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Timing of Meal Insulin and Its Relation to Adherence to Therapy in Type 1 Diabetes.
Datye KA, Boyle CT, Simmons J, Moore DJ, Jaser SS, Sheanon N, Kittelsrud JM, Woerner SE, Miller KM, T1D Exchange
(2017) J Diabetes Sci Technol : 1932296817728525
Show Abstract · Added September 13, 2017
The purpose of this study is to examine timing of meal insulin and further determine whether an association exists between timing of meal insulin and missed meal insulin doses. The cohort included 4768 T1D Exchange clinic registry participants <26 years with type 1 diabetes ≥1 year. Chi-square tests, t-tests, and regression were used to assess the relationship between participant characteristics and timing of meal insulin and missed meal doses, respectively. Timing of meal insulin and association with missed meal doses was analyzed using logistic regression. In all, 21% reported administering insulin several minutes before, 44% immediately before, 10% during, and 24% after meal. Participants who gave insulin prior to a meal had significantly lower HbA1c than those who gave insulin during or after meal (8.4% ± 1.5% vs 8.8% ± 1.6%, adjusted P < .001), but no significant association was observed regarding DKA events. Those who reported missing ≥1 insulin dose per week had higher HbA1c (9.8% ± 1.9% vs 8.3% ± 1.3%, adjusted P < .001) and were more likely to experience at least one DKA event (9% vs 5%, adjusted P = .001) compared with those who rarely missed a meal insulin dose. Participants who reported administering insulin during or after a meal were more likely to report missing ≥1 meal insulin dose per week compared with those who administered insulin before a meal (28% vs 14%, adjusted P < .001). Premeal insulin was associated with lower HbA1c and fewer missed meal insulin doses. Providers may use this information to discuss the benefits of premeal insulin on glycemic control and adherence to therapy.
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Defining a Novel Role for the PDX1 Transcription Factor in Islet β Cell Maturation and Proliferation During Weaning.
Spaeth JM, Gupte M, Perelis M, Yang YP, Cyphert H, Guo S, Liu JH, Guo M, Bass J, Magnuson MA, Wright C, Stein R
(2017) Diabetes :
Show Abstract · Added August 1, 2017
The transcription factor encoded by the Pancreas Duodenum Homeobox-1 (Pdx1) gene is a critical transcriptional regulator, as it has fundamental actions in the formation of all pancreatic cell types, islet β cell development, and adult islet β cell function. Transgenic- and cell line-based experiments have identified 5'-flanking conserved sequences that control pancreatic and β cell-type-specific transcription, which are found within Area I (base pairs (bp) -2694 to -2561), II (bp -2139 to -1958), III (bp -1879 to -1799), and IV (bp -6200 to -5670). Because of the presence in Area IV of binding sites for transcription factors associated with pancreas development and islet cell function, we analyzed how an endogenous deletion mutant affected Pdx1 expression embryonically and postnatally. The most striking result was observed in male Pdx1(ΔIV) mutant mice after 3 weeks of birth (i.e., the onset of weaning), with only a small effect on pancreas organogenesis and no deficiencies in their female counterparts. Compromised Pdx1 mRNA and protein levels in weaned male mutant β cells was tightly linked with hyperglycemia, decreased β cell proliferation, reduced β cell area, and altered expression of Pdx1 bound genes that are important in β cell replication, endoplasmic reticulum function as well as mitochondrial activity. We discuss the impact of these novel findings to Pdx1 gene regulation and islet β cell maturation postnatally.
© 2017 by the American Diabetes Association.
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Chronic β-Cell Depolarization Impairs β-Cell Identity by Disrupting a Network of Ca(2+)-Regulated Genes.
Stancill JS, Cartailler JP, Clayton HW, O'Connor JT, Dickerson MT, Dadi PK, Osipovich AB, Jacobson DA, Magnuson MA
(2017) Diabetes :
Show Abstract · Added June 2, 2017
We used mice lacking Abcc8, a key component of the β-cell KATP-channel, to analyze the effects of a sustained elevation in the intracellular Ca(2+) concentration ([Ca(2+)]i) on β-cell identity and gene expression. Lineage tracing analysis revealed the conversion of β-cells lacking Abcc8 into PP-cells, but not to α- or δ-cells. RNA-Seq analysis of FACS-purified Abcc8(-/-) β-cells confirmed an increase in Ppy gene expression, and revealed altered expression of over 4,200 genes, many of which are involved in Ca(2+)-signaling, the maintenance of β-cell identity, and cell adhesion. The expression of S100a6 and S100a4, two highly up-regulated genes, is closely correlated with membrane depolarization, suggesting their use as markers for an increase in [Ca(2+)]i Moreover, a bioinformatics analysis predicts that many of the dysregulated genes are regulated by common transcription factors, one of which, Ascl1, was confirmed to be directly controlled by Ca(2+) influx in β-cells. Interestingly, among the upregulated genes is Aldh1a3, a putative marker of β-cell de-differentiation, and other genes associated with β-cell failure. Taken together, our results suggest that chronically-elevated β-cell [Ca(2+)]i in Abcc8(-/-) islets contributes to the alteration of β-cell identity, islet cell numbers and morphology, and gene expression, by disrupting a network of Ca(2+)-regulated genes.
