Journal Cover Diabetes
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   ISSN (Print) 0012-1797 - ISSN (Online) 1939-327X
   Published by American Diabetes Association Homepage  [4 journals]
  • In This Issue of Diabetes
    • Pages: 1 - 2
      PubDate: 2017-12-20T12:06:27-08:00
      DOI: 10.2337/db18-ti01
      Issue No: Vol. 67, No. 1 (2017)
  • Diabetes in China: Epidemiology and Genetic Risk Factors and Their
           Clinical Utility in Personalized Medication
    • Authors: Hu; C.; Jia, W.
      Pages: 3 - 11
      Abstract: The incidence of type 2 diabetes (T2D) has rapidly increased over recent decades, and T2D has become a leading public health challenge in China. Compared with European descents, Chinese patients with T2D are diagnosed at a relatively young age and low BMI. A better understanding of the factors contributing to the diabetes epidemic is crucial for determining future prevention and intervention programs. In addition to environmental factors, genetic factors contribute substantially to the development of T2D. To date, more than 100 susceptibility loci for T2D have been identified. Individually, most T2D genetic variants have a small effect size (10–20% increased risk for T2D per risk allele); however, a genetic risk score that combines multiple T2D loci could be used to predict the risk of T2D and to identify individuals who are at a high risk. Furthermore, individualized antidiabetes treatment should be a top priority to prevent complications and mortality. In this article, we review the epidemiological trends and recent progress in the understanding of T2D genetic etiology and further discuss personalized medicine involved in the treatment of T2D.
      Keywords: Genetics-Type 2 Diabetes
      PubDate: 2017-12-20T12:06:27-08:00
      DOI: 10.2337/dbi17-0013
      Issue No: Vol. 67, No. 1 (2017)
  • The Adiponectin Paradox for All-Cause and Cardiovascular Mortality
    • Authors: Menzaghi; C.; Trischitta, V.
      Pages: 12 - 22
      Abstract: Basic science studies have shown beneficial effects of adiponectin on glucose homeostasis, chronic low-grade inflammation, apoptosis, oxidative stress, and atherosclerotic processes, so this molecule usually has been considered a salutary adipokine. It was therefore quite unexpected that large prospective human studies suggested that adiponectin is simply a marker of glucose homeostasis, with no direct favorable effect on the risk of type 2 diabetes and cardiovascular disease. But even more unforeseen were data addressing the role of adiponectin on the risk of death. In fact, a positive, rather than the expected negative, relationship was reported between adiponectin and mortality rate across many clinical conditions, comprising diabetes. The biology underlying this paradox is unknown. Several explanations have been proposed, including adiponectin resistance and the confounding role of natriuretic peptides. In addition, preliminary genetic evidence speaks in favor of a direct role of adiponectin in increasing the risk of death. However, none of these hypotheses are based on robust data, so further efforts are needed to unravel the elusive role of adiponectin on cardiometabolic health and, most important, its paradoxical association with mortality rate.
      Keywords: Epidemiology-Other
      PubDate: 2017-12-20T12:06:27-08:00
      DOI: 10.2337/dbi17-0016
      Issue No: Vol. 67, No. 1 (2017)
  • SCP4: A Small Nuclear Phosphatase Having a Big Effect on FoxOs in
    • Authors: Dong; X. C.
      Pages: 23 - 25
      Keywords: Integrated Physiology-Liver
      PubDate: 2017-12-20T12:06:27-08:00
      DOI: 10.2337/dbi17-0042
      Issue No: Vol. 67, No. 1 (2017)
  • {beta}-Cell Replacement in Mice Using Human Type 1 Diabetes Nuclear
           Transfer Embryonic Stem Cells
    • Authors: Sui; L.; Danzl, N.; Campbell, S. R.; Viola, R.; Williams, D.; Xing, Y.; Wang, Y.; Phillips, N.; Poffenberger, G.; Johannesson, B.; Oberholzer, J.; Powers, A. C.; Leibel, R. L.; Chen, X.; Sykes, M.; Egli, D.
