Browsing by Author "Lachin, John M."

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    Association of Glycemia with Insulin Sensitivity and β-cell Function in Adults with Early Type 2 Diabetes on Metformin Alone
    (Elsevier, 2021) Utzschneider, Kristina M.; Younes, Naji; Rasouli, Neda; Barzilay, Joshua; Banerji, Mary Ann; Cohen, Robert M.; Gonzalez, Erica V.; Mather, Kieren J.; Ismail-Beigi, Faramarz; Raskin, Philip; Wexler, Deborah J.; Lachin, John M.; Kahn, Steven E.; GRADE Research Group; Medicine, School of Medicine
    Aims: Evaluate the relationship between measures of glycemia with β-cell function and insulin sensitivity in adults with early type 2 diabetes mellitus (T2DM). Methods: This cross-sectional analysis evaluated baseline data from 3108 adults with T2DM <10 years treated with metformin alone enrolled in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study. Insulin and C-peptide responses and insulin sensitivity were calculated from 2-hour oral glucose tolerance tests. Regression models evaluated the relationships between glycemic measures (HbA1c, fasting and 2-hour glucose), measures of β-cell function and insulin sensitivity. Results: Insulin and C-peptide responses were inversely associated with insulin sensitivity. Glycemic measures were inversely associated with insulin and C-peptide responses adjusted for insulin sensitivity. HbA1c demonstrated modest associations with β-cell function (range: r −0.22 to −0.35). Fasting and 2-hour glucose were associated with early insulin and C-peptide responses (range: r −0.37 to −0.40) as well as late insulin and total insulin and C-peptide responses (range: r −0.50 to −0.60). Conclusion: Glycemia is strongly associated with β-cell dysfunction in adults with early T2DM treated with metformin alone. Efforts to improve glycemia should focus on interventions aimed at improving β-cell function.
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    Failure to Preserve β-Cell Function With Mycophenolate Mofetil and Daclizumab Combined Therapy in Patients With New- Onset Type 1 Diabetes
    (American Diabetes Association, 2010-04) Gottlieb, Peter A.; Quinlan, Scott; Krause-Steinrauf, Heidi; Greenbaum, Carla J.; Wilson, Darrell M.; Rodriguez, Henry; Schatz, Desmond A.; Moran, Antoinette M.; Lachin, John M.; Skyler, Jay S.; Type 1 Diabetes TrialNet MMF/DZB Study Group; Pediatrics, School of Medicine
    OBJECTIVE This trial tested whether mycophenolate mofetil (MMF) alone or with daclizumab (DZB) could arrest the loss of insulin-producing β-cells in subjects with new-onset type 1 diabetes. RESEARCH DESIGN AND METHODS A multi-center, randomized, placebo-controlled, double-masked trial was initiated by Type 1 Diabetes TrialNet at 13 sites in North America and Europe. Subjects diagnosed with type 1 diabetes and with sufficient C-peptide within 3 months of diagnosis were randomized to either MMF alone, MMF plus DZB, or placebo, and then followed for 2 years. The primary outcome was the geometric mean area under the curve (AUC) C-peptide from the 2-h mixed meal tolerance test. RESULTS One hundred and twenty-six subjects were randomized and treated during the trial. The geometric mean C-peptide AUC at 2 years was unaffected by MMF alone or MMF plus DZB versus placebo. Adverse events were more frequent in the active therapy groups relative to the control group, but not significantly. CONCLUSIONS Neither MMF alone nor MMF in combination with DZB had an effect on the loss of C-peptide in subjects with new-onset type 1 diabetes. Higher doses or more targeted immunotherapies may be needed to affect the autoimmune process.
