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  • American Diabetes Association  (39)
  • 2020-2024  (39)
  • 1
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    Islet Autoimmunity Is Highly Prevalent and Associated With Diminished β-Cell Function in Patients With Type 2 Diabetes in the GRADE Study
    American Diabetes Association ; 2022
    In:  Diabetes Vol. 71, No. 6 ( 2022-06-01), p. 1261-1271
    Details
    In: Diabetes, American Diabetes Association, Vol. 71, No. 6 ( 2022-06-01), p. 1261-1271
    Abstract: Islet autoimmunity may contribute to β-cell dysfunction in type 2 diabetes (T2D). Its prevalence and clinical significance have not been rigorously determined. In this ancillary study to the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), we investigated the prevalence of cellular and humoral islet autoimmunity in patients with T2D duration of 4.0 ± 3.0 years (HbA1c 7.5 ± 0.5% on metformin alone). We measured T-cell autoreactivity against islet proteins, islet autoantibodies against 65-kDa GAD antigen, IA-2, and zinc transporter-8, and β-cell function. Cellular islet autoimmunity was present in 41.3%, humoral islet autoimmunity in 13.5%, and both in 5.3%. β-Cell function calculated as incremental area under the curve of glucose from 0–120 min (iAUC-CG) and ΔC-peptide(0–30)/Δglucose(0–30) from an oral glucose tolerance test was lower among T-cell–positive (T+) than T-cell–negative (T−) individuals using two different adjustments for insulin sensitivity (iAUC-CG: 13.2% [95% CI 0.3, 24.4] or 11.4% [95% CI 0.4, 21.2] lower; ΔC-peptide[0–30]/Δglucose[0–30] : 19% [95% CI 3.1, 32.3] or 17.7% [95% CI 2.6, 30.5%] lower). T+ patients had 17% higher HbA1c (95% CI 0.07, 0.28) and 7.7 mg/dL higher fasting plasma glucose levels (95% CI 0.2, 15.3) than T− patients. We conclude that islet autoimmunity is much more prevalent in patients with T2D than previously reported. T-cell–mediated autoimmunity is associated with diminished β-cell function and worse glycemic control.
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db21-0590
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
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  • 2
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    Association of Baseline Characteristics With Insulin Sensitivity and β-Cell Function in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study Cohort
    American Diabetes Association ; 2021
    In:  Diabetes Care Vol. 44, No. 2 ( 2021-02-01), p. 340-349
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 44, No. 2 ( 2021-02-01), p. 340-349
    Abstract: We investigated sex and racial differences in insulin sensitivity, β-cell function, and glycated hemoglobin (HbA1c) and the associations with selected phenotypic characteristics. RESEARCH DESIGN AND METHODS This is a cross-sectional analysis of baseline data from 3,108 GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) participants. All had type 2 diabetes diagnosed & lt;10 years earlier and were on metformin monotherapy. Insulin sensitivity and β-cell function were evaluated using the HOMA of insulin sensitivity and estimates from oral glucose tolerance tests, including the Matsuda Index, insulinogenic index, C-peptide index, and oral disposition index (DI). RESULTS The cohort was 56.6 ± 10 years of age (mean ± SD), 63.8% male, with BMI 34.2 ± 6.7 kg/m2, HbA1c 7.5 ± 0.5%, and type 2 diabetes duration 4.0 ± 2.8 years. Women had higher DI than men but similar insulin sensitivity. DI was the highest in Black/African Americans, followed by American Indians/Alaska Natives, Asians, and Whites in descending order. Compared with Whites, American Indians/Alaska Natives had significantly higher HbA1c, but Black/African Americans and Asians had lower HbA1c. However, when adjusted for glucose levels, Black/African Americans had higher HbA1c than Whites. Insulin sensitivity correlated inversely with BMI, waist-to-hip ratio, triglyceride-to-HDL-cholesterol ratio (TG/HDL-C), and the presence of metabolic syndrome, whereas DI was associated directly with age and inversely with BMI, HbA1c, and TG/HDL-C. CONCLUSIONS In the GRADE cohort, β-cell function differed by sex and race and was associated with the concurrent level of HbA1c. HbA1c also differed among the races, but not by sex. Age, BMI, and TG/HDL-C were associated with multiple measures of β-cell function and insulin sensitivity.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc20-1787
