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Endocrine pancreas regulates glucose homeostasis and prevents diabetes. Type-1 diabetes is characterized by destruction of the insulin secreting beta-cells within the endocrine pancreatic islets, resulting in lower insulin release. People with type-1 diabetes can be transplanted with pancreatic islets obtained from deceased donors which restores the beta-cell function. There are around 70 human islet isolation centers around the world which mostly collect endocrine pancreas from deceased donors. They assess the islet yield, functionality, viability, secretory capacity, and purity for transplantation and distribute this to donors. They also distribute a part of the pancreatic tissue for research, so that the cellular mechanisms in the human pancreatic tissue can be understood. This is crucial since human islet tissue has a unique cytoarchitecture compared to murine counterparts and therefore islet research with murine islets does not give complete picture of diabetes in humans. India is poised to take the mantle of the diabetes capital of the world in the near future. Despite this, there are no human islet isolation centers which can facilitate islet transplantation and diabetes research in India. This article highlights the glaring gap in the current infrastructure for diabetes care and provides critical insights into the role and potential of setting up islet tissue banks in the most populous country of the world.

Endocrine pancreas regulates glucose homeostasis and prevents diabetes. Type-1 diabetes is characterized by destruction of the insulin secreting beta-cells within the endocrine pancreatic islets, resulting in lower insulin release. People with type-1 diabetes can be transplanted with pancreatic islets obtained from deceased donors which restores the beta-cell function. There are around 70 human islet isolation centers around the world which mostly collect endocrine pancreas from deceased donors. They assess the islet yield, functionality, viability, secretory capacity, and purity for transplantation and distribute this to donors. They also distribute a part of the pancreatic tissue for research, so that the cellular mechanisms in the human pancreatic tissue can be understood. This is crucial since human islet tissue has a unique cytoarchitecture compared to murine counterparts and therefore islet research with murine islets does not give complete picture of diabetes in humans. India is poised to take the mantle of the diabetes capital of the world in the near future. Despite this, there are no human islet isolation centers which can facilitate islet transplantation and diabetes research in India. This article highlights the glaring gap in the current infrastructure for diabetes care and provides critical insights into the role and potential of setting up islet tissue banks in the most populous country of the world.

Endocrine pancreas regulates glucose homeostasis and prevents diabetes. Type-1 diabetes is characterized by destruction of the insulin secreting beta-cells within the endocrine pancreatic islets, resulting in lower insulin release. People with type-1 diabetes can be transplanted with pancreatic islets obtained from deceased donors which restores the beta-cell function. There are around 70 human islet isolation centers around the world which mostly collect endocrine pancreas from deceased donors. They assess the islet yield, functionality, viability, secretory capacity, and purity for transplantation and distribute this to donors. They also distribute a part of the pancreatic tissue for research, so that the cellular mechanisms in the human pancreatic tissue can be understood. This is crucial since human islet tissue has a unique cytoarchitecture compared to murine counterparts and therefore islet research with murine islets does not give complete picture of diabetes in humans. India is poised to take the mantle of the diabetes capital of the world in the near future. Despite this, there are no human islet isolation centers which can facilitate islet transplantation and diabetes research in India. This article highlights the glaring gap in the current infrastructure for diabetes care and provides critical insights into the role and potential of setting up islet tissue banks in the most populous country of the world.

Endocrine pancreas regulates glucose homeostasis and prevents diabetes. Type-1 diabetes is characterized by destruction of the insulin secreting beta-cells within the endocrine pancreatic islets, resulting in lower insulin release. People with type-1 diabetes can be transplanted with pancreatic islets obtained from deceased donors which restores the beta-cell function. There are around 70 human islet isolation centers around the world which mostly collect endocrine pancreas from deceased donors. They assess the islet yield, functionality, viability, secretory capacity, and purity for transplantation and distribute this to donors. They also distribute a part of the pancreatic tissue for research, so that the cellular mechanisms in the human pancreatic tissue can be understood. This is crucial since human islet tissue has a unique cytoarchitecture compared to murine counterparts and therefore islet research with murine islets does not give complete picture of diabetes in humans. India is poised to take the mantle of the diabetes capital of the world in the near future. Despite this, there are no human islet isolation centers which can facilitate islet transplantation and diabetes research in India. This article highlights the glaring gap in the current infrastructure for diabetes care and provides critical insights into the role and potential of setting up islet tissue banks in the most populous country of the world.