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    Rituximab, B-lymphocyte depletion, and preservation of beta-cell function
    (Massachusetts Medical Society, 2009-11-26) Pescovitz, Mark D.; Greenbaum, Carla J.; Krause-Steinrauf, Heidi; Becker, Dorothy J.; Gitelman, Stephen E.; Goland, Robin; Gottlieb, Peter A.; Marks, Jennifer B.; McGee, Paula F.; Moran, Antoinette M.; Raskin, Philip; Rodriguez, Henry; Schatz, Desmond A.; Wherrett, Diane; Wilson, Darrell M.; Lachin, John M.; Skyler, Jay S.; Type 1 Diabetes TrialNet Anti-CD20 Study Group; Medicine, School of Medicine
    BACKGROUND: The immunopathogenesis of type 1 diabetes mellitus is associated with T-lymphocyte autoimmunity. However, there is growing evidence that B lymphocytes play a role in many T-lymphocyte-mediated diseases. It is possible to achieve selective depletion of B lymphocytes with rituximab, an anti-CD20 monoclonal antibody. This phase 2 study evaluated the role of B-lymphocyte depletion in patients with type 1 diabetes. METHODS: We conducted a randomized, double-blind study in which 87 patients between 8 and 40 years of age who had newly diagnosed type 1 diabetes were assigned to receive infusions of rituximab or placebo on days 1, 8, 15, and 22 of the study. The primary outcome, assessed 1 year after the first infusion, was the geometric mean area under the curve (AUC) for the serum C-peptide level during the first 2 hours of a mixed-meal tolerance test. Secondary outcomes included safety and changes in the glycated hemoglobin level and insulin dose. RESULTS: At 1 year, the mean AUC for the level of C peptide was significantly higher in the rituximab group than in the placebo group. The rituximab group also had significantly lower levels of glycated hemoglobin and required less insulin. Between 3 months and 12 months, the rate of decline in C-peptide levels in the rituximab group was significantly less than that in the placebo group. CD19+ B lymphocytes were depleted in patients in the rituximab group, but levels increased to 69% of baseline values at 12 months. More patients in the rituximab group than in the placebo group had adverse events, mostly grade 1 or grade 2, after the first infusion. The reactions appeared to be minimal with subsequent infusions. There was no increase in infections or neutropenia with rituximab. CONCLUSIONS: A four-dose course of rituximab partially preserved beta-cell function over a period of 1 year in patients with type 1 diabetes. The finding that B lymphocytes contribute to the pathogenesis of type 1 diabetes may open a new pathway for exploration in the treatment of patients with this condition.
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    Shape of the OGTT glucose response curve: relationship with β-cell function and differences by sex, race, and BMI in adults with early type 2 diabetes treated with metformin
    (BMJ, 2021) Utzschneider, Kristina M.; Younes, Naji; Rasouli, Neda; Barzilay, Joshua I.; Banerji, Mary Ann; Cohen, Robert M.; Gonzalez, Erica V.; Ismail-Beigi, Faramarz; Mather, Kieren J.; Raskin, Philip; Wexler, Deborah J.; Lachin, John M.; Kahn, Steven E.; GRADE Research Group; Medicine, School of Medicine
    Introduction: The shape of the glucose curve during an oral glucose tolerance test (OGTT) reflects β-cell function in populations without diabetes but has not been as well studied in those with diabetes. A monophasic shape has been associated with higher risk of diabetes, while a biphasic pattern has been associated with lower risk. We sought to determine if phenotypic or metabolic characteristics were associated with glucose response curve shape in adults with type 2 diabetes treated with metformin alone. Research design and methods: This is a cross-sectional analysis of 3108 metformin-treated adults with type 2 diabetes diagnosed <10 years who underwent 2-hour 75 g OGTT at baseline as part of the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). Insulin sensitivity (homeostasis model of insulin sensitivity, HOMA2-S) and β-cell function (early, late, and total incremental insulin and C peptide responses adjusted for HOMA2-S) were calculated. Glucose curve shape was classified as monophasic, biphasic, or continuous rise. Results: The monophasic profile was the most common (67.8% monophasic, 5.5% biphasic, 26.7% continuous rise). The monophasic subgroup was younger, more likely male and white, and had higher body mass index (BMI), while the continuous rise subgroup was more likely female and African American/black. HOMA2-S and fasting glucose did not differ among the subgroups. The biphasic subgroup had the highest early, late, and total insulin and C peptide responses (all p<0.05 vs monophasic and continuous rise). Compared with the monophasic subgroup, the continuous rise subgroup had similar early insulin (p=0.3) and C peptide (p=0.6) responses but lower late insulin (p<0.001) and total insulin (p=0.008) and C peptide (p<0.001) responses. Conclusions: Based on the large multiethnic GRADE cohort, sex, race, age, and BMI were found to be important determinants of the shape of the glucose response curve. A pattern of a continuously rising glucose at 2 hours reflected reduced β-cell function and may portend increased glycemic failure rates.