      Pages: 26 - 35
      Abstract: β-Cells derived from stem cells hold great promise for cell replacement therapy for diabetes. Here we examine the ability of nuclear transfer embryonic stem cells (NT-ESs) derived from a patient with type 1 diabetes to differentiate into β-cells and provide a source of autologous islets for cell replacement. NT-ESs differentiate in vitro with an average efficiency of 55% into C-peptide–positive cells, expressing markers of mature β-cells, including MAFA and NKX6.1. Upon transplantation in immunodeficient mice, grafted cells form vascularized islet-like structures containing MAFA/C-peptide–positive cells. These β-cells adapt insulin secretion to ambient metabolite status and show normal insulin processing. Importantly, NT-ES-β-cells maintain normal blood glucose levels after ablation of the mouse endogenous β-cells. Cystic structures, but no teratomas, were observed in NT-ES-β-cell grafts. Isogenic induced pluripotent stem cell lines showed greater variability in β-cell differentiation. Even though different methods of somatic cell reprogramming result in stem cell lines that are molecularly indistinguishable, full differentiation competence is more common in ES cell lines than in induced pluripotent stem cell lines. These results demonstrate the suitability of NT-ES-β-cells for cell replacement for type 1 diabetes and provide proof of principle for therapeutic cloning combined with cell therapy.
      Keywords: Islet Biology-Beta Cell-Development and Postnatal Growth
      PubDate: 2017-12-20T12:06:27-08:00
      DOI: 10.2337/db17-0120
      Issue No: Vol. 67, No. 1 (2017)
  • IL-6-Type Cytokine Signaling in Adipocytes Induces Intestinal GLP-1
    • Authors: Wueest; S.; Laesser, C. I.; Böni-Schnetzler, M.; Item, F.; Lucchini, F. C.; Borsigova, M.; Müller, W.; Donath, M. Y.; Konrad, D.
      Pages: 36 - 45
      Abstract: We recently showed that interleukin (IL)-6–type cytokine signaling in adipocytes induces free fatty acid release from visceral adipocytes, thereby promoting obesity-induced hepatic insulin resistance and steatosis. In addition, IL-6–type cytokines may increase the release of leptin from adipocytes and by those means induce glucagon-like peptide 1 (GLP-1) secretion. We thus hypothesized that IL-6–type cytokine signaling in adipocytes may regulate insulin secretion. To this end, mice with adipocyte-specific knockout of gp130, the signal transducer protein of IL-6, were fed a high-fat diet for 12 weeks. Compared with control littermates, knockout mice showed impaired glucose tolerance and circulating leptin, GLP-1, and insulin levels were reduced. In line, leptin release from isolated adipocytes was reduced, and intestinal proprotein convertase subtilisin/kexin type 1 (Pcsk1) expression, the gene encoding PC1/3, which controls GLP-1 production, was decreased in knockout mice. Importantly, treatment with the GLP-1 receptor antagonist exendin 9–39 abolished the observed difference in glucose tolerance between control and knockout mice. Ex vivo, supernatant collected from isolated adipocytes of gp130 knockout mice blunted Pcsk1 expression and GLP-1 release from GLUTag cells. In contrast, glucose- and GLP-1–stimulated insulin secretion was not affected in islets of knockout mice. In conclusion, adipocyte-specific IL-6 signaling induces intestinal GLP-1 release to enhance insulin secretion, thereby counteracting insulin resistance in obesity.
      Keywords: Integrated Physiology-Other Hormones
      PubDate: 2017-12-20T12:06:27-08:00
      DOI: 10.2337/db17-0637
      Issue No: Vol. 67, No. 1 (2017)
  • SCP4 Promotes Gluconeogenesis Through FoxO1/3a Dephosphorylation
    • Authors: Cao; J.; Yu, Y.; Zhang, Z.; Chen, X.; Hu, Z.; Tong, Q.; Chang, J.; Feng, X.-H.; Lin, X.