Endocrine pancreas regulates glucose homeostasis and prevents diabetes. Type-1 diabetes is characterized by destruction of the insulin secreting beta-cells within the endocrine pancreatic islets, resulting in lower insulin release. People with type-1 diabetes can be transplanted with pancreatic islets obtained from deceased donors which restores the beta-cell function. There are around 70 human islet isolation centers around the world which mostly collect endocrine pancreas from deceased donors. They assess the islet yield, functionality, viability, secretory capacity, and purity for transplantation and distribute this to donors. They also distribute a part of the pancreatic tissue for research, so that the cellular mechanisms in the human pancreatic tissue can be understood. This is crucial since human islet tissue has a unique cytoarchitecture compared to murine counterparts and therefore islet research with murine islets does not give complete picture of diabetes in humans. India is poised to take the mantle of the diabetes capital of the world in the near future. Despite this, there are no human islet isolation centers which can facilitate islet transplantation and diabetes research in India. This article highlights the glaring gap in the current infrastructure for diabetes care and provides critical insights into the role and potential of setting up islet tissue banks in the most populous country of the world.

In obese children with high circulating concentrations of free fatty acid palmitate, we have observed that insulin levels at fasting and in response to a glucose challenge were several times higher than in obese children with low concentrations of the fatty acid as well as in lean controls. Declining and even insufficient insulin levels were observed in obese adolescents with high levels of the fatty acid. In isolated human islets exposed to palmitate we have observed insulin hypersecretion after 2 days exposure. In contrast, insulin secretion from the islets was reduced after 7 days culture in the presence of the fatty acid. This study aims at identifying islet-related biological events potentially linked with the observed insulin hypersecretion and later secretory decline in these obese children and adolescents using the islet model. We analyzed protein expression data obtained from human islets exposed to elevated palmitate levels for 2 and 7 days by an improved methodology for statistical analysis of differentially expressed proteins. Protein profiling of islet samples by liquid chromatography-tandem mass spectrometry identified 115 differentially expressed proteins (DEPs). Several DEPs including sorcin were associated with increased glucose-stimulated insulin secretion in islets after 2 days of exposure to palmitate. Similarly, several metabolic pathways including altered protein degradation, increased autophagy, altered redox condition, and hampered insulin processing were coupled to the functional impairment of islets after 7 days of culture in the presence of palmitate. Such biological events, once validated in the islets, may give rise to novel treatment strategies aiming at normalizing insulin levels in obese children with high palmitate levels, which may reduce or even prevent obesity-related type 2 diabetes mellitus.

Background: Free fatty acids (FFAs) acutely stimulate insulin secretion from pancreatic islets. Conflicting results have been presented regarding this effect at non-stimulatory glucose concentration, however. The aim of our study was to investigate how long-chain FFAs affect insulin secretion from isolated human pancreatic islets in the presence of physiologically fasting glucose concentrations and to explore the contribution of mitochondria to the effects on secretion. Methods: Insulin secretion from human pancreatic islets was measured from short-term static incubation or perfusion system at fasting glucose concentration (5.5 mM) with or without 4 different FFAs (palmitate, palmitoleate, stearate, and oleate). The contribution of mitochondrial metabolism to the effects of fatty acid-stimulated insulin secretion was explored. Results: The average increase in insulin secretion, measured from statically incubated and dynamically perifused human islets, was about 2-fold for saturated free fatty acids (SFAs) (palmitate and stearate) and 3-fold for mono-unsaturated free fatty acids (MUFAs) (palmitoleate and oleate) compared with 5.5 mmol/l glucose alone. Accordingly, MUFAs induced 50 % and SFAs 20 % higher levels of oxygen consumption compared with islets exposed to 5.5 mmol/l glucose alone. The effect was due to increased glycolysis. When glucose was omitted from the medium, addition of the FFAs did not affect oxygen consumption. However, the FFAs still stimulated insulin secretion from the islets although secretion was more than halved. The mitochondria-independent action was via fatty acid metabolism and FFAR1/GPR40 signaling. Conclusions: The findings suggest that long-chain FFAs acutely induce insulin secretion from human islets at physiologically fasting glucose concentrations, with MUFAs being more potent than SFAs, and that this effect is associated with increased glycolytic flux and mitochondrial respiration.

