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Sökning: WFRF:(Wierup Nils)

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1.
  • Sharoyko, Vladimir, et al. (författare)
  • Loss of TFB1M results in mitochondrial dysfunction that leads to impaired insulin secretion and diabetes.
  • 2014
  • Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:21, s. 5733-5749
  • Tidskriftsartikel (refereegranskat)abstract
    • We have previously identified Transcription Factor B1 Mitochondrial (TFB1M) as a Type 2 Diabetes (T2D) risk gene, using human and mouse genetics. To further understand the function of TFB1M and how it is associated with T2D we created a β-cell specific knockout of Tfb1 m, which gradually developed diabetes. Prior to the onset of diabetes, β-Tfb1 m(-/-) mice exhibited retarded glucose clearance due to impaired insulin secretion. β-Tfb1 m(-/-) islets released less insulin in response to fuels, contained less insulin and secretory granules, and displayed reduced β-cell mass. Moreover, mitochondria in Tfb1 m-deficient β-cells were more abundant with disrupted architecture. TFB1M is known to control mitochondrial protein translation by adenine-dimethylation of 12S ribosomal RNA (rRNA). Here, we found that levels of TFB1M and mitochondrial encoded proteins, mitochondrial 12S rRNA methylation, ATP production and oxygen consumption were reduced in β-Tfb1 m(-/-) islets. Furthermore, levels of reactive oxygen species in response to cellular stress were increased while induction of defense mechanisms was attenuated. We also show increased apoptosis and necrosis as well as infiltration of macrophages and CD4(+)-cells in the islets. Taken together, our findings demonstrate that Tfb1 m-deficiency in β-cells caused mitochondrial dysfunction and subsequently diabetes due to combined loss of β-cell function and mass. These observations reflect pathogenetic processes in human islets: using RNA sequencing, we found that the TFB1M risk variant exhibited a negative gene-dosage effect on islet TFB1M mRNA levels, as well as insulin secretion. Our findings highlight the role of mitochondrial dysfunction in impairments of β-cell function and mass, the hallmarks of T2D.
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2.
  • Abels, Mia, et al. (författare)
  • CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretion
  • 2016
  • Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 59:9, s. 1928-1937
  • Tidskriftsartikel (refereegranskat)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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3.
  • Abels, Mia, et al. (författare)
  • Overexpressed beta cell CART increases insulin secretion in mouse models of insulin resistance and diabetes
  • 2022
  • Ingår i: Peptides. - : Elsevier BV. - 0196-9781. ; 151
  • Tidskriftsartikel (refereegranskat)abstract
    • Impaired beta cell function and beta cell death are key features of type 2 diabetes (T2D). Cocaine- and amphetamine-regulated transcript (CART) is necessary for normal islet function in mice. CART increases glucose-stimulated insulin secretion in vivo in mice and in vitro in human islets and CART protects beta cells against glucotoxicity-induced cell death in vitro in rats. Furthermore, beta cell CART is upregulated in T2D patients and in diabetic rodent models as a consequence of hyperglycaemia. The aim of this study was to assess the impact of upregulated beta cell CART on islet hormone secretion and glucose homeostasis in a transgenic mouse model. To this end, mice with beta cell-specific overexpression of CART (CARTtg mice) were generated. CARTtg mice challenged by aging, high fat diet feeding or streptozotocin treatment were phenotyped with respect to in vivo and in vitro insulin and glucagon secretion, glucose homeostasis, and beta cell mass. In addition, the impact of adenoviral overexpression of CART on insulin secretion was studied in INS-1 832/13 cells. CARTtg mice had a normal metabolic phenotype under basal conditions. On the other hand, with age CARTtg mice displayed increased insulin secretion and improved glucose elimination, compared with age-matched WT mice. Furthermore, compared with WT controls, CARTtg mice had increased insulin secretion after feeding a high fat diet, as well as lower glucose levels and higher insulin secretion after streptozotocin treatment. Viral overexpression of CART in INS-1 832/13 cells resulted in increased glucose-stimulated insulin secretion. Together, these results imply that beta cell CART acts to increase insulin secretion when beta cell function is challenged. We propose that the increase in beta cell CART is part of a compensatory mechanisms trying to counteract the hyperglycaemia in T2D.
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4.
  • Ahlqvist, Emma, et al. (författare)
  • A link between GIP and osteopontin in adipose tissue and insulin resistance.
  • 2013
  • Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 62:6, s. 2088-2094
  • Tidskriftsartikel (refereegranskat)abstract
    • Low grade inflammation in obesity is associated with accumulation of the macrophagederived cytokine osteopontin in adipose tissue and induction of local as well as systemic insulin resistance. Since GIP (glucose-dependent insulinotropic polypeptide) is a strong stimulator of adipogenesis and may play a role in the development of obesity, we explored whether GIP directly would stimulate osteopontin (OPN) expression in adipose tissue and thereby induce insulin resistance. GIP stimulated OPN protein expression in a dose-dependent fashion in rat primary adipocytes. The level of OPN mRNA was higher in adipose tissue of obese individuals (0.13±}0.04 vs 0.04±}0.01, P<0.05) and correlated inversely with measures of insulin sensitivity (r=-0.24, P=0.001). A common variant of the GIP receptor (GIPR) (rs10423928) gene was associated with lower amount of the exon 9 containing isoform required for transmembrane activity. Carriers of the A-allele with a reduced receptor function showed lower adipose tissue OPN mRNA levels and better insulin sensitivity. Together, these data suggest a role for GIP not only as an incretin hormone, but also as a trigger of inflammation and insulin resistance in adipose tissue. Carriers of GIPR rs10423928 A-allele showed protective properties via reduced GIP effects. Identification of this unprecedented link between GIP and OPN in adipose tissue might open new avenues for therapeutic interventions.
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5.
  • Ahrén, Bo, et al. (författare)
  • DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with beta-cell-specific overexpression of human islet amyloid polypeptide.
  • 2007
  • Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 143:1-3, s. 97-103
  • Tidskriftsartikel (refereegranskat)abstract
    • Inhibition of dipeptidyl peptidase-4 (DPP-4) is currently explored as a novel therapy of type 2 diabetes. The strategy has been shown to improve glycemia in most, but not all, rodent forms of glucose intolerance. In this study, we explored the effects of DPP-4 inhibition in mice with [beta-cell overexpression of human islet amyloid polypeptide (IAPP). We therefore administered the orally active and highly selective DPP-4 inhibitor, vildagliptin (3 pmol/mouse daily) to female mice with [beta-cell overexpression of human IAPP. Controls were given plain water, and a series of untreated wildtype mice was also included. After five weeks, an intravenous glucose tolerance test showed improved glucose disposal and a markedly enhanced insulin response in mice treated with vildagliptin. After eight weeks, a gastric tolerance test showed that vildagliptin improved glucose tolerance and markedly (approximately ten-fold) augmented the insulin response in association with augmented (approximately five-fold) levels of intact glucagon-like peptide-1 (GLP-1). Furthermore, after nine weeks, islets were isolated. Islets from vildagliptin-treated mice showed augmented glucose-stimulated insulin response and a normalization of the islet insulin content, which was reduced by approximately 50% in transgenic controls versus wildtype animals. Double immunostaining of pancreatic islets for insulin and glucagon revealed that transgenic islets displayed severely disturbed intra-islet topography with frequently observed centrally located a-cells. Treatment with vildagliptin restored the islet topography. We therefore conclude that DPP-4 inhibition improves islet function and islet topography in mice with [beta-cell specific transgenic overexpression of human IAPP. (c) 2007 Elsevier B.V. All rights reserved.
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6.
  • Ahrén, Bo, et al. (författare)
  • Neuropeptides and the regulation of islet function.
  • 2006
  • Ingår i: Diabetes. - 1939-327X. ; 55:Suppl 2, s. 98-107
  • Tidskriftsartikel (refereegranskat)abstract
    • The pancreatic islets are richly innervated by autonomic nerves. The islet parasympathetic nerves emanate from intrapancreatic ganglia, which are controlled by preganglionic vagal nerves. The islet sympathetic nerves are postganglionic with the nerve cell bodies located in ganglia outside the pancreas. The sensory nerves originate from dorsal root ganglia near the spinal cord. Inside the islets, nerve terminals run close to the endocrine cells. In addition to the classic neurotransmitters acetylcholine and norepinephrine, several neuropeptides exist in the islet nerve terminals. These neuropeptides are vasoactive intestinal polypeptide, pituitary adenylate cyclase-activating polypeptide, gastrin-releasing polypeptide, and cocaine-and amphetamine-regulated transcript in parasympathetic nerves; neuropeptide Y and galanin in the sympathetic nerves; and calcitonin gene-related polypeptide in sensory nerves. Activation of the parasympathetic nerves and administration of their neurotransmitters stimulate insulin and glucagon secretion, whereas activation of the sympathetic nerves and administration of their neurotransmitters inhibit insulin but stimulate glucagon secretion. The autonomic nerves contribute to the cephalic phase of insulin secretion, to glucagon secretion during hypoglycemia, to pancreatic polypeptide secretion, and to the inhibition of insulin secretion, which is seen during stress. In rodent models of diabetes, the number of islet autonomic nerves is upregulated. This review focuses on neural regulation of islet function, with emphasis on the neuropeptides.
