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The Pdx1 Bound Swi/Snf Chromatin Remodeling Complex Regulates Pancreatic Progenitor Cell Proliferation and Mature Islet β Cell Function.
Spaeth JM, Liu JH, Peters D, Guo M, Osipovich AB, Mohammadi F, Roy N, Bhushan A, Magnuson MA, Hebrok M, Wright CVE, Stein R
(2019) Diabetes :
Show Abstract · Added June 28, 2019
Transcription factors positively and/or negatively impact gene expression by recruiting coregulatory factors, which interact through protein-protein binding. Here we demonstrate that mouse pancreas size and islet β cell function are controlled by the ATP-dependent Swi/Snf chromatin remodeling coregulatory complex that physically associates with Pdx1, a diabetes-linked transcription factor essential to pancreatic morphogenesis and adult islet-cell function and maintenance. Early embryonic deletion of just the Swi/Snf Brg1 ATPase subunit reduced multipotent pancreatic progenitor cell proliferation and resulted in pancreas hypoplasia. In contrast, removal of both Swi/Snf ATPase subunits, Brg1 and Brm, was necessary to compromise adult islet β cell activity, which included whole animal glucose intolerance, hyperglycemia and impaired insulin secretion. Notably, lineage-tracing analysis revealed Swi/Snf-deficient β cells lost the ability to produce the mRNAs for and other key metabolic genes without effecting the expression of many essential islet-enriched transcription factors. Swi/Snf was necessary for Pdx1 to bind to the gene enhancer, demonstrating the importance of this association in mediating chromatin accessibility. These results illustrate how fundamental the Pdx1:Swi/Snf coregulator complex is in the pancreas and we discuss how disrupting their association could influence Type 1 and Type 2 diabetes susceptibility.
© 2019 by the American Diabetes Association.
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Peripherally Delivered Hepatopreferential Insulin Analog Insulin-406 Mimics the Hypoglycemia-sparing Effect of Portal Vein Human Insulin Infusion in Dogs.
Gregory JM, Kraft G, Scott MF, Neal DW, Farmer B, Smith MS, Hastings JR, Madsen P, Kjeldsen TB, Hostrup S, Brand CL, Fledelius C, Nishimura E, Cherrington AD
(2019) Diabetes Obes Metab :
Show Abstract · Added June 26, 2019
AIMS - We previously quantified the hypoglycemia-sparing effect of portal vs peripheral human insulin delivery. This investigation determined whether a bioequivalent peripheral vein infusion of a hepatopreferential insulin analog (insulin-406) could similarly protect against hypoglycemia.
MATERIALS AND METHODS - Dogs received human insulin infusions into either the hepatic portal vein (PoHI, n=7) or a peripheral vein (PeHI, n=7) for 180 min at a rate 4x basal (6.6 pmol/kg/min) in a previous study. Insulin-406 (Pe406, n=7) was peripherally infused at 6.0 pmol/kg/min-a rate determined to decrease plasma glucose by the same amount in the first 60 min as PoHI. Glucagon was fixed at basal concentrations, mimicking the diminished α-cell response seen in type 1 diabetes.
RESULTS - Glucose fell quickly in PeHI, reaching 41 ± 3 mg/dL at 60 min, but more slowly in PoHI and Pe406 (67 ± 2 and 72 ± 4 mg/dL, respectively, p<0.01 vs. PeHI for both). The hypoglycemic nadir (≈40 mg/dL) occurred at 60 min in PeHI vs. 120 min in PoHI and Pe406. ΔAUC during the 180-min insulin infusion period was two-fold higher for PeHI compared with PoHI and Pe406. Glucose production (mg/kg/min) was least suppressed in PeHI (Δ=0.79 ± 0.33) and equivalently suppressed in PoHI and Pe406 (Δ=1.16 ± 0.21 and 1.18 ± 0.17, respectively, p=NS). Peak glucose utilization (mg/kg/min) was highest in PeHI (4.94 ± 0.17) and less in PoHI and Pe406 (3.58 ± 0.58 and 3.26 ± 0.08, respectively, p<0.05 vs Pe for both).