Background: Free fatty acids (FFAs) acutely stimulate insulin secretion from pancreatic islets. Conflicting results have been presented regarding this effect at non-stimulatory glucose concentration, however. The aim of our study was to investigate how long-chain FFAs affect insulin secretion from isolated human pancreatic islets in the presence of physiologically fasting glucose concentrations and to explore the contribution of mitochondria to the effects on secretion. Methods: Insulin secretion from human pancreatic islets was measured from short-term static incubation or perfusion system at fasting glucose concentration (5.5 mM) with or without 4 different FFAs (palmitate, palmitoleate, stearate, and oleate). The contribution of mitochondrial metabolism to the effects of fatty acid-stimulated insulin secretion was explored. Results: The average increase in insulin secretion, measured from statically incubated and dynamically perifused human islets, was about 2-fold for saturated free fatty acids (SFAs) (palmitate and stearate) and 3-fold for mono-unsaturated free fatty acids (MUFAs) (palmitoleate and oleate) compared with 5.5 mmol/l glucose alone. Accordingly, MUFAs induced 50 % and SFAs 20 % higher levels of oxygen consumption compared with islets exposed to 5.5 mmol/l glucose alone. The effect was due to increased glycolysis. When glucose was omitted from the medium, addition of the FFAs did not affect oxygen consumption. However, the FFAs still stimulated insulin secretion from the islets although secretion was more than halved. The mitochondria-independent action was via fatty acid metabolism and FFAR1/GPR40 signaling. Conclusions: The findings suggest that long-chain FFAs acutely induce insulin secretion from human islets at physiologically fasting glucose concentrations, with MUFAs being more potent than SFAs, and that this effect is associated with increased glycolytic flux and mitochondrial respiration.

Background: Free fatty acids (FFAs) acutely stimulate insulin secretion from pancreatic islets. Conflicting results have been presented regarding this effect at non-stimulatory glucose concentration, however. The aim of our study was to investigate how long-chain FFAs affect insulin secretion from isolated human pancreatic islets in the presence of physiologically fasting glucose concentrations and to explore the contribution of mitochondria to the effects on secretion. Methods: Insulin secretion from human pancreatic islets was measured from short-term static incubation or perfusion system at fasting glucose concentration (5.5 mM) with or without 4 different FFAs (palmitate, palmitoleate, stearate, and oleate). The contribution of mitochondrial metabolism to the effects of fatty acid-stimulated insulin secretion was explored. Results: The average increase in insulin secretion, measured from statically incubated and dynamically perifused human islets, was about 2-fold for saturated free fatty acids (SFAs) (palmitate and stearate) and 3-fold for mono-unsaturated free fatty acids (MUFAs) (palmitoleate and oleate) compared with 5.5 mmol/l glucose alone. Accordingly, MUFAs induced 50 % and SFAs 20 % higher levels of oxygen consumption compared with islets exposed to 5.5 mmol/l glucose alone. The effect was due to increased glycolysis. When glucose was omitted from the medium, addition of the FFAs did not affect oxygen consumption. However, the FFAs still stimulated insulin secretion from the islets although secretion was more than halved. The mitochondria-independent action was via fatty acid metabolism and FFAR1/GPR40 signaling. Conclusions: The findings suggest that long-chain FFAs acutely induce insulin secretion from human islets at physiologically fasting glucose concentrations, with MUFAs being more potent than SFAs, and that this effect is associated with increased glycolytic flux and mitochondrial respiration.

Background: Free fatty acids (FFAs) acutely stimulate insulin secretion from pancreatic islets. Conflicting results have been presented regarding this effect at non-stimulatory glucose concentration, however. The aim of our study was to investigate how long-chain FFAs affect insulin secretion from isolated human pancreatic islets in the presence of physiologically fasting glucose concentrations and to explore the contribution of mitochondria to the effects on secretion. Methods: Insulin secretion from human pancreatic islets was measured from short-term static incubation or perfusion system at fasting glucose concentration (5.5 mM) with or without 4 different FFAs (palmitate, palmitoleate, stearate, and oleate). The contribution of mitochondrial metabolism to the effects of fatty acid-stimulated insulin secretion was explored. Results: The average increase in insulin secretion, measured from statically incubated and dynamically perifused human islets, was about 2-fold for saturated free fatty acids (SFAs) (palmitate and stearate) and 3-fold for mono-unsaturated free fatty acids (MUFAs) (palmitoleate and oleate) compared with 5.5 mmol/l glucose alone. Accordingly, MUFAs induced 50 % and SFAs 20 % higher levels of oxygen consumption compared with islets exposed to 5.5 mmol/l glucose alone. The effect was due to increased glycolysis. When glucose was omitted from the medium, addition of the FFAs did not affect oxygen consumption. However, the FFAs still stimulated insulin secretion from the islets although secretion was more than halved. The mitochondria-independent action was via fatty acid metabolism and FFAR1/GPR40 signaling. Conclusions: The findings suggest that long-chain FFAs acutely induce insulin secretion from human islets at physiologically fasting glucose concentrations, with MUFAs being more potent than SFAs, and that this effect is associated with increased glycolytic flux and mitochondrial respiration.

