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  • 1. Abrahamsson, Niclas
    et al.
    Borjesson, Joey Lau
    Sundbom, Magnus
    Wiklund, Urban
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Karlsson, F. Anders
    Eriksson, Jan W.
    Gastric Bypass Reduces Symptoms and Hormonal Responses in Hypoglycemia2016Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, nr 9, s. 2667-2675Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Gastric bypass (GBP) surgery, one of the most common bariatric procedures, induces weight loss and metabolic effects. The mechanisms are not fully understood, but reduced food intake and effects on gastrointestinal hormones are thought to contribute. We recently observed that GBP patients have lowered glucose levels and frequent asymptomatic hypoglycemic episodes. Here, we subjected patients before and after undergoing GBP surgery to hypoglycemia and examined symptoms and hormonal and autonomic nerve responses. Twelve obese patients without diabetes (8 women, mean age 43.1 years [SD 10.8] and BMI 40.6 kg/m(2) [SD 3.1]) were examined before and 23 weeks (range 19-25) after GBP surgery with hyperinsulinemic-hypoglycemic clamp (stepwise to plasma glucose 2.7 mmol/L). The mean change in Edinburgh Hypoglycemia Score during clamp was attenuated from 10.7 (6.4) before surgery to 5.2 (4.9) after surgery. There were also marked postsurgery reductions in levels of glucagon, cortisol, and catecholamine and the sympathetic nerve responses to hypoglycemia. In addition, growth hormone displayed a delayed response but to a higher peak level. Levels of glucagon-like peptide 1 and gastric inhibitory polypeptide rose during hypoglycemia but rose less postsurgery compared with presurgery. Thus, GBP surgery causes a resetting of glucose homeostasis, which reduces symptoms and neurohormonal responses to hypoglycemia. Further studies should address the underlying mechanisms as well as their impact on the overall metabolic effects of GBP surgery.

  • 2.
    Alanentalo, Tomas
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Hörnblad, Andreas
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Mayans, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Nilsson, Anna Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sharpe, James
    Larefalk, Åsa
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Holmberg, Dan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Quantification and 3-D imaging of the insulitis-induced destruction of β-cells in murine type 1 diabetes2010Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 59, nr 7, s. 1756-1764Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: The aim of this study was to refine the information regarding the quantitative and spatial dynamics of infiltrating lymphocytes and remaining beta-cell volume during the progression of type 1 diabetes in the NOD mouse model of the disease.

    Research design and methods: Using an ex vivo technique, optical projection tomography (OPT), we quantified and assessed the 3D spatial development and progression of insulitis and beta-cell destruction in pancreas from diabetes prone NOD and non-diabetes prone congenic NOD.H-2b mice between 3 and 16 weeks of age.

    Results: Together with results showing the spatial dynamics of the insulitis process we provide data of beta-cell volume distributions down to the level of the individual islets and throughout the pancreas during the development and progression of type 1 diabetes. Our data provide evidence for a compensatory growth potential of the larger insulin(+) islets during the later stages of the disease around the time point for development of clinical diabetes. This is in contrast to smaller islets, which appear less resistant to the autoimmune attack. We also provide new information on the spatial dynamics of the insulitis process itself, including its apparently random distribution at onset, the local variations during its further development, and the formation of structures resembling tertiary lymphoid organs at later phases of insulitis progression.

    Conclusions: Our data provides a powerful tool for phenotypic analysis of genetic and environmental effects on type 1 diabetes etiology as well as for evaluating the potential effect of therapeutic regimes.

  • 3. Benedict, Christian
    et al.
    Axelsson, Tomas
    Söderberg, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi. Heart Centre.
    Larsson, Anders
    Ingelsson, Erik
    Lind, Lars
    Schioeth, Helgi B.
    Fat Mass and Obesity-Associated Gene (FTO) Is Linked to Higher Plasma Levels of the Hunger Hormone Ghrelin and Lower Serum Levels of the Satiety Hormone Leptin in Older Adults2014Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, nr 11, s. 3955-3959Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The mechanisms through which common polymorphisms in the fat mass and obesity-associated gene (FTO) drive the development of obesity in humans are poorly understood. Using cross-sectional data from 985 older people (50% females) who participated at age 70 years in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), circulating levels of ghrelin and leptin were measured after an overnight fast. In addition, subjects were genotyped for FTO rs17817449 (AA, n = 345 [35%]; AC/CA, n = 481 [48.8%]; CC, n = 159 [16.1%]). Linear regression analyses controlling for sex, selfreported physical activity level, fasting plasma glucose, and BMI were used. A positive relationship between the number of FTO C risk alleles and plasma ghrelin levels was found (P = 0.005; relative plasma ghrelin difference between CC and AA carriers = similar to 9%). In contrast, serum levels of the satiety-enhancing hormone leptin were inversely linked to the number of FTO C risk alleles (P = 0.001; relative serum leptin difference between CC and AA carriers = similar to 11%). These associations were also found when controlling for waist circumference. The present findings suggest that FTO may facilitate weight gain in humans by shifting the endocrine balance from the satiety hormone leptin toward the hunger-promoting hormone ghrelin.

  • 4.
    Bergman, Marie-Louise
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Duarte, Nadia
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Instituto Gulbenkian de Ciencia, Oeiras, Portugal .
    Campino, Susana
    Instituto Gulbenkian de Ciencia, Oeiras, Portugal .
    Lundholm, Marie
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Motta, Vinicius
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Lejon, Kristina
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Penha-Gonçalves, Carlos
    Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
    Holmberg, Dan
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Instituto Gulbenkian de Ciencia, Oeiras, Portugal.
    Diabetes protection and restoration of thymocyte apoptosis in NOD Idd6 congenic strains2003Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 52, nr 7, s. 1677-1682Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Type 1 diabetes in the nonobese diabetic (NOD) mouse is a multifactorial and polygenic disease. The NOD-derived genetic factors that contribute to type 1 diabetes are named Idd (insulin-dependent diabetes) loci. To date, the biological functions of the majority of the Idd loci remain unknown. We have previously reported that resistance of NOD immature thymocytes to depletion by dexamethazone (Dxm) maps to the Idd6 locus. Herein, we refine this phenotype using a time-course experiment of apoptosis induction upon Dxm treatment. We confirm that the Idd6 region controls apoptosis resistance in immature thymocytes. Moreover, we establish reciprocal Idd6 congenic NOD and B6 strains to formally demonstrate that the Idd6 congenic region mediates restoration of the apoptosis resistance phenotype. Analysis of the Idd6 congenic strains indicates that a 3-cM chromosomal region located within the distal part of the Idd6 region controls apoptosis resistance in NOD immature thymocytes. Together, these data support the hypothesis that resistance to Dxm-induced apoptosis in NOD immature thymocytes is controlled by a genetic factor within the region that also contributes to type 1 diabetes pathogenesis. We propose that the diabetogenic effect of the Idd6 locus is exerted at the level of the thymic selection process.

  • 5.
    Berhan, Yonas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Waernbaum, Ingeborg
    Umeå universitet, Samhällsvetenskapliga fakulteten, Statistiska institutionen.
    Lind, Torbjörn
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Möllsten, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Dahlqvist, Gisela
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Thirty years of prospective nationwide incidence of childhood type 1 diabetes: the accelerating increase by time tends to level off in Sweden.2011Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, nr 2, s. 577-81Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Childhood T1D increased dramatically and shifted to a younger age at onset the first 22 years of the study period. We report a reversed trend, starting in 2000, indicating a change in nongenetic risk factors affecting specifically young children.