      Pages: 46 - 57
      Abstract: FoxO1 and FoxO3a (collectively FoxO1/3a) proteins regulate a wide array of cellular processes, including hepatic gluconeogenesis. Phosphorylation of FoxO1/3a is a key event that determines its subcellular location and transcriptional activity. During glucose synthesis, the activity of FoxO1/3a is negatively regulated by Akt-mediated phosphorylation, which leads to the cytoplasmic retention of FoxO1/3a. However, the nuclear phosphatase that directly regulates FoxO1/3a remains to be identified. In this study, we discovered a nuclear phosphatase, SCP4/CTDSPL2 (SCP4), that dephosphorylated FoxO1/3a and promoted FoxO1/3a transcription activity. We found that SCP4 enhanced the transcription of FoxO1/3a target genes encoding PEPCK1 and G6PC, key enzymes in hepatic gluconeogenesis. Ectopic expression of SCP4 increased, while knockdown of SCP4 inhibited, glucose production. Moreover, we demonstrated that gene ablation of SCP4 led to hypoglycemia in neonatal mice. Consistent with the positive role of SCP4 in gluconeogenesis, expression of SCP4 was regulated under pathophysiological conditions. SCP4 expression was induced by glucose deprivation in vitro and in vivo and was elevated in obese mice caused by genetic (Avy) and dietary (high-fat) changes. Thus, our findings provided experimental evidence that SCP4 regulates hepatic gluconeogenesis and could serve as a potential target for the prevention and treatment of diet-induced glucose intolerance and type 2 diabetes.
      Keywords: Genetics-Type 2 Diabetes
      PubDate: 2017-12-20T12:06:27-08:00
      DOI: 10.2337/db17-0546
      Issue No: Vol. 67, No. 1 (2017)
  • Inhibition of Cdk5 Promotes {beta}-Cell Differentiation From Ductal
    • Authors: Liu; K.-C.; Leuckx, G.; Sakano, D.; Seymour, P. A.; Mattsson, C. L.; Rautio, L.; Staels, W.; Verdonck, Y.; Serup, P.; Kume, S.; Heimberg, H.; Andersson, O.
      Pages: 58 - 70
      Abstract: Inhibition of notch signaling is known to induce differentiation of endocrine cells in zebrafish and mouse. After performing an unbiased in vivo screen of ~2,200 small molecules in zebrafish, we identified an inhibitor of Cdk5 (roscovitine), which potentiated the formation of β-cells along the intrapancreatic duct during concurrent inhibition of notch signaling. We confirmed and characterized the effect with a more selective Cdk5 inhibitor, (R)-DRF053, which specifically increased the number of duct-derived β-cells without affecting their proliferation. By duct-specific overexpression of the endogenous Cdk5 inhibitors Cdk5rap1 or Cdkal1 (which previously have been linked to diabetes in genome-wide association studies), as well as deleting cdk5, we validated the role of chemical Cdk5 inhibition in β-cell differentiation by genetic means. Moreover, the cdk5 mutant zebrafish displayed an increased number of β-cells independently of inhibition of notch signaling, in both the basal state and during β-cell regeneration. Importantly, the effect of Cdk5 inhibition to promote β-cell formation was conserved in mouse embryonic pancreatic explants, adult mice with pancreatic ductal ligation injury, and human induced pluripotent stem (iPS) cells. Thus, we have revealed a previously unknown role of Cdk5 as an endogenous suppressor of β-cell differentiation and thereby further highlighted its importance in diabetes.
      Keywords: Islet Biology-Beta Cell-Development and Postnatal Growth
      PubDate: 2017-12-20T12:06:27-08:00
      DOI: 10.2337/db16-1587
      Issue No: Vol. 67, No. 1 (2017)
  • Deletion of Protein Kinase D1 in Pancreatic {beta}-Cells Impairs Insulin
           Secretion in High-Fat Diet-Fed Mice
    • Authors: Bergeron; V.; Ghislain, J.; Vivot, K.; Tamarina, N.; Philipson, L. H.; Fielitz, J.; Poitout, V.