Background: Free fatty acids (FFAs) acutely stimulate insulin secretion from pancreatic islets. Conflicting results have been presented regarding this effect at non-stimulatory glucose concentration, however. The aim of our study was to investigate how long-chain FFAs affect insulin secretion from isolated human pancreatic islets in the presence of physiologically fasting glucose concentrations and to explore the contribution of mitochondria to the effects on secretion. Methods: Insulin secretion from human pancreatic islets was measured from short-term static incubation or perfusion system at fasting glucose concentration (5.5 mM) with or without 4 different FFAs (palmitate, palmitoleate, stearate, and oleate). The contribution of mitochondrial metabolism to the effects of fatty acid-stimulated insulin secretion was explored. Results: The average increase in insulin secretion, measured from statically incubated and dynamically perifused human islets, was about 2-fold for saturated free fatty acids (SFAs) (palmitate and stearate) and 3-fold for mono-unsaturated free fatty acids (MUFAs) (palmitoleate and oleate) compared with 5.5 mmol/l glucose alone. Accordingly, MUFAs induced 50 % and SFAs 20 % higher levels of oxygen consumption compared with islets exposed to 5.5 mmol/l glucose alone. The effect was due to increased glycolysis. When glucose was omitted from the medium, addition of the FFAs did not affect oxygen consumption. However, the FFAs still stimulated insulin secretion from the islets although secretion was more than halved. The mitochondria-independent action was via fatty acid metabolism and FFAR1/GPR40 signaling. Conclusions: The findings suggest that long-chain FFAs acutely induce insulin secretion from human islets at physiologically fasting glucose concentrations, with MUFAs being more potent than SFAs, and that this effect is associated with increased glycolytic flux and mitochondrial respiration.

Islet dysfunction is central to the development and progression of type 2 diabetes (T2D). Epigenetic modifications are essential for establishing and maintaining cell identity and function in normal circumstances. Exposure to adverse environmental factors may alter the epigenome, and result in changes of gene expression and the resulting phenotype. The aim of this thesis was to analyze DNA methylation levels of specific genes, as well as genome-wide DNA methylation, in order to determine whether epigenetic dysregulation of pancreatic islets contributes to islet dysfunction in subjects with T2D. We also assessed the relationship between genetic variation and DNA methylation. We further examined the potential use of DNA methylation in blood DNA to predict future T2D. At the specific gene level, we found that DNA methylation of INS and PDX-1 was increased in pancreatic islets from subjects with T2D (Studies I and II). Conversely, their mRNA expression, insulin content and glucose-stimulated insulin secretion (GSIS) were decreased in the same islets. We next analyzed genome-wide DNA methylation in human pancreatic islets from both T2D and non-diabetic donors (Study III). Nearly 1,500 CpG sites (853 genes) were differentially methylated in T2D islets, with the majority showing decreased DNA methylation. 102 genes showed both altered DNA methylation and mRNA expression in T2D islets, including CDKN1A, PDE7B, SEPT9 and EXOC3L2. Our functional experiments provided further evidence that altering the expression of these genes, by modeling the situation in T2D, results in impaired insulin and glucagon secretion in cell line models. Furthermore, we showed that nearly half of the single nucleotide polymorphisms (SNPs) associated with T2D are CpG-SNPs, which can introduce or remove a CpG site (Study IV). Accordingly, we found that the degree of DNA methylation at CpG-SNP sites varied between individuals with different genotypes, and that some of the CpG-SNPs were associated with

Type 1 diabetes mellitus is believed to be triggered, in part, by one or more environmental factors and human enteroviruses (HEVs) are among the candidates. Therefore, this study has examined whether two strains of HEV may differentially affect the induction of genes involved in pathways leading to the synthesis of islet hormones, chemokines and cytokines in isolated, highly purified, human islets. Isolated, purified human pancreatic islets were infected with strains of Coxsackievirus B1. Viral replication and the degree of CPE/islet dissociation were monitored. The expression of insulin, glucagon, CXCL10, TLR3, IF1H1, CCL5, OAS-1, IFN beta, and DDX58 was analyzed. Both strains replicated in islets but only one of strain caused rapid islet dissociation/CPE. Expression of the insulin gene was reduced during infection of islets with either viral strain but the gene encoding glucagon was unaffected. All genes analyzed which are involved in viral sensing and the development of innate immunity were induced by Coxsackie B viruses, with the notable exception of TLR3. There was no qualitative difference in the expression pattern between each strain but the magnitude of the response varied between donors. The lack of virus induced expression of TLR3, together with the differential regulation of IF1H1, OAS1 and IFN beta, (each of which has polymorphic variants influence the predisposition to type 1 diabetes), that might result in defective clearance of virus from islet cells. The reduced expression of the insulin gene and the unaffected expression of the gene encoding glucagon by Coxsackie B1 infection is consistent with the preferential beta-cell tropism of the virus.