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
    detail.hit.zdb_id: 1490520-6
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  • 3
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    1388-P: Clinical Features Associated with Glutamic Acid Decarboxylase Autoantibodies (GADA) in Adults with Type 2 Diabetes
    American Diabetes Association ; 2023
    In:  Diabetes Vol. 72, No. Supplement_1 ( 2023-06-20)
    Details
    In: Diabetes, American Diabetes Association, Vol. 72, No. Supplement_1 ( 2023-06-20)
    Abstract: Islet autoantibodies in adults classified as having type 2 diabetes (T2D) have been associated with lower adiposity and early insulin requirement. We examined the association between GADA, the most prevalent islet autoantibody, and baseline clinical features in Look AHEAD (Action for Health in Diabetes), a randomized trial of adults with clinically-diagnosed T2D and overweight/obesity from 16 geographically diverse U.S. study centers. GADA was measured by radioligand binding assay in 87% of the randomized cohort at study baseline and categorized as negative (GADA-), low-level (35-199 U/mL, GADA+) or high-level (≥200 U/mL, GADA++). We compared clinical features across GADA categories using Fisher’s exact or Kruskal-Wallis tests. There were 4,492 participants who had a median age 59 years and diabetes duration 5 years. Participants were 59% female, 67% white, 16% Black and 13% Hispanic. GADA was positive (≥35 U/mL) in 216 participants (4.8%); 131 were GADA+ (2.9%) and 85 GADA++ (1.9%). Insulin was used by 15% of GADA-, 25% of GADA+, and 40% of GADA++ (p & lt;0.001). The median HbA1c was 7.0% in GADA-, 7.1% in GADA+, and 7.4% in GADA++ (p=0.004). There was a history of hypothyroidism in 12% of GADA-, 14% of GADA+, and 29% of GADA++ (p & lt;0.001). There was a history of hyperthyroidism in 2% of GADA-, 2% of GADA+, and 7% of GADA++ (p=0.006). GADA level was not associated with age, sex, race/ethnicity, diabetes duration, BMI, waist circumference, or history of microvascular or macrovascular complications. In conclusion, a substantial minority of this population of adults with overweight/obesity who were clinically diagnosed as T2D have GADA positivity, and high levels were strongly associated with phenotypic differences including insulin use and thyroid disease. In contrast to prior studies, GADA was not associated with lower adiposity. These findings highlight the heterogeneity of this population and the need to further study the clinical implications of GADA positivity. Disclosure S.J.Pilla: None. A.Ramelius: None. R.Bennet: None. Å.Lernmark: Advisory Panel; Diamyd Medical. N.N.Mathioudakis: None. J.Clark: None. N.M.Maruthur: Other Relationship; Johns Hopkins HealthCare Solutions. W.C.Knowler: None. A.Balasubramanyam: None. C.S.Hampe: Employee; Immusoft corp. S.Pietropaolo: None. A.M.Anderson: None. M.Li: None. N.Zhao: None. S.L.Zeger: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK126825, K23DK128572)
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db23-1388-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
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  • 4
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    1712-P: HIV-1 Vpr Couples Metabolic Inflexibility with White Adipose Tissue Thermogenesis
    American Diabetes Association ; 2020
    In:  Diabetes Vol. 69, No. Supplement_1 ( 2020-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 69, No. Supplement_1 ( 2020-06-01)
