scholarly journals Genetic Composition and Autoantibody Titers Model the Probability of Detecting C-Peptide Following Type 1 Diabetes Diagnosis

2021 ◽  
Author(s):  
MacKenzie D. Williams ◽  
Rhonda Bacher ◽  
Daniel J. Perry ◽  
C. Ramsey Grace ◽  
Kieran M. McGrail ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Disease Duration ◽  
Cell Function ◽  
Age At Onset ◽  
Diabetes Diagnosis ◽  
Β Cell ◽  
C Peptide ◽  
Peptide Detection ◽  
Β Cell Function

We and others previously demonstrated that a type 1 diabetes genetic risk score (GRS) improves the ability to predict disease progression and onset in at-risk subjects with islet autoantibodies. Here, we hypothesized that GRS and islet autoantibodies, combined with age at onset and disease duration, could serve as markers of residual β-cell function following type 1 diabetes diagnosis. Generalized estimating equations were used to investigate whether GRS along with insulinoma-associated protein-2 autoantibody (IA-2A), zinc transporter 8 autoantibody (ZnT8A) and GAD autoantibody (GADA) titers were predictive of C-peptide detection in a largely cross-sectional cohort of 401 subjects with type 1 diabetes (duration median = 4.5 years, range 0-60). Indeed, a combined model incorporating disease duration, age at onset, GRS, and titers of IA-2A, ZnT8A and GADA provided superior capacity to predict C-peptide detection (QIC=334.6) compared with disease duration, age at onset, and GRS as the sole parameters (QIC=359.2). These findings support the need for longitudinal validation of our combinatorial model. The ability to project the rate and extent of decline in residual C-peptide production for individuals with type 1 diabetes could critically inform enrollment and benchmarking for clinical trials seeking to preserve or restore endogenous β-cell function.

scholarly journals Genetic Composition and Autoantibody Titers Model the Probability of Detecting C-Peptide Following Type 1 Diabetes Diagnosis

2021 ◽  
Author(s):  
MacKenzie D. Williams ◽  
Rhonda Bacher ◽  
Daniel J. Perry ◽  
C. Ramsey Grace ◽  
Kieran M. McGrail ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Disease Duration ◽  
Cell Function ◽  
Age At Onset ◽  
Diabetes Diagnosis ◽  
Β Cell ◽  
C Peptide ◽  
Peptide Detection ◽  
Β Cell Function

We and others previously demonstrated that a type 1 diabetes genetic risk score (GRS) improves the ability to predict disease progression and onset in at-risk subjects with islet autoantibodies. Here, we hypothesized that GRS and islet autoantibodies, combined with age at onset and disease duration, could serve as markers of residual β-cell function following type 1 diabetes diagnosis. Generalized estimating equations were used to investigate whether GRS along with insulinoma-associated protein-2 autoantibody (IA-2A), zinc transporter 8 autoantibody (ZnT8A) and GAD autoantibody (GADA) titers were predictive of C-peptide detection in a largely cross-sectional cohort of 401 subjects with type 1 diabetes (duration median = 4.5 years, range 0-60). Indeed, a combined model incorporating disease duration, age at onset, GRS, and titers of IA-2A, ZnT8A and GADA provided superior capacity to predict C-peptide detection (QIC=334.6) compared with disease duration, age at onset, and GRS as the sole parameters (QIC=359.2). These findings support the need for longitudinal validation of our combinatorial model. The ability to project the rate and extent of decline in residual C-peptide production for individuals with type 1 diabetes could critically inform enrollment and benchmarking for clinical trials seeking to preserve or restore endogenous β-cell function.

scholarly journals Systemic TNFα correlates with residual β-cell function in children and adolescents newly diagnosed with type 1 diabetes

