J S Skyler

University of Miami, كورال غيبلز، فلوريدا, Florida, United States

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Publications (226)1388.81 Total impact

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    ABSTRACT: We developed a scale to serve as a potential end point for 6-month glycemic progression (PS6M) toward type 1 diabetes (T1D) in autoantibody-positive relatives of individuals with T1D. The PS6M was developed from Diabetes Prevention Trial-Type 1 (DPT-1) data and tested in the TrialNet Pathway to Prevention Study (PTP). It is the difference between 6-month glucose sum values (30-120 min oral glucose tolerance test values) and values predicted for nonprogressors. The PS6M predicted T1D in the PTP (P < 0.001). The area under the receiver operating chacteristic curve was greater (P < 0.001) for the PS6M than for the baseline-to-6-month difference. PS6M values were higher in those with two or more autoantibodies, 30-0 min C-peptide values <2.00 ng/mL, or DPT-1 Risk Scores >7.00 (P < 0.001 for all). The PS6M is an indicator of short-term glycemic progression to T1D that could be a useful tool for assessing preventive treatments and biomarkers. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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    ABSTRACT: High-carbohydrate diets have been associated with ß-cell strain, dyslipidemia, and endothelial dysfunction. We examined how β-cell and endothelial function adapt to carbohydrate overloading and the influence of insulin resistance. On sequential days in randomized order, nondiabetic subjects (classified as insulin-sensitive (IS, n=64) or insulin-resistant (IR, n=79) by euglycemic clamp) received 4 mixed meals over 14 hours with either standard (300 kcal) or double carbohydrate content. β-cell function was reconstructed by mathematical modeling; brachial artery flow-mediated dilation (FMD) was measured before and after each meal. Compared with IS, IR subjects showed higher glycemias and insulin hypersecretion due to greater ß-cell glucose and rate sensitivity; potentiation of insulin secretion, however, was impaired. Circulating FFA were less suppressed in IR than IS subjects. Baseline FMD was reduced in IR, and postprandial FMD attenuation occurred after each meal, particularly with high carbohydrate, similarly in IR and IS. Throughout the 2 study days, higher FFA levels were significantly associated with lower (incretin-induced) potentiation and impaired FMD. In nondiabetic individuals, enhanced glucose sensitivity and potentiation upregulate the insulin secretory response to carbohydrate overloading. With insulin resistance this adaptation is impaired. Defective suppression of endogenous FFA is one common link between impaired potentiation and vascular endothelial dysfunction. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes 03/2015; DOI:10.2337/db15-0106 · 8.47 Impact Factor
  • Jay S Skyler
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    ABSTRACT: 2014 was a good year for developments in automated insulin delivery systems for patients with diabetes mellitus. Clinical trials shifted from research units to the outpatient setting, included both adult and adolescent individuals and were conducted over periods from overnight to 24 h, with improvements seen in time spent in the target glycaemic range and reduced risk of hypoglycaemia.
    Nature Reviews Endocrinology 12/2014; 11(2). DOI:10.1038/nrendo.2014.228 · 12.96 Impact Factor
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    ABSTRACT: We assessed whether type 1 diabetes (T1D) can be diagnosed earlier using a new approach based on prediction and natural history in autoantibody-positive individuals. Diabetes Prevention Trial-Type 1 (DPT-1) and TrialNet Natural History Study (TNNHS) participants were studied. A metabolic index, the T1D Diagnostic Index60 (Index60), was developed from 2-h oral glucose tolerance tests (OGTTs) using the log fasting C-peptide, 60-min C-peptide, and 60-min glucose. OGTTs with Index60 ≥2.00 and 2-h glucose <200 mg/dL (Ind60+Only) were compared with Index60 <2.00 and 2-h glucose ≥200 mg/dL (2hglu+Only) OGTTs as criteria for T1D. Individuals were assessed for C-peptide loss from the first Ind60+Only OGTT to diagnosis. Areas under receiver operating characteristic curves were significantly higher for Index60 than for the 2-h glucose (P < 0.001 for both DPT-1 and the TNNHS). As a diagnostic criterion, sensitivity was higher for Ind60+Only than for 2hglu+Only (0.44 vs. 0.15 in DPT-1; 0.26 vs. 0.17 in the TNNHS) OGTTs. Specificity was somewhat higher for 2hglu+Only OGTTs in DPT-1 (0.97 vs. 0.91) but equivalent in the TNNHS (0.98 for both). Positive and negative predictive values were higher for Ind60+Only OGTTs in both studies. Postchallenge C-peptide levels declined significantly at each OGTT time point from the first Ind60+Only OGTT to the time of standard diagnosis (range -22 to -34% in DPT-1 and -14 to -27% in the TNNHS). C-peptide and glucose patterns differed markedly between Ind60+Only and 2hglu+Only OGTTs. An approach based on prediction and natural history appears to have utility for diagnosing T1D. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes Care 12/2014; DOI:10.2337/dc14-1813 · 8.57 Impact Factor
  • Jay S Skyler
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    ABSTRACT: Patients with type 1 diabetes (T1D) rapidly lose β cell function and/or mass, leading to a life-long dependence on insulin therapy. β Cell destruction is mediated by aberrant immune responses; therefore, immune modulation has potential to ameliorate disease. While immune intervention in animal models of diabetes has shown promising results, treatment of patients with T1D with the same agents has not been as successful. In this issue of the JCI, Haller and colleagues present data from a small clinical trial that tested the efficacy of a combination of immunomodulatory agents, anti-thymocyte globulin and pegylated granulocyte CSF, neither of which have shown benefit for T1D as single treatment agents. Many patients that received combination therapy maintained β cell function at baseline levels up to a year after treatment. The results from this study challenge current trial design paradigm that for combined therapy to be successful individual agents should show benefit.