    Abstract: The HIV accessory protein Vpr contributes to cardinal metabolic defects noted in persons living with HIV (PLWH), including accelerated lipolysis, impaired fatty acid oxidation, slowed fatty acid export, and steatohepatitis (Agarwal et al, Sci Trans Med 2017). PLWH also manifest “beiging” and markers of thermogenesis within some white adipose tissue (WAT) depots, but paradoxically these changes correlate with decreased insulin sensitivity and hyperlipidemia. We sought to determine whether Vpr activity affects thermogenesis and the dynamics of beiging in two Vpr mouse models. UCP1 expression was strongly increased in subcutaneous fat of Vpr mice and showed equivalent copy number in WAT biopsies from PLWH. Histology confirmed browning of subcutaneous but not visceral WAT in the Vpr mouse models. Adipocytes derived from these depots showed increased oxygen consumption rate in subcutaneous but not visceral fat cells, also strongly indicative of beiging. Measurements of energy balance indicated Vpr mice display metabolic inflexibility and cannot shift efficiently from carbohydrates to fat during day-night cycles. Furthermore, Vpr mice mice showed a marked inability to defend body temperature when exposed to 4oC for 6 hours. Thus HIV-1 Vpr disrupts metabolic efficiency coupled with maladaptive subcutaneous WAT beiging. These data suggest an expanded role for Vpr in the pathogenesis of HIV-associated metabolic disorders. Disclosure N. Agarwal: None. P. Saha: None. S.M. Hartig: None. A. Balasubramanyam: None. Funding National Institutes of Health (R21/R33AI116208)
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-1712-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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  • 5
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    1872-P: Metabolomic Profiling during Diabetic Ketoacidosis (DKA) Demonstrates Unique Defects Underlying the Pathophysiology of Ketosis-Prone Diabetes
    American Diabetes Association ; 2020
    In:  Diabetes Vol. 69, No. Supplement_1 ( 2020-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 69, No. Supplement_1 ( 2020-06-01)
    Abstract: Obese patients with ketosis-prone type 2 diabetes (“A-β+ KPD”) have increased catabolism of the ketogenic amino acids leucine/isoleucine (Leu/Ile) and impaired ketone oxidation when stable and normoglycemic (Patel et al, Diabetes 2013). We performed comparative serum metabolomics on patients at presentation with hyperglycemic crisis without (N = 29) or with (N = 73) DKA compared to healthy controls (N = 17). The diabetic groups included normal weight and overweight/obese subgroups. DKA patients had higher plasma cortisol and catecholamines and lower C-peptide than the other groups. Three metabolite patterns distinguished the DKA patients from the other groups: 1) Elevated levels of Leu/Ile and of their respective ketoacids, no difference in isovaleryl carnitine (C5) but markedly lower ratio of C5 to C2 (acetyl carnitine) - implying accelerated shunting of Leu/Ile into their catabolic pathways but impaired oxidation because defective TCA cycle activity restrains acetyl CoA entry and metabolism. These changes were most pronounced in obese DKA patients, recapitulating the pattern of A-β+ KPD patients when stable; 2) Markedly decreased levels of glutamate, ammonia and many non-essential amino acids including citrulline, in the presence of increased glutamine, suggesting a defect in glutaminase activity; 3) Low levels of 3-methyl histidine, suggesting a surprising decrease in muscle protein breakdown. The pattern of amino acids and their metabolites among the DKA (especially obese) patients indicate that both increased ketone production from Leu/Ile and their blunted oxidation contribute to the proclivity to develop DKA; elevated leucine and low citrulline could contribute to beta cell dysfunction via mTOR hyperactivity and diminished intracellular arginine availability. Thus serum metabolomic profiling during an acute DKA episode helps define a unique pathophysiology underlying the phenotype of obese ketosis-prone T2D. Disclosure J.W. Hsu: None. P. Mehta: None. K.R. Keene: None. S.N. Mulukutla: None. E.I. Caducoy: None. W. Peacock: None. A. Balasubramanyam: None. F. Jahoor: None. Funding National Institutes of Health (R01DK101411)
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-1872-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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  • 6
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    Weight Change During the Postintervention Follow-up of Look AHEAD
    American Diabetes Association ; 2022
    In:  Diabetes Care Vol. 45, No. 6 ( 2022-06-02), p. 1306-1314
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 45, No. 6 ( 2022-06-02), p. 1306-1314