© 2017 by the American Diabetes Association.
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Metabolic responses to exogenous ghrelin in obesity and early after Roux-en-Y gastric bypass in humans.
Tamboli RA, Antoun J, Sidani RM, Clements BA, Eckert EA, Marks-Shulman P, Gaylinn BD, Williams DB, Clements RH, Albaugh VL, Abumrad NN
(2017) Diabetes Obes Metab :
Show Abstract · Added April 3, 2017
AIMS - Ghrelin is a gastric-derived hormone that stimulates growth hormone (GH) secretion and has a multi-faceted role in the regulation of energy homeostasis, including glucose metabolism. Circulating ghrelin concentrations are modulated in response to nutritional status, but responses to ghrelin in altered metabolic states are poorly understood. We investigated the metabolic effects of ghrelin in obesity and early after Roux-en-Y gastric bypass (RYGB).
MATERIALS AND METHODS - We assessed central and peripheral metabolic responses to acyl ghrelin infusion (1 pmol kg(-1) min(-1) ) in healthy, lean subjects (n = 9) and non-diabetic, obese subjects (n = 9) before and two weeks after RYGB. Central responses were assessed by GH and pancreatic polypeptide (surrogate for vagal activity) secretion. Peripheral responses were assessed by hepatic and skeletal muscle insulin sensitivity during a hyperinsulinemic-euglycemic clamp.
RESULTS - Ghrelin-stimulated GH secretion was attenuated in obese subjects, but was restored by RYGB to a response similar to lean subjects. The heightened pancreatic polypeptide response to ghrelin infusion in the obese was attenuated after RYGB. Hepatic glucose production and hepatic insulin sensitivity were not altered by ghrelin infusion in the RYGB subjects. Skeletal muscle insulin sensitivity was impaired to a similar degree in the lean, obese, and post-RYGB in response to ghrelin infusion.
CONCLUSIONS - These data suggest that obesity is characterized by abnormal central, but not peripheral, responsiveness to ghrelin that can be restored early after RYGB before significant weight loss. Further work is necessary to fully elucidate the role of ghrelin in the metabolic changes that occur in obesity and after RYGB.
This article is protected by copyright. All rights reserved.
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A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.
Manning A, Highland HM, Gasser J, Sim X, Tukiainen T, Fontanillas P, Grarup N, Rivas MA, Mahajan A, Locke AE, Cingolani P, Pers TH, Viñuela A, Brown AA, Wu Y, Flannick J, Fuchsberger C, Gamazon ER, Gaulton KJ, Im HK, Teslovich TM, Blackwell TW, Bork-Jensen J, Burtt NP, Chen Y, Green T, Hartl C, Kang HM, Kumar A, Ladenvall C, Ma C, Moutsianas L, Pearson RD, Perry JR, Rayner NW, Robertson NR, Scott LJ, van de Bunt M, Eriksson JG, Jula A, Koskinen S, Lehtimäki T, Palotie A, Raitakari OT, Jacobs SB, Wessel J, Chu AY, Scott RA, Goodarzi MO, Blancher C, Buck G, Buck D, Chines PS, Gabriel S, Gjesing AP, Groves CJ, Hollensted M, Huyghe JR, Jackson AU, Jun G, Justesen JM, Mangino M, Murphy J, Neville M, Onofrio R, Small KS, Stringham HM, Trakalo J, Banks E, Carey J, Carneiro MO, DePristo M, Farjoun Y, Fennell T, Goldstein JI, Grant G, Hrabé de Angelis M, Maguire J, Neale BM, Poplin R, Purcell S, Schwarzmayr T, Shakir K, Smith JD, Strom TM, Wieland T, Lindstrom J, Brandslund I, Christensen C, Surdulescu GL, Lakka TA, Doney AS, Nilsson P, Wareham NJ, Langenberg C, Varga TV, Franks PW, Rolandsson O, Rosengren AH, Farook VS, Thameem F, Puppala S, Kumar S, Lehman DM, Jenkinson CP, Curran JE, Hale DE, Fowler SP, Arya R, DeFronzo RA, Abboud HE, Syvänen AC, Hicks PJ, Palmer ND, Ng MC, Bowden DW, Freedman BI, Esko T, Mägi R, Milani L, Mihailov E, Metspalu A, Narisu N, Kinnunen L, Bonnycastle LL, Swift A, Pasko D, Wood AR, Fadista J, Pollin TI, Barzilai N, Atzmon G, Glaser B, Thorand B, Strauch