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7.
  • Ahren, Jonatan, et al. (författare)
  • Increased beta-cell volume in mice fed a high-fat diet A dynamic study over 12 months
  • 2010
  • Ingår i: Islets. - : Informa UK Limited. - 1938-2022 .- 1938-2014. ; 2:6, s. 353-356
  • Tidskriftsartikel (refereegranskat)abstract
    • As we previously demonstrated, there is an adaptive increase in insulin secretion in insulin resistance in the model of high-fat fed female mice. Since it is assumed that islets also adapt to insulin resistance with beta-cell expansion, we have now examined beta-cell volume in this experimental model. Female C57BL/6JBomTac mice were therefore fed a high-fat diet (60% fat from lard) for three, six or twelve months and beta-cell volume was estimated as beta-cell area per islet, individual beta-cell size and beta-cell number per islet. Control animals were fed a normal chow (11% fat). We found that beta-cell area per islet and total number of beta-cells per islet were increased already after three months of high-fat feeding and that this increase was sustained throughout the twelve month study period. In contrast, individual beta-cell size showed a dynamic pattern with a reduction after three months followed by increase after six and twelve months. The number of apoptosis (caspase-3) positive beta-cells was reduced after three months, whereas there was no difference in proliferation (Ki-67) positive cells, although these were generally rarely observed. Thus, we conclude that insulin resistance accompanying high-fat feeding in mice is followed by progressive beta-cell expansion as evident by early increased islet beta-cell volume and total number of beta-cells, whereas individual beta-cell size showed a dynamic response. The model is also associated with an early reduced apoptosis, which may contribute to the increased beta-cell volume.
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8.
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9.
  • Andersson, Lotta E., et al. (författare)
  • Glutamine-elicited secretion of glucagon-like peptide 1 is governed by an activated glutamate dehydrogenase
  • 2018
  • Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 67:3, s. 372-384
  • Tidskriftsartikel (refereegranskat)abstract
    • 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. We investigated how GLP-1 secretion is metabolically coupled in L cells (GLUTag) and in vivo inmice using the insulin-secreting cell line INS-1 832/13 as reference. A membrane-permeable glutamate analog (dimethylglutamate [DMG]), acting downstream of electrogenic transporters, elicited similar alterations in metabolism as glutamine in both cell lines. Both DMG and glutamine alone elicited GLP-1 secretion in GLUTag cells and in vivo, whereas activation of glutamate dehydrogenase (GDH) was required to stimulate insulin secretion from INS-1 832/13 cells. Pharmacological inhibition in vivo of GDH blocked secretion of GLP-1 in response to DMG. In conclusion, our results suggest that nonelectrogenic nutrient uptake and metabolism play an important role in L cell stimulus-secretion coupling. Metabolism of glutamine and related analogs by GDH in the L cell may explain why GLP-1 secretion, but not that of insulin, is activated by these secretagogues in vivo.
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10.
  • Asad, Samina, et al. (författare)
  • HTR1A a Novel Type 1 Diabetes Susceptibility Gene on Chromosome 5p13-q13
  • 2012
  • Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 7:5
  • Tidskriftsartikel (refereegranskat)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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11.
  • Asplund, Olof, et al. (författare)
  • Islet Gene View-a tool to facilitate islet research
  • 2022
  • Ingår i: Life Science Alliance. - : Life Science Alliance, LLC. - 2575-1077. ; 5:12
  • Tidskriftsartikel (refereegranskat)abstract
    • Characterization of gene expression in pancreatic islets and its alteration in type 2 diabetes (T2D) are vital in understanding islet function and T2D pathogenesis. We leveraged RNA sequencing and genome-wide genotyping in islets from 188 donors to create the Islet Gene View (IGW) platform to make this information easily accessible to the scientific community. Expression data were related to islet phenotypes, diabetes status, other islet-expressed genes, islet hormone-encoding genes and for expression in insulin target tissues. The IGW web application produces output graphs for a particular gene of interest. In IGW, 284 differentially expressed genes (DEGs) were identified in T2D donor islets compared with controls. Forty percent of DEGs showed cell-type enrichment and a large proportion significantly co-expressed with islet hormone-encoding genes; glucagon (GCG, 56%), amylin (IAPP, 52%), insulin (INS, 44%), and somatostatin (SST, 24%). Inhibition of two DEGs, UNC5D and SERPINE2, impaired glucose-stimulated insulin secretion and impacted cell survival in a human beta-cell model. The exploratory use of IGW could help designing more comprehensive functional follow-up studies and serve to identify therapeutic targets in T2D.
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12.
  • Axelsson, Annika S., et al. (författare)
  • Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes
  • 2017
  • Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 9:394
  • Tidskriftsartikel (refereegranskat)abstract
    • A potentially useful approach for drug discovery is to connect gene expression profiles of disease-affected tissues ("disease signatures") to drug signatures, but it remains to be shown whether it can be used to identify clinically relevant treatment options. We analyzed coexpression networks and genetic data to identify a disease signature for type 2 diabetes in liver tissue. By interrogating a library of 3800 drug signatures, we identified sulforaphane as a compound that may reverse the disease signature. Sulforaphane suppressed glucose production from hepatic cells by nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2) and decreased expression of key enzymes in gluconeogenesis. Moreover, sulforaphane reversed the disease signature in the livers from diabetic animals and attenuated exaggerated glucose production and glucose intolerance by a magnitude similar to that of metformin. Finally, sulforaphane, provided as concentrated broccoli sprout extract, reduced fasting blood glucose and glycated hemoglobin (HbA1c) in obese patients with dysregulated type 2 diabetes.
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13.
  • Axling, Ulrika, et al. (författare)
  • A low glycaemic diet improves oral glucose tolerance but has no effect on β-cell function in C57BL/6J mice.
  • 2010
  • Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902. ; 12:11, s. 976-982
  • Tidskriftsartikel (refereegranskat)abstract
    • AIM: Clinical studies have suggested a role for dietary glycaemic index (GI) in body weight regulation and diabetes risk. Here, we investigated the long-term metabolic effects of low and high glycaemic diets using the C57BL/6J mouse model. METHODS: Female C57BL/6J mice were fed low or high glycaemic starch in either low-fat or medium-fat diets for 22 weeks. Oral and intravenous glucose tolerance tests were performed to investigate the effect of the experimental diets on glucose tolerance and insulin resistance. RESULTS: In this study, a high glycaemic diet resulted in impaired oral glucose tolerance compared to a low glycaemic diet. This effect was more pronounced in the group fed a medium-fat diet, suggesting that a lower dietary fat content ameliorates the negative effect of a high glycaemic diet. No effect on body weight or body fat content was observed in either a low-fat diet or a medium-fat diet. Static incubation of isolated islets did not show any differences in basal (3.3 mM glucose) or glucose-stimulated (8.6 and 16.7 mM glucose) insulin secretion between mice fed a low or high glycaemic diet. CONCLUSION: Together, our data suggest that the impaired glucose tolerance seen after a high glycaemic diet is not explained by altered β-cell function.
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14.
  • Axling, Ulrika, et al. (författare)
  • Metabolic effects of whole grain wheat and whole grain rye in the C57BL/6J mouse.
  • 2010
  • Ingår i: Nutrition. - : Elsevier BV. - 1873-1244 .- 0899-9007. ; 26, s. 230-239
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: A diet rich in whole grain cereals is suggested to protect against type 2 diabetes and facilitate body weight regulation. However, little is known about the impact of different cereals and the underlying mechanisms. The objective of this study was to compare the long-term metabolic effects of diets supplemented with whole grain wheat or whole grain rye in the C57BL/6J mouse. METHODS: Mice were fed the whole grain supplements in a low-fat background diet for 22 wk. Oral and intravenous glucose tolerance tests were performed during the study and in vitro insulin secretion assays were performed at the end of the study. Body weight, energy intake, body fat content, and plasma parameters were measured during the study. RESULTS: A dietary supplement of whole grain rye suppressed body weight gain and resulted in significantly decreased adiposity, plasma leptin, total plasma cholesterol, and triacylglycerols compared with a supplement of whole grain wheat. Also, a slight improvement in insulin sensitivity was observed in the rye group compared with the wheat group. The decreases in body weight and adiposity were observed in the absence of differences in energy intake. CONCLUSION: Long-term administration of whole grain rye evokes a different metabolic profile compared with whole grain wheat in the C57BL/6J mouse, the primary difference being that whole grain rye reduces body weight and adiposity compared with whole grain wheat. In addition, whole grain rye slightly improves insulin sensitivity and lowers total plasma cholesterol.