      Pages: 71 - 77
      Abstract: Bβ-Cell adaptation to insulin resistance is necessary to maintain glucose homeostasis in obesity. Failure of this mechanism is a hallmark of type 2 diabetes (T2D). Hence, factors controlling functional β-cell compensation are potentially important targets for the treatment of T2D. Protein kinase D1 (PKD1) integrates diverse signals in the β-cell and plays a critical role in the control of insulin secretion. However, the role of β-cell PKD1 in glucose homeostasis in vivo is essentially unknown. Using β-cell–specific, inducible PKD1 knockout mice (βPKD1KO), we examined the role of β-cell PKD1 under basal conditions and during high-fat feeding. βPKD1KO mice under a chow diet presented no significant difference in glucose tolerance or insulin secretion compared with mice expressing the Cre transgene alone; however, when compared with wild-type mice, both groups developed glucose intolerance. Under a high-fat diet, deletion of PKD1 in β-cells worsened hyperglycemia, hyperinsulinemia, and glucose intolerance. This was accompanied by impaired glucose-induced insulin secretion both in vivo in hyperglycemic clamps and ex vivo in isolated islets from high-fat diet–fed βPKD1KO mice without changes in islet mass. This study demonstrates an essential role for PKD1 in the β-cell adaptive secretory response to high-fat feeding in mice.
      Keywords: Islet Biology-Beta Cell-Stimulus-Secretion Coupling and Metabolism
      PubDate: 2017-12-20T12:06:27-08:00
      DOI: 10.2337/db17-0982
      Issue No: Vol. 67, No. 1 (2017)
  • Mitochondrial Protein UCP2 Controls Pancreas Development
    • Authors: Broche; B.; Ben Fradj, S.; Aguilar, E.; Sancerni, T.; Benard, M.; Makaci, F.; Berthault, C.; Scharfmann, R.; Alves-Guerra, M.-C.; Duvillie, B.
      Pages: 78 - 84
      Abstract: The mitochondrial carrier uncoupling protein (UCP) 2 belongs to the family of the UCPs. Despite its name, it is now accepted that UCP2 is rather a metabolite transporter than a UCP. UCP2 can regulate oxidative stress and/or energetic metabolism. In rodents, UCP2 is involved in the control of α- and β-cell mass as well as insulin and glucagon secretion. Our aim was to determine whether the effects of UCP2 observed on β-cell mass have an embryonic origin. Thus, we used Ucp2 knockout mice. We found an increased size of the pancreas in Ucp2–/– fetuses at embryonic day 16.5, associated with a higher number of α- and β-cells. This phenotype was caused by an increase of PDX1+ progenitor cells. Perinatally, an increase in the proliferation of endocrine cells also participates in their expansion. Next, we analyzed the oxidative stress in the pancreata. We quantified an increased nuclear translocation of nuclear factor erythroid 2–related factor 2 (NRF2) in the mutant, suggesting an increased production of reactive oxygen species (ROS). Phosphorylation of AKT, an ROS target, was also activated in the Ucp2–/– pancreata. Finally, administration of the antioxidant N-acetyl-l-cysteine to Ucp2–/– pregnant mice alleviated the effect of knocking out UCP2 on pancreas development. Together, these data demonstrate that UCP2 controls pancreas development through the ROS-AKT signaling pathway.
      Keywords: Islet Biology-Beta Cell-Development and Postnatal Growth
      PubDate: 2017-12-20T12:06:27-08:00
      DOI: 10.2337/db17-0118
      Issue No: Vol. 67, No. 1 (2017)
  • Uncoupling Exercise Bioenergetics From Systemic Metabolic Homeostasis by
           Conditional Inactivation of Baf60 in Skeletal Muscle
    • Authors: Meng; Z.-X.; Tao, W.; Sun, J.; Wang, Q.; Mi, L.; Lin, J. D.