    Abstract: Patients with type 2 diabetes are encouraged to lose weight, but excessive weight loss in older adults may be a marker of poor health and subsequent mortality. We examined weight change during the postintervention period of Look AHEAD, a randomized trial comparing intensive lifestyle intervention (ILI) with diabetes support and education (DSE) (control) in overweight/obese individuals with type 2 diabetes and sought to identify predictors of excessive postintervention weight loss and its association with mortality. RESEARCH DESIGN AND METHODS These secondary analyses compared postintervention weight change (year 8 to final visit; median 16 years) in ILI and DSE in 3,999 Look AHEAD participants. Using empirically derived trajectory categories, we compared four subgroups: weight gainers (n = 307), weight stable (n = 1,561), steady losers (n = 1,731), and steep losers (n = 380), on postintervention mortality, demographic variables, and health status at randomization and year 8. RESULTS Postintervention weight change averaged −3.7 ± 9.5%, with greater weight loss in the DSE than the ILI group. The steep weight loss trajectory subgroup lost on average 17.7 ± 6.6%; 30% of steep losers died during postintervention follow-up versus 10–18% in other trajectories (P & lt; 0001). The following variables distinguished steep losers from weight stable: baseline, older, longer diabetes duration, higher BMI, and greater multimorbidity; intervention, randomization to control group and less weight loss in years 1–8; and year 8, higher prevalence of frailty, multimorbidity, and depressive symptoms and lower use of weight control strategies. CONCLUSIONS Steep weight loss postintervention was associated with increased risk of mortality. Older individuals with longer duration of diabetes and multimorbidity should be monitored for excessive unintentional weight loss.
    Type of Medium: Online Resource
    ISSN: 0149-5992
    URL: Article
    DOI: 10.2337/dc21-1990
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
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  • 7
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    254-OR: Islet Autoimmunity Is Highly Prevalent and Associated with Diminished Beta-Cell Function in Patients with Type 2 Diabetes (T2D) in the GRADE Study
    American Diabetes Association ; 2020
    In:  Diabetes Vol. 69, No. Supplement_1 ( 2020-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 69, No. Supplement_1 ( 2020-06-01)
    Abstract: We hypothesized that islet autoimmunity, hitherto considered the pathophysiologic basis of type 1 diabetes (T1D) and latent autoimmune diabetes of adults (LADA), could contribute to ß cell dysfunction in patients with type 2 diabetes (T2D). To evaluate this question, the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study - Beta Cell Ancillary Study Network measured humoral islet autoimmunity (autoantibodies against 65 kDa glutamic acid decarboxylase (GAD65-Ab), islet autoantigen-2 (IA2-Ab) and zinc transporter-8 (ZnT8-Ab)) in 392 participants (age 57.2 ± 10.1 y; BMI 33.5 ± 6.2 kg/m2; diabetes duration 4.0 ± 3.0 y; HbA1c 7.5 ± 0.5 %; on metformin as the sole glucose-lowering medication), and cellular islet autoimmunity (T cell autoreactivity against a broad range of islet antigens) in 322 of the same participants. 41.4% had evidence of cellular islet autoimmunity and 13.5% had evidence of humoral islet autoimmunity, but only 5.4% had both. T cell autoreactivity to islet antigens, but not autoantibody-positivity, was associated with diminished ß cell function, as assessed by the ratio of incremental area under the curve (iAUC) of C-peptide to iAUC of glucose during 0-120 min of an OGTT (ß = -0.1403; se = 0.0612; p = 0.0219) or ∆C-peptide/∆glucose during 0-30 min of an OGTT (ß = -0.2113; se = 0.0728; p = 0.0037), adjusted for insulin sensitivity. T cell positive participants also had higher fasting plasma glucose (p = 0.045) and HbA1c (p = 0.001) than T cell negative participants. These findings indicate that islet autoimmunity in T2D patients is far more prevalent than previously recognized; T cell mediated islet autoimmunity is associated with diminished ß cell function. Disclosure B. Brooks-Worrell: None. C.S. Hampe: None. E.V. Gonzalez: None. B.M. Palomino: None. S.Z. Zangeneh: None. K. Utzschneider: Other Relationship; Self; Medtronic. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc. M.E. Larkin: None. M.L. Johnson: Consultant; Self; Jaeb Center for Health Research. Research Support; Self; Abbott, Dexcom, Inc., Insulet Corporation, JDRF, Lilly Diabetes, Medtronic, National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk Inc. K.J. Mather: Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. N. Younes: None. N. Rasouli: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; Allergan plc., Novo Nordisk Inc. C. Desouza: Consultant; Self; AstraZeneca, Bayer AG, Novo Nordisk A/S. R.M. Cohen: Stock/Shareholder; Self; Bristol-Myers Squibb. J.Y. Park: None. H. Florez: None. W. Valencia: None. A. Shojaie: None. J.P. Palmer: None. A. Balasubramanyam: None. Funding National Institutes of Health (R01DK104832, U01DK098246)
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-254-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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  • 8
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    1308-P: Glutamic Acid Decarboxylase Autoantibodies (GADA) in Type 2 Diabetes Do Not Predict Long-Term Diabetes Complications
    American Diabetes Association ; 2023
    In:  Diabetes Vol. 72, No. Supplement_1 ( 2023-06-20)
    Details
    In: Diabetes, American Diabetes Association, Vol. 72, No. Supplement_1 ( 2023-06-20)
    Abstract: Some adults with type 2 diabetes (T2D) have islet autoantibodies that may explain clinical heterogeneity, yet limited long-term studies have examined their relationship with diabetes outcomes. We investigated the association between GADA, the most prevalent islet autoantibody, and diabetes complications and mortality in Look AHEAD (Action for Health in Diabetes), a trial that randomized adults with clinically-diagnosed T2D to intensive lifestyle intervention vs. control for 9.6 years, and then followed them observationally. GADA was measured by radioligand binding assay in 87% of the cohort at baseline and categorized as negative, low-level (35-199 U/mL) or high-level (≥200 U/mL). We used Cox proportional hazards regression adjusted for age, sex, race/ethnicity, and study arm to analyze the association between GADA category and time-to-event outcomes: CVD (MI, stroke, hospitalized angina, CVD death), incident eGFR & lt;45 ml/min/1.73m2, incident end stage kidney disease, and all-cause mortality. Among 4,492 participants, the median age was 59 years and diabetes duration 5 years. GADA was low-level and high-level positive in 131 (2.9%) and 85 (1.9%), respectively. Over a median follow-up of 17 years, there was no significant association between GADA levels and outcomes (Table). Overall, the presence of GADA above 35 U/mL was not predictive of CVD, or renal outcomes or mortality. Disclosure S.J.Pilla: None. A.Ramelius: None. R.Bennet: None. Å.Lernmark: Advisory Panel; Diamyd Medical. N.N.Mathioudakis: None. J.Clark: None. N.M.Maruthur: Other Relationship; Johns Hopkins HealthCare Solutions. W.C.Knowler: None. A.Balasubramanyam: None. C.S.Hampe: Employee; Immusoft corp. S.Pietropaolo: None. A.M.Anderson: None. M.Li: None. N.Zhao: None. S.L.Zeger: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK126825, K23DK128572)
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db23-1308-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
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  • 9
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    1463-P: Heterozygous Variant in NFKB1 Presenting with Autoantibody-Negative (AbNeg) Insulin-Dependent Diabetes (IDDM)
    American Diabetes Association ; 2023
    In:  Diabetes Vol. 72, No. Supplement_1 ( 2023-06-20)
    Details
    In: Diabetes, American Diabetes Association, Vol. 72, No. Supplement_1 ( 2023-06-20)