CONCLUSIONS - Peripheral infusion of hepatopreferential insulin can achieve a metabolic profile that closely mimics portal insulin delivery, which reduces hypoglycemia risk compared with peripheral insulin infusion. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
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Iatrogenic Hyperinsulinemia, Not Hyperglycemia, Drives Insulin Resistance in Type 1 Diabetes as Revealed by Comparison to GCK-MODY (MODY2).
Gregory JM, Smith TJ, Slaughter JC, Mason HR, Hughey CC, Smith MS, Kandasamy B, Greeley SAW, Philipson LH, Naylor RN, Letourneau LR, Abumrad NN, Cherrington AD, Moore DJ
(2019) Diabetes :
Show Abstract · Added May 17, 2019
Although insulin resistance consistently occurs with type 1 diabetes, its predominant driver is uncertain. We therefore determined the relative contributions of hyperglycemia and iatrogenic hyperinsulinemia to insulin resistance using hyperinsulinemic-euglycemic clamps in three participant groups (n=10/group) with differing insulinemia and glycemia: healthy controls (euinsulinemia, euglycemia), glucokinase maturity-onset of the young (GCK-MODY; euinsulinemia, hyperglycemia), and type 1 diabetes (hyperinsulinemia, hyperglycemia matching GCK-MODY). We assessed the contribution of hyperglycemia by comparing insulin sensitivity in control and GCK-MODY and the contribution of hyperinsulinemia by comparing GCK-MODY and type 1 diabetes. HbA1c was normal in controls and similarly elevated for type 1 diabetes and GCK-MODY. Basal insulin levels in control and GCK-MODY were nearly equal but were 2.5-fold higher in type 1 diabetes. Low-dose insulin infusion suppressed endogenous glucose production similarly in all groups and suppressed nonesterified fatty acids similarly between control and GCK-MODY, but to a lesser extent for type 1 diabetes. High-dose insulin infusion stimulated glucose disposal similarly in control and GCK-MODY, but was 29% and 22% less effective in type 1 diabetes, respectively. Multivariable linear regression showed insulinemia-but not glycemia-was significantly associated with muscle insulin sensitivity. These data suggest iatrogenic hyperinsulinemia predominates in driving insulin resistance in type 1 diabetes. Clinicaltrials.gov:NCT02971202.
© 2019 by the American Diabetes Association.
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Pancreas Volume Declines During the First Year After Diagnosis of Type 1 Diabetes and Exhibits Altered Diffusion at Disease Onset.
Virostko J, Williams J, Hilmes M, Bowman C, Wright JJ, Du L, Kang H, Russell WE, Powers AC, Moore DJ
(2019) Diabetes Care 42: 248-257
Show Abstract · Added December 18, 2018
OBJECTIVE - This study investigated the temporal dynamics of pancreas volume and microstructure in children and adolescents with recent-onset type 1 diabetes (T1D) and individuals without diabetes, including a subset expressing autoantibodies associated with the early stages of T1D.
RESEARCH DESIGN AND METHODS - MRI was performed in individuals with recent-onset stage 3 T1D ( = 51; median age 13 years) within 100 days after diagnosis (mean 67 days), 6 months, and 1 year postdiagnosis. Longitudinal MRI measurements were also made in similarly aged control participants ( = 57) and in autoantibody-positive individuals without diabetes ( = 20). The MRI protocol consisted of anatomical imaging to determine pancreas volume and quantitative MRI protocols interrogating tissue microstructure and composition.
RESULTS - Within 100 days of diabetes onset, individuals with T1D had a smaller pancreas (median volume 28.6 mL) than control participants (median volume 48.4 mL; < 0.001), including when normalized by individual weight ( < 0.001). Longitudinal measurements of pancreas volume increased in control participants over the year, consistent with adolescent growth, but pancreas volume declined over the first year after T1D diagnosis ( < 0.001). In multiple autoantibody-positive individuals, the pancreas volume was significantly larger than that of the T1D cohort ( = 0.017) but smaller than that of the control cohort ( = 0.04). Diffusion-weighted MRI showed that individuals with recent-onset T1D had a higher apparent diffusion coefficient ( = 0.012), suggesting a loss of cellular structural integrity, with heterogeneous pancreatic distribution.