      Pages: 85 - 97
      Abstract: Impaired skeletal muscle energy metabolism is linked to the pathogenesis of insulin resistance and glucose intolerance in type 2 diabetes. The contractile and metabolic properties of myofibers exhibit a high degree of heterogeneity and plasticity. The regulatory circuitry underpinning skeletal muscle energy metabolism is critically linked to exercise endurance and systemic homeostasis. Recent work has identified the Baf60 subunits of the SWI/SNF chromatin-remodeling complex as powerful regulators of the metabolic gene programs. However, their role in integrating myofiber energy metabolism with exercise endurance and metabolic physiology remains largely unknown. In this study, we conditionally inactivated Baf60a, Baf60c, or both in mature skeletal myocytes to delineate their contribution to muscle bioenergetics and metabolic physiology. Our work revealed functional redundancy between Baf60a and Baf60c in maintaining oxidative and glycolytic metabolism in skeletal myofibers and exercise endurance. Unexpectedly, mice lacking these two factors in skeletal muscle were protected from diet-induced and age-associated metabolic disorders. Transcriptional profiling analysis identified the muscle thermogenic gene program and myokine secretion as key pathways that integrate myofiber metabolism with systemic energy balance. As such, Baf60 deficiency in skeletal muscle illustrates a surprising disconnect between exercise endurance and systemic metabolic homeostasis.
      Keywords: Integrated Physiology-Muscle
      PubDate: 2017-12-20T12:06:27-08:00
      DOI: 10.2337/db17-0367
      Issue No: Vol. 67, No. 1 (2017)
  • Negative Regulation of TRPA1 by AMPK in Primary Sensory Neurons as a
           Potential Mechanism of Painful Diabetic Neuropathy
    • Authors: Wang; S.; Kobayashi, K.; Kogure, Y.; Yamanaka, H.; Yamamoto, S.; Yagi, H.; Noguchi, K.; Dai, Y.
      Pages: 98 - 109
      Abstract: AMPK is a widely expressed intracellular energy sensor that monitors and modulates energy expenditure. Transient receptor potential ankyrin 1 (TRPA1) channel is a widely recognized chemical and thermal sensor that plays vital roles in pain transduction. In this study, we discovered a functional link between AMPK and TRPA1 in dorsal root ganglion (DRG) neurons, in which AMPK activation rapidly resulted in downregulation of membrane-associated TRPA1 and its channel activity within minutes. Treatment with two AMPK activators, metformin or AICAR, inhibited TRPA1 activity in DRG neurons by decreasing the amount of membrane-associated TRPA1. Metformin induced a dose-dependent inhibition of TRPA1-mediated calcium influx. Conversely, in diabetic db/db mice, AMPK activity was impaired in DRG neurons, and this was associated with a concomitant increase in membrane-associated TRPA1 and mechanical allodynia. Notably, these molecular and behavioral changes were normalized following treatment with AMPK activators. Moreover, high-glucose exposure decreased activated AMPK levels and increased agonist-evoked TRPA1 currents in cultured DRG neurons, and these effects were prevented by treatment with AMPK activators. Our results identify AMPK as a previously unknown regulator of TRPA1 channels. AMPK modulation of TRPA1 could thus serve as an underlying mechanism and potential therapeutic molecular target in painful diabetic neuropathy.
      Keywords: Complications-Neuropathy
      PubDate: 2017-12-20T12:06:27-08:00
      DOI: 10.2337/db17-0503
      Issue No: Vol. 67, No. 1 (2017)
  • Deletion of the Akt/mTORC1 Repressor REDD1 Prevents Visual Dysfunction in
           a Rodent Model of Type 1 Diabetes
    • Authors: Miller; W. P.; Yang, C.; Mihailescu, M. L.; Moore, J. A.; Dai, W.; Barber, A. J.; Dennis, M. D.