  • 6.
    Brito, Ema C
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Lyssenko, V
    Renström, Frida
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Berglund, G
    Nilsson, PM
    Groop, L
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Previously associated type 2 diabetes variants may interact with physical activity to modify the risk of impaired glucose regulation and type 2 diabetes: a study of 16,003 Swedish adults2009Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 58, nr 6, s. 1411-1418Artikel i tidskrift (Refereegranskat)
  • 7.
    Einarsdottir, Elisabet
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. Medicinsk och klinisk genetik.
    Mayans, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. Medicinsk och klinisk genetik.
    Ruikka, Karin
    Andersson Escher, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. Medicinsk och klinisk genetik.
    Lindgren, Petter
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. Medicinsk och klinisk genetik.
    Ågren, Åsa
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning. Näringsforskning.
    Eliasson, Mats
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Holmberg, Dan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. Medicinsk och klinisk genetik.
    Linkage but not association of calpain-10 to type 2 diabetes replicated in northern Sweden2006Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 55, nr 6, s. 1879-1883Artikel i tidskrift (Refereegranskat)
  • 8. Fawcett, Katherine A
    et al.
    Wheeler, Eleanor
    Morris, Andrew P
    Ricketts, Sally L
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Daly, Allan
    Wasson, Jon
    Permutt, Alan
    Hattersley, Andrew T
    Glaser, Benjamin
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    McCarthy, Mark I
    Wareham, Nicholas J
    Sandhu, Manjinder S
    Barroso, Inês
    Detailed investigation of the role of common and low-frequency WFS1 variants in type 2 diabetes risk2010Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 59, nr 3, s. 741-746Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We identified six highly correlated SNPs that show strong and comparable associations with risk of type 2 diabetes, but further refinement of these associations will require large sample sizes (>100,000) or studies in ethnically diverse populations. Low frequency variants in WFS1 are unlikely to have a large impact on type 2 diabetes risk in white U.K. populations, highlighting the complexities of undertaking association studies with low-frequency variants identified by resequencing.

  • 9.
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Diabetes family history: a metabolic storm you should not sit out2010Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 59, nr 11, s. 2732-2734Artikel i tidskrift (Refereegranskat)
  • 10. Graham, Jinko
    et al.
    Hagopian, William A
    Kockum, Ingrid
    Li, Lou Sheng
    Sanjeevi, Carani B
    Lowe, Robert M
    Schaefer, Jonathan B
    Zarghami, Marjan
    Day, Heather L
    Landin-Olsson, Mona
    Palmer, Jerry P
    Janer-Villanueva, Marta
    Hood, Leroy
    Sundkvist, Göran
    Lernmark, Ake
    Breslow, Norman
    Dahlquist, Gisela
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Blohmé, Göran
    Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes.2002Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 51, nr 5, s. 1346-55Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Age-dependent associations between type 1 diabetes risk genes HLA, INS VNTR, and CTLA-4 and autoantibodies to GAD65 (GADAs), ICA512/IA-2, insulin, and islet cells were determined by logistic regression analysis in 971 incident patients with type 1 diabetes and 702 control subjects aged 0-34 years. GADAs were associated with HLA-DQ2 in young but not in older patients (P = 0.009). Autoantibodies to insulin were negatively associated with age (P < 0.0001) but positively associated with DQ8 (P = 0.03) and with INS VNTR (P = 0.04), supporting possible immune tolerance induction. ICA512/IA-2 were negatively associated with age (P < 0.0001) and with DQ2 (P < 0.0001) but positively associated with DQ8 (P = 0.04). Males were more likely than females to be negative for GADA (P < 0.0001), autoantibodies to islet cells (P = 0.04), and all four autoantibody markers (P = 0.004). The CTLA-4 3' end microsatellite marker was not associated with any of the autoantibodies. We conclude that age and genetic factors such as HLA-DQ and INS VNTR need to be combined with islet autoantibody markers when evaluating the risk for type 1 diabetes development.

  • 11. Hartling, Svend G
    et al.
    Lindgren, Fredrik
    Dahlquist, Gisela
    Sachs' Children's Hospital, Stockholm.
    Persson, Bengt
    Binder, Christian
    Elevated proinsulin in healthy siblings of IDDM patients independent of HLA identity1989Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 38, nr 10, s. 1271-1274Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Based on the recent demonstration of elevated serum proinsulin levels in cystic fibrosis patients with impaired glucose tolerance, it was hypothesized that proinsulin could be an indicator of altered β-cell function. We therefore analyzed fasting proinsulin levels in 99 siblings of insulin-dependent diabetes mellitus (IDDM) patients, most of them discordant for diabetes for >6 yr. The results from this group were compared with the results from 41 healthy age- and sex-matched control subjects with no family history of diabetes. Median (range) fasting proinsulin in siblings was 8.9 pM (1.7–58 pM) vs. 3.8 pM (<1.2–28 pM) in control subjects (P < .00001). There was no difference between the groups in fasting blood glucose concentrations. Both groups had fasting insulin concentrations within the normal range with a tendency toward lower values in the siblings: 108 pM (60–237 pM) vs. 118 pM (71–175 pM) (P = .07). The 99 siblings were subdivided into groups according to HLA sharing with their diabetic proband. The concentration of proinsulin, insulin, and blood glucose among the groups of 33 HLA-identical, 40 HLA-haploidentical, and 26 nonidentical siblings did not differ significantly. The fasting proinsulin level did not correlate with fasting levels of insulin, blood glucose, age, or body weight. We conclude that fasting proinsulin is elevated in healthy siblings of IDDM patients, whereas fasting insulin is normal or slightly decreased independent of HLA identity with their diabetic sibling. Elevated proinsulin levels could represent a family trait, perhaps mirroring a β-cell more vulnerable to destruction, or it could reflect previous β-cell damage that does not lead to IDDM.

  • 12. Hivert, Marie-France
    et al.
    Christophi, Costas A.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Jablonski, Kathleen A.
    Ehrmann, David A.
    Kahn, Steven E.
    Horton, Edward S.
    Pollin, Toni I.
    Mather, Kieren J.
    Perreault, Leigh
    Barrett-Connor, Elizabeth
    Knowler, William C.
    Florez, Jose C.
    Lifestyle and Metformin Ameliorate Insulin Sensitivity Independently of the Genetic Burden of Established Insulin Resistance Variants in Diabetes Prevention Program Participants2016Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, nr 2, s. 520-526Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Large genome-wide association studies of glycemic traits have identified genetics variants that are associated with insulin resistance (IR) in the general population. It is unknown whether people with genetic enrichment for these IR variants respond differently to interventions that aim to improve insulin sensitivity. We built a genetic risk score (GRS) based on 17 established IR variants and effect sizes (weighted IR-GRS) in 2,713 participants of the Diabetes Prevention Program (DPP) with genetic consent. We tested associations between the weighted IR-GRS and insulin sensitivity index (ISI) at baseline in all participants, and with change in ISI over 1 year of follow-up in the DPP intervention (metformin and lifestyle) and control (placebo) arms. All models were adjusted for age, sex, ethnicity, and waist circumference at baseline (plus baseline ISI for 1-year ISI change models). A higher IR-GRS was associated with lower baseline ISI (beta= -0.754 [SE = 0.229] log-ISI per unit, P = 0.001 in fully adjusted models). There was no differential effect of treatment for the association between the IR-GRS on the change in ISI; higher IR-GRS was associated with an attenuation in ISI improvement over 1 year (beta = -0.520 [SE = 0.233], P = 0.03 in fully adjusted models; all treatment arms). Lifestyle intervention and metformin treatment improved the ISI, regardless of the genetic burden of IR variants.

  • 13. Hivert, Marie-France
    et al.
    Jablonski, Kathleen A
    Perreault, Leigh
    Saxena, Richa
    McAteer, Jarred B
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Hamman, Richard F
    Kahn, Steven E
    Haffner, Steven
    Meigs, James B
    Altshuler, David
    Knowler, William C
    Florez, Jose C
    Updated genetic score based on 34 confirmed type 2 diabetes Loci is associated with diabetes incidence and regression to normoglycemia in the diabetes prevention program2011Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, nr 4, s. 1340-1348Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A high GRS is associated with increased risk of developing diabetes and lower probability of returning to NGR in high-risk individuals, but a lifestyle intervention attenuates this risk.

  • 14. Jablonski, Kathleen A
    et al.
    McAteer, Jarred B
    de Bakker, Paul I W
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Pollin, Toni I
    Hanson, Robert L
    Saxena, Richa
    Fowler, Sarah
    Shuldiner, Alan R
    Knowler, William C
    Altshuler, David
    Florez, Jose C
    Common variants in 40 genes assessed for diabetes incidence and response to metformin and lifestyle intervention in the diabetes prevention program2010Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 59, nr 10, s. 2672-2681Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have identified potential genetic determinants of metformin response. These results merit confirmation in independent samples.