CONCLUSIONS - These results indicate that pancreas volume is decreased in stages 1, 2, and 3 of T1D and decreases during the first year after diabetes onset and that this loss of pancreatic volume is accompanied by microstructural changes.
© 2018 by the American Diabetes Association.
1 Communities
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A Call for Improved Reporting of Human Islet Characteristics in Research Articles.
Poitout V, Satin LS, Kahn SE, Stoffers DA, Marchetti P, Gannon M, Verchere CB, Herold KC, Myers MG, Marshall SM
(2019) Diabetes 68: 239-240
Added April 15, 2019
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Examining How the MAFB Transcription Factor Affects Islet β-Cell Function Postnatally.
Cyphert HA, Walker EM, Hang Y, Dhawan S, Haliyur R, Bonatakis L, Avrahami D, Brissova M, Kaestner KH, Bhushan A, Powers AC, Stein R
(2019) Diabetes 68: 337-348
Show Abstract · Added January 8, 2019
The sustained expression of the MAFB transcription factor in human islet β-cells represents a distinct difference in mice. Moreover, mRNA expression of closely related and islet β-cell-enriched MAFA does not peak in humans until after 9 years of age. We show that the MAFA protein also is weakly produced within the juvenile human islet β-cell population and that expression is postnatally restricted in mouse β-cells by de novo DNA methylation. To gain insight into how MAFB affects human β-cells, we developed a mouse model to ectopically express in adult mouse β-cells using transcriptional control sequences. Coexpression of MafB with MafA had no overt impact on mouse β-cells, suggesting that the human adult β-cell MAFA/MAFB heterodimer is functionally equivalent to the mouse MafA homodimer. However, MafB alone was unable to rescue the islet β-cell defects in a mouse mutant lacking MafA in β-cells. Of note, transgenic production of MafB in β-cells elevated tryptophan hydroxylase 1 mRNA production during pregnancy, which drives the serotonin biosynthesis critical for adaptive maternal β-cell responses. Together, these studies provide novel insight into the role of MAFB in human islet β-cells.
© 2018 by the American Diabetes Association.
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Increased Reporting of Immune Checkpoint Inhibitor-Associated Diabetes.
Wright JJ, Salem JE, Johnson DB, Lebrun-Vignes B, Stamatouli A, Thomas JW, Herold KC, Moslehi J, Powers AC
(2018) Diabetes Care 41: e150-e151
Added December 13, 2018
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Sleep in Teens With Type 1 Diabetes: Perspectives From Adolescents and Their Caregivers.
Bergner EM, Williams R, Hamburger ER, Lyttle M, Davis AC, Malow B, Simmons JH, Lybarger C, Capin R, Jaser SS
(2018) Diabetes Educ 44: 541-548
MeSH Terms: Adolescent, Caregivers, Diabetes Mellitus, Type 1, Female, Humans, Male, Perception, Qualitative Research, Sleep, Sleep Wake Disorders
Show Abstract · Added January 30, 2019
PURPOSE - The purpose of this study is to identify barriers, facilitators, and consequences of obtaining sufficient sleep in adolescents with type 1 diabetes.
METHODS - Semistructured interviews were conducted with 25 adolescents (52% female, mean age = 15.6 years) and 25 caregivers. Interviews were transcribed and coded using Atlas.ti. A thematic analytic approach was used to identify and organize significant patterns of meaning (themes) and interpret themes across the data.
RESULTS - Several barriers were identified, with the most common being the use of electronics before bed and sleep disturbances related to diabetes management. Caregivers described strategies for helping adolescents achieve sufficient sleep, such as enforcing bedtimes and limiting distractions, but many adolescents could not identify facilitators of sleep. Weekday/weekend discrepancies in sleep timing were commonly disclosed.
CONCLUSIONS - This study is the first to examine the perceptions of barriers and facilitators to obtaining sufficient sleep in adolescents with T1D and their caregivers. Results have the potential to inform providers' recommendations regarding sleep, including possible interventions to promote sleep in this high-risk population.