      Pages: 110 - 119
      Abstract: Diabetes-induced visual dysfunction is associated with significant neuroretinal cell death. The current study was designed to investigate the role of the Protein Regulated in Development and DNA Damage Response 1 (REDD1) in diabetes-induced retinal cell death and visual dysfunction. We recently demonstrated that REDD1 protein expression was elevated in response to hyperglycemia in the retina of diabetic rodents. REDD1 is an important regulator of Akt and mammalian target of rapamycin and as such plays a key role in neuronal function and survival. In R28 retinal cells in culture, hyperglycemic conditions enhanced REDD1 protein expression concomitant with caspase activation and cell death. By contrast, in REDD1-deficient R28 cells, neither hyperglycemic conditions nor the absence of insulin in culture medium were sufficient to promote cell death. In the retinas of streptozotocin-induced diabetic mice, retinal apoptosis was dramatically elevated compared with nondiabetic controls, whereas no difference was observed in diabetic and nondiabetic REDD1-deficient mice. Electroretinogram abnormalities observed in b-wave and oscillatory potentials of diabetic wild-type mice were also absent in REDD1-deficient mice. Moreover, diabetic wild-type mice exhibited functional deficiencies in visual acuity and contrast sensitivity, whereas diabetic REDD1-deficient mice had no visual dysfunction. The results support a role for REDD1 in diabetes-induced retinal neurodegeneration.
      Keywords: Complications-Retinopathy
      PubDate: 2017-12-20T12:06:27-08:00
      DOI: 10.2337/db17-0728
      Issue No: Vol. 67, No. 1 (2017)
  • Thioredoxin-1 Overexpression in the Ventromedial Nucleus of the
           Hypothalamus Preserves the Counterregulatory Response to Hypoglycemia
           During Type 1 Diabetes in Male Rats
    • Authors: Zhou; C.; Routh, V. H.
      Pages: 120 - 130
      Abstract: We previously showed that the glutathione precursor, N-acetylcysteine (NAC), prevented hypoglycemia-associated autonomic failure (HAAF) and impaired activation of ventromedial hypothalamus (VMH) glucose-inhibited (GI) neurons by low glucose after recurrent hypoglycemia (RH) in nondiabetic rats. However, NAC does not normalize glucose sensing by VMH GI neurons when RH occurs during diabetes. We hypothesized that recruiting the thioredoxin (Trx) antioxidant defense system would prevent HAAF and normalize glucose sensing after RH in diabetes. To test this hypothesis, we overexpressed Trx-1 (cytosolic form of Trx) in the VMH of rats with streptozotocin (STZ)-induced type 1 diabetes. The counterregulatory response (CRR) to hypoglycemia in vivo and the activation of VMH GI neurons in low glucose using membrane potential sensitive dye in vitro was measured before and after RH. VMH Trx-1 overexpression normalized both the CRR and glucose sensing by VMH GI neurons in STZ rats. VMH Trx-1 overexpression also lowered the insulin requirement to prevent severe hyperglycemia in STZ rats. However, like NAC, VMH Trx-1 overexpression did not prevent HAAF or normalize activation of VMH GI neurons by low glucose in STZ rats after RH. We conclude that preventing HAAF in type 1 diabetes may require the recruitment of both antioxidant systems.
      Keywords: Complications-Hypoglycemia
      PubDate: 2017-12-20T12:06:27-08:00
      DOI: 10.2337/db17-0930
      Issue No: Vol. 67, No. 1 (2017)
  • Evidence That Differences in Fructosamine-3-Kinase Activity May Be
           Associated With the Glycation Gap in Human Diabetes
    • Authors: Dunmore; S. J.; Al-Derawi, A. S.; Nayak, A. U.; Narshi, A.; Nevill, A. M.; Hellwig, A.; Majebi, A.; Kirkham, P.; Brown, J. E.; Singh, B. M.