  • 15. Kanoni, Stavroula
    et al.
    Nettleton, Jennifer A
    Hivert, Marie-France
    Ye, Zheng
    van Rooij, Frank JA
    Shungin, Dmitry
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Sonestedt, Emily
    Ngwa, Julius S
    Wojczynski, Mary K
    Lemaitre, Rozenn N
    Gustafsson, Stefan
    Anderson, Jennifer S
    Tanaka, Toshiko
    Hindy, George
    Saylor, Georgia
    Renström, Frida
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Clinical Sciences, Lund University, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts.
    Bennett, Amanda J
    van Duijn, Cornelia M
    Florez, Jose C
    Fox, Caroline S
    Hofman, Albert
    Hoogeveen, Ron C
    Houston, Denise K
    Hu, Frank B
    Jacques, Paul F
    Johansson, Ingegerd
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Lind, Lars
    Liu, Yongmei
    McKeown, Nicola
    Ordovas, Jose
    Pankow, James S
    Sijbrands, Eric JG
    Syvänen, Ann-Christine
    Uitterlinden, André G
    Yannakoulia, Mary
    Zillikens, M Carola
    Wareham, Nick J
    Prokopenko, Inga
    Bandinelli, Stefania
    Forouhi, Nita G
    Cupples, L Adrienne
    Loos, Ruth J
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Dupuis, Josée
    Langenberg, Claudia
    Ferrucci, Luigi
    Kritchevsky, Stephen B
    McCarthy, Mark I
    Ingelsson, Erik
    Borecki, Ingrid B
    Witteman, Jacqueline CM
    Orho-Melander, Marju
    Siscovick, David S
    Meigs, James B
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Clinical Sciences, Lund University, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts.
    Dedoussis, George V
    Total zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant: a 14-cohort meta-analysis2011Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, nr 9, s. 2407-2416Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants.

    RESEARCH DESIGN AND METHODS We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes.

    RESULTS We observed a significant association of total zinc intake with lower fasting glucose levels (β-coefficient ± SE per 1 mg/day of zinc intake: -0.0012 ± 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (β-coefficient ± SE per A allele for 1 mg/day of greater total zinc intake: -0.0017 ± 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant.

    CONCLUSIONS Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels.

  • 16. Korpos, Eva
    et al.
    Kadri, Nadir
    Kappelhoff, Reinhild
    Wegner, Jeannine
    Overall, Christopher M
    Weber, Ekkehard
    Holmberg, Dan
    Center for Infection and Inflammation Research, Copenhagen University, Denmark.
    Cardell, Susanna
    Sorokin, Lydia
    The Peri-islet Basement Membrane, a Barrier to Infiltrating Leukocytes in Type 1 Diabetes in Mouse and Human2013Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 62, nr 2, s. 531-542Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We provide the first comprehensive analysis of the extracellular matrix (ECM) composition of peri-islet capsules, composed of the peri-islet basement membrane (BM) and subjacent interstitial matrix (IM), in development of type 1 diabetes in NOD mice and in human type 1 diabetes. Our data demonstrate global loss of peri-islet BM and IM components only at sites of leukocyte infiltration into the islet. Stereological analyses reveal a correlation between incidence of insulitis and the number of islets showing loss of peri-islet BM versus islets with intact BMs, suggesting that leukocyte penetration of the peri-islet BM is a critical step. Protease- and protease inhibitor-specific microarray analyses (CLIP-CHIP) of laser-dissected leukocyte infiltrated and noninfiltrated pancreatic islets and confirmatory quantitative real time PCR and protein analyses identified cathepsin S, W, and C activity at sites of leukocyte penetration of the peri-islet BM in association with a macrophage subpopulation in NOD mice and human type 1 diabetic samples and, hence, potentially a novel therapeutic target specifically acting at the islet penetration stage. Interestingly, the peri-islet BM and underlying IM are reconstituted once inflammation subsides, indicating that the peri-islet BM-producing cells are not lost due to the inflammation, which has important ramifications to islet transplantation studies.

  • 17.
    Lundholm, Marie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Motta, Vinicius
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Löfgren-Burström, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Duarte, Nadia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Bergman, Marie-Louise
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Mayans, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Holmberg, Dan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Defective induction of CTLA-4 in the NOD mouse is controlled by the NOD allele of Idd3/IL-2 and a novel locus (Ctex) telomeric on chromosome 12006Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 55, nr 2, s. 538-544Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4), or CD152, is a negative regulator of T-cell activation and has been shown to be associated with autoimmune diseases. Previous work has demonstrated a defect in the expression of this molecule in nonobese diabetic (NOD) mice upon anti-CD3 stimulation in vitro. Using a genetic approach we here demonstrate that a novel locus (Ctex) telomeric on chromosome 1 together with the Idd3 (Il-2) gene confers optimal CTLA-4 expression upon CD3 activation of T-cells. Based on these data, we provide a model for how gene interaction between Idd3 (IL-2), Ctex, and Idd5.1 (Ctla-4) could confer susceptibility to autoimmune diabetes in the NOD mouse. Additionally, we showed that the Ctex and the Idd3 regions do not influence inducible T-cell costimulator (ICOS) protein expression in NOD mice. Instead, as previously shown, higher ICOS levels in NOD mice appear to be controlled by gene(s) in the Idd5.1 region, possibly a polymorphism in the Icos gene itself.

  • 18. Ma, Lijun
    et al.
    Hanson, Robert L
    Traurig, Michael T
    Muller, Yunhua L
    Kaur, Bakhshish P
    Perez, Jessica M
    Meyre, David
    Fu, Mao
    Körner, Antje
    Franks, Paul W
    Clinical Research Center, Malmö General Hospital, Lund University, Malmö, Sweden.
    Kiess, Wieland
    Kobes, Sayuko
    Knowler, William C
    Kovacs, Peter
    Froguel, Philippe
    Shuldiner, Alan R
    Bogardus, Clifton
    Baier, Leslie J
    Evaluation of A2BP1 as an obesity gene2010Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 59, nr 11, s. 2837-2845Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Association analysis suggests that variation in A2BP1 influences obesity, and functional studies suggest that A2BP1 could potentially affect adiposity via the hypothalamic MC4R pathway.