    Journal of Clinical Investigation 12/2014; 125(1):1-3. DOI:10.1172/JCI79190 · 13.77 Impact Factor
  • Jay S Skyler
    Diabetes 11/2014; 63(11):3578-80. DOI:10.2337/db14-1160 · 8.47 Impact Factor
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    ABSTRACT: Objective Type 1 diabetes (T1D) results from the inflammatory destruction of pancreatic β-cells. In this study, we investigated the effect of docosahexaenoic acid (DHA) supplementation on stimulated inflammatory cytokine production in white blood cells (WBC) from infants with a high genetic risk for T1D.Research design and methodsThis was a multicenter, two-arm, randomized, double-blind pilot trial of DHA supplementation, beginning either in the last trimester of pregnancy (41 infants) or in the first 5 months after birth (57 infants). Levels of DHA in infant and maternal red blood cell (RBC) membranes and in breast milk were analyzed by gas chromatography/mass spectrometry. Inflammatory cytokines were assayed from whole blood culture supernatants using the Luminex multiplex assay after stimulation with high dose lipopolysaccharide (LPS), 1 µg/mL.ResultsThe levels of RBC DHA were increased by 61–100% in treated compared to control infants at ages 6–36 months. There were no statistically significant reductions in production of the inflammatory cytokines, IL-1β, TNFα, or IL-12p40 at any of the six timepoints measured. The inflammatory marker, high-sensitivity C-reactive protein (hsCRP), was significantly lower in breast-fed DHA-treated infants compared to all formula-fed infants at the age of 12 months. Three infants (two received DHA) were removed from the study as a result of developing ≥two persistently positive biochemical islet autoantibodies.Conclusions This pilot trial showed that supplementation of infant diets with DHA is safe and fulfilled the pre-study goal of increasing infant RBC DHA levels by at least 20%. Inflammatory cytokine production was not consistently reduced.
    Pediatric Diabetes 07/2014; DOI:10.1111/pedi.12170 · 2.13 Impact Factor
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    ABSTRACT: Aims: Prandial treatment with human regular insulin for diabetes may result in early postprandial hyperglycaemia and late hypoglycaemia due to its slow onset and long duration of action. This study compared injections of recombinant human insulin (rHI) formulated with recombinant human hyaluronidase [rHuPH20] (INSULIN-PH20) to insulin lispro for prandial treatment in subjects with type 1 diabetes (T1D). Methods: After a 1-month run-in period using twice-daily insulin glargine (or usual basal insulin therapy for pump users) with prandial lispro, 46 subjects with T1D (42 +/- 13 years; body mass index: 26 +/- 4 kg/m(2); A1c: 6.8 +/- 0.5%) were assigned to INSULIN-PH20 or lispro in a random sequence for two consecutive, 12-week periods as the prandial insulin in an intensive treatment regimen. Results: The mean glycaemic excursion for INSULIN-PH20 (0.96 +/- 2.00 mmol/l) was comparable (p=0.322) to lispro (0.80 +/- 1.95 mmol/l). The 8-point self-monitored blood glucose profiles were also comparable in the two groups. Good glycaemic control (A1c) was maintained for both treatments at 12 weeks (INSULIN-PH20: 7.0 +/- 0.5%; lispro: 6.9 +/- 0.6%). Overall rates of hypoglycaemia (<= 3.9 mmol/l) were 24 events per patient per 4 weeks for INSULIN-PH20 and 22 events for lispro. There were no significant differences in adverse events or immunogenicity between treatments and both treatments were well tolerated. Conclusions: Unlike commercially available formulations of regular human insulin, a formulation of rHI with rHuPH20 was comparable to lispro for postprandial glucose excursions in a basal-bolus treatment regimen for T1D patients. Glycaemic control, safety and tolerability profiles were comparable for both treatments.