      Pages: 131 - 136
      Abstract: The phenomenon of a discrepancy between glycated hemoglobin levels and other indicators of average glycemia may be due to many factors but can be measured as the glycation gap (GGap). This GGap is associated with differences in complications in patients with diabetes and may possibly be explained by dissimilarities in deglycation in turn leading to altered production of advanced glycation end products (AGEs). We hypothesized that variations in the level of the deglycating enzyme fructosamine-3-kinase (FN3K) might be associated with the GGap. We measured erythrocyte FN3K concentrations and enzyme activity in a population dichotomized for a large positive or negative GGap. FN3K protein was higher and we found a striking threefold greater activity (323%) at any given FN3K protein level in the erythrocytes of the negative-GGap group compared with the positive-GGap group. This was associated with lower AGE levels in the negative-GGap group (79%), lower proinflammatory adipokines (leptin-to-adiponectin ratio) (73%), and much lower prothrombotic PAI-1 levels (19%). We conclude that FN3K may play a key role in the GGap and thus diabetes complications such that FN3K may be a potential predictor of the risk of diabetes complications. Pharmacological modifications of its activity may provide a novel approach to their prevention.
      Keywords: Complications-Macrovascular-Atherosclerotic Cardiovascular Disease and Human Diabetes
      PubDate: 2017-12-20T12:06:27-08:00
      DOI: 10.2337/db17-0441
      Issue No: Vol. 67, No. 1 (2017)
  • Insights From Molecular Characterization of Adult Patients of Families
           With Multigenerational Diabetes
    • Authors: Pezzilli; S.; Ludovico, O.; Biagini, T.; Mercuri, L.; Alberico, F.; Lauricella, E.; Dallali, H.; Capocefalo, D.; Carella, M.; Miccinilli, E.; Piscitelli, P.; Scarale, M. G.; Mazza, T.; Trischitta, V.; Prudente, S.
      Pages: 137 - 145
      Abstract: Multigenerational diabetes of adulthood is a mostly overlooked entity, simplistically lumped into the large pool of type 2 diabetes. The general aim of our research in the past few years is to unravel the genetic causes of this form of diabetes. Identifying among families with multigenerational diabetes those who carry mutations in known monogenic diabetes genes is the first step to then allow us to concentrate on remaining pedigrees in which to unravel new diabetes genes. Targeted next-generation sequencing of 27 monogenic diabetes genes was carried out in 55 family probands and identified mutations verified among their relatives by Sanger sequencing. Nine variants (in eight probands) survived our filtering/prioritization strategy. After likelihood of causality assessment by established guidelines, six variants were classified as "pathogenetic/likely pathogenetic" and two as "of uncertain significance." Combining present results with our previous data on the six genes causing the most common forms of maturity-onset diabetes of the young allows us to infer that 23.6% of families with multigenerational diabetes of adulthood carry mutations in known monogenic diabetes genes. Our findings indicate that the genetic background of hyperglycemia is unrecognized in the vast majority of families with multigenerational diabetes of adulthood. These families now become the object of further research aimed at unraveling new diabetes genes.