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10 MeSH Terms
High CD8 T-Cell Receptor Clonality and Altered CDR3 Properties Are Associated With Elevated Isolevuglandins in Adipose Tissue During Diet-Induced Obesity.
McDonnell WJ, Koethe JR, Mallal SA, Pilkinton MA, Kirabo A, Ameka MK, Cottam MA, Hasty AH, Kennedy AJ
(2018) Diabetes 67: 2361-2376
MeSH Terms: Adipose Tissue, Animals, CD8-Positive T-Lymphocytes, Complementarity Determining Regions, Diet, High-Fat, Glucose Tolerance Test, Insulin Resistance, Liver, Male, Mice, Obesity, Prostaglandins
Show Abstract · Added March 26, 2019
Adipose tissue (AT) CD4 and CD8 T cells contribute to obesity-associated insulin resistance. Prior studies identified conserved T-cell receptor (TCR) chain families in obese AT, but the presence and clonal expansion of specific TCR sequences in obesity has not been assessed. We characterized AT and liver CD8 and CD4 TCR repertoires of mice fed a low-fat diet (LFD) and high-fat diet (HFD) using deep sequencing of the TCRβ chain to quantify clonal expansion, gene usage, and CDR3 sequence. In AT CD8 T cells, HFD reduced TCR diversity, increased the prevalence of public TCR clonotypes, and selected for TCR CDR3 regions enriched in positively charged and less polarized amino acids. Although TCR repertoire alone could distinguish between LFD- and HFD-fed mice, these properties of the CDR3 region of AT CD8 T cells from HFD-fed mice led us to examine the role of negatively charged and nonpolar isolevuglandin (isoLG) adduct-containing antigen-presenting cells within AT. IsoLG-adducted protein species were significantly higher in AT macrophages of HFD-fed mice; isoLGs were elevated in M2-polarized macrophages, promoting CD8 T-cell activation. Our findings demonstrate that clonal TCR expansion that favors positively charged CDR3s accompanies HFD-induced obesity, which may be an antigen-driven response to isoLG accumulation in macrophages.
© 2018 by the American Diabetes Association.
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MeSH Terms
Association of abdominal muscle composition with prediabetes and diabetes: The CARDIA study.
Granados A, Gebremariam A, Gidding SS, Terry JG, Carr JJ, Steffen LM, Jacobs DR, Lee JM
(2019) Diabetes Obes Metab 21: 267-275
Show Abstract · Added September 11, 2018
AIM - To evaluate the relationship of abdominal muscle lean tissue and adipose tissue volumes with prediabetes and diabetes.
RESEARCH DESIGN AND METHODS - We measured abdominal muscle composition in 3170 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study who underwent computed tomography (CT) at Year 25 of follow-up (ages, 43-55 years). Multinomial regression analysis was used to evaluate the associations of CT-measured intermuscular adipose tissue (IMAT), lean muscle tissue (lean) and visceral adipose tissue (VAT) volumes with diabetes at any point during the CARDIA study, newly detected prediabetes, prior history of prediabetes, and normal glucose tolerance. Models were adjusted for potential confounding factors: age, sex, race, height, smoking status, hypertension, hyperlipidaemia, cardiorespiratory fitness and study centre.
RESULTS - Higher IMAT, lean and VAT volumes were all separately associated with a higher prevalence of prediabetes and diabetes. Inclusion of VAT volume in models with both IMAT volume and lean volume attenuated the association of IMAT with both prediabetes and diabetes, but higher lean volume retained its association with prediabetes and diabetes. Individuals in the highest IMAT quartile, coupled with VAT in its lower three quartiles, had a higher prevalence of diabetes, but not of prediabetes, than those with both IMAT and VAT in their respective lower three quartiles. Adjusting for cardiorespiratory fitness did not substantially change the findings.
CONCLUSION - Higher IMAT volume was associated with a higher prevalence of diabetes even after adjustment for VAT volume. However, further study is warranted to understand the complicated relationship between abdominal muscle and adipose tissues.
© 2018 John Wiley & Sons Ltd.
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