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15.
  • Bacos, Karl, et al. (författare)
  • Islet beta-cell area and hormone expression are unaltered in Huntington's disease.
  • 2008
  • Ingår i: Histochemistry and Cell Biology. - : Springer Science and Business Media LLC. - 1432-119X .- 0948-6143. ; 129, s. 623-629
  • Tidskriftsartikel (refereegranskat)abstract
    • Neurodegenerative disorders are often associated with metabolic alterations. This has received little attention, but might be clinically important because it can contribute to symptoms and influence the course of the disease. Patients with Huntington's disease (HD) exhibit increased incidence of diabetes mellitus (DM). This is replicated in mouse models of HD, e.g., the R6/2 mouse, in which DM is primarily caused by a deficiency of beta-cells with impaired insulin secretion. Pancreatic tissue from HD patients has previously not been studied and, thus, the pathogenesis of DM in HD is unclear. To address this issue, we examined pancreatic tissue sections from HD patients at different disease stages. We found that the pattern of insulin immunostaining, levels of insulin transcripts and islet beta-cell area were similar in HD patients and controls. Further, there was no sign of amyloid deposition in islets from HD patients. Thus, our data show that pancreatic islets in HD patients appear histologically normal. Functional studies of HD patients with respect to insulin secretion and islet function are required to elucidate the pathogenesis of DM in HD. This may lead to a better understanding of HD and provide novel therapeutic targets for symptomatic treatment in HD.
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16.
  • Bacos, Karl, et al. (författare)
  • Type 2 diabetes candidate genes, including PAX5, cause impaired insulin secretion in human pancreatic islets
  • 2023
  • Ingår i: The Journal of clinical investigation. - 0021-9738 .- 1558-8238. ; 133:4
  • 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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17.
  • Banke, Elin, et al. (författare)
  • Cocaine- and amphetamine-regulated transcript is expressed in adipocytes and regulate lipid- and glucose homeostasis.
  • 2013
  • Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 182:Jan.,11, s. 35-40
  • Tidskriftsartikel (refereegranskat)abstract
    • Cocaine- and amphetamine-regulated transcript (CART) is a regulatory peptide expressed in the nervous system and in endocrine cells, e.g. in pancreatic islets. CART deficient mice exhibit islet dysfunction, impaired insulin secretion and increased body weight. A mutation in the CART gene in humans is associated with reduced metabolic rate, obesity and diabetes. Furthermore, CART is upregulated in islets of type-2 diabetic rats and regulates islet hormone secretion in vitro. While the function of CART in the nervous system has been extensively studied, there is no information on its expression or function in white adipose tissue. CART mRNA and protein were found to be expressed in both subcutaneous and visceral white adipose tissues from rat and man. Stimulating rat primary adipocytes with CART significantly potentiated isoprenaline-induced lipolysis, and hormone sensitive lipase activation (phosphorylation of Ser 563). On the other hand, CART significantly potentiated the inhibitory effect of insulin on isoprenaline-induced lipolysis. CART inhibited insulin-induced glucose uptake, which was associated with inhibition of PKB phosphorylation. In conclusion, CART is a novel constituent of human and rat adipocytes and affects several biological processes central in both lipid- and glucose homeostasis. Depending on the surrounding conditions, the effects of CART are insulin-like or insulin-antagonistic.
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18.
  • Bennet, Hedvig, et al. (författare)
  • Altered serotonin (5-HT) 1D and 2A receptor expression may contribute to defective insulin and glucagon secretion in human type 2 diabetes.
  • 2015
  • Ingår i: Peptides. - : Elsevier BV. - 1873-5169 .- 0196-9781. ; 71, s. 113-120
  • Tidskriftsartikel (refereegranskat)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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19.
  • Bennet, Hedvig, et al. (författare)
  • Serotonin (5-HT) receptor 2b activation augments glucose-stimulated insulin secretion in human and mouse islets of Langerhans.
  • 2016
  • Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 59:4, s. 744-754
  • Tidskriftsartikel (refereegranskat)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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21.
  • Berger, Karin, et al. (författare)
  • Phosphodiesterase 3B is localized in caveolae and smooth ER in mouse hepatocytes and is important in the regulation of glucose and lipid metabolism.
  • 2009
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Cyclic nucleotide phosphodiesterases (PDEs) are important regulators of signal transduction processes mediated by cAMP and cGMP. One PDE family member, PDE3B, plays an important role in the regulation of a variety of metabolic processes such as lipolysis and insulin secretion. In this study, the cellular localization and the role of PDE3B in the regulation of triglyceride, cholesterol and glucose metabolism in hepatocytes were investigated. PDE3B was identified in caveolae, specific regions in the plasma membrane, and smooth endoplasmic reticulum. In caveolin-1 knock out mice, which lack caveolae, the amount of PDE3B protein and activity were reduced indicating a role of caveolin-1/caveolae in the stabilization of enzyme protein. Hepatocytes from PDE3B knock out mice displayed increased glucose, triglyceride and cholesterol levels, which was associated with increased expression of gluconeogenic and lipogenic genes/enzymes including, phosphoenolpyruvate carboxykinase, peroxisome proliferator-activated receptor gamma, sterol regulatory element-binding protein 1c and hydroxyl-3-methylglutaryl coenzyme A reductase. In conclusion, hepatocyte PDE3B is localized in caveolae and smooth endoplasmic reticulum and plays important roles in the regulation of glucose, triglyceride and cholesterol metabolism. Dysregulation of PDE3B could have a role in the development of fatty liver, a condition highly relevant in the context of type 2 diabetes.
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22.
  • Berggren, Johan, et al. (författare)
  • GASTRIC BYPASS SURGERY HAS GREATER EFFECT THAN CALORIE RESTRICTION ON INCRETIN RELEASE AND INSULIN SECRETION ALREADY ON POSTOP. DAY 1
  • 2015
  • Ingår i: Obesity Surgery. - 1708-0428. ; 25:Suppl 1, s. 85-85
  • Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
    • Background: Gastric bypass surgery (GBP) provokes rapid improvement of type 2 diabetes (T2D) prior to significant weight loss. Thishas been attributed to altered secretion of the two incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependentinsulinotropic polypeptide (GIP). Here we studied the effects of very low calorie diet (VLCD) vs. the immediate effects of GBP onglycaemia and incretin release.Methods: Eight T2D obese women and 8 obese controls (C) underwent mixed meal tests (MMT) 4 w before (MMT-4w), 1 day before(MMT-1d), 1 day after (MMT+1d) and six weeks after (MMT+6w) gastric bypass. MMT-4w was performed before VLCD and MMT+1dconstituted the first postoperative meal. Glucose, insulin and incretins were analyzed. Gastric bypass surgery was standardized to a 50cm biliary limb and 150 cm alimentary limb and a 5 cm gastric pouch.OBES SURG (2015) 25 (Suppl 1):S1–S364 S85Results: Despite similar glucose levels, the insulin response was markedly increased at MMT+1d, compared to MMT-4w and MMT-1d(2.4- and 2.8-fold). At MMT+6w a more rapid rise was evident. GLP-1 levels were similar in all MMTs except MMT+6w where anincreased response was seen; this was stronger in T2D vs. C. The GIP-response was higher at MMT+1d, compared to MMT-4w andMMT-1d (1.6- and 1.4-fold). The increased GIP-response was attenuated in C at MMT+6w, but still evident in T2D.Conclusions: VLCD has minor impact on the parameters analyzed; rather GBP per se elicits an immediate stimulatory effect on insulinand GIP levels in response to an MMT as first meal on day 1 after surgery.
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23.
