Browsing by Subject "Islet autoimmunity"

Now showing 1 - 4 of 4
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    Early Impairment of Insulin Sensitivity, β-Cell Responsiveness, and Insulin Clearance in Youth with Stage 1 Type 1 Diabetes
    (Oxford University Press, 2021) Galderisi, Alfonso; Moran, Antoinette; Evans-Molina, Carmella; Martino, Mariangela; Santoro, Nicola; Caprio, Sonia; Cobelli, Claudio; Pediatrics, School of Medicine
    Context: Clinical onset of type 1 diabetes (Stage 3 T1D) is preceded by a presymptomatic phase characterized by multiple islet autoantibodies with normal glucose tolerance (Stage 1 T1D). Objective: The aim was to explore the metabolic phenotypes of β-cell function and insulin sensitivity and clearance in normoglycemic youth with Stage 1 T1D and compare them with healthy nonrelated peers during a 3-hour oral glucose tolerance test (OGTT). Methods: Twenty-eight lean youth, 14 with ≥2 islet autoantibodies (cases) and 14 healthy controls underwent a 3-hour 9-point OGTT with measurement of glucose, C-peptide, and insulin. The oral minimal model was used to quantitate β-cell responsiveness (φtotal) and insulin sensitivity (SI), allowing assessment of β-cell function by the disposition index (DI=φtotal×SI). Fasting insulin clearance (CL0) was calculated as the ratio between the fasting insulin secretion rate (ISR) and plasma insulin levels (ISR0/I0), while postload clearance (CL180) was estimated by the ratio of AUC of ISR over the plasma insulin AUC for the 3-hour OGTT (ISRAUC/IAUC). Participants with impaired fasting glucose, impaired glucose tolerance, or any OGTT glucose concentration ≥200 mg/dL were excluded. Results: Cases (10.5 years [8, 15]) exhibited reduced DI (P < .001) due to a simultaneous reduction in both φtotal (P < 0.001) and SI (P = .008) compared with controls (11.5 years [10.4, 14.9]). CL0 and CL180 were lower in cases than in controls (P = .005 and P = .019). Conclusion: Presymptomatic Stage 1 T1D in youth is associated with reduced insulin sensitivity and lower β-cell responsiveness, and the presence of blunted insulin clearance.
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    Islet Autoimmunity in Adults With Impaired Glucose Tolerance and Recently Diagnosed, Treatment Naïve Type 2 Diabetes in the Restoring Insulin SEcretion (RISE) Study
    (Frontiers Media, 2021-04-26) Brooks-Worrell, Barbara M.; Tjaden, Ashley H.; Edelstein, Sharon L.; Palomino, Brenda; Utzschneider, Kristina M.; Arslanian, Silva; Mather, Kieren J.; Buchanan, Thomas A.; Nadeau, Kristen J.; Atkinson, Karen; Barengolts, Elena; Kahn, Steven E.; Palmer, Jerry P.; RISE Consortium; Medicine, School of Medicine
    The presence of islet autoantibodies and islet reactive T cells (T+) in adults with established type 2 diabetes (T2D) have been shown to identify those patients with more severe β-cell dysfunction. However, at what stage in the progression toward clinical T2D does islet autoimmunity emerge as an important component influencing β-cell dysfunction? In this ancillary study to the Restoring Insulin SEcretion (RISE) Study, we investigated the prevalence of and association with β-cell dysfunction of T+ and autoantibodies to the 65 kDa glutamic acid decarboxylase antigen (GADA) in obese pre-diabetes adults with impaired glucose tolerance (IGT) and recently diagnosed treatment naïve (Ndx) T2D. We further investigated the effect of 12 months of RISE interventions (metformin or liraglutide plus metformin, or with 3 months of insulin glargine followed by 9 months of metformin or placebo) on islet autoimmune reactivity. We observed GADA(+) in 1.6% of NdxT2D and 4.6% of IGT at baseline, and in 1.6% of NdxT2D and 5.3% of IGT at 12 months, but no significant associations between GADA(+) and β-cell function. T(+) was observed in 50% of NdxT2D and 60.4% of IGT at baseline, and in 68.4% of NdxT2D and 83.9% of IGT at 12 months. T(+) NdxT2D were observed to have significantly higher fasting glucose (p = 0.004), and 2 h glucose (p = 0.0032), but significantly lower steady state C-peptide (sscpep, p = 0.007) compared to T(-) NdxT2D. T(+) IGT participants demonstrated lower but not significant (p = 0.025) acute (first phase) C-peptide response to glucose (ACPRg) compared to T(-) IGT. With metformin treatment, T(+) participants were observed to have a significantly lower Hemoglobin A1c (HbA1c, p = 0.002) and fasting C-peptide (p = 0.002) compared to T(-), whereas T(+) treated with liraglutide + metformin had significantly lower sscpep (p = 0.010) compared to T(-) participants. In the placebo group, T(+) participants demonstrated significantly lower ACPRg (p = 0.001) compared to T(-) participants. In summary, T(+) were found in a large percentage of obese pre-diabetes adults with IGT and in recently diagnosed T2D. Moreover, T(+) were significantly correlated with treatment effects and β-cell dysfunction. Our results demonstrate that T(+) are an important component in T2D.