  • 19. Manning, Alisa
    et al.
    Highland, Heather M.
    Gasser, Jessica
    Sim, Xueling
    Tukiainen, Taru
    Fontanillas, Pierre
    Grarup, Niels
    Rivas, Manuel A.
    Mahajan, Anubha
    Locke, Adam E.
    Cingolani, Pablo
    Pers, Tune H.
    Vinuela, Ana
    Brown, Andrew A.
    Wu, Ying
    Flannick, Jason
    Fuchsberger, Christian
    Gamazon, Eric R.
    Gaulton, Kyle J.
    Im, Hae Kyung
    Teslovich, Tanya M.
    Blackwell, Thomas W.
    Bork-Jensen, Jette
    Burtt, Noel P.
    Chen, Yuhui
    Green, Todd
    Hartl, Christopher
    Kang, Hyun Min
    Kumar, Ashish
    Ladenvall, Claes
    Ma, Clement
    Moutsianas, Loukas
    Pearson, Richard D.
    Perry, John R. B.
    Rayner, N. William
    Robertson, Neil R.
    Scott, Laura J.
    van de Bunt, Martijn
    Eriksson, Johan G.
    Jula, Antti
    Koskinen, Seppo
    Lehtimaki, Terho
    Palotie, Aarno
    Raitakari, Olli T.
    Jacobs, Suzanne B. R.
    Wessel, Jennifer
    Chu, Audrey Y.
    Scott, Robert A.
    Goodarzi, Mark O.
    Blancher, Christine
    Buck, Gemma
    Buck, David
    Chines, Peter S.
    Gabriel, Stacey
    Gjesing, Anette P.
    Groves, Christopher J.
    Hollensted, Mette
    Huyghe, Jeroen R.
    Jackson, Anne U.
    Jun, Goo
    Justesen, Johanne Marie
    Mangino, Massimo
    Murphy, Jacquelyn
    Neville, Matt
    Onofrio, Robert
    Small, Kerrin S.
    Stringham, Heather M.
    Trakalo, Joseph
    Banks, Eric
    Carey, Jason
    Carneiro, Mauricio O.
    DePristo, Mark
    Farjoun, Yossi
    Fennell, Timothy
    Goldstein, Jacqueline I.
    Grant, George
    de Angelis, Martin Hrabe
    Maguire, Jared
    Neale, Benjamin M.
    Poplin, Ryan
    Purcell, Shaun
    Schwarzmayr, Thomas
    Shakir, Khalid
    Smith, Joshua D.
    Strom, Tim M.
    Wieland, Thomas
    Lindstrom, Jaana
    Brandslund, Ivan
    Christensen, Cramer
    Surdulescu, Gabriela L.
    Lakka, Timo A.
    Doney, Alex S. F.
    Nilsson, Peter
    Wareham, Nicholas J.
    Langenberg, Claudia
    Varga, Tibor V.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Clinical Sciences, Lund University Diabetes Centre, and Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, MA.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Rosengren, Anders H.
    Farook, Vidya S.
    Thameem, Farook
    Puppala, Sobha
    Kumar, Satish
    Lehman, Donna M.
    Jenkinson, Christopher P.
    Curran, Joanne E.
    Hale, Daniel Esten
    Fowler, Sharon P.
    Arya, Rector
    DeFronzo, Ralph A.
    Abboud, Hanna E.
    Syvanen, Ann-Christine
    Hicks, Pamela J.
    Palmer, Nicholette D.
    Ng, Maggie C. Y.
    Bowden, Donald W.
    Freedman, Barry I.
    Esko, Tonu
    Magi, Reedik
    Milani, Lili
    Mihailov, Evelin
    Metspalu, Andres
    Narisu, Narisu
    Kinnunen, Leena
    Bonnycastle, Lori L.
    Swift, Amy
    Pasko, Dorota
    Wood, Andrew R.
    Fadista, Joao
    Pollin, Toni I.
    Barzilai, Nir
    Atzmon, Gil
    Glaser, Benjamin
    Thorand, Barbara
    Strauch, Konstantin
    Peters, Annette
    Roden, Michael
    Mueller-Nurasyid, Martina
    Liang, Liming
    Kriebel, Jennifer
    Illig, Thomas
    Grallert, Harald
    Gieger, Christian
    Meisinger, Christa
    Lannfelt, Lars
    Musani, Solomon K.
    Griswold, Michael
    Taylor, Herman A., Jr.
    Wilson, Gregory, Sr.
    Correa, Adolfo
    Oksa, Heikki
    Scott, William R.
    Afzal, Uzma
    Tan, Sian-Tsung
    Loh, Marie
    Chambers, John C.
    Sehmi, Jobanpreet
    Kooner, Jaspal Singh
    Lehne, Benjamin
    Cho, Yoon Shin
    Lee, Jong-Young
    Han, Bok-Ghee
    Karajamaki, Annemari
    Qi, Qibin
    Qi, Lu
    Huang, Jinyan
    Hu, Frank B.
    Melander, Olle
    Orho-Melander, Marju
    Below, Jennifer E.
    Aguilar, David
    Wong, Tien Yin
    Liu, Jianjun
    Khor, Chiea-Chuen
    Chia, Kee Seng
    Lim, Wei Yen
    Cheng, Ching-Yu
    Chan, Edmund
    Tai, E. Shyong
    Aung, Tin
    Linneberg, Allan
    Isomaa, Bo
    Meitinger, Thomas
    Tuomi, Tiinamaija
    Hakaste, Liisa
    Kravic, Jasmina
    Jorgensen, Marit E.
    Lauritzen, Torsten
    Deloukas, Panos
    Stirrups, Kathleen E.
    Owen, Katharine R.
    Farmer, Andrew J.
    Frayling, Timothy M.
    O'Rahilly, Stephen P.
    Walker, Mark
    Levy, Jonathan C.
    Hodgkiss, Dylan
    Hattersley, Andrew T.
    Kuulasmaa, Teemu
    Stancakova, Alena
    Barroso, Ines
    Bharadwaj, Dwaipayan
    Chan, Juliana
    Chandak, Giriraj R.
    Daly, Mark J.
    Donnelly, Peter J.
    Ebrahim, Shah B.
    Elliott, Paul
    Fingerlin, Tasha
    Froguel, Philippe
    Hu, Cheng
    Jia, Weiping
    Ma, Ronald C. W.
    McVean, Gilean
    Park, Taesung
    Prabhakaran, Dorairaj
    Sandhu, Manjinder
    Scott, James
    Sladek, Rob
    Tandon, Nikhil
    Teo, Yik Ying
    Zeggini, Eleftheria
    Watanabe, Richard M.
    Koistinen, Heikki A.
    Kesaniemi, Y. Antero
    Uusitupa, Matti
    Spector, Timothy D.
    Salomaa, Veikko
    Rauramaa, Rainer
    Palmer, Colin N. A.
    Prokopenko, Inga
    Morris, Andrew D.
    Bergman, Richard N.
    Collins, Francis S.
    Lind, Lars
    Ingelsson, Erik
    Tuomilehto, Jaakko
    Karpe, Fredrik
    Groop, Leif
    Jorgensen, Torben
    Hansen, Torben
    Pedersen, Oluf
    Kuusisto, Johanna
    Abecasis, GonOalo
    Bell, Graeme I.
    Blangero, John
    Cox, Nancy J.
    Duggirala, Ravindranath
    Seielstad, Mark
    Wilson, James G.
    Dupuis, Josee
    Ripatti, Samuli
    Hanis, Craig L.
    Florez, Jose C.
    Mohlke, Karen L.
    Meigs, James B.
    Laakso, Markku
    Morris, Andrew P.
    Boehnke, Michael
    Altshuler, David
    McCarthy, Mark I.
    Gloyn, Anna L.
    Lindgren, Cecilia M.
    A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk2017Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, nr 7, s. 2019-2032Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.

  • 20. Moore, Allan F
    et al.
    Jablonski, Kathleen A
    McAteer, Jarred B
    Saxena, Richa
    Pollin, Toni I
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Hanson, Robert L
    Shuldiner, Alan R
    Knowler, William C
    Altshuler, David
    Florez, Jose C
    Extension of type 2 diabetes genome-wide association scan results in the diabetes prevention program2008Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 57, nr 9, s. 2503-2510Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: Genome-wide association scans (GWASs) have identified novel diabetes-associated genes. We evaluated how these variants impact diabetes incidence, quantitative glycemic traits, and response to preventive interventions in 3,548 subjects at high risk of type 2 diabetes enrolled in the Diabetes Prevention Program (DPP), which examined the effects of lifestyle intervention, metformin, and troglitazone versus placebo.

    RESEARCH DESIGN AND METHODS: We genotyped selected single nucleotide polymorphisms (SNPs) in or near diabetes-associated loci, including EXT2, CDKAL1, CDKN2A/B, IGF2BP2, HHEX, LOC387761, and SLC30A8 in DPP participants and performed Cox regression analyses using genotype, intervention, and their interactions as predictors of diabetes incidence. We evaluated their effect on insulin resistance and secretion at 1 year.

    RESULTS: None of the selected SNPs were associated with increased diabetes incidence in this population. After adjustments for ethnicity, baseline insulin secretion was lower in subjects with the risk genotype at HHEX rs1111875 (P = 0.01); there were no significant differences in baseline insulin sensitivity. Both at baseline and at 1 year, subjects with the risk genotype at LOC387761 had paradoxically increased insulin secretion; adjustment for self-reported ethnicity abolished these differences. In ethnicity-adjusted analyses, we noted a nominal differential improvement in beta-cell function for carriers of the protective genotype at CDKN2A/B after 1 year of troglitazone treatment (P = 0.01) and possibly lifestyle modification (P = 0.05).

    CONCLUSIONS: We were unable to replicate the GWAS findings regarding diabetes risk in the DPP. We did observe genotype associations with differences in baseline insulin secretion at the HHEX locus and a possible pharmacogenetic interaction at CDKNA2/B.