  • BERGGREN, JOHAN, et al. (författare)
  • Roux-en-Y gastric bypass versus calorie restriction: support for surgery as the direct contributor to aloncltered responses of insulin and incretins to a mixed meal
  • 2017
  • Ingår i: Surgery for Obesity and Related Diseases. - : Elsevier BV. - 1550-7289. ; 13:2, s. 234-242
  • Tidskriftsartikel (refereegranskat)abstract
    • AbstractObjectiveTo study the immediate effects of Roux-en-Y gastric bypass (RYGB) on glucose homeostasis, insulin, and incretin responses to mixed-meal tests compared with the effects of calorie restriction (CR).SettingUniversity-affiliated bariatric surgery clinic.BackgroundRYGB induces remission of type 2 diabetes (T2 D) long before significant weight loss occurs. The time course and underlying mechanisms of this remission remain enigmatic. A prevailing theory is that secretory patterns of incretin hormones are altered due to rearrangement of the gastrointestinal tract. To what extent reduced calorie intake contributes to the remission of T2 D is unknown.MethodsNine normoglycemic patients and 10 T2 D patients were subjected to mixed-meal tests (MMT) 4 weeks before surgery before initiation of a very low calorie diet regimen (MMT-4 w), 1 day before surgery on a very low calorie diet regimen (MMT-1 d), on the morning of the first day after surgery (MMT+1 d; first postsurgical meal), and 6 weeks after surgery (MMT+6 w). Insulin, glucose, active glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) were measured.ResultsCR lowered insulin in T2 D patients, whereas glucose, GIP, and GLP-1 were unaffected. RYGB immediately increased plasma insulin and GIP. The GLP-1 response was delayed compared with the GIP response. T2 D patients exhibited lower insulin responses after RYGB compared with normoglycemic patients. GIP responses were similar in both groups at all occasions, whereas T2 D patients displayed markedly elevated GLP-1 responses 6 weeks after RYGB. Glucose was unaffected by CR and RYGB in both groups. Insulin sensitivity was unaffected by CR but improved with RYGB.ConclusionRYGB exerts powerful and immediate effects on insulin and incretin responses to food, independently of changes caused by CR.
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24.
  • Björkqvist, Maria, et al. (författare)
  • The R6/2 transgenic mouse model of Huntington's disease develops diabetes due to deficient {beta}-cell mass and exocytosis.
  • 2005
  • Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 14:5, s. 565-574
  • Tidskriftsartikel (refereegranskat)abstract
    • Diabetes frequently develops in Huntington's disease (HD) patients and in transgenic mouse models of HD such as the R6/2 mouse. The underlying mechanisms have not been clarified. Elucidating the pathogenesis of diabetes in HD would improve our understanding of the molecular mechanisms involved in HD neuropathology. With this aim, we examined our colony of R6/2 mice with respect to glucose homeostasis and islet function. At week 12, corresponding to end-stage HD, R6/2 mice were hyperglycemic and hypoinsulinemic and failed to release insulin in an intravenous glucose tolerance test. In vitro, basal and glucose-stimulated insulin secretion was markedly reduced. Islet nuclear huntingtin inclusions increased dramatically over time, predominantly in ß-cells. ß-cell mass failed to increase normally with age in R6/2 mice. Hence, at week 12, ß-cell mass and pancreatic insulin content in R6/2 mice were 35±5 and 16±3% of that in wild-type mice, respectively. The normally occurring replicating cells were largely absent in R6/2 islets, while no abnormal cell death could be detected. Single cell patch-clamp experiments revealed unaltered electrical activity in R6/2 ß-cells. However, exocytosis was virtually abolished in ß- but not in {alpha}-cells. The blunting of exocytosis could be attributed to a 96% reduction in the number of insulin-containing secretory vesicles. Thus, diabetes in R6/2 mice is caused by a combination of deficient ß-cell mass and disrupted exocytosis.
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25.
  • Borg, Jörgen, et al. (författare)
  • Perilipin is present in islets of Langerhans and protects against lipotoxicity when overexpressed in the beta-cell line INS-1.
  • 2009
  • Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 150:7, s. 3049-3057
  • Tidskriftsartikel (refereegranskat)abstract
    • Lipids have been shown to play a dual role in pancreatic beta-cells - a lipid-derived signal appears to be necessary for glucose-stimulated insulin secretion, whereas lipid accumulation causes impaired insulin secretion and apoptosis. The ability of the protein perilipin to regulate lipolysis prompted an investigation of the presence of perilipin in the islets of Langerhans. In this study evidence is presented for perilipin expression in rat, mouse and human islets of Langerhans as well as in the rat clonal beta-cell line INS-1. In rat and mouse islets, perilipin was verified to be present in beta-cells. In order to examine if the development of lipotoxicity could be prevented by manipulating the conditions for lipid storage in the beta-cell, INS-1 cells with adenoviral-mediated overexpression of perilipin were exposed to lipotoxic conditions for 72 hours. In cells exposed to palmitate, perilipin overexpression caused increased accumulation of triacylglycerols and decreased lipolysis compared to control cells. Whereas glucose-stimulated insulin secretion was retained following palmitate exposure in cells overexpressing perilipin, it was completely abolished in control beta-cells. Thus, overexpression of perilipin appears to confer protection against the development of beta-cell dysfunction following prolonged exposure to palmitate by promoting lipid storage and limiting lipolysis.
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26.
  • Chu, Lianhe, et al. (författare)
  • In vivo drug discovery for increasing incretin-expressing cells identifies DYRK inhibitors that reinforce the enteroendocrine system
  • 2022
  • Ingår i: Cell Chemical Biology. - : Elsevier BV. - 2451-9456 .- 2451-9448. ; 29:9, s. 5-1380
  • Tidskriftsartikel (refereegranskat)abstract
    • Analogs of the incretin hormones Gip and Glp-1 are used to treat type 2 diabetes and obesity. Findings in experimental models suggest that manipulating several hormones simultaneously may be more effective. To identify small molecules that increase the number of incretin-expressing cells, we established a high-throughput in vivo chemical screen by using the gip promoter to drive the expression of luciferase in zebrafish. All hits increased the numbers of neurogenin 3-expressing enteroendocrine progenitors, Gip-expressing K-cells, and Glp-1-expressing L-cells. One of the hits, a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) inhibitor, additionally decreased glucose levels in both larval and juvenile fish. Knock-down experiments indicated that nfatc4, a downstream mediator of DYRKs, regulates incretin+ cell number in zebrafish, and that Dyrk1b regulates Glp-1 expression in an enteroendocrine cell line. DYRK inhibition also increased the number of incretin-expressing cells in diabetic mice, suggesting a conserved reinforcement of the enteroendocrine system, with possible implications for diabetes.
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27.
  • Dekker Nitert, Marloes, et al. (författare)
  • Impact of an Exercise Intervention on DNA Methylation in Skeletal Muscle From First-Degree Relatives of Patients With Type 2 Diabetes.
  • 2012
  • Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797.
  • Tidskriftsartikel (refereegranskat)abstract
    • To identify epigenetic patterns, which may predispose to type 2 diabetes (T2D) due to a family history (FH) of the disease, we analyzed DNA methylation genome-wide in skeletal muscle from individuals with (FH(+)) or without (FH(-)) an FH of T2D. We found differential DNA methylation of genes in biological pathways including mitogen-activated protein kinase (MAPK), insulin, and calcium signaling (P ≤ 0.007) and of individual genes with known function in muscle, including MAPK1, MYO18B, HOXC6, and the AMP-activated protein kinase subunit PRKAB1 in skeletal muscle of FH(+) compared with FH(-) men. We further validated our findings from FH(+) men in monozygotic twin pairs discordant for T2D, and 40% of 65 analyzed genes exhibited differential DNA methylation in muscle of both FH(+) men and diabetic twins. We further examined if a 6-month exercise intervention modifies the genome-wide DNA methylation pattern in skeletal muscle of the FH(+) and FH(-) individuals. DNA methylation of genes in retinol metabolism and calcium signaling pathways (P < 3 × 10(-6)) and with known functions in muscle and T2D including MEF2A, RUNX1, NDUFC2, and THADA decreased after exercise. Methylation of these human promoter regions suppressed reporter gene expression in vitro. In addition, both expression and methylation of several genes, i.e., ADIPOR1, BDKRB2, and TRIB1, changed after exercise. These findings provide new insights into how genetic background and environment can alter the human epigenome.
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28.