The prevalence of type 2 diabetes (T2D) is increasing worldwide. T2D is a heterogeneous disease caused by a complex interplay between multiple genetic, epigenetic and non-genetic factors. The disease is characterised by impaired insulin secretion from pancreatic β-cells and insulin resistance in peripheral tissues. Mitochondrial ATP production by oxidative phosphorylation (OXPHOS) is known to play a critical regulatory role in glucose stimulated insulin secretion (GSIS). The overall aim of this thesis was to explore the influence of genetic and epigenetic variation on OXPHOS, islet function and T2D in humans. In study I, we identified a single nucleotide polymorphism (SNP) in TFB1M, a nuclear-encoded factor involved in the translational control in mitochondria, that is associated with decreased insulin secretion in response to glucose, increased future risk of T2D, and reduced expression of TFB1M in human pancreatic islets. In mice with a heterozygous deficiency of Tfb1m and in clonal β-cells where Tfb1m had been silenced, we found that reduced levels of TFB1M caused impaired OXPHOS and, consequently, reduced insulin secretion. This study concludes that deficiency in TFB1M contributes to the pathogenesis of T2D by causing impaired insulin secretion. In study II, we showed that SNPs located adjacent to OXPHOS genes are nominally associated with decreased GSIS. Therefore, we cannot rule out the possibility that SNPs in or near genes involved in OXPHOS may influence β-cell function. In study III, we demonstrated that a set of OXPHOS genes is down-regulated in pancreatic islets from patients with T2D compared to donors not diagnosed with diabetes. Islet expression of multiple OXPHOS genes correlated positively with GSIS. This result suggests that decreased expression of OXPHOS genes in pancreatic islets may contribute to T2D by impaired GSIS. In study IV, we performed a genome-wide methylation quantitative trait locus (mQTL) analysis to assess the effects of SNPs on DNA

Enterovirus (EV) infections have been associated with the pathogenesis of Type 1 Diabetes (T1D). However, the pathway(s) by which EV may induce or accelerate diabetes is not well understood. The purpose of this thesis was to obtain new information on the mechanism by which EV infections, with different strains of EV, could cause damage to the insulin-producing β-cells in isolated human islets and in a rat insulin-producing cell line (RINm5F). Infection with EV strains isolated from T1D patients revealed replication/cell destruction in human islets and EV-like particles in the cytoplasm of the β-cell and infection with the isolates affected the release of insulin in response to glucose stimulation as early as three days post infection, before any decrease in cell viability was observed. A decrease in the induction/secretion of the chemokine RANTES in human islets during EV infection was also detected. When islets were cultured with nicotinamide (NA) the secretion of RANTES was increased irrespectively if the islets were infected or not. In addition, the degree of virus-induced cytolysis of human islets was reduced by NA, suggesting an antiviral effect of NA. Infection with EV strains revealed permissiveness to islet-derived cells. All EV strains used for infection were able to replicate in the RIN cell clusters (RCC) but not in the RIN cells that were cultured as a monolayer. This might be due to the differences in expression of the Coxsackie-adenovirus receptor (CAR), which only could be detected on the RCC. Infection of RCC with a CBV-4 strain did not affect cell viability and did not induce nitric oxide (NO) production alone or with the addition of IFN-γ. This was in contrast to the results obtained with synthetic dsRNA, poly(IC), which induced NO, suggesting that synthetic dsRNA does not mimic enteroviral intermediate dsRNA. During analyses performed with the samples from a family where the mother and one son where diagnosed with T1D on the same day, the results