    Diabetes Obesity and Metabolism 05/2014; 16(11). DOI:10.1111/dom.12315 · 5.46 Impact Factor
  • Jay S Skyler
    Diabetes care 05/2014; 37(5):1173-5. DOI:10.2337/dc13-2878 · 8.57 Impact Factor
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    ABSTRACT: Recent advances in insulins, insulin pumps, continuous glucose-monitoring systems, and control algorithms have resulted in an acceleration of progress in the development of artificial pancreas devices. This review discusses progress in the development of external systems that are based on subcutaneous drug delivery and subcutaneous continuous glucose monitoring. There are two major system-level approaches to achieving closed-loop control of blood glucose in diabetic individuals. The unihormonal approach uses insulin to reduce blood glucose and relies on complex safety mitigation algorithms to reduce the risk of hypoglycemia. The bihormonal approach uses both insulin to lower blood glucose and glucagon to raise blood glucose, and also relies on complex algorithms to provide for safety of the user. There are several major strategies for the design of control algorithms and supervision control for application to the artificial pancreas: proportional–integral–derivative, model predictive control, fuzzy logic, and safety supervision designs. Advances in artificial pancreas research in the first decade of this century were based on the ongoing computer revolution and miniaturization of electronic technology. The advent of modern smartphones has created the ability to utilize smartphone technology as the engineering centerpiece of an artificial pancreas. With these advances, an artificial or bionic pancreas is within reach.
    Annals of the New York Academy of Sciences 04/2014; 1311(1). DOI:10.1111/nyas.12431 · 4.31 Impact Factor
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    ABSTRACT: OBJECTIVE We studied the utility of the Diabetes Prevention Trial-Type 1 Risk Score (DPTRS) for improving the accuracy of type 1 diabetes (T1D) risk classification in TrialNet Natural History Study (TNNHS) participants.RESEARCH DESIGN AND METHODS The cumulative incidence of T1D was compared between normoglycemic individuals with DPTRS values >7.00 and dysglycemic individuals in the TNNHS (n = 991). The cumulative incidence was compared between individuals with DPTRS values <7.00 and >7.00 among those with dysglycemia and those with multiple autoantibodies in the TNNHS. DPTRS values >7.00 were compared with dysglycemia for characterizing risk in Diabetes Prevention Trial-Type 1 (DPT-1) (n = 670) and TNNHS participants. The reliability of DPTRS values >7.00 was compared with dysglycemia in the TNNHS.RESULTSThe cumulative incidence of T1D for normoglycemic TNNHS participants with DPTRS values >7.00 was comparable to those with dysglycemia. Among those with dysglycemia, the cumulative incidence was much higher (P < 0.001) for those with DPTRS values >7.00 than for those with values <7.00 (3-year risks: 0.16 for <7.00 and 0.46 for >7.00). Dysglycemic individuals in DPT-1 were at much higher risk for T1D than those with dysglycemia in the TNNHS (P < 0.001); there was no significant difference in risk between the studies among those with DPTRS values >7.00. The proportion in the TNNHS reverting from dysglycemia to normoglycemia at the next visit was higher than the proportion reverting from DPTRS values >7.00 to values <7.00 (36 vs. 23%).CONCLUSIONSDPTRS thresholds can improve T1D risk classification accuracy by identifying high-risk normoglycemic and low-risk dysglycemic individuals. The 7.00 DPTRS threshold characterizes risk more consistently between populations and has greater reliability than dysglycemia.