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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, 2022-01-21) Brooks-Worrell, Barbara; Hampe, Christiane S.; Hattery, Erica G.; Palomino, Brenda; Zangeneh, Sahar Z.; Utzschneider, Kristina; Kahn, Steven E.; Larkin, Mary E.; Johnson, Mary L.; Mather, Kieren J.; Younes, Naji; Rasouli, Neda; Desouza, Cyrus; Cohen, Robert M.; Park, Jean Y.; Florez, Hermes J.; Valencia, Willy Marcos; GRADE β-cell Ancillary Study Network; Shojaie, Ali; Palmer, Jerry P.; Balasubramanyam, Ashok; Medicine, School of Medicine
    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 (GRADE) Study, we investigated the prevalence of cellular and humoral islet autoimmunity in patients with T2D duration 4·0±3·0 y, HbA1c 7·5±0·5% on metformin alone. We measured T cell autoreactivity against islet proteins, islet autoantibodies against GAD65, IA2, ZnT8, 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 iAUC-CG and ΔC-peptide(0- 30)/Δglucose(0-30) from an oral glucose tolerance test was lower among T cell-positives (T+) than T cell-negatives (T-) 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 T2D patients than previously reported. T cell-mediated autoimmunity is associated with diminished β-cell function and worse glycemic control.
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    β-Cell Function and Insulin Sensitivity in Youth With Early Type 1 Diabetes From a 2-Hour 7-Sample OGTT
    (The Endocrine Society, 2023) Galderisi, Alfonso; Evans-Molina, Carmella; Martino, Mariangela; Caprio, Sonia; Cobelli, Claudio; Moran, Antoinette; Pediatrics, School of Medicine
    Context: The oral minimal model is a widely accepted noninvasive tool to quantify both β-cell responsiveness and insulin sensitivity (SI) from glucose, C-peptide, and insulin concentrations during a 3-hour 9-point oral glucose tolerance test (OGTT). Objective: Here, we aimed to validate a 2-hour 7-point protocol against the 3-hour OGTT and to test how variation in early sampling frequency impacts estimates of β-cell responsiveness and SI. Methods: We conducted a secondary analysis on 15 lean youth with stage 1 type 1 diabetes (T1D; ≥ 2 islet autoantibodies with no dysglycemia) who underwent a 3-hour 9-point OGTT. The oral minimal model was used to quantitate β-cell responsiveness (φtotal) and insulin sensitivity (SI), allowing assessment of β-cell function by the disposition index (DI = φtotal × SI). Seven- and 5-point 2-hour OGTT protocols were tested against the 3-hour 9-point gold standard to determine agreement between estimates of φtotal and its dynamic and static components, SI, and DI across different sampling strategies. Results: The 2-hour estimates for the disposition index exhibited a strong correlation with 3-hour measures (r = 0.975; P < .001) with similar results for β-cell responsiveness and SI (r = 0.997 and r = 0.982; P < .001, respectively). The agreement of the 3 estimates between the 7-point 2-hour and 9-point 3-hour protocols fell within the 95% CI on the Bland-Altman grid with a median difference of 16.9% (-35.3 to 32.5), 0.2% (-0.6 to 1.3), and 14.9% (-1.4 to 28.3) for DI, φtotal, and SI. Conversely, the 5-point protocol did not provide reliable estimates of φ dynamic and static components. Conclusion: The 2-hour 7-point OGTT is reliable in individuals with stage 1 T1D for assessment of β-cell responsiveness, SI, and DI. Incorporation of these analyses into current 2-hour diabetes staging and monitoring OGTTs offers the potential to more accurately quantify risk of progression in the early stages of T1D.