| 1. |
- Abels, Mia, et al.
(author)
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CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretion
- 2016
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In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 59:9, s. 1928-1937
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Journal article (peer-reviewed)abstract
- Aims/hypothesis Insufficient insulin release and hyperglucagonaemia are culprits in type 2 diabetes. Cocaine- and amphetamine-regulated transcript (CART, encoded by Cartpt) affects islet hormone secretion and beta cell survival in vitro in rats, and Cart(-/-) mice have diminished insulin secretion. We aimed to test if CART is differentially regulated in human type 2 diabetic islets and if CART affects insulin and glucagon secretion in vitro in humans and in vivo in mice. Methods CART expression was assessed in human type 2 diabetic and non-diabetic control pancreases and rodent models of diabetes. Insulin and glucagon secretion was examined in isolated islets and in vivo in mice. Ca2+ oscillation patterns and exocytosis were studied in mouse islets. Results We report an important role of CART in human islet function and glucose homeostasis in mice. CART was found to be expressed in human alpha and beta cells and in a subpopulation of mouse beta cells. Notably, CART expression was several fold higher in islets of type 2 diabetic humans and rodents. CART increased insulin secretion in vivo in mice and in human and mouse islets. Furthermore, CART increased beta cell exocytosis, altered the glucose-induced Ca2+ signalling pattern in mouse islets from fast to slow oscillations and improved synchronisation of the oscillations between different islet regions. Finally, CART reduced glucagon secretion in human and mouse islets, as well as in vivo in mice via diminished alpha cell exocytosis. Conclusions/interpretation We conclude that CART is a regulator of glucose homeostasis and could play an important role in the pathophysiology of type 2 diabetes. Based on the ability of CART to increase insulin secretion and reduce glucagon secretion, CART-based agents could be a therapeutic modality in type 2 diabetes.
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| 2. |
- Asad, Samina, et al.
(author)
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HTR1A a Novel Type 1 Diabetes Susceptibility Gene on Chromosome 5p13-q13
- 2012
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In: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 7:5
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Journal article (peer-reviewed)abstract
- Background: We have previously performed a genome-wide linkage study in Scandinavian Type 1 diabetes (T1D) families. In the Swedish families, we detected suggestive linkage (LOD less than= 2.2) to the chromosome 5p13-q13 region. The aim of our study was to investigate the linked region in search for possible T1D susceptibility genes. Methodology/Principal Findings: Microsatellites were genotyped in the Scandinavian families to fine-map the previously linked region. Further, SNPs were genotyped in Swedish and Danish families as well as Swedish sporadic cases. In the Swedish families we detected genome-wide significant linkage to the 5-hydroxytryptamine receptor 1A (HTR1A) gene (LOD 3.98, pless than9.8x10(-6)). Markers tagging two separate genes; the ring finger protein 180 (RNF180) and HTR1A showed association to T1D in the Swedish and Danish families (pless than0.002, pless than0.001 respectively). The association was not confirmed in sporadic cases. Conditional analysis indicates that the primary association was to HTR1A. Quantitative PCR show that transcripts of both HTR1A and RNF180 are present in human islets of Langerhans. Moreover, immunohistochemical analysis confirmed the presence of the 5-HTR1A protein in isolated human islets of Langerhans as well as in sections of human pancreas. Conclusions: We have identified and confirmed the association of both HTR1A and RFN180, two genes in high linkage disequilibrium (LD) to T1D in two separate family materials. As both HTR1A and RFN180 were expressed at the mRNA level and HTR1A as protein in human islets of Langerhans, we suggest that HTR1A may affect T1D susceptibility by modulating the initial autoimmune attack or either islet regeneration, insulin release, or both.
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| 3. |
- Bennet, Hedvig, et al.
(author)
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Altered serotonin (5-HT) 1D and 2A receptor expression may contribute to defective insulin and glucagon secretion in human type 2 diabetes.