Enterovirus (EV) infections have been associated with the pathogenesis of Type 1 Diabetes (T1D). However, the pathway(s) by which EV may induce or accelerate diabetes is not well understood. The purpose of this thesis was to obtain new information on the mechanism by which EV infections, with different strains of EV, could cause damage to the insulin-producing β-cells in isolated human islets and in a rat insulin-producing cell line (RINm5F). Infection with EV strains isolated from T1D patients revealed replication/cell destruction in human islets and EV-like particles in the cytoplasm of the β-cell and infection with the isolates affected the release of insulin in response to glucose stimulation as early as three days post infection, before any decrease in cell viability was observed. A decrease in the induction/secretion of the chemokine RANTES in human islets during EV infection was also detected. When islets were cultured with nicotinamide (NA) the secretion of RANTES was increased irrespectively if the islets were infected or not. In addition, the degree of virus-induced cytolysis of human islets was reduced by NA, suggesting an antiviral effect of NA. Infection with EV strains revealed permissiveness to islet-derived cells. All EV strains used for infection were able to replicate in the RIN cell clusters (RCC) but not in the RIN cells that were cultured as a monolayer. This might be due to the differences in expression of the Coxsackie-adenovirus receptor (CAR), which only could be detected on the RCC. Infection of RCC with a CBV-4 strain did not affect cell viability and did not induce nitric oxide (NO) production alone or with the addition of IFN-γ. This was in contrast to the results obtained with synthetic dsRNA, poly(IC), which induced NO, suggesting that synthetic dsRNA does not mimic enteroviral intermediate dsRNA. During analyses performed with the samples from a family where the mother and one son where diagnosed with T1D on the same day, the results

The process of β-cell destruction that leads to type 1 diabetes (T1D) is incompletely understood and it is believed to be a result of both genetic and environmental factors. Enterovirus (EV) infections of the β-cells have been proposed to be involved, however, the effects of EV infections on human β-cells have been little investigated. This thesis summarises studies of three different Coxsackie B4 virus strains that have previously been shown to infect human islets. The effects of infections with these EV were studied in vitro in human islets and in a rat insulin-producing cell line. In addition, a pilot study was performed on isolated human islets to investigate the ability to treat such infections with an antiviral compound. It was found that one of the virus strains replicated in human β-cells without affecting their main function for at least seven days, which in vivo may increase a virus’s ability to persist in islets. Nitric oxide was induced by synthetic dsRNA, poly(IC), but not by viral dsRNA in rat insulinoma cells in the presence of IFN-γ, suggesting that this mediator is not induced by EV infection in β-cells and that poly(IC) does not mimic an EV infection in this respect. All three virus strains were able to induce production of the T-cell chemoattractant interferon-γ-inducible protein 10 (IP-10) during infection of human islets, suggesting that an EV infection of the islets might trigger insulitis in vivo. Antiviral treatment was feasible in human islets, but one strain was resistant to the antiviral compound used in this study. To conclude, a potential mechanism is suggested for the involvement of EV infections in T1D. If EV infections induce IP-10 production in human islet cells in vivo, they might recruit immune cells to the islets. Together with viral persistence and/or virus-induced β-cell damage, this might trigger further immune-mediated β-cell destruction in vivo.

The process of β-cell destruction that leads to type 1 diabetes (T1D) is incompletely understood and it is believed to be a result of both genetic and environmental factors. Enterovirus (EV) infections of the β-cells have been proposed to be involved, however, the effects of EV infections on human β-cells have been little investigated. This thesis summarises studies of three different Coxsackie B4 virus strains that have previously been shown to infect human islets. The effects of infections with these EV were studied in vitro in human islets and in a rat insulin-producing cell line. In addition, a pilot study was performed on isolated human islets to investigate the ability to treat such infections with an antiviral compound. It was found that one of the virus strains replicated in human β-cells without affecting their main function for at least seven days, which in vivo may increase a virus’s ability to persist in islets. Nitric oxide was induced by synthetic dsRNA, poly(IC), but not by viral dsRNA in rat insulinoma cells in the presence of IFN-γ, suggesting that this mediator is not induced by EV infection in β-cells and that poly(IC) does not mimic an EV infection in this respect. All three virus strains were able to induce production of the T-cell chemoattractant interferon-γ-inducible protein 10 (IP-10) during infection of human islets, suggesting that an EV infection of the islets might trigger insulitis in vivo. Antiviral treatment was feasible in human islets, but one strain was resistant to the antiviral compound used in this study. To conclude, a potential mechanism is suggested for the involvement of EV infections in T1D. If EV infections induce IP-10 production in human islet cells in vivo, they might recruit immune cells to the islets. Together with viral persistence and/or virus-induced β-cell damage, this might trigger further immune-mediated β-cell destruction in vivo.

SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published