K, Peters A, Roden M, Müller-Nurasyid M, Liang L, Kriebel J, Illig T, Grallert H, Gieger C, Meisinger C, Lannfelt L, Musani SK, Griswold M, Taylor HA, Wilson G, Correa A, Oksa H, Scott WR, Afzal U, Tan ST, Loh M, Chambers JC, Sehmi J, Kooner JS, Lehne B, Cho YS, Lee JY, Han BG, Käräjämäki A, Qi Q, Qi L, Huang J, Hu FB, Melander O, Orho-Melander M, Below JE, Aguilar D, Wong TY, Liu J, Khor CC, Chia KS, Lim WY, Cheng CY, Chan E, Tai ES, Aung T, Linneberg A, Isomaa B, Meitinger T, Tuomi T, Hakaste L, Kravic J, Jørgensen ME, Lauritzen T, Deloukas P, Stirrups KE, Owen KR, Farmer AJ, Frayling TM, O'Rahilly SP, Walker M, Levy JC, Hodgkiss D, Hattersley AT, Kuulasmaa T, Stančáková A, Barroso I, Bharadwaj D, Chan J, Chandak GR, Daly MJ, Donnelly PJ, Ebrahim SB, Elliott P, Fingerlin T, Froguel P, Hu C, Jia W, Ma RC, McVean G, Park T, Prabhakaran D, Sandhu M, Scott J, Sladek R, Tandon N, Teo YY, Zeggini E, Watanabe RM, Koistinen HA, Kesaniemi YA, Uusitupa M, Spector TD, Salomaa V, Rauramaa R, Palmer CN, Prokopenko I, Morris AD, Bergman RN, Collins FS, Lind L, Ingelsson E, Tuomilehto J, Karpe F, Groop L, Jørgensen T, Hansen T, Pedersen O, Kuusisto J, Abecasis G, Bell GI, Blangero J, Cox NJ, Duggirala R, Seielstad M, Wilson JG, Dupuis J, Ripatti S, Hanis CL, Florez JC, Mohlke KL, Meigs JB, Laakso M, Morris AP, Boehnke M, Altshuler D, McCarthy MI, Gloyn AL, Lindgren CM
(2017) Diabetes :
Show Abstract · Added April 13, 2017
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 insulin, 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 fasting plasma insulin (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-hour 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.
© 2017 by the American Diabetes Association.
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The novel adipokine/hepatokine fetuin B in severe human and murine diabetic kidney disease.
Kralisch S, Hoffmann A, Klöting N, Bachmann A, Kratzsch J, Blüher M, Zhang MZ, Harris RC, Stumvoll M, Fasshauer M, Ebert T
(2017) Diabetes Metab :
Added June 2, 2017
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Type 1 Diabetes Prevention: A Goal Dependent on Accepting a Diagnosis of an Asymptomatic Disease.
Ziegler AG, Bonifacio E, Powers AC, Todd JA, Harrison LC, Atkinson MA
(2016) Diabetes 65: 3233-3239
Show Abstract · Added April 26, 2017
Type 1 diabetes, a disease defined by absolute insulin deficiency, is considered a chronic autoimmune disorder resulting from the destruction of insulin-producing pancreatic β-cells. The incidence of childhood-onset type 1 diabetes has been increasing at a rate of 3%-5% per year globally. Despite the introduction of an impressive array of therapies aimed at improving disease management, no means for a practical "cure" exist. This said, hope remains high that any of a number of emerging technologies (e.g., continuous glucose monitoring, insulin pumps, smart algorithms), alongside advances in stem cell biology, cell encapsulation methodologies, and immunotherapy, will eventually impact the lives of those with recently diagnosed or established type 1 diabetes. However, efforts aimed at reversing insulin dependence do not address the obvious benefits of disease prevention. Hence, key "stretch goals" for type 1 diabetes research include identifying improved and increasingly practical means for diagnosing the disease at earlier stages in its natural history (i.e., early, presymptomatic diagnosis), undertaking such efforts in the population at large to optimally identify those with presymptomatic type 1 diabetes, and introducing safe and effective therapeutic options for prevention.
© 2016 by the American Diabetes Association.
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Integrin-Linked Kinase Is Necessary for the Development of Diet-Induced Hepatic Insulin Resistance.