  • 21.
    Möllsten, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Marklund, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Wessman, Maija
    Svensson, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Forsblom, Carol
    Parkkonen, Maikki
    Brismar, Kerstin
    Groop, Per-Henrik
    Dahlquist, Gisela
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    A functional polymorphism in the manganese superoxide dismutase gene and diabetic nephropathy.2007Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 56, nr 1, s. 265-269Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Oxidative stress has been suggested to contribute to the development of diabetic nephropathy. Manganese superoxide dismutase (MnSOD) protects the cells from oxidative damage by scavenging free radicals. The demand for antioxidants is increased by smoking, which could disturb the balance between antioxidants and radicals. The present study aimed to determine whether a valine/alanine polymorphism in MnSOD (V16A, rs4880), alone or in combination with smoking, can contribute to development of diabetic nephropathy in 1,510 Finnish and Swedish patients with type 1 diabetes. Overt diabetic nephropathy (n = 619) was defined as having an albumin excretion rate (AER) >200 microg/min or renal replacement therapy; incipient diabetic nephropathy was defined as having an AER of 20-200 microg/min (n = 336). The control subjects had diabetes duration of >or=20 years, without albuminuria (AER <20 microg/min) and without antihypertensive treatment (n = 555). In addition to male sex and elevated A1C, smoking was significantly associated with diabetic nephropathy (overt plus incipient), odds ratio (OR) 2.00 (95% CI 1.60-2.50). When controlling for age at onset, diabetes duration, A1C, smoking, and sex, the Val/Val genotype was associated with an increase in risk of diabetic nephropathy (1.32 [1.00-1.74], P = 0.049). When evaluating the combined effect of genotype and smoking, we used logistic regression with stratification according to smoking status and genotype. The high-risk group (ever smoking plus Val/Val genotype) had 2.52 times increased risk of diabetic nephropathy (95% CI 1.73-3.69) compared with the low-risk group, but no departure from additivity was found. Our results indicate that smoking and homozygosity for the MnSOD Val allele is associated with an increased risk of diabetic nephropathy, which supports the hypothesis that oxidative stress contributes to the development of diabetic nephropathy.

  • 22.
    Möllsten, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Svensson, Maria
    Department of Nephrology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Waernbaum, Ingeborg
    Umeå universitet, Samhällsvetenskapliga fakulteten, Statistiska institutionen.
    Berhan, Yonas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Schön, Staffan
    Department of Internal Medicine, Ryhov County Hospital, Jönköping, Sweden.
    Nyström, Lennarth
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Arnqvist, Hans J.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Dahlquist, Gisela
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Cumulative risk, age at onset, and sex-specific differences for developing end-stage renal disease in young patients with type 1 diabetes: A nationwide population-based cohort study2010Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 59, nr 7, s. 1803-1808Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE—This study aimed to estimate the current cumulativerisk of end-stage renal disease (ESRD) due to diabeticnephropathy in a large, nationwide, population-based prospectivetype 1 diabetes cohort and specifically study the effects ofsex and age at onset.RESEARCH DESIGN AND METHODS—In Sweden, all incidentcases of type 1 diabetes aged 0–14 years and 15–34 years arerecorded in validated research registers since 1977 and 1983,respectively. These registers were linked to the Swedish RenalRegistry, which, since 1991, collects data on patients who receiveactive uremia treatment. Patients with 13 years duration of type1 diabetes were included (n 11,681).RESULTS—During a median time of follow-up of 20 years, 127patients had developed ESRD due to diabetic nephropathy. Thecumulative incidence at 30 years of type 1 diabetes duration waslow, with a male predominance (4.1% [95% CI 3.1–5.3] vs. 2.5%[1.7–3.5]). In both male and female subjects, onset of type 1diabetes before 10 years of age was associated with the lowestrisk of developing ESRD. The highest risk of ESRD was found inmale subjects diagnosed at age 20–34 years (hazard ratio 3.0 [95%CI 1.5–5.7]). In female subjects with onset at age 20–34 years, therisk was similar to patients’ diagnosed before age 10 years.CONCLUSIONS—The cumulative incidence of ESRD is exceptionallylow in young type 1 diabetic patients in Sweden. There isa striking difference in risk for male compared with femalepatients. The different patterns of risk by age at onset and sexsuggest a role for puberty and sex hormones.

  • 23.
    Norlin, Stefan
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Parekh, Vishal S.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Naredi, Peter
    Edlund, Helena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Asna1/TRC40 Controls beta-Cell Function and Endoplasmic Reticulum Homeostasis by Ensuring Retrograde Transport2016Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, nr 1, s. 110-119Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Type 2 diabetes (T2D) is characterized by insulin resistance and beta-cell failure. Insulin resistance per se, however, does not provoke overt diabetes as long as compensatory beta-cell function is maintained. The increased demand for insulin stresses the beta-cell endoplasmic reticulum (ER) and secretory pathway, and ER stress is associated with beta-cell failure in T2D. The tail recognition complex (TRC) pathway, including Asna1/TRC40, is implicated in the maintenance of endomembrane trafficking and ER homeostasis. To gain insight into the role of Asna1/TRC40 in maintaining endomembrane homeostasis and beta-cell function, we inactivated Asnal in beta-cells of mice. We show that Asna1 beta(-/-) mice develop hypoinsulinemia, impaired insulin secretion, and glucose intolerance that rapidly progresses to overt diabetes. Loss of Asnal function leads to perturbed plasma membrane-to-trans Golgi network and Golgi-to-ER retrograde transport as well as to ER stress in beta-cells. Of note, pharmacological inhibition of retrograde transport in isolated islets and insulinoma cells mimicked the phenotype of Asna1(beta-/-) beta-cells and resulted in reduced insulin content and ER stress. These data support a model where Asnal ensures retrograde transport and, hence, ER and insulin homeostasis in beta-cells.

  • 24.
    Papadopoulou, Stella
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Edlund, Helena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Attenuated Wnt signaling perturbs pancreatic growth but not pancreatic function.2005Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 54, nr 10, s. 2844-2851Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mesenchymal-epithelial interactions are pivotal for proper pancreatic growth and development. We have earlier shown that the fibroblast growth factor (FGF) receptor 2 is expressed in pancreatic progenitor cells and that FGF10, the high-affinity ligand of the FGF receptor 2 isoform FGF receptor 2b, promotes expansion of pancreatic progenitors. The Wnt family of ligands, which signal to the Frizzled (Frz) type receptors, have also been shown to mediate mesenchymal-epithelial interactions and cell proliferation in a variety of different systems. Here, we show that Frz3, like FGF receptor 2, is expressed in the pancreatic epithelium during the proliferative phase of the embryonic pancreas in mice and that overexpression of a dominant-negative form of mouse Frz8 in pancreatic progenitors severely perturbs pancreatic growth. Nevertheless, the transgenic mice remain normoglycemic and display normal glucose tolerance and glucose-stimulated insulin secretion when challenged with exogenous glucose. The maintenance of normoglycemia in these mice appears to be the consequence of a relative increase in endocrine cell number per pancreatic area combined with enhanced insulin biosynthesis and insulin secretion. Collectively, our data provide evidence that Wnt signaling is required for pancreatic growth but not adult beta-cell function.

  • 25. Papandonatos, George D
    et al.
    Pan, Qing
    Pajewski, Nicholas M
    Delahanty, Linda M
    Peter, Inga
    Erar, Bahar
    Ahmad, Shafqat
    Harden, Maegan
    Chen, Ling
    Fontanillas, Pierre
    Wagenknecht, Lynne E
    Kahn, Steven E
    Wing, Rena R
    Jablonski, Kathleen A
    Huggins, Gordon S
    Knowler, William C
    Florez, Jose C
    McCaffery, Jeanne M
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skåne University Hospital Malmö, Malmö, Sweden; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA.
    Genetic Predisposition to Weight Loss and Regain With Lifestyle Intervention: Analyses From the Diabetes Prevention Program and the Look AHEAD Randomized Controlled Trials2015Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, nr 12, s. 4312-4321Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Clinically relevant weight loss is achievable through lifestyle modification, but unintentional weight regain is common. We investigated whether recently discovered genetic variants affect weight loss and/or weight regain during behavioral intervention. Participants at high-risk of type 2 diabetes (Diabetes Prevention Program [DPP]; N = 917/907 intervention/comparison) or with type 2 diabetes (Look AHEAD [Action for Health in Diabetes]; N = 2,014/1,892 intervention/comparison) were from two parallel arm (lifestyle vs. comparison) randomized controlled trials. The associations of 91 established obesity-predisposing loci with weight loss across 4 years and with weight regain across years 2-4 after a minimum of 3% weight loss were tested. Each copy of the minor G allele of MTIF3 rs1885988 was consistently associated with greater weight loss following lifestyle intervention over 4 years across the DPP and Look AHEAD. No such effect was observed across comparison arms, leading to a nominally significant single nucleotide polymorphism x treatment interaction (P = 4.3 x 10-3). However, this effect was not significant at a study-wise significance level (Bonferroni threshold P < 5.8 x 10-4). Most obesity-predisposing gene variants were not associated with weight loss or regain within the DPP and Look AHEAD trials, directly or via interactions with lifestyle.