    Diabetes care 02/2014; 37(4). DOI:10.2337/dc13-2359 · 8.57 Impact Factor
  • Jay S Skyler
    Diabetes Technology &amp Therapeutics 02/2014; 16(S1):S85-S91. DOI:10.1089/dia.2014.1510 · 2.29 Impact Factor
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    ABSTRACT: Objective We previously reported that two years of co-stimulation modulation with abatacept slowed decline of beta-cell function in recent-onset type 1 diabetes mellitus (T1DM). Subsequently, abatacept was discontinued, and subjects followed to determine whether there was persistence of effect.Research Design and Methods In 112 subjects (ages 6-36) with T1DM, 77 received abatacept and 35 received placebo infusions intravenously for 27 infusions over two years. The primary outcome - baseline-adjusted geometric mean 2-hour area under the curve (AUC) serum C-peptide during a mixed meal tolerance test (MMTT) at two years - showed higher C-peptide with abatacept versus placebo. Subjects were followed an additional year, off treatment, with MMTTs performed at 30 and 36 months.ResultsC-peptide AUC means, adjusted for age and baseline C-peptide, at 36 months were 0.217 (95% CI: 0.168, 0.268) and 0.141 (95% CI: 0.071, 0.215) nmol/L for abatacept and placebo groups, respectively (p=0.046). The C-peptide decline from baseline remained parallel with an estimated 9.5 months' delay with abatacept. Moreover, HbA1c levels remainded lower in the abatacept group than in the placebo group. The slightly lower (non-significant) mean total insulin dose among the abatacept group reported at 2 years was the same as the placebo group by 3 years.Conclusions Co-stimulation modulation with abatacept slowed decline of beta-cell function and improved HbA1c in recent-onset T1DM. The beneficial effect was sustained for at least one year after cessation of abatacept infusions, or three years from T1DM diagnosis.
    Diabetes care 12/2013; 37(4). DOI:10.2337/dc13-0604 · 8.57 Impact Factor
  • Jay S Skyler
    12/2013; 1(4):265-6. DOI:10.1016/S2213-8587(13)70087-1
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    Jay S Skyler
    Diabetes 11/2013; 62(11):3656-7. DOI:10.2337/db13-1157 · 8.47 Impact Factor
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    ABSTRACT: Objective We previously reported that selective depletion of B-lymphocytes with rituximab, an anti-CD20 monoclonal antibody, slowed decline of beta-cell function in recent-onset type 1 diabetes mellitus (T1DM) at one year. Subjects were followed further to determine whether there was persistence of effect.Research Design and Methods Eighty-seven subjects (ages 8-40) were randomly assigned to, and 81 received, infusions of rituximab or placebo on days 1, 8, 15, and 22. The primary outcome - baseline-adjusted mean 2-hour area under the curve (AUC) serum C-peptide during a mixed meal tolerance test (MMTT) at one year - showed higher C-peptide AUC with rituximab versus placebo. Subjects were further followed with additional MMTTs every 6 months.ResultsThe rate of decline of C-peptide was parallel between groups, but shifted by 8.2 months in rituximab treated subjects. Over 30 months, AUC, insulin dose, and HbA1c were similar for rituximab and placebo. However, in evaluating change in C-peptide over the entire follow-up period, the rituximab group means were significantly larger as compared within assessment times to the placebo group means using a global test (p = 0.03). Odds ratio for loss of C-peptide to < 0.2 nmol/L following rituximab was 0.565 (p= 0.064). B-lymphocytes recovered to baseline values by 18 months. Serum IgG levels were maintained in the normal range but IgM levels were depressed.Conclusions Like several other immunotherapeutic approaches tested, in recent-onset T1DM, rituximab delays the fall in C-peptide, but does not appear to fundamentally alter the underlying pathophysiology of the disease.
    Diabetes care 09/2013; 37(2). DOI:10.2337/dc13-0626 · 8.57 Impact Factor
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    ABSTRACT: OBJECTIVE We assessed whether a risk score that incorporates levels of multiple islet autoantibodies could enhance the prediction of type 1 diabetes (T1D).RESEARCH DESIGN AND METHODS TrialNet Natural History Study participants (n = 784) were tested for three autoantibodies (GADA, IA-2A, and mIAA) at their initial screening. Samples from those positive for at least one autoantibody were subsequently tested for ICA and ZnT8A. An autoantibody risk score (ABRS) was developed from a proportional hazards model that combined autoantibody levels from each autoantibody along with their designations of positivity and negativity.RESULTS The ABRS was strongly predictive of T1D (hazard ratio [with 95% CI] 2.72 [2.23-3.31], P < 0.001). Receiver operating characteristic curve areas (with 95% CI) for the ABRS revealed good predictability (0.84 [0.78-0.90] at 2 years, 0.81 [0.74-0.89] at 3 years, P < 0.001 for both). The composite of levels from the five autoantibodies was predictive of T1D before and after an adjustment for the positivity or negativity of autoantibodies (P < 0.001). The findings were almost identical when ICA was excluded from the risk score model. The combination of the ABRS and the previously validated Diabetes Prevention Trial-Type 1 Risk Score (DPTRS) predicted T1D more accurately (0.93 [0.88-0.98] at 2 years, 0.91 [0.83-0.99] at 3 years) than either the DPTRS or the ABRS alone (P 0.01 for all comparisons).CONCLUSIONS These findings show the importance of considering autoantibody levels in assessing the risk of T1D. Moreover, levels of multiple autoantibodies can be incorporated into an ABRS that accurately predicts T1D.