- 2015
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In: Peptides. - : Elsevier BV. - 1873-5169 .- 0196-9781. ; 71, s. 113-120
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Journal article (peer-reviewed)abstract
- Islet produced 5-hydroxy tryptamine (5-HT) is suggested to regulate islet hormone secretion in a paracrine and autocrine manner in rodents. Hitherto, no studies demonstrate a role for this amine in human islet function, nor is it known if 5-HT signaling is involved in the development of beta cell dysfunction in type 2 diabetes (T2D). To clarify this, we performed a complete transcriptional mapping of 5-HT receptors and processing enzymes in human islets and investigated differential expression of these genes in non-diabetic and T2D human islet donors. We show the expression of fourteen 5-HT receptors as well as processing enzymes involved in the biosynthesis of 5-HT at the mRNA level in human islets. Two 5-HT receptors (HTR1D and HTR2A) were over-expressed in T2D islet donors. Both receptors (5-HT1d and 5-HT2a) were localized to human alpha, beta and delta cells. 5-HT inhibited both insulin and glucagon secretion in non-diabetic islet donors. In islets isolated from T2D donors the amine significantly increased release of insulin in response to glucose. Our results suggest that 5-HT signaling participates in regulation of overall islet hormone secretion in non- diabetic individuals and over-expression of HTR1D and HTR2A may either contribute to islet dysfunction in T2D or arise as a consequence of an already dysfunctional islet.
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| 4. |
- Bennet, Hedvig
(author)
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Novel insights into the role of serotonin in control of β-cell fuction
- 2016
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Doctoral thesis (other academic/artistic)abstract
- Inadequate insulin secretion is a central component in the development of Diabetes Mellitus, resulting from reduced pancreatic β-cell mass, as well as diminished β-cell function. Islet produced 5-hydroxy tryptamine (5-HT) is suggested to regulate insulin secretion and β-cell mass in rodents during pregnancy and in metabolically challenged states. However, the role of 5-HT in control of insulin release in humans is still controversial. Virtually all 5-HT receptors are coupled to G-proteins and activate different second messenger systems, with the exception of the 5-HT3-receptor family which are ligand-gated ion channels. In this thesis I have studied 5-HT signaling in human islets of Langerhans employing a number of physiological and biochemical techniques. Moreover, different pharmacological compounds targeting specific 5-HT receptors to improve insulin release are investigated. A complete transcriptional mapping of 5-HT receptors in human islets of Langerhans revealed expression of fourteen 5-HT receptors, as well as the enzymes involved in the biosynthesis of 5-HT. Two 5-HT receptor genes (HTR1D and HTR2A) were over-expressed in type 2 diabetic (T2D) islet donors and while 5-HT inhibited both insulin and glucagon secretion in non-diabetic islet donors, 5-HT increased the release of insulin in response to glucose in diabetic T2D islet donors. When investigating the specific function of receptors 5-HT1d and 5-HT2a in non-diabetic islets, we found that a 5-HT1d receptor agonist inhibited insulin release, while a 5-HT1d antagonist potentiated insulin release. Similarly, a 5-HT2a receptor agonist significantly potentiated insulin release, and an antagonist blunted the response of insulin to glucose. When stimulating human and mouse islets, as well as INS-1 (832/13) cells with a specific 5-HT2b receptor agonist GSIS was enhanced. Moreover, silencing Htr2b in INS-1 (832/13) cells resulted in a 30% reduction in GSIS. In addition, 5-HT2b receptor-activation produced robust, regular and sustained Ca2+ oscillations, paralleled with an increase in oxidative consumption rate in mouse islets. In vivo studies showed that AMS significantly decreased the insulinogenic index in AMS treated HFD fed mice as compared to untreated mice. Moreover, isolated pancreatic islets from AMS-treated mice given a control diet secreted less insulin in response to glucose compared to islets from untreated control diet fed mice. Taken together, we show that differential expression levels of 5-HT receptors have functional consequences on islet hormone secretion that may contribute to islet dysfunction as observed in T2D. Furthermore, we provide evidence for an important role of 5-HT2b receptor signaling in control of insulin secretion in vitro. In conclusion, our data suggests an important role for 5-HT signaling in control of islet hormone secretion.
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| 5. |
- Bennet, Hedvig, et al.
(author)
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Serotonin (5-HT) receptor 2b activation augments glucose-stimulated insulin secretion in human and mouse islets of Langerhans.
- 2016
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In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 59:4, s. 744-754
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Journal article (peer-reviewed)abstract
- The Gq-coupled 5-hydroxytryptamine 2B (5-HT2B) receptor is known to regulate the proliferation of islet beta cells during pregnancy. However, the role of serotonin in the control of insulin release is still controversial. The aim of the present study was to explore the role of the 5-HT2B receptor in the regulation of insulin secretion in mouse and human islets, as well as in clonal INS-1(832/13) cells.
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| 6. |
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| 7. |
- Cataldo Bascuñan, Luis Rodrigo, et al.
(author)
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Serotonergic Regulation of Insulin Secretion
- 2019
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In: Acta Physiologica. - : Wiley. - 1748-1716 .- 1748-1708. ; 225:1
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Research review (peer-reviewed)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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| 8. |
- Ganic, Elvira, et al.