      Keywords: Genetics-Type 2 Diabetes
      PubDate: 2017-12-20T12:06:27-08:00
      DOI: 10.2337/db17-0867
      Issue No: Vol. 67, No. 1 (2017)
  • Plasma 25-Hydroxyvitamin D Concentration and Risk of Islet Autoimmunity
    • Authors: Norris; J. M.; Lee, H.-S.; Frederiksen, B.; Erlund, I.; Uusitalo, U.; Yang, J.; Lernmark, A.; Simell, O.; Toppari, J.; Rewers, M.; Ziegler, A.-G.; She, J.-X.; Onengut-Gumuscu, S.; Chen, W.-M.; Rich, S. S.; Sundvall, J.; Akolkar, B.; Krischer, J.; Virtanen, S. M.; Hagopian, W.; for the TEDDY Study Group
      Pages: 146 - 154
      Abstract: We examined the association between plasma 25-hydroxyvitamin D [25(OH)D] concentration and islet autoimmunity (IA) and whether vitamin D gene polymorphisms modify the effect of 25(OH)D on IA risk. We followed 8,676 children at increased genetic risk of type 1 diabetes at six sites in the U.S. and Europe. We defined IA as positivity for at least one autoantibody (GADA, IAA, or IA-2A) on two or more visits. We conducted a risk set sampled nested case-control study of 376 IA case subjects and up to 3 control subjects per case subject. 25(OH)D concentration was measured on all samples prior to, and including, the first IA positive visit. Nine polymorphisms in VDR, CYP24A, CYP27B1, GC, and RXRA were analyzed as effect modifiers of 25(OH)D. Adjusting for HLA-DR-DQ and ancestry, higher childhood 25(OH)D was associated with lower IA risk (odds ratio = 0.93 for a 5 nmol/L difference; 95% CI 0.89, 0.97). Moreover, this association was modified by VDR rs7975232 (interaction P = 0.0072), where increased childhood 25(OH)D was associated with a decreasing IA risk based upon number of minor alleles: 0 (1.00; 0.93, 1.07), 1 (0.92; 0.89, 0.96), and 2 (0.86; 0.80, 0.92). Vitamin D and VDR may have a combined role in IA development in children at increased genetic risk for type 1 diabetes.
      Keywords: Epidemiology-Type 1 Diabetes
      PubDate: 2017-12-20T12:06:27-08:00
      DOI: 10.2337/db17-0802
      Issue No: Vol. 67, No. 1 (2017)
  • Shared Genetic Control of Brain Activity During Sleep and Insulin
           Secretion: A Laboratory-Based Family Study
    • Authors: Morselli; L. L.; Gamazon, E. R.; Tasali, E.; Cox, N. J.; Van Cauter, E.; Davis, L. K.
      Pages: 155 - 164
      Abstract: Over the past 20 years, a large body of experimental and epidemiologic evidence has linked sleep duration and quality to glucose homeostasis, although the mechanistic pathways remain unclear. The aim of the current study was to determine whether genetic variation influencing both sleep and glucose regulation could underlie their functional relationship. We hypothesized that the genetic regulation of electroencephalographic (EEG) activity during non–rapid eye movement sleep, a highly heritable trait with fingerprint reproducibility, is correlated with the genetic control of metabolic traits including insulin sensitivity and β-cell function. We tested our hypotheses through univariate and bivariate heritability analyses in a three-generation pedigree with in-depth phenotyping of both sleep EEG and metabolic traits in 48 family members. Our analyses accounted for age, sex, adiposity, and the use of psychoactive medications. In univariate analyses, we found significant heritability for measures of fasting insulin sensitivity and β-cell function, for time spent in slow-wave sleep, and for EEG spectral power in the delta, theta, and sigma ranges. Bivariate heritability analyses provided the first evidence for a shared genetic control of brain activity during deep sleep and fasting insulin secretion rate.
      Keywords: Genetics-Type 2 Diabetes
      PubDate: 2017-12-20T12:06:27-08:00
      DOI: 10.2337/db16-1229
      Issue No: Vol. 67, No. 1 (2017)
  • Erratum. Deletion of p66Shc Longevity Gene Protects Against Experimental
           Diabetic Glomerulopathy by Preventing Diabetes-Induced Oxidative Stress.
           Diabetes 2006;55:1642-1650
    • Authors: Menini; S.; Amadio, L.; Oddi, G.; Ricci, C.; Pesce, C.; Pugliese, F.; Giorgio, M.; Migliaccio, E.; Pelicci, P.; Iacobini, C.; Pugliese, G.
      Pages: 165 - 165
      PubDate: 2017-12-20T12:06:27-08:00
      DOI: 10.2337/db18-er01a
      Issue No: Vol. 67, No. 1 (2017)
  • Issues and Events
    • Pages: 166 - 166
      PubDate: 2017-12-20T12:06:27-08:00
      DOI: 10.2337/db18-ie01
      Issue No: Vol. 67, No. 1 (2017)
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