  • 26.
    Parsa, Roham
    et al.
    Applied Immunology, Center for Molecular Medicine, Karolinska University Hospital at Solna, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Andresen, Pernilla
    Applied Immunology, Center for Molecular Medicine, Karolinska University Hospital at Solna, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Gillett, Alan
    Neuroimmunology, Center for Molecular Medicine, Karolinska University Hospital at Solna, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Mia, Sohel
    Applied Immunology, Center for Molecular Medicine, Karolinska University Hospital at Solna, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden .
    Zhang, Xing-Mei
    Applied Immunology, Center for Molecular Medicine, Karolinska University Hospital at Solna, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Mayans, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Holmberg, Dan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Harris, Robert A.
    Applied Immunology, Center for Molecular Medicine, Karolinska University Hospital at Solna, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Adoptive transfer of immunomodulatory M2 Macrophages prevents type 1 Diabetes in NOD Mice2012Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 61, nr 11, s. 2881-2892Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Macrophages are multifunctional immune cells that may either drive or modulate disease pathogenesis depending on their activation phenotype. Autoimmune type 1 diabetes (T1D) is a chronic proinflammatory condition characterized by unresolved destruction of pancreatic islets. Adoptive cell transfer of macrophages with immunosuppressive properties represents a novel immunotherapy for treatment of such chronic autoimmune diseases. We used a panel of cytokines and other stimuli to discern the most effective regimen for in vitro induction of immunosuppressive macrophages (M2r) and determined interleukin (IL)-4/IL-10/transforming growth factor-beta (TGF-beta) to be optimal. M2r cells expressed programmed cell death 1 ligand-2, fragment crystallizable region gamma receptor IIlb, IL-10, and TGF-beta, had a potent deactivating effect on proinflammatory lipopolysaccharide/interferon-gamma-stimulated macrophages, and significantly suppressed T-cell proliferation. Clinical therapeutic efficacy was assessed after adoptive transfer in NOD T1D mice, and after a single transfer of M2r macrophages, >80% of treated NOD mice were protected against T1D for at least 3 months, even when transfer was conducted just prior to clinical onset. Fluorescent imaging analyses revealed that adoptively transferred M2r macrophages specifically homed to the inflamed pancreas, promoting 3-cell survival. We suggest that M2r macrophage therapy represents a novel intervention that stops ongoing autoimmune T1D and may have relevance in a clinical setting. Diabetes 61:2881-2892, 2012

  • 27.
    Renström, Frida
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Shungin, Dmitry
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Johansson, Ingegerd
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Kariologi.
    Florez, Jose C
    Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Hu, Frank B
    Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts.
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Genetic predisposition to long-term nondiabetic deteriorations in glucose homeostasis: Ten-year follow-up of the GLACIER study.2011Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, nr 1, s. 345-54Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Our findings imply that genetic profiling might facilitate the early detection of persons who are genetically susceptible to deteriorating glucose control; studies of incident type 2 diabetes and discrete cardiovascular end points will help establish whether the magnitude of these changes is clinically relevant.

  • 28. Rudberg, S
    et al.
    Stattin, Eva-Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Dahlquist, G
    Familial and perinatal risk factors for micro- and macroalbuminuria in young IDDM patients.1998Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 47, nr 7, s. 1121-1126Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    It has been suggested that hereditary risk for hypertension and cardiovascular disease (CVD) as well as intrauterine growth may be involved in the pathogenesis of diabetic nephropathy. In the present study, we investigated the influence of familial and perinatal risk factors on the occurrence of micro- and macroalbuminuria in young IDDM patients. A cohort of 1,150 young patients with > or =5 years' duration of IDDM was screened for microalbuminuria. Data on family history of hypertension, CVD, IDDM, and NIDDM; perinatal factors such as birth weight, gestational age, and duration of breastfeeding; and maternal education, smoking, hypertension, and proteinuria during pregnancy were collected. We identified 75 patients with an albumin excretion rate > or =15 microg/min in more than two overnight urinary samples and compared them in a nested case-control study with three normoalbuminuric control subjects per patient from the same cohort, matched for diabetes duration. Perinatal factors were analyzed in all patients born at term (+/- 2 weeks), 59 of the 75 patients and 155 of the 225 control subjects. In univariate analysis, hypertension in parents (odds ratio [OR] 4.21), CVD in parents and grandparents (OR 1.26), maternal smoking during pregnancy (OR 3.21), and a low level of maternal education (OR 2.33) were significantly associated with the development of micro- and macroalbuminuria. When adjusted for other familial and perinatal factors, current mean blood pressure, HbA1c, smoking, BMI, sex, age, and postpubertal diabetes duration, using logistic regression analyses, only parental hypertension in all patients and maternal smoking during pregnancy and low level of maternal education in full-term patients were independent risk factors. When patients with poor glycemic control were analyzed separately, familial CVD, poor metabolic control, parental hypertension, maternal smoking during pregnancy, and level of maternal education were independent risk factors, with the adjusted OR markedly increased, compared with the matched subgroup with better HbA1c. In conclusion, familial hypertension and CVD, maternal smoking during pregnancy, and low level of maternal education may independently increase the risk for incipient nephropathy in full-term offspring who later develop IDDM. Current poor glycemic control seemed to increase the effect of these risk factors.

  • 29. Scott, Robert A
    et al.
    Chu, Audrey Y
    Grarup, Niels
    Manning, Alisa K
    Hivert, Marie-France
    Shungin, Dmitry
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Tönjes, Anke
    Yesupriya, Ajay
    Barnes, Daniel
    Bouatia-Naji, Nabila
    Glazer, Nicole L
    Jackson, Anne U
    Kutalik, Zoltán
    Lagou, Vasiliki
    Marek, Diana
    Rasmussen-Torvik, Laura J
    Stringham, Heather M
    Tanaka, Toshiko
    Aadahl, Mette
    Arking, Dan E
    Bergmann, Sven
    Boerwinkle, Eric
    Bonnycastle, Lori L
    Bornstein, Stefan R
    Brunner, Eric
    Bumpstead, Suzannah J
    Brage, Soren
    Carlson, Olga D
    Chen, Han
    Chen, Yii-Der Ida
    Chines, Peter S
    Collins, Francis S
    Couper, David J
    Dennison, Elaine M
    Dowling, Nicole F
    Egan, Josephine S
    Ekelund, Ulf
    Erdos, Michael R
    Forouhi, Nita G
    Fox, Caroline S
    Goodarzi, Mark O
    Grässler, Jürgen
    Gustafsson, Stefan
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Hansen, Torben
    Hingorani, Aroon
    Holloway, John W
    Hu, Frank B
    Isomaa, Bo
    Jameson, Karen A
    Johansson, Ingegerd
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Kariologi.
    Jonsson, Anna
    Jørgensen, Torben
    Kivimaki, Mika
    Kovacs, Peter
    Kumari, Meena
    Kuusisto, Johanna
    Laakso, Markku
    Lecoeur, Cécile
    Lévy-Marchal, Claire
    Li, Guo
    Loos, Ruth J F
    Lyssenko, Valeri
    Marmot, Michael
    Marques-Vidal, Pedro
    Morken, Mario A
    Müller, Gabriele
    North, Kari E
    Pankow, James S
    Payne, Felicity
    Prokopenko, Inga
    Psaty, Bruce M
    Renström, Frida
    Rice, Ken
    Rotter, Jerome I
    Rybin, Denis
    Sandholt, Camilla H
    Sayer, Avan A
    Shrader, Peter
    Schwarz, Peter E H
    Siscovick, David S
    Stancáková, Alena
    Stumvoll, Michael
    Teslovich, Tanya M
    Waeber, Gérard
    Williams, Gordon H
    Witte, Daniel R
    Wood, Andrew R
    Xie, Weijia
    Boehnke, Michael
    Cooper, Cyrus
    Ferrucci, Luigi
    Froguel, Philippe
    Groop, Leif
    Kao, W H Linda
    Vollenweider, Peter
    Walker, Mark
    Watanabe, Richard M
    Pedersen, Oluf
    Meigs, James B
    Ingelsson, Erik
    Barroso, Inês
    Florez, Jose C
    Franks, Paul W
    Dupuis, Josée
    Wareham, Nicholas J
    Langenberg, Claudia
    No Interactions Between Previously Associated 2-Hour Glucose Gene Variants and Physical Activity or BMI on 2-Hour Glucose Levels2012Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 61, nr 5, s. 1291-1296Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Gene-lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-gram glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × Physical Activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (β = 0.22 mmol/L [95% CI 0.13-0.31], P = 1.63 × 10(-6)). All SNPs were associated with 2-h glucose (β = 0.06-0.12 mmol/allele, P ≤ 1.53 × 10(-7)), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene-lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions.