(author)
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Islet-specific monoamine oxidase A and B expression depends on MafA transcriptional activity and is compromised in type 2 diabetes.
- 2015
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In: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 468:4, s. 629-635
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Journal article (peer-reviewed)abstract
- Lack or dysfunction of insulin producing β cells results in the development of type 1 and type 2 diabetes mellitus, respectively. Insulin secretion is controlled by metabolic stimuli (glucose, fatty acids), but also by monoamine neurotransmitters, like dopamine, serotonin, and norepinephrine. Intracellular monoamine levels are controlled by monoamine oxidases (Mao) A and B. Here we show that MaoA and MaoB are expressed in mouse islet β cells and that inhibition of Mao activity reduces insulin secretion in response to metabolic stimuli. Moreover, analysis of MaoA and MaoB protein expression in mouse and human type 2 diabetic islets shows a significant reduction of MaoB in type 2 diabetic β cells suggesting that loss of Mao contributes to β cell dysfunction. MaoB expression was also reduced in β cells of MafA-deficient mice, a mouse model for β cell dysfunction, and biochemical studies showed that MafA directly binds to and activates MaoA and MaoB transcriptional control sequences. Taken together, our results show that MaoA and MaoB expression in pancreatic islets is required for physiological insulin secretion and lost in type 2 diabetic mouse and human β cells. These findings demonstrate that regulation of monoamine levels by Mao activity in β cells is pivotal for physiological insulin secretion and that loss of MaoB expression may contribute to the β cell dysfunction in type 2 diabetes.
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| 9. |
- Ganic, Elvira, et al.
(author)
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MafA-Controlled Nicotinic Receptor Expression Is Essential for Insulin Secretion and Is Impaired in Patients with Type 2 Diabetes.
- 2016
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In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 14:8, s. 1991-2002
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Journal article (peer-reviewed)abstract
- Monoamine and acetylcholine neurotransmitters from the autonomic nervous system (ANS) regulate insulin secretion in pancreatic islets. The molecular mechanisms controlling neurotransmitter signaling in islet β cells and their impact on diabetes development are only partially understood. Using a glucose-intolerant, MafA-deficient mouse model, we demonstrate that MAFA controls ANS-mediated insulin secretion by activating the transcription of nicotinic (ChrnB2 and ChrnB4) and adrenergic (Adra2A) receptor genes, which are integral parts of acetylcholine- and monoamine-signaling pathways. We show that acetylcholine-mediated insulin secretion requires nicotinic signaling and that nicotinic receptor expression is positively correlated with insulin secretion and glycemic control in human donor islets. Moreover, polymorphisms spanning MAFA-binding regions within the human CHRNB4 gene are associated with type 2 diabetes. Our data show that MAFA transcriptional activity is required for establishing β cell sensitivity to neurotransmitter signaling and identify nicotinic signaling as a modulator of insulin secretion impaired in type 2 diabetes.
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| 10. |
- Kanatsuna, Norio, et al.
(author)
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Autoimmunity against INS-IGF2 expressed in human pancreatic islets.
- 2013
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In: Journal of Biological Chemistry. - 1083-351X. ; 288:40, s. 29013-29023
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Journal article (peer-reviewed)abstract
- Insulin is a major autoantigen in islet autoimmunity and progression to type 1 diabetes. It has been suggested that the insulin B-chain may be critical to insulin autoimmunity in type 1 diabetes. INS-IGF2 consists of the preproinsulin signal peptide, the insulin B-chain and eight amino acids of the C-peptide in addition to 138 amino acids from the IGF2 gene. We aimed to determine 1) expression of INS-IGF2 in human pancreatic islets and 2) autoantibodies in newly diagnosed type 1 diabetes children and controls. INS-IGF2, expressed primarily in beta cells, showed higher levels of expression in islets from normal compared to donors with either type 2 diabetes (p=0.006) or high HbA1c levels (p<0.001). INS-IGF2 autoantibody levels were increased in newly diagnosed type 1 diabetes patients (n=304) compared to healthy controls (n=355; p<0.001). Displacement with cold insulin and INS-IGF2 revealed that more patients than controls had doubly reactive insulin-INS-IGF2 autoantibodies. These data suggest that INS-IGF2, which contains the preproinsulin signal peptide, the B-chain and eight amino acids of the C-peptide may be an autoantigen in type 1 diabetes. INS-IGF2 and insulin may share autoantibody binding sites, thus complicating the notion that insulin is the primary autoantigen in type 1 diabetes.
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