Williams AS, Trefts E, Lantier L, Grueter CA, Bracy DP, James FD, Pozzi A, Zent R, Wasserman DH
(2017) Diabetes 66: 325-334
Show Abstract · Added April 26, 2017
The liver extracellular matrix (ECM) expands with high-fat (HF) feeding. This finding led us to address whether receptors for the ECM, integrins, are key to the development of diet-induced hepatic insulin resistance. Integrin-linked kinase (ILK) is a downstream integrin signaling molecule involved in multiple hepatic processes, including those related to differentiation, wound healing, and metabolism. We tested the hypothesis that deletion of ILK in mice on an HF diet would disrupt the ECM-integrin signaling axis, thereby preventing the transformation into the insulin-resistant liver. To determine the role of ILK in hepatic insulin action in vivo, male C57BL/6J ILK(lox/lox) mice were crossed with Albcre mice to produce a hepatocyte-specific ILK deletion (ILK(lox/lox)Albcre). Results from this study show that hepatic ILK deletion has no effect on insulin action in lean mice but sensitizes the liver to insulin during the challenge of HF feeding. This effect corresponds to changes in the expression and activation of key insulin signaling pathways as well as a greater capacity for hepatic mitochondrial glucose oxidation. This demonstrates that ILK contributes to hepatic insulin resistance and highlights the previously undefined role of integrin signaling in the pathogenesis of diet-induced hepatic insulin resistance.
© 2017 by the American Diabetes Association.
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Macrophage Cyclooxygenase-2 Protects Against Development of Diabetic Nephropathy.
Wang X, Yao B, Wang Y, Fan X, Wang S, Niu A, Yang H, Fogo A, Zhang MZ, Harris RC
(2017) Diabetes 66: 494-504
Show Abstract · Added April 26, 2017
Diabetic nephropathy (DN) is characterized by increased macrophage infiltration, and proinflammatory M1 macrophages contribute to development of DN. Previous studies by us and others have reported that macrophage cyclooxygenase-2 (COX-2) plays a role in polarization and maintenance of a macrophage tissue-reparative M2 phenotype. We examined the effects of macrophage COX-2 on development of DN in type 1 diabetes. Cultured macrophages with COX-2 deletion exhibited an M1 phenotype, as demonstrated by higher inducible nitric oxide synthase and nuclear factor-κB levels but lower interleukin-4 receptor-α levels. Compared with corresponding wild-type diabetic mice, mice with COX-2 deletion in hematopoietic cells (COX-2 knockout bone marrow transplantation) or macrophages (CD11b-Cre COX2(f/f)) developed severe DN, as indicated by increased albuminuria, fibrosis, and renal infiltration of T cells, neutrophils, and macrophages. Although diabetic kidneys with macrophage COX-2 deletion had more macrophage infiltration, they had fewer renal M2 macrophages. Diabetic kidneys with macrophage COX-2 deletion also had increased endoplasmic reticulum stress and decreased number of podocytes. Similar results were found in diabetic mice with macrophage PGE2 receptor subtype 4 deletion. In summary, these studies have demonstrated an important but unexpected role for macrophage COX-2/prostaglandin E2/PGE2 receptor subtype 4 signaling to lessen progression of diabetic kidney disease, unlike the pathogenic effects of increased COX-2 expression in intrinsic renal cells.
© 2017 by the American Diabetes Association.
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Hematopoietic Stem Cell Mobilization Is Necessary but Not Sufficient for Tolerance in Islet Transplantation.
Stocks BT, Thomas AB, Elizer SK, Zhu Y, Marshall AF, Wilson CS, Moore DJ
(2017) Diabetes 66: 127-133
Show Abstract · Added November 1, 2016
Overcoming the immune response to establish durable immune tolerance in type 1 diabetes remains a substantial challenge. The ongoing effector immune response involves numerous immune cell types but is ultimately orchestrated and sustained by the hematopoietic stem cell (HSC) niche. We therefore hypothesized that tolerance induction also requires these pluripotent precursors. In this study, we determined that the tolerance-inducing agent anti-CD45RB induces HSC mobilization in nonautoimmune B6 mice but not in diabetes-prone NOD mice. Ablation of HSCs impaired tolerance to allogeneic islet transplants in B6 recipients. Mobilization of HSCs resulted in part from decreasing osteoblast expression of HSC retention factors. Furthermore, HSC mobilization required a functioning sympathetic nervous system; sympathectomy prevented HSC mobilization and completely abrogated tolerance induction. NOD HSCs were held in their niche by excess expression of CXCR4, which, when blocked, led to HSC mobilization and prolonged islet allograft survival. Overall, these findings indicate that the HSC compartment plays an underrecognized role in the establishment and maintenance of immune tolerance, and this role is disrupted in diabetes-prone NOD mice. Understanding the stem cell response to immune therapies in ongoing human clinical studies may help identify and maximize the effect of immune interventions for type 1 diabetes.
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