  • Edlund, Anna, et al. (författare)
  • CFTR is involved in the regulation of glucagon secretion in human and rodent alpha cells
  • 2017
  • Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1, s. 90-
  • Tidskriftsartikel (refereegranskat)abstract
    • Glucagon is the main counterregulatory hormone in the body. Still, the mechanism involved in the regulation of glucagon secretion from pancreatic alpha cells remains elusive. Dysregulated glucagon secretion is common in patients with Cystic Fibrosis (CF) that develop CF related diabetes (CFRD). CF is caused by a mutation in the Cl− channel Cystic fibrosis transmembrane conductance regulator (CFTR), but whether CFTR is present in human alpha cells and regulate glucagon secretion has not been investigated in detail. Here, both human and mouse alpha cells showed CFTR protein expression, whereas CFTR was absent in somatostatin secreting delta cells. CFTR-current activity induced by cAMP was measured in single alpha cells. Glucagon secretion at different glucose levels and in the presence of forskolin was increased by CFTR-inhibition in human islets, whereas depolarization-induced glucagon secretion was unaffected. CFTR is suggested to mainly regulate the membrane potential through an intrinsic alpha cell effect, as supported by a mathematical model of alpha cell electrophysiology. In conclusion, CFTR channels are present in alpha cells and act as important negative regulators of cAMP-enhanced glucagon secretion through effects on alpha cell membrane potential. Our data support that loss-of-function mutations in CFTR contributes to dysregulated glucagon secretion in CFRD.
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29.
  • Edlund, Anna, et al. (författare)
  • Defective exocytosis and processing of insulin in a cystic fibrosis mouse model
  • 2019
  • Ingår i: Journal of Endocrinology. - 1479-6805. ; 241:1, s. 45-57
  • Tidskriftsartikel (refereegranskat)abstract
    • Cystic fibrosis-related diabetes (CFRD) is a common complication for patients with cystic fibrosis (CF), a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). The cause of CFRD is unclear, but a commonly observed reduction in first-phase insulin secretion suggests defects at the beta cell level. Here we aimed to examine beta- and alpha-cell function in the Cftrtm1EUR/F508del mouse model (C57BL/6J), which carries the most common human mutation in CFTR, the F508del mutation. CFTR expression, beta cell mass, insulin granule distribution, hormone secretion and single cell capacitance changes were evaluated using islets (or beta cells) from F508del mice and age-matched wild-type mice aged 7-10 weeks. Granular pH was measured with DND-189 fluorescence. Serum glucose, insulin and glucagon levels were measured in vivo, and glucose tolerance was assessed using IPGTT. We show increased secretion of proinsulin and concomitant reduced secretion of C-peptide in islets from F508del mice compared to WT mice. Exocytosis and number of docked granules was reduced. We confirmed reduced granular pH by CFTR stimulation. We detected decreased pancreatic beta cell area, but unchanged beta cell number. Moreover, the F508del mutation caused failure to suppress glucagon secretion leading to hyperglucagonemia. In conclusion, F508del mice have beta cell defects resulting in 1) reduced number of docked insulin granules and reduced exocytosis, and 2) potential defective proinsulin cleavage and secretion of immature insulin. These observations provide insight into the functional role of CFTR in pancreatic islets and contribute to increased understanding of the pathogenesis of CFRD.
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30.
  • Egerod, Kristoffer L, et al. (författare)
  • A Major Lineage of Enteroendocrine Cells Coexpress CCK, Secretin, GIP, GLP-1, PYY, and Neurotensin but Not Somatostatin.
  • 2012
  • Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170.
  • Tidskriftsartikel (refereegranskat)abstract
    • Enteroendocrine cells such as duodenal cholecystokinin (CCK cells) are generally thought to be confined to certain segments of the gastrointestinal (GI) tract and to store and release peptides derived from only a single peptide precursor. In the current study, however, transgenic mice expressing enhanced green fluorescent protein (eGFP) under the control of the CCK promoter demonstrated a distribution pattern of CCK-eGFP positive cells that extended throughout the intestine. Quantitative PCR and liquid chromatography-mass spectrometry proteomic analyses of isolated, FACS-purified CCK-eGFP-positive cells demonstrated expression of not only CCK but also glucagon-like peptide 1 (GLP-1), gastric inhibitory peptide (GIP), peptide YY (PYY), neurotensin, and secretin, but not somatostatin. Immunohistochemistry confirmed this expression pattern. The broad coexpression phenomenon was observed both in crypts and villi as demonstrated by immunohistochemistry and FACS analysis of separated cell populations. Single-cell quantitative PCR indicated that approximately half of the duodenal CCK-eGFP cells express one peptide precursor in addition to CCK, whereas an additional smaller fraction expresses two peptide precursors in addition to CCK. The coexpression pattern was further confirmed through a cell ablation study based on expression of the human diphtheria toxin receptor under the control of the proglucagon promoter, in which activation of the receptor resulted in a marked reduction not only in GLP-1 cells, but also PYY, neurotensin, GIP, CCK, and secretin cells, whereas somatostatin cells were spared. Key elements of the coexpression pattern were confirmed by immunohistochemical double staining in human small intestine. It is concluded that a lineage of mature enteroendocrine cells have the ability to coexpress members of a group of functionally related peptides: CCK, secretin, GIP, GLP-1, PYY, and neurotensin, suggesting a potential therapeutic target for the treatment and prevention of diabetes and obesity.
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31.
  • Egerod, Kristoffer L., et al. (författare)
  • beta-Cell Specific Overexpression of GPR39 Protects against Streptozotocin-Induced Hyperglycemia
  • 2011
  • Ingår i: International Journal of Endocrinology. - : Hindawi Limited. - 1687-8337 .- 1687-8345.
  • Tidskriftsartikel (refereegranskat)abstract
    • Mice deficient in the zinc-sensor GPR39, which has been demonstrated to protect cells against endoplasmatic stress and cell death in vitro, display moderate glucose intolerance and impaired glucose-induced insulin secretion. Here, we use the Tet-On system under the control of the proinsulin promoter to selectively overexpress GPR39 in the beta cells in a double transgenic mouse strain and challenge them with multiple low doses of streptozotocin, which in the wild-type littermates leads to a gradual increase in nonfasting glucose levels and glucose intolerance observed during both food intake and OGTT. Although the overexpression of the constitutively active GPR39 receptor in animals not treated with streptozotocin appeared by itself to impair the glucose tolerance slightly and to decrease the beta-cell mass, it nevertheless totally protected against the gradual hyperglycemia in the steptozotocin-treated animals. It is concluded that GPR39 functions in a beta-cell protective manner and it is suggested that it is involved in some of the beneficial, beta-cell protective effects observed for Zn(++) and that GPR39 may be a target for antidiabetic drug intervention.
  •  
32.
  • Ekblad, Eva, et al. (författare)
  • Cocaine- and amphetamine-regulated transcript: distribution and function in rat gastrointestinal tract.
  • 2003
  • Ingår i: Neurogastroenterology and Motility. - : Wiley. - 1350-1925 .- 1365-2982. ; 15:5, s. 545-557
  • Tidskriftsartikel (refereegranskat)abstract
    • Cocaine- and amphetamine-regulated transcript (CART) peptide, originally isolated from brain, is also expressed in the peripheral nervous system. The distribution, origin and projections of CART-expressing enteric neurones by immunocytochemistry and in situ hybridization in rat gastrointestinal (GI) tract were studied. Possible motor functions of CART were studied in vitro using longitudinal muscle strips from stomach, ileum and colon. Cocaine- and amphetamine-regulated transcript peptide was found in numerous myenteric neurones throughout the GI tract while CART-expressing submucous neurones were scarce. Cocaine- and amphetamine-regulated transcript was also expressed in the antral gastrin cells. Myenteric CART-expressing neurones in both small and large intestine issued short descending projections. In atrophic ileum, CART mRNA-expressing neurones increased in number while neurones containing CART peptide decreased. In hypertrophied ileum, no change in CART peptide or CART mRNA containing myenteric neurones was detected. Cocaine- and amphetamine-regulated transcript 55-102 (10-9-10-7 mol L-1) did not induce any contractile or relaxatory responses in the muscle strips, neither did it affect responses induced by vasoactive intestinal peptide, pituitary adenylate cyclase-activating peptide or neuronal stimulation. In colonic, but not in ileal, strips addition of CART attenuated nitric oxide (NO) donor-induced relaxations. Although CART does not seem to play a pivotal role in classic neurotransmission to the longitudinal muscle, it may serve a modulatory role in NO transmission. It may, moreover, be involved in intestinal adaptation, and an additional hormonal role is also possible.
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33.
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34.