    Abstract: Due to its uncertain etiology and clinical management, AbNeg IDDM is a phenotype of interest for the NIH-funded Rare and Atypical Diabetes Network (RADIANT), which aims to identify and characterize people with unknown forms of diabetes (DM). We report a case of childhood-onset AbNeg IDDM found to have a likely pathogenic variant in NFKB1. A 17-year-old female presented with DM at age 7 with A1c 10.8%; random C-peptide 0.21 ng/ml; no diabetic ketoacidosis; negative GAD65, insulin, IA-2 and ZnT8 Ab; normal BMI%ile; no signs of insulin resistance; and negative genetic testing for monogenic DM. She has required continuous insulin therapy. Past medical history: IgA deficiency, vitamin D deficiency, orthostatic intolerance, neurocardiogenic pre-syncope and chronic migraine. Family history: Autoimmune adult-onset DM and hypothyroidism in mother, frequent upper respiratory infections in sisters, Addison’s disease in maternal grandfather, hemochromatosis in paternal grandmother and pericarditis at age 30 in paternal grandfather. Physical exam: Unremarkable. RADIANT Labs: Undetectable serum C-peptide. Negative Ab. Whole genome sequencing: Heterozygous likely pathogenic variant in NFKB1 impacting the canonical splice acceptor sequence (NM_003998.4:c.1753-1G & gt;C). This is a case of youth-onset AbNeg IDDM found to have a likely pathogenic variant in NFKB1. Heterozygous loss-of-function variants in NFKB1 are associated with Common Variable Immunodeficiency (CVID) type 12 (OMIM #616576), characterized by incomplete penetrance and variable expressivity of immunodeficiency and autoimmunity, including features of IDDM. Immune dysregulation may explain lack of classic Ab. There are no prior reports of CVID first ascertained through a DM phenotype. Thus, this case represents a phenotype expansion of NFKB1-associated disease, and contributes to our understanding of the heterogeneity of AbNeg IDDM. Genetic testing of first-degree relatives is underway. Disclosure M.J.Redondo: None. A.Balasubramanyam: None. P.Liu: Other Relationship; Baylor Genetics. A.N.Alkanaq: None. M.Tosur: Advisory Panel; Provention Bio, Inc. N.Ram: None. R.J.Kreienkamp: None. E.A.Oral: Advisory Panel; Amryt Pharma Plc, Regeneron, Rejuvenate Bio, Third Rock Ventures, Consultant; Amryt Pharma Plc, Ionis Pharmaceuticals, Regeneron, Other Relationship; Amryt Pharma Plc, Research Support; Amryt Pharma Plc, Novo Nordisk, Fractyl Health, Inc., Ionis Pharmaceuticals, Regeneron, GI Dynamics, Rejuvenate Bio. C.Pihoker: None. J.Posey: None. Funding National Institutes of Health (U54DK118638)
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db23-1463-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
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  • 10
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    HIV-1 Viral Protein R Couples Metabolic Inflexibility With White Adipose Tissue Thermogenesis
    American Diabetes Association ; 2021
    In:  Diabetes Vol. 70, No. 9 ( 2021-09-01), p. 2014-2025
    Details
    In: Diabetes, American Diabetes Association, Vol. 70, No. 9 ( 2021-09-01), p. 2014-2025
    Abstract: Persons living with HIV (PLWH) manifest chronic disorders of brown and white adipose tissues that lead to diabetes and metabolic syndrome. The mechanisms that link viral factors to defective adipose tissue function and abnormal energy balance in PLWH remain incompletely understood. Here, we explored how the HIV accessory protein viral protein R (Vpr) contributes to adaptive thermogenesis in two mouse models and human adipose tissues. Uncoupling protein 1 (UCP1) gene expression was strongly increased in subcutaneous white adipose tissue (WAT) biopsy specimens from PLWH and in subcutaneous WAT of the Vpr mice, with nearly equivalent mRNA copy number. Histology and functional studies confirmed beige transformation in subcutaneous but not visceral WAT in the Vpr mice. Measurements of energy balance indicated Vpr mice displayed metabolic inflexibility and could not shift efficiently from carbohydrate to fat metabolism during day-night cycles. Furthermore, Vpr mice showed a marked inability to defend body temperature when exposed to 4°C. Importantly, Vpr couples higher tissue catecholamine levels with UCP1 expression independent of β-adrenergic receptors. Our data reveal surprising deficits of adaptive thermogenesis that drive metabolic inefficiency in HIV-1 Vpr mouse models, providing an expanded role for viral factors in the pathogenesis of metabolic disorders in PLWH.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-0888
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
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