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Glucocorticoids Reprogram Beta Cell Signaling to Preserve Insulin Secretion.
Fine NHF, Doig CL, Elhassan YS, Vierra NC, Marchetti P, Bugliani M, Nano R, Piemonti L, Rutter GA, Jacobson DA, Lavery GG, Hodson DJ
(2017) Diabetes :
Show Abstract · Added December 6, 2017
Excessive glucocorticoid exposure has been shown to be deleterious for pancreatic beta cell function and insulin release. However, glucocorticoids at physiological levels are essential for many homeostatic processes, including glycemic control. Here, we show that corticosterone and cortisol and their less active precursors, 11-dehydrocorticosterone (11-DHC) and cortisone, suppress voltage-dependent Ca2+ channel function and Ca2+ fluxes in rodent as well as human beta cells. However, insulin secretion, maximal ATP/ADP responses to glucose and beta cell identity were all unaffected. Further examination revealed the upregulation of parallel amplifying cAMP signals, and an increase in the number of membrane-docked insulin secretory granules. Effects of 11-DHC could be prevented by lipotoxicity and were associated with paracrine regulation of glucocorticoid activity, since global deletion of 11β-hydroxysteroid dehydrogenase type 1 normalized Ca2+ and cAMP responses. Thus, we have identified an enzymatically-amplified feedback loop whereby glucocorticoids boost cAMP to maintain insulin secretion in the face of perturbed ionic signals. Failure of this protective mechanism may contribute to diabetes in states of glucocorticoid excess such as Cushing's syndrome, which are associated with frank dyslipidemia.
© 2017 by the American Diabetes Association.
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Shared Genetic Control of Brain Activity During Sleep and Insulin Secretion: A Laboratory-Based Family Study.
Morselli LL, Gamazon ER, Tasali E, Cox NJ, Van Cauter E, Davis LK
(2017) Diabetes :
Show Abstract · Added November 29, 2017
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 present 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-REM sleep, a highly heritable trait with fingerprint reproducibility, is correlated with the genetic control of metabolic traits including insulin sensitivity and beta-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 beta-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.
© 2017 by the American Diabetes Association.
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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.
2 Communities
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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.
3 Communities
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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
1 Communities
1 Members
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0 MeSH Terms
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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The Hypothalamic Glucagon-Like Peptide 1 Receptor Is Sufficient but Not Necessary for the Regulation of Energy Balance and Glucose Homeostasis in Mice.
Burmeister MA, Ayala JE, Smouse H, Landivar-Rocha A, Brown JD, Drucker DJ, Stoffers DA, Sandoval DA, Seeley RJ, Ayala JE
(2017) Diabetes 66: 372-384
MeSH Terms: Animals, Body Composition, Diet, High-Fat, Eating, Energy Metabolism, Gene Knockdown Techniques, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Glucose, Glucose Tolerance Test, Homeostasis, Hypothalamus, Incretins, Liraglutide, Male, Mice, Neurons, Paraventricular Hypothalamic Nucleus, Peptides, Pro-Opiomelanocortin, Venoms, Weight Gain
Show Abstract · Added October 23, 2017
Pharmacological activation of the hypothalamic glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) promotes weight loss and improves glucose tolerance. This demonstrates that the hypothalamic GLP-1R is sufficient but does not show whether it is necessary for the effects of exogenous GLP-1R agonists (GLP-1RA) or endogenous GLP-1 on these parameters. To address this, we crossed mice harboring floxed Glp1r alleles to mice expressing Nkx2.1-Cre to knock down Glp1r expression throughout the hypothalamus (GLP-1RKD(ΔNkx2.1cre)). We also generated mice lacking Glp1r expression specifically in two GLP-1RA-responsive hypothalamic feeding nuclei/cell types, the paraventricular nucleus (GLP-1RKD(ΔSim1cre)) and proopiomelanocortin neurons (GLP-1RKD(ΔPOMCcre)). Chow-fed GLP-1RKD(ΔNkx2.1cre) mice exhibited increased food intake and energy expenditure with no net effect on body weight. When fed a high-fat diet, these mice exhibited normal food intake but elevated energy expenditure, yielding reduced weight gain. None of these phenotypes were observed in GLP-1RKD(ΔSim1cre) and GLP-1RKD(ΔPOMCcre) mice. The acute anorectic and glucose tolerance effects of peripherally dosed GLP-1RA exendin-4 and liraglutide were preserved in all mouse lines. Chronic liraglutide treatment reduced body weight in chow-fed GLP-1RKD(ΔNkx2.1cre) mice, but this effect was attenuated with high-fat diet feeding. In sum, classic homeostatic control regions are sufficient but not individually necessary for the effects of GLP-1RA on nutrient homeostasis.
© 2017 by the American Diabetes Association.
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MeSH Terms