  • Falkmer, Ursula G., et al. (författare)
  • Malignant presacral ghrelinoma with long-standing hyperghrelinaemia
  • 2015
  • Ingår i: Uppsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 120:4, s. 299-304
  • Tidskriftsartikel (refereegranskat)abstract
    • Background. A 57-year old man with low-back pain was found to have a 3 x 3 x 3 cm presacral neuroendocrine tumour (NET) with widespread metastases, mainly to the skeleton. His neoplastic disease responded well to peptide receptor radionuclide therapy (PRRT) with the radiotagged somatostatin agonist Lu-177-DOTATATE. During almost 10 years he was fit for a normal life. He succumbed to an intraspinal dissemination. Procedures. A resection of the rectum, with a non-radical excision of the adjacent NET, was made. In addition to computerized tomography (CT), receptor positron emission tomography (PET) with Ga-68-labelled somatostatin analogues was used. Observations. The NET showed the growth pattern and immunoprofile of a G2 carcinoid. A majority cell population displayed immunoreactivity to ghrelin, exceptionally with co-immunoreactivity to motilin. Somatostatin receptor scintigraphy and Ga-68-DOTATATE PET-CT demonstrated uptake in the metastatic lesions. High serum concentrations of total (desacyl-)ghrelin were found with fluctuations reflecting the severity of the symptoms. In contrast, the concentrations of active (acyl-)ghrelin were consistently low, as were those of chromogranin A (CgA).Conclusions. Neoplastically transformed ghrelin cells can release large amounts of desacyl-ghrelin, evoking an array of non-specific clinical symptoms. Despite an early dissemination to the skeleton, a ghrelinoma can be compatible with longevity after adequate radiotherapy.
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35.
  • Fex, Malin, et al. (författare)
  • A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis.
  • 2009
  • Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 52, s. 271-280
  • Tidskriftsartikel (refereegranskat)abstract
    • AIMS/HYPOTHESIS: The enzyme hormone-sensitive lipase (HSL) is produced and is active in pancreatic beta cells. Because lipids are known to play a crucial role in normal control of insulin release and in the deterioration of beta cell function, as observed in type 2 diabetes, actions of HSL in beta cells may be critical. This notion has been addressed in different lines of HSL knockout mice with contradictory results. METHODS: To resolve this, we created a transgenic mouse lacking HSL specifically in beta cells, and characterised this model with regard to glucose metabolism and insulin secretion, using both in vivo and in vitro methods. RESULTS: We found that fasting basal plasma glucose levels were significantly elevated in mice lacking HSL in beta cells. An IVGTT at 12 weeks revealed a blunting of the initial insulin response to glucose with delayed elimination of the sugar. Additionally, arginine-stimulated insulin secretion was markedly diminished in vivo. Investigation of the exocytotic response in single HSL-deficient beta cells showed an impaired response to depolarisation of the plasma membrane. Beta cell mass and islet insulin content were increased, suggesting a compensatory mechanism, by which beta cells lacking HSL strive to maintain normoglycaemia. CONCLUSIONS/INTERPRETATION: Based on these results, we suggest that HSL, which is located in close proximity of the secretory granules, may serve as provider of a lipid-derived signal essential for normal insulin secretion.
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36.
  • Fex, Malin, et al. (författare)
  • Enhanced mitochondrial metabolism may account for the adaptation to insulin resistance in islets from C57BL/6J mice fed a high-fat diet.
  • 2007
  • Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 50:1, s. 74-83
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim/hypothesis Hyperinsulinaemia maintains euglycaemia in insulin-resistant states. The precise cellular mechanisms by which the beta cells adapt are still unresolved. A peripherally derived cue, such as increased circulating fatty acids, may instruct the beta cell to initiate an adaptive programme to maintain glucose homeostasis. When this fails, type 2 diabetes ensues. Because mitochondria play a key role in beta cell pathophysiology, we tested the hypothesis that mitochondrial metabolism is critical for beta cell adaptation to insulin resistance. Methods C57BL/6J mice were given high-fat (HF) diet for 12 weeks. We then analysed islet hormone secretion, metabolism in vivo and in vitro, and beta cell morphology. Results HF diet resulted in insulin resistance and glucose intolerance but not frank diabetes. Basal insulin secretion was elevated in isolated islets from HF mice with almost no additional response provoked by high glucose. In contrast, a strong secretory response was seen when islets from HF mice were stimulated with fuels that require mitochondrial metabolism, such as glutamate, glutamine, alpha-ketoisocaproic acid and succinate. Moreover, while glucose oxidation was impaired in islets from HF mice, oxidation of glutamine and palmitate was enhanced. Ultrastructural analysis of islets in HF mice revealed an accumulation of lipid droplets in beta cells and a twofold increase in mitochondrial area. Conclusions/interpretation We propose that beta cells exposed to increased lipid flux in insulin resistance respond by increasing mitochondrial volume. This expansion is associated with enhanced mitochondrial metabolism as a means of beta cell compensation. Electronic supplementary material Supplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s00125-006-0464-4 and is accessible to authorised users.
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37.
  • Fex, Malin, et al. (författare)
  • Rat insulin promoter 2-Cre recombinase mice bred onto a pure C57BL/6J background exhibit unaltered glucose tolerance
  • 2007
  • Ingår i: Journal of Endocrinology. - 1479-6805. ; 194:3, s. 551-555
  • Tidskriftsartikel (refereegranskat)abstract
    • beta-Cell-specific gene targeting is a widely used tool when studying genes involved in beta-cell function. For this purpose, several conditional beta-cell knockouts have been generated using the rat insulin promoter 2-Cre recombinase (RIP2-Cre) mouse. However, it was recently observed that expression of Cre alone in P-cells may affect whole body glucose homeostasis. Therefore, we investigated glucose homeostasis, insulin secretion, and beta-cell mass in our line of RIP2-Cre mice bred onto the C57BL/6J genetic background. We used 12- and 28-week-old female RIP2-Cre mice for analyses of insulin secretion in vitro, glucose homeostasis in vivo and beta-cell mass. Our mouse line has been backcrossed for 14 generations to yield a near 100% pure C57BL/6J background. We found that fasting plasma glucose and insulin levels were similar in both genotypes. An i.v. glucose tolerance test revealed no differences in glucose clearance and insulin secretion between 12-week-old RIP2-Cre and WT mice. Moreover, insulin secretion hi vitro in islets isolated from 28-week-old RIP2-Cre mice and controls was similar. In addition, beta-cell mass was not different between the two genotypes at 28 weeks of age. In our experiments, we observed no differences in glucose tolerance, insulin secretion in vivo and in vitro, or in beta-cell mass between the genotypes. As our RIP2-Cre mice are on a near 100% pure genetic background (C57BL/6J), we suggest that the perturbations in glucose homeostasis previously reported in RIP2-Cre mouse lines can be accounted for by differences in genetic background.
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38.
  • Friis-Hansen, L, et al. (författare)
  • Antral G-cell in gastrin and gastrin-cholecystokinin knockout animals
  • 2005
  • Ingår i: Cell and Tissue Research. - : Springer Science and Business Media LLC. - 1432-0878 .- 0302-766X. ; 321:1, s. 141-146
  • Tidskriftsartikel (refereegranskat)abstract
    • The antral hormone gastrin is the key regulator of gastric acid secretion, mucosal growth and differentiation. Gastrin is synthesized in the endocrine G-cells in the antroduodenal mucosa. We have now examined the way in which the loss of gastrin alone or gastrin plus cholecystokinin (CCK) affects the antral G-cell. Immunohistochemistry, radioimmunoassay and quantitative real-time polymerase chain reaction techniques were employed to examine the expression of genes belonging to the G-cell secretory pathway in gastrin and gastrin-CCK knockout mice. Transmission electron microscopy was used to examine the ultrastructure of the G-cells. The number of G-cells increased but the secretory granules were few and abnormally small in the G-cells of both mouse models compared with wildtypes. Thus, gastrin is not necessary for the formation of G-cells as such but the lack of gastrin reduces the number and size of their secretory granules suggesting that gastrin is vital for the formation and/or maintenance of secretory granules in G-cells.
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39.
  • Friis-Hansen, Lennart, et al. (författare)
  • Reduced ghrelin, IAPP and PYY expression in the stomach of gastrin-cholecystokinin knockout mice.
  • 2005
  • Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 146:10, s. 4464-4471
  • Tidskriftsartikel (refereegranskat)abstract
    • The antral hormone gastrin and its intestinal relative, cholecystokinin (CCK), are pivotal in the regulation of gastric functions. Other gastric hormones like ghrelin, peptide YY (PYY), and islet amyloid polypeptide (IAPP), however, also contribute to the regulation of acid secretion, motility, and feeding. Because gastrin and CCK are crucial for gastric homeostasis, we examined how loss of gastrin alone and gastrin plus CCK affected the expression of ghrelin, IAPP, and PYY and ghrelin secretion. The expression of ghrelin, IAPP, and PYY and the CCK-A receptor genes were examined in both gastrin and gastrin-CCK double-knockout (KO) mice using immunocytochemistry and quantitative RT-PCR. Ghrelin concentrations in plasma were measured using RIA. Gastrin and CCK were infused in gastrin-CCK KO mice using osmotic minipumps. The number of ghrelin cells and ghrelin gene expression were unaffected, albeit the ghrelin cells were located closer to the base of the glands in both KO mouse strains when freely fed. However, lack of both gastrin and CCK attenuated fasting-induced ghrelin expression and secretion. Fundic ghrelin cells expressed the CCK-A receptor, and ghrelin expression increased after CCK infusion. Furthermore, gastric IAPP and PYY expression as well as the number of IAPP- and PYY-containing cells were reduced in both gastrin and gastrin-CCK KO mice. Gastrin infusion increased gastric IAPP but not PYY expression. In conclusion, lack of gastrin plus CCK but not gastrin alone reduced ghrelin secretion in response to fasting through both direct and indirect mechanisms. Both gastrin and combined gastrin-CCK deficiency reduced the gastric IAPP and PYY expression.