  • 30. Scott, Robert A.
    et al.
    Fall, Tove
    Pasko, Dorota
    Barker, Adam
    Sharp, Stephen J.
    Arriola, Larraitz
    Balkau, Beverley
    Barricarte, Aurelio
    Barroso, Ines
    Boeing, Heiner
    Clavel-Chapelon, Francoise
    Crowe, Francesca L.
    Dekker, Jacqueline M.
    Fagherazzi, Guy
    Ferrannini, Ele
    Forouhi, Nita G.
    Franks, Paul
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Gavrila, Diana
    Giedraitis, Vilmantas
    Grioni, Sara
    Groop, Leif C.
    Kaaks, Rudolf
    Key, Timothy J.
    Kuehn, Tilman
    Lotta, Luca A.
    Nilsson, Peter M.
    Overvad, Kim
    Palli, Domenico
    Panico, Salvatore
    Quiros, J. Ramon
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Roswall, Nina
    Sacerdote, Carlotta
    Sala, Nuria
    Sanchez, Maria-Jose
    Schulze, Matthias B.
    Siddiq, Afshan
    Slimani, Nadia
    Sluijs, Ivonne
    Spijkerman, Annemieke M. W.
    Tjonneland, Anne
    Tumino, Rosario
    van der A, Daphne L.
    Yaghootkar, Hanieh
    McCarthy, Mark I.
    Semple, Robert K.
    Riboli, Elio
    Walker, Mark
    Ingelsson, Erik
    Frayling, Tim M.
    Savage, David B.
    Langenberg, Claudia
    Wareham, Nicholas J.
    Common Genetic Variants Highlight the Role of Insulin Resistance and Body Fat Distribution in Type 2 Diabetes, Independent of Obesity2014Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, nr 12, s. 4378-4387Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterize their association with intermediate phenotypes, and to investigate their role in type 2 diabetes (T2D) risk among normal-weight, overweight, and obese individuals. We investigated the association of genetic scores with euglycemic-hyperinsulinemic clamp- and oral glucose tolerance test-based measures of insulin resistance and secretion and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight, and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (beta in SDs per allele [95% CI], -0.03 [-0.04, -0.01]; P = 0.004). This score was associated with lower BMI (-0.01 [-0.01, -0.0]; P = 0.02) and gluteofemoral fat mass (-0.03 [-0.05,-0.02; P = 1.4x10(-6) and with higher alanine transaminase (0.02 [0.01, 0.03]; P = 0.002) and gamma-glutamyl transferase (0.02 [0.01, 0.03]; P = 0.001). While the secretion score had a stronger association with T2D in leaner individuals (P-interaction = 0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI or waist strata (P-interaction > 0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.

  • 31. Scott, Robert A.
    et al.
    Scott, Laura J.
    Maegi, Reedik
    Marullo, Letizia
    Gaulton, Kyle J.
    Kaakinen, Marika
    Pervjakova, Natalia
    Pers, Tune H.
    Johnson, Andrew D.
    Eicher, John D.
    Jackson, Anne U.
    Ferreira, Teresa
    Lee, Yeji
    Ma, Clement
    Steinthorsdottir, Valgerdur
    Thorleifsson, Gudmar
    Qi, Lu
    Van Zuydam, Natalie R.
    Mahajan, Anubha
    Chen, Han
    Almgren, Peter
    Voight, Ben F.
    Grallert, Harald
    Mueller-Nurasyid, Martina
    Ried, Janina S.
    Rayner, Nigel W.
    Robertson, Neil
    Karssen, Lennart C.
    Van Leeuwen, Elisabeth M.
    Willems, Sara M.
    Fuchsberger, Christian
    Kwan, Phoenix
    Teslovich, Tanya M.
    Chanda, Pritam
    Li, Man
    Lu, Yingchang
    Dina, Christian
    Thuillier, Dorothee
    Yengo, Loic
    Jiang, Longda
    Sparso, Thomas
    Kestler, Hans A.
    Chheda, Himanshu
    Eisele, Lewin
    Gustafsson, Stefan
    Franberg, Mattias
    Strawbridge, Rona J.
    Benediktsson, Rafn
    Hreidarsson, Astradur B.
    Kong, Augustine
    Sigurdsson, Gunnar
    Kerrison, Nicola D.
    Luan, Jian'an
    Liang, Liming
    Meitinger, Thomas
    Roden, Michael
    Thorand, Barbara
    Esko, Tonu
    Mihailov, Evelin
    Fox, Caroline
    Liu, Ching-Ti
    Rybin, Denis
    Isomaa, Bo
    Lyssenko, Valeriya
    Tuomi, Tiinamaija
    Couper, David J.
    Pankow, James S.
    Grarup, Niels
    Have, Christian T.
    Jorgensen, Marit E.
    Jorgensen, Torben
    Linneberg, Allan
    Cornelis, Marilyn C.
    Van Dam, Rob M.
    Hunter, David J.
    Kraft, Peter
    Sun, Qi
    Edkins, Sarah
    Owen, Katharine R.
    Perry, John R. B.
    Wood, Andrew R.
    Zeggini, Eleftheria
    Tajes-Fernandes, Juan
    Abecasis, Goncalo R.
    Bonnycastle, Lori L.
    Chines, Peter S.
    Stringham, Heather M.
    Koistinen, Heikki A.
    Kinnunen, Leena
    Sennblad, Bengt
    Muehleisen, Thomas W.
    Noethen, Markus M.
    Pechlivanis, Sonali
    Baldassarre, Damiano
    Gertow, Karl
    Humphries, Steve E.
    Tremoli, Elena
    Klopp, Norman
    Meyer, Julia
    Steinbach, Gerald
    Wennauer, Roman
    Eriksson, Johan G.
    Mannisto, Satu
    Peltonen, Leena
    Tikkanen, Emmi
    Charpentier, Guillaume
    Eury, Elodie
    Lobbens, Stephane
    Gigante, Bruna
    Leander, Karin
    McLeod, Olga
    Bottinger, Erwin P.
    Gottesman, Omri
    Ruderfer, Douglas
    Blueher, Matthias
    Kovacs, Peter
    Tonjes, Anke
    Maruthur, Nisa M.
    Scapoli, Chiara
    Erbel, Raimund
    Joeckel, Karl-Heinz
    Moebus, Susanne
    De Faire, Ulf
    Hamsten, Anders
    Stumvoll, Michael
    Deloukas, Panagiotis
    Donnelly, Peter J.
    Frayling, Timothy M.
    Hattersley, Andrew T.
    Ripatti, Samuli
    Salomaa, Veikko
    Pedersen, Nancy L.
    Boehm, Bernhard O.
    Bergman, Richard N.
    Collins, Francis S.
    Mohlke, Karen L.
    Tuomilehto, Jaakko
    Hansen, Torben
    Pedersen, Oluf
    Barroso, Ines
    Lannfelt, Lars
    Ingelsson, Erik
    Lind, Lars
    Lindgren, Cecilia M.
    Cauchi, Stephane
    Froguel, Philippe
    Loos, Ruth J. F.
    Balkau, Beverley
    Boeing, Heiner
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Lund University, Malmö, Sweden .
    Gurrea, Aurelio Barricarte
    Palli, Domenico
    Van der Schouw, Yvonne T.
    Altshuler, David
    Groop, Leif C.
    Langenberg, Claudia
    Wareham, Nicholas J.
    Sijbrands, Eric
    Van Duijn, Cornelia M.
    Florez, Jose C.
    Meigs, James B.
    Boerwinkle, Eric
    Gieger, Christian
    Strauch, Konstantin
    Metspalu, Andres
    Morris, Andrew D.
    Palmer, Colin N. A.
    Hu, Frank B.
    Thorsteinsdottir, Unnur
    Stefansson, Kari
    Dupuis, Josee
    Morris, Andrew P.
    Boehnke, Michael
    McCarthy, Mark I.
    Prokopenko, Inga
    An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans2017Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, nr 11, s. 2888-2902Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

