPDR1 is a human batokine that plays a role in regulating mitochondrial respiration and thermogenesis in brown fat, but its effects on pancreatic β-cells and glucose metabolism remain unexplored.
  • Research showed that EPDR1 levels were higher in pancreatic islets from type 2 diabetes (T2D) and obese donors and were linked to insulin secretion (GSIS) and other metabolic metrics.
  • Silencing EPDR1 in β-cell models reduced insulin secretion and disrupted mitochondrial function, suggesting that increasing EPDR1 may help improve β-cell activity and glucose regulation in obese individuals.
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Aim: The influence of dietary carbohydrates and fats on weight gain is inconclusively understood. We studied the acute impact of these nutrients on the overall metabolic state utilizing the insulin:glucagon ratio (IGR).

Methods: Following in vitro glucose and palmitate treatment, insulin and glucagon secretion from islets isolated from C57Bl/6J mice was measured.

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Glucose-induced insulin secretion depends on β-cell electrical activity. Inhibition of ATP-regulated potassium (K) channels is a key event in this process. However, K channel closure alone is not sufficient to induce β-cell electrical activity; activation of a depolarizing membrane current is also required.

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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.

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The human forebrain has expanded in size and complexity compared to chimpanzees despite limited changes in protein-coding genes, suggesting that gene expression regulation is an important driver of brain evolution. Here, we identify a KRAB-ZFP transcription factor, ZNF558, that is expressed in human but not chimpanzee forebrain neural progenitor cells. ZNF558 evolved as a suppressor of LINE-1 transposons but has been co-opted to regulate a single target, the mitophagy gene SPATA18.

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Background: Diabetes has been recognized as a risk factor contributing to the incidence and progression of Parkinson's disease (PD). Although several hypotheses suggest a number of different mechanisms underlying the aggravation of PD caused by diabetes, less attention has been paid to the fact that diabetes and PD share pathological microvascular alterations in the brain. The characteristics of the interaction of diabetes in combination with PD at the vascular interface are currently not known.

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The depleting Vβ13a T cell receptor monoclonal antibody (mAb) 17D5 prevents both induced and spontaneous autoimmune diabetes in BB rats. Here it was tested in congenic DR rats, all of which spontaneously developed diabetes. Starting at 40 days of age, rats were injected once weekly with either saline, His42 Vβ16 mAb, or 17D5 mAb and monitored for hyperglycemia.

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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.

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Type 2 diabetes, characterized by dysfunction of pancreatic β-cells and insulin resistance in peripheral organs, accounts for more than 90% of all diabetes. Despite current developments of new drugs and strategies to prevent/treat diabetes, there is no ideal therapy targeting all aspects of the disease. Restoration, however, of insulin-producing β-cells, as well as insulin-responsive cells, would be a logical strategy for the treatment of diabetes.

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Article Synopsis
  • The study investigates the link between enteroviruses and type 1 diabetes, focusing on how enterovirus affects autophagy in beta cells, which are crucial for insulin production.
  • Researchers used INS(832/13) cells and human islet cells infected with echovirus 16 to observe changes in autophagy-related processes, measuring factors like autophagosome accumulation and related gene expressions.
  • Results showed that E16 infection led to increased autophagosome formation and a significant rise in markers of autophagy, indicating that the virus may disrupt normal beta cell function, potentially contributing to the development of type 1 diabetes.
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Differences in pancreatic islet susceptibility during type 1 diabetes development may be explained by interislet variations. This study aimed to investigate if heterogeneities in vascular support and metabolic activity in rat and human islets may explain why some islets are attacked earlier than other islets. In rats, highly blood perfused islets were identified by injection of microspheres into the ascending aorta, whereas a combination of anterograde and retrograde injections of microspheres into pancreas was used to determine the islet vascular drainage system.

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Maf transcription factors are critical regulators of beta-cell function. We have previously shown that reduced MafA expression in human and mouse islets is associated with a pro-inflammatory gene signature. Here, we investigate if the loss of Maf transcription factors induced autoimmune processes in the pancreas.

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Most peripheral serotonin (5-hydroxytryptamine (5HT)) is synthetized in the gut with platelets being its main circulating reservoir. 5HT is acting as a hormone in key organs to regulate glucose and lipid metabolism. However, the relation between platelet 5HT levels and traits related to glucose homeostasis and lipid metabolism in humans remains poorly explored.

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Reduced glucose metabolism and formation of polyglucosan bodies (PGB) are, beside amyloid beta plaques and neurofibrillary tangles, well-known pathological findings associated with Alzheimer's disease (AD). Since both glucose availability and PGB are regulated by enzymatic degradation of glycogen, we hypothesize that dysfunctional glycogen degradation is a critical event in AD progression. We therefore investigated whether alpha (α)-amylase, an enzyme known to efficiently degrade polysaccharides in the gastrointestinal tract, is expressed in the hippocampal CA1/subiculum and if the expression is altered in AD patients.

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Mitochondrial metabolism is a major determinant of insulin secretion from pancreatic β-cells. Type 2 diabetes evolves when β-cells fail to release appropriate amounts of insulin in response to glucose. This results in hyperglycemia and metabolic dysregulation.

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Glucagon-like peptide 1 (GLP-1), secreted from intestinal L cells, glucose dependently stimulates insulin secretion from β-cells. This glucose dependence prevents hypoglycemia, rendering GLP-1 analogs a useful and safe treatment modality in type 2 diabetes. Although the amino acid glutamine is a potent elicitor of GLP-1 secretion, the responsible mechanism remains unclear.

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Aims/hypothesis: Genetic studies show coupling of genes affecting beta cell function to type 1 diabetes, but hitherto no studies on whether beta cell dysfunction could precede insulitis and clinical onset of type 1 diabetes are available.

Methods: We used 40-day-old BioBreeding (BB) DRLyp/Lyp rats (a model of spontaneous autoimmune type 1 diabetes) and diabetes-resistant DRLyp/+ and DR+/+ littermates (controls) to investigate beta cell function in vivo, and insulin and glucagon secretion in vitro. Beta cell mass was assessed by optical projection tomography (OPT) and morphometry.

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Increased narcolepsy incidence was observed in Sweden following the 2009 influenza vaccination with Pandemrix. A substitution of the 2009 nucleoprotein for the 1934 variant has been implicated in narcolepsy development. The aims were to determine (a) antibody levels toward wild-type A/H1N1-2009[A/California/04/2009(H1N1)] (NP-CA2009) and Pandemrix-[A/Puerto Rico/8/1934(H1N1)] (NP-PR1934) nucleoproteins in 43 patients and 64 age-matched controls; (b) antibody affinity in reciprocal competitive assays in 11 childhood narcolepsy patients compared with 21 age-matched controls; and (c) antibody levels toward wild-type A/H1N1-2009[A/California/04/2009(H1N1)] (H1N1 NS1), not a component of the Pandemrix vaccine.

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Objective: Insulin release from pancreatic β-cells is controlled by plasma glucose levels via mitochondrial fuel metabolism. Therefore, insulin secretion is critically dependent on mitochondrial DNA (mtDNA) and the genes it encodes. Mitochondrial transcription factor B2 (TFB2M) controls transcription of mitochondrial-encoded genes.

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