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40.
  • Fåk, Frida, et al. (författare)
  • Gastric ghrelin cell development is hampered and plasma ghrelin is reduced by delayed weaning in rats
  • 2007
  • Ingår i: Journal of Endocrinology. - : Bioscientifica. - 1479-6805 .- 0022-0795. ; 192:2, s. 345-352
  • Tidskriftsartikel (refereegranskat)abstract
    • The duration of breastfeeding has attracted much interest, as a prolonged period of breastfeeding has been shown to reduce the risk of developing obesity. The mechanism behind the reduced risk is, however, poorly understood. The novel hormone ghrelin augments appetite, promotes body. weight increase and increases adiposity. The majority of circulating ghrelin emanates from endocrine cells in the oxyntic mucosa of the stomach. In newborn humans and rodents, the number of ghrelin cells is low after birth until weaning, when the cell population is greatly expanded. To date, information about the influence of weaning perturbations on ghrelin cell development is scarce. Therefore, we studied the effect of delayed weaning on gastric ghrelin expression and plasma ghrelin concentration. To this end, special food separator cages were used to prevent the pups from eating solid food, forcing them to drink milk up to 21 days of age. Gastric ghrelin expression was examined by immunocytochemistry and in situ hybridisation, and plasma concentrations were assessed by RIA. Our data showed that gastric ghrelin expression and plasma ghrelin concentration are maintained at a lower level by delayed weaning. We also found that the relation between gastric ghrelin expression and body weight was altered by delayed weaning. Thus, control rats displayed a positive correlation between ghrelin expression and body weight, while no such correlation was evident in animals with delayed weaning. We conclude that delayed weaning exerts a negative influence on ghrelin expression, and that the onset of solid food intake may trigger normal ghrelin expression. Therefore, we suggest that ghrelin may constitute a hormonal link between the duration of breastfeeding and body weight development.
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41.
  • Gao, Xiang, et al. (författare)
  • Effects of GIP on regional blood flow during normoglycemia and hyperglycemia in anesthetized rats
  • 2018
  • Ingår i: Physiological Reports. - : Wiley. - 2051-817X. ; 6:8
  • Tidskriftsartikel (refereegranskat)abstract
    • The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) potentiates glucose-stimulated insulin secretion, and affects -cell turnover. This study aimed at evaluating if some of the beneficial effects of GIP on glucose homeostasis can be explained by modulation of islet blood flow. Anesthetized Sprague-Dawley rats were infused intravenously with different doses of GIP (10, 20, or 60ng/kg*min) for 30min. Subsequent organ blood flow measurements were performed with microspheres. In separate animals, islets were perfused exvivo with GIP (10(-6)-10(-12)mol/L) during normo- and hyperglycemia and arteriolar responsiveness was recorded. The highest dose of GIP potentiated insulin secretion during hyperglycemia, but had no effect in normoglycemic rats. The highest GIP concentration decreased blood perfusion of whole pancreas, pancreatic islets, duodenum, colon, liver and kidneys. The decrease in blood flow was unaffected by ganglion blockade or adenosine receptor inhibition. In contrast to this, in single perfused islets GIP induced a dose-dependent arteriolar dilation. Thus, high doses of GIP exert a direct dilatory effect on islet arterioles in isolated islets, but induce a generalized vasoconstriction in splanchnic organs, including the whole pancreas and islets, invivo. The latter effect is unlikely to be mediated by adenosine, the autonomic nervous system, or endothelial mediators.
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42.
  • Gram, Dorte X., et al. (författare)
  • Capsaicin-sensitive sensory fibers in the islets of Langerhans contribute to defective insulin secretion in Zucker diabetic rat, an animal model for some aspects of human type 2 diabetes
  • 2007
  • Ingår i: European Journal of Neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 25:1, s. 213-223
  • Tidskriftsartikel (refereegranskat)abstract
    • The system that regulates insulin secretion from beta-cells in the islet of Langerhans has a capsaicin-sensitive inhibitory component. As calcitonin gene-related peptide (CGRP)-expressing primary sensory fibers innervate the islets, and a major proportion of the CGRP-containing primary sensory neurons is sensitive to capsaicin, the islet-innervating sensory fibers may represent the capsaicin-sensitive inhibitory component. Here, we examined the expression of the capsaicin receptor, vanilloid type 1 transient receptor potential receptor (TRPV1) in CGRP-expressing fibers in the pancreatic islets, and the effect of selective elimination of capsaicin-sensitive primary afferents on the decline of glucose homeostasis and insulin secretion in Zucker diabetic fatty (ZDF) rats, which are used to study various aspects of human type 2 diabetes mellitus. We found that CGRP-expressing fibers in the pancreatic islets also express TRPV1. Furthermore, we also found that systemic capsaicin application before the development of hyperglycemia prevents the increase of fasting, non-fasting, and mean 24-h plasma glucose levels, and the deterioration of glucose tolerance assessed on the fifth week following the injection. These effects were accompanied by enhanced insulin secretion and a virtually complete loss of CGRP- and TRPV1-coexpressing islet-innervating fibers. These data indicate that CGRP-containing fibers in the islets are capsaicin sensitive, and that elimination of these fibers contributes to the prevention of the deterioration of glucose homeostasis through increased insulin secretion in ZDF rats. Based on these data we propose that the activity of islet-innervating capsaicin-sensitive fibers may have a role in the development of reduced insulin secretion in human type 2 diabetes mellitus.
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43.
  • Gunnarsdottir, Anna, et al. (författare)
  • CART-peptide immunoreactivity in enteric nerves in patients with Hirschsprung's disease
  • 2007
  • Ingår i: European Journal of Pediatric Surgery. - : Georg Thieme Verlag KG. - 1439-359X .- 0939-7248. ; 17:3, s. 184-189
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims: Cocaine- and amphetamine-regulated transcript (CART)-peptide is found in the brain and participates in the control of feeding behavior. It is also expressed in the peripheral nervous system and is suggested to have neuromodulatory and/or neurotrophic effects in rat intestine. The aims of this study were to investigate the presence of CART-peptide in the normal ganglionic as well as aganglionic intestine from patients with Hirschsprung's disease and the pepticle's possible coexistence with other neurotransmitters. Methods: Intestinal specimens from nine patients with Hirschsprung's disease were examined using immunohistochemistry. A double immunostaining technique was used in order to elucidate the presence of CART-peptide in NOS and VIP-containing enteric neurons. Results: in ganglionic intestine, CART-peptide was found in numerous nerve fibers, predominantly within the smooth muscle layers and in myenteric nerve cell bodies. A high degree of co-localization of CART with NOS and VIP was seen. Only very few CART immunoreactive nerve fibers and no nerve cell bodies were found in the aganglionic intestine. Conclusions: This is the first report on the presence of CART-peptide in the human intestine. In the ganglionic intestine CART was detected mainly in myenteric neurons, while only very few CART-IR nerve fibers were found in the aganglionic intestine. This, together with the coexistence of CART with NOS and VIP, indicates an intrinsic origin of the CART-containing neurons and suggests that CART may influence NO and VIP-induced effects.
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44.
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45.
  • Herzog, Katharina, et al. (författare)
  • Metabolic Effects of Gastric Bypass Surgery : Is It All About Calories?
  • 2020
  • Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 69:9, s. 2027-2035
  • Tidskriftsartikel (refereegranskat)abstract
    • Bariatric surgery is an efficient method to induce weight loss and also, frequently, remission of type 2 diabetes (T2D). Unpaired studies have shown bariatric surgery and dietary interventions to differentially affect multiple hormonal and metabolic parameters, suggesting that bariatric surgery causes T2D remission at least partially via unique mechanisms. In the current study, plasma metabolite profiling was conducted in patients with (n = 10) and without T2D (n = 9) subjected to Roux-en-Y gastric bypass surgery (RYGB). Mixed-meal tests were conducted at baseline, after the presurgical very-low-calorie diet (VLCD) intervention, immediately after RYGB, and after a 6-week recovery period. Thereby, we could compare fasted and postprandial metabolic consequences of RYGB and VLCD in the same patients. VLCD yielded a pronounced increase in fasting acylcarnitine levels, whereas RYGB, both immediately and after a recovery period, resulted in a smaller but opposite effect. Furthermore, we observed profound changes in lipid metabolism following VLCD but not in response to RYGB. Most changes previously associated with RYGB were found to be consequences of the presurgical dietary intervention. Overall, our results question previous findings of unique metabolic effects of RYGB and suggest that the effect of RYGB on the metabolite profile is mainly attributed to caloric restriction.