  • 32. Sluijs, Ivonne
    et al.
    Holmes, Michael V.
    van der Schouw, Yvonne T.
    Beulens, Joline W. J.
    Asselbergs, Folkert W.
    Maria Huerta, Jose
    Palmer, Tom M.
    Arriola, Larraitz
    Balkau, Beverley
    Barricarte, Aurelio
    Boeing, Heiner
    Clavel-Chapelon, Francoise
    Fagherazzi, Guy
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Gavrila, Diana
    Kaaks, Rudolf
    Khaw, Kay Tee
    Kuehn, Tilman
    Molina-Montes, Esther
    Mortensen, Lotte Maxild
    Nilsson, Peter M.
    Overvad, Kim
    Palli, Domenico
    Panico, Salvatore
    Ramon Quiros, J.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Sacerdote, Carlotta
    Sala, Nuria
    Schmidt, Julie A.
    Scott, Robert A.
    Sieri, Sabina
    Slimani, Nadia
    Spijkerman, Annemieke M. W.
    Tjonneland, Anne
    Travis, Ruth C.
    Tumino, Rosario
    Daphne, L. van der A.
    Sharp, Stephen J.
    Forouhi, Nita G.
    Langenberg, Claudia
    Riboli, Elio
    Wareham, Nicholas J.
    A Mendelian Randomization Study of Circulating Uric Acid and Type 2 Diabetes2015Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, nr 8, s. 3028-3036Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We aimed to investigate the causal effect of circulating uric acid concentrations on type 2 diabetes risk. A Mendelian randomization study was performed using a genetic score with 24 uric acid-associated loci. We used data of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, comprising 24,265 individuals of European ancestry from eight European countries. During a mean (SD) follow-up of 10 (4) years, 10,576 verified incident case subjects with type 2 diabetes were ascertained. Higher uric acid was associated with a higher diabetes risk after adjustment for confounders, with a hazard ratio (HR) of 1.20 (95% CI 1.11, 1.30) per 59.48 mu mol/L (1mg/dL) uric acid. The genetic score raised uric acid by 17 mu mol/L (95% CI 15, 18) per SD increase and explained 4% of uric acid variation. By using the genetic score to estimate the unconfounded effect, we found that a 59.48 mu mol/L higher uric acid concentration did not have a causal effect on diabetes (HR 1.01 [95% CI 0.87, 1.16]). Including data from the Diabetes Genetics Replication And Meta-analysis (DIAGRAM) consortium, increasing our dataset to 41,508 case subjects with diabetes, the summary odds ratio estimate was 0.99 (95% CI 0.92, 1.06). In conclusion, our study does not support a causal effect of circulating uric acid on diabetes risk. Uric acid-lowering therapies may therefore not be beneficial in reducing diabetes risk.

  • 33.
    Steneberg, Pär
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Bernardo, Lisandro
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Edfalk, Sara
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Lundberg, Lisa
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Backlund, Fredrik
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Ostenson, Claes-Goran
    Edlund, Helena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    The Type 2 Diabetes-Associated Gene Ide Is Required for Insulin Secretion and Suppression of alpha-Synuclein Levels in beta-Cells2013Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 62, nr 6, s. 2004-2014Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Genome-wide association studies have identified several type 2 diabetes (T2D) risk loci linked to impaired beta-cell function. The identity and function of the causal genes in these susceptibility loci remain, however, elusive. The HHEX/IDE T2D locus is associated with decreased insulin secretion in response to oral glucose stimulation in humans. Here we have assessed beta-cell function in Ide knockout (KO) mice. We find that glucose-stimulated insulin secretion (GSIS) is decreased in Ide KO mice due to impaired replenishment of the releasable pool of granules and that the Ide gene is haploinsufficient. We also show that autophagic flux and microtubule content are reduced in beta-cells of Ide KO mice. One important cellular role for IDE involves the neutralization of amyloidogenic proteins, and we find that a-synuclein and IDE levels are inversely correlated in beta-cells of Ide KO mice and T2D patients. Moreover, we provide evidence that both gain and loss of function of a-synuclein in beta-cells in vivo impair not only GSIS but also autophagy. Together, these data identify the Ide gene as a regulator of GSIS, suggest a molecular mechanism for beta-cell degeneration as a consequence of Ide deficiency, and corroborate and extend a previously established important role for a-synuclein in beta-cell function.

  • 34. Stimson, Roland H
    et al.
    Andersson, Jonas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Andrew, Ruth
    Redhead, Doris N
    Karpe, Fredrik
    Hayes, Peter C
    Olsson, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Walker, Brian R
    Cortisol release from adipose tissue by 11beta-hydroxysteroid dehydrogenase type 1 in humans2009Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 58, nr 1, s. 46-53Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) regenerates cortisol from cortisone. 11beta-HSD1 mRNA and activity are increased in vitro in subcutaneous adipose tissue from obese patients. Inhibition of 11beta-HSD1 is a promising therapeutic approach in type 2 diabetes. However, release of cortisol by 11beta-HSD1 from adipose tissue and its effect on portal vein cortisol concentrations have not been quantified in vivo.

    RESEARCH DESIGN AND METHODS: Six healthy men underwent 9,11,12,12-[(2)H](4)-cortisol infusions with simultaneous sampling of arterialized and superficial epigastric vein blood sampling. Four men with stable chronic liver disease and a transjugular intrahepatic porto-systemic shunt in situ underwent tracer infusion with simultaneous sampling from the portal vein, hepatic vein, and an arterialized peripheral vein.

    RESULTS: Significant cortisol and 9,12,12-[(2)H](3)-cortisol release were observed from subcutaneous adipose tissue (15.0 [95% CI 0.4-29.5] and 8.7 [0.2-17.2] pmol . min(-1) . 100 g(-1) adipose tissue, respectively). Splanchnic release of cortisol and 9,12,12-[(2)H](3)-cortisol (13.5 [3.6-23.5] and 8.0 [2.6-13.5] nmol/min, respectively) was accounted for entirely by the liver; release of cortisol from visceral tissues into portal vein was not detected.

    CONCLUSIONS: Cortisol is released from subcutaneous adipose tissue by 11beta-HSD1 in humans, and increased enzyme expression in obesity is likely to increase local glucocorticoid signaling and contribute to whole-body cortisol regeneration. However, visceral adipose 11beta-HSD1 activity is insufficient to increase portal vein cortisol concentrations and hence to influence intrahepatic glucocorticoid signaling.

  • 35.
    Yang, Lingling
    et al.
    State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
    Di, Guohu
    State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
    Qi, Xia
    State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
    Qu, Mingli
    State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
    Wang, Yao
    State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
    Duan, Haoyun
    State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
    Danielson, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Xie, Lixin
    State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
    Zhou, Qingjun
    State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China.
    Substance P promotes diabetic corneal epithelial wound healing through molecular mechanisms mediated via the neurokinin-1 receptor.2014Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, nr 12, s. 4262-4274Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Substance P (SP) is a neuropeptide, predominantly released from sensory nerve fibers, with a potentially protective role in diabetic corneal epithelial wound healing. However, the molecular mechanism remains unclear. We investigated the protective mechanism of SP against hyperglycemia-induced corneal epithelial wound healing defects, using type 1 diabetic mice and high glucose-treated corneal epithelial cells. Hyperglycemia induced delayed corneal epithelial wound healing, accompanied with attenuated corneal sensation, mitochondrial dysfunction, and impairments of Akt-, EGFR-, and Sirt1-activation, as well as decreased reactive oxygen species (ROS) scavenging capacity. However, SP application promoted the epithelial wound healing, the recovery of corneal sensation, the improvement of mitochondrial function, and the reactivation of Akt, EGFR and Sirt1, as well as increased ROS scavenging capacity, in both diabetic mouse corneal epithelium and high glucose-treated corneal epithelial cells. The promotion of SP on diabetic corneal epithelial healing was completely abolished by a NK-1 receptor antagonist. Moreover, the subconjunctival injection of NK-1 receptor antagonist also caused diabetic corneal pathological changes in normal mice. In conclusion, the results suggest that SP-NK-1 receptor signaling plays a critical role in the maintenance of corneal epithelium homeostasis, and that SP signaling through the NK-1 recssssseptor contributes to the promotion of diabetic corneal epithelial wound healing by rescued activation of Akt, EGFR, and Sirt1, improvement of mitochondrial function, and increased ROS scavenging capacity.

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