    Diabetes Care 08/2013; 36(9):2615-2620. DOI:10.2337/dc13-0425 · 8.57 Impact Factor
  • Evis Harja, Jonathan Lord, Jay S Skyler
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    ABSTRACT: Abstract A recent autopsy analysis asserted that incretin drugs have the potential of increasing the risk for pancreatic cancer and for pancreatic neuroendocrine tumors. We examined the Network for Pancreatic Organ Donors with Diabetes (nPOD) database from which that analysis was derived. Our findings raise important questions about the comparability of the two groups of diabetes patients used for the analysis. Our review of the data available on the nPOD Web site and our reading of the earlier article lead us to the conclusion that the data, and the implications of the data, as expressed by the authors of the autopsy analysis are vastly overstated and are a misrepresentation of the information available.
    Diabetes Technology &amp Therapeutics 08/2013; DOI:10.1089/dia.2013.0177 · 2.29 Impact Factor
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    ABSTRACT: We studied the change in the first-phase insulin response (FPIR) during the progression to type 1 diabetes (T1D). Seventy-four oral insulin trial progressors to T1D of the Diabetes Prevention Trial-Type 1 with at least one FPIR measurement after baseline and before diagnosis were studied. The FPIR was examined longitudinally in 26 progressors who had FPIR measurements during each of the 3 years before diagnosis. The association between the change from the baseline FPIR to the last FPIR and time to diagnosis was studied in the remainder (n=48). The 74 progressors had lower baseline FPIR values than non-progressors (n=270) with adjustments for age and BMI. In the longitudinal analysis of the 26 progressors, there was a greater decline in the FPIR from 1.5 to 0.5 years before diagnosis than from 2.5 to 1.5 years before diagnosis. This accelerated decline was also evident in a regression analysis of the 48 remaining progressors in whom the rate of decline became more marked with the approaching diagnosis. The patterns of decline were similar between the longitudinal and regression analyses. There is an acceleration of decline in the FPIR during the progression to T1D which becomes especially marked between 1.5 and 0.5 years before diagnosis.
    Diabetes 07/2013; 62(12). DOI:10.2337/db13-0656 · 8.47 Impact Factor
  • Jay S Skyler, Jay M Sosenko
    JAMA The Journal of the American Medical Association 06/2013; 309(23):2491-2. DOI:10.1001/jama.2013.6286 · 30.39 Impact Factor

Publication Stats

6k Citations
1,388.81 Total Impact Points

Institutions

  • 1984–2015
    • University of Miami
      • • Miller School of Medicine
      • • Diabetes Research Institute
      • • Department of Medicine
      • • Behavioral Medicine Research Center
      • • Department of Psychology
      • • Department of Pediatrics
      كورال غيبلز، فلوريدا, Florida, United States
  • 2014
    • Yale University
      • Department of Pediatrics
      New Haven, Connecticut, United States
  • 1982–2014
    • University of Miami Miller School of Medicine
      • • Diabetes Research Institute (DRI)
      • • Department of Medicine
      • • Division of Hospital Medicine
      • • Division of Pediatric Psychology
      Miami, Florida, United States
  • 2012
    • Benaroya Research Institute
      Seattle, Washington, United States
  • 2010
    • University of Colorado
      • Barbara Davis Center for Childhood Diabetes
      Denver, CO, United States
  • 2009
    • Indiana University-Purdue University Indianapolis
      Indianapolis, Indiana, United States
  • 2006–2007
    • Columbia University
      New York, New York, United States
  • 2003
    • University of Leeds
      Leeds, England, United Kingdom
  • 2002
    • Diabetes Australia, Victoria
      Melbourne, Victoria, Australia
  • 1999
    • University at Buffalo, The State University of New York
      • Department of Social and Preventive Medicine
      Buffalo, NY, United States
    • Deakin University
      Geelong, Victoria, Australia
  • 1997
    • Rochester Center for Behavioral Medicine
      Rochester Hills, Michigan, United States
  • 1994
    • University Of Miami Hospital
      Miami, Florida, United States
  • 1976
    • Duke University Medical Center
      Durham, North Carolina, United States