  •  
46.
  • Holst, Birgitte, et al. (författare)
  • G Protein-Coupled Receptor 39 Deficiency Is Associated with Pancreatic Islet Dysfunction
  • 2009
  • Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 150, s. 2577-2585
  • Tidskriftsartikel (refereegranskat)abstract
    • G protein-coupled receptor (GPR)-39 is a seven-transmembrane receptor expressed mainly in endocrine and metabolic tissues that acts as a Zn++ sensor signaling mainly through the G(q) and G(12/13) pathways. The expression of GPR39 is regulated by hepatocyte nuclear factor (HNF)-1 alpha and HNF-4 alpha, and in the present study, we addressed the importance of GPR39 for glucose homeostasis and pancreatic islets function. The expression and localization of GPR39 were characterized in the endocrine pancreas and pancreatic cell lines. Gpr39(-/-) mice were studied in vivo, especially in respect of glucose tolerance and insulin sensitivity, and in vitro in respect of islet architecture, gene expression, and insulin secretion. Gpr39 was down-regulated on differentiation of the pluripotent pancreatic cell line AR42J cells toward the exocrine phenotype but was along with Pdx-1 strongly up-regulated on differentiation toward the endocrine phenotype. Immunohistochemistry demonstrated that GRP39 is localized selectively in the insulin-storing cells of the pancreatic islets as well as in the duct cells of the exocrine pancreas. Gpr39(-/-) mice displayed normal insulin sensitivity but moderately impaired glucose tolerance both during oral and iv glucose tolerance tests, and Gpr39(-/-) mice had decreased plasma insulin response to oral glucose. Islet architecture was normal in the Gpr39 null mice, but expression of Pdx-1 and Hnf-1 alpha was reduced. Isolated, perifused islets from Gpr39 null mice secreted less insulin in response to glucose stimulation than islets from wild-type littermates. It is concluded that GPR39 is involved in the control of endocrine pancreatic function, and it is suggested that this receptor could be a novel potential target for the treatment of diabetes. (Endocrinology 150: 2577-2585, 2009)
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47.
  • Honka, Henri, et al. (författare)
  • Bariatric surgery enhances splanchnic vascular responses in patients with type 2 diabetes
  • 2017
  • Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:4, s. 880-885
  • Tidskriftsartikel (refereegranskat)abstract
    • Bariatric surgery results in notable weight loss and alleviates hyperglycemia in patients with type 2 diabetes (T2D). We aimed to characterize the vascular effects of a mixedmeal and infusion of exogenous glucose-dependent insulinotropic polypeptide (GIP) in the splanchnic region in 10 obese patients with T2D before and after bariatric surgery and in 10 lean control subjects. The experiments were carried out on two separate days. Pancreatic and intestinal blood flow (BF) were measured at baseline, 20 min, and 50 min with 15O-water by using positron emission tomography and MRI. Before surgery, pancreatic and intestinal BF responses to a mixed meal did not differ between obese and lean control subjects. Compared with presurgery, the mixed meal induced a greater increase in plasma glucose, insulin, and GIP concentrations after surgery, which was accompanied by a marked augmentation of pancreatic and intestinal BF responses. GIP infusion decreased pancreatic but increased small intestinal BF similarly in all groups both before and after surgery. Taken together, these results demonstrate that bariatric surgery leads to enhanced splanchnic vascular responses as a likely consequence of rapid glucose appearance and GIP hypersecretion.
  •  
48.
  • Honka, Henri, et al. (författare)
  • Liver blood dynamics after bariatric surgery : The effects of mixed-meal test and incretin infusions
  • 2018
  • Ingår i: Endocrine Connections. - 2049-3614. ; 7:7, s. 888-896
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims/hypothesis: The mechanisms for improved glycemic control after bariatric surgery in subjects with type 2 diabetes (T2D) are not fully known. We hypothesized that dynamic hepatic blood responses to a mixed-meal are changed after bariatric surgery in parallel with an improvement in glucose tolerance. Methods: A total of ten morbidly obese subjects with T2D were recruited to receive a mixed-meal and a glucose-dependent insulinotropic polypeptide (GIP) infusion before and early after (within a median of less than three months) bariatric surgery, and hepatic blood flow and volume (HBV) were measured repeatedly with combined positron emission tomography/MRI. Ten lean non-diabetic individuals served as controls. Results: Bariatric surgery leads to a significant decrease in weight, accompanied with an improved β-cell function and glucagon-like peptide 1 (GLP-1) secretion, and a reduction in liver volume. Blood flow in portal vein (PV) was increased by 1.65-fold (P = 0.026) in response to a mixed-meal in subjects after surgery, while HBV decreased in all groups (P < 0.001). When the effect of GIP infusion was tested separately, no change in hepatic arterial and PV flow was observed, but HBV decreased as seen during the mixed-meal test. Conclusions/interpretation: Early after bariatric surgery, PV flow response to a mixed-meal is augmented, improving digestion and nutrient absorption. GIP influences the post-prandial reduction in HBV thereby diverting blood to the extrahepatic sites.
  •  
49.
  • Härndahl, Linda, et al. (författare)
  • Beta-cell-targeted overexpression of phosphodiesterase 3B in mice causes impaired insulin secretion, glucose intolerance, and deranged islet morphology.
  • 2004
  • Ingår i: The Journal of biological chemistry. - 0021-9258 .- 1083-351X. ; 279:15, s. 15214-22
  • Tidskriftsartikel (refereegranskat)abstract
    • The second messenger cAMP mediates potentiation of glucose-stimulated insulin release. Use of inhibitors of cAMP-hydrolyzing phosphodiesterase (PDE) 3 and overexpression of PDE3B in vitro have demonstrated a regulatory role for this enzyme in insulin secretion. In this work, the physiological significance of PDE3B-mediated degradation of cAMP for the regulation of insulin secretion in vivo and glucose homeostasis was investigated in transgenic mice overexpressing PDE3B in pancreatic beta-cells. A 2-fold overexpression of PDE3B protein and activity blunted the insulin response to intravenous glucose, resulting in reduced glucose disposal. The effects were "dose"-dependent because mice overexpressing PDE3B 7-fold failed to increase insulin in response to glucose and hence exhibited pronounced glucose intolerance. Also, the insulin secretory response to intravenous glucagon-like peptide 1 was reduced in vivo. Similarly, islets stimulated in vitro exhibited reduced insulin secretory capacity in response to glucose and glucagon-like peptide 1. Perifusion experiments revealed that the reduction specifically affected the first phase of glucose-stimulated insulin secretion. Furthermore, morphological examinations demonstrated deranged islet cytoarchitecture. In conclusion, these results are consistent with an essential role for PDE3B in cAMP-mediated regulation of insulin release and glucose homeostasis.
  •  
50.
  • Johansson, Bente Berg, et al. (författare)
  • Nuclear import of glucokinase in pancreatic beta-cells is mediated by a nuclear localization signal and modulated by SUMOylation
  • 2017
  • Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207. ; 454, s. 146-157
  • Tidskriftsartikel (refereegranskat)abstract
    • The localization of glucokinase in pancreatic beta-cell nuclei is a controversial issue. Although previous reports suggest such a localization, the mechanism for its import has so far not been identified. Using immunofluorescence, subcellular fractionation and mass spectrometry, we present evidence in support of glucokinase localization in beta-cell nuclei of human and mouse pancreatic sections, as well as in human and mouse isolated islets, and murine MIN6 cells. We have identified a conserved, seven-residue nuclear localization signal (30LKKVMRR36) in the human enzyme. Substituting the residues KK31,32 and RR35,36 with AA led to a loss of its nuclear localization in transfected cells. Furthermore, our data indicates that SUMOylation of glucokinase modulates its nuclear import, while high glucose concentrations do not significantly alter the enzyme nuclear/cytosolic ratio. Thus, for the first time, we provide data in support of a nuclear import of glucokinase mediated by a redundant mechanism, involving a nuclear localization signal, and which is modulated by its SUMOylation. These findings add new knowledge to the functional role of glucokinase in the pancreatic beta-cell.
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