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Anne Julie Overgaard ◽  
Jens Otto Broby Madsen ◽  
Flemming Pociot ◽  
Jesper Johannesen ◽  
Joachim Størling
Keyword(s):  
Type 1 Diabetes ◽  
Cell Function ◽  
Disease Onset ◽  
Newly Diagnosed ◽  
Β Cell ◽  
Entire Study ◽  
C Peptide ◽  
Disease Remission ◽  
Β Cell Function

Abstract Background Type 1 diabetes (T1D) is caused by immune-mediated destruction of the β-cells. After initiation of insulin therapy many patients experience a period of improved residual β-cell function leading to partial disease remission. Cytokines are important immune-modulatory molecules and contribute to β-cell damage in T1D. The patterns of systemic circulating cytokines during T1D remission are not clear but may constitute biomarkers of disease status and progression. In this study, we investigated if the plasma levels of various pro- and anti-inflammatory cytokines around time of diagnosis were predictors of remission and residual β-cell function in children with T1D followed for one year after disease onset. Methods In a cohort of 63 newly diagnosed children (33% females) with T1D with a mean age of 11.3 years (3.3–17.7), ten cytokines were measured of which eight were detectable in plasma samples by Mesoscale Discovery multiplex technology at study start and after 6 and 12 months. Linear regression models were used to evaluate association of cytokines with stimulated C-peptide. Results Systemic levels of tumor necrosis factor (TNF)-α, interleukin (IL)-2 and IL-6 inversely correlated with stimulated C-peptide levels over the entire study (P < 0.05). The concentrations of TNFα and IL-10 at study start predicted stimulated C-peptide level at 6 months (P = 0.011 and P = 0.043, respectively, adjusted for sex, age, HbA1c and stage of puberty). Conclusions In recent-onset T1D, systemic cytokine levels, and in particular that of TNFα, correlate with residual β-cell function and may serve as prognostic biomarkers of disease remission and progression to optimize treatment strategies. Trial Registration The study was performed according to the criteria of the Helsinki II Declaration and was approved by the Danish Capital Region Ethics Committee on Biomedical Research Ethics (journal number H-3-2014-052). The parents of all participants gave written consent.

scholarly journals The Pathological Evolution of Glucose Response Curves During the Progression to Type 1 Diabetes in the TrialNet Pathway to Prevention Study

2020 ◽  
Author(s):  
Heba M. Ismail ◽  
Mario A. Cleves ◽  
Ping Xu ◽  
Ingrid M. Libman ◽  
Dorothy J. Becker ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Cell Function ◽  
Prevention Study ◽  
Β Cell ◽  
Response Curves ◽  
Glucose Response ◽  
Continuous Increase ◽  
C Peptide ◽  
Β Cell Function

<b>Objective: </b>Glucose response curves (GRCs) during oral glucose tolerance tests (OGTTs) are predictive of type 1 diabetes. We performed a longitudinal analysis in pancreatic autoantibody positive (Ab+) individuals to assess: 1) characteristic GRC changes during progression to type 1 diabetes, and 2) GRC changes in relation to β-cell function changes and to combined glucose and C-peptide response curve (GCRC) changes. <b>Research Design and Methods:</b> Among Ab+ individuals with serial OGTTs in the TrialNet Pathway to Prevention study, GRC changes from first to last OGTTs were compared between progressors (n=298) to type 1 diabetes and non-progressors (n=2216). GRC changes from last before diagnosis to diagnostic OGTTs were studied in progressors. <b>Results:</b> GRCs changed more frequently from Biphasic (2 peaks) to Monophasic (1 peak) GRCs between first and last OGTTs in progressors than in non-progressors [75.4% vs. 51.0%; p<0.001]. In contrast, progressors changed less frequently from Monophasic to Biphasic than non-progressors [12.6% vs. 30.6%; p <0.001]. Monotonic (continuous increase) GRCs were present in 47.7% of progressors at diagnosis. The early (30-0 min) C-peptide response decreased in progressors changing from Biphasic to Monophasic between first and last OGTTs (p<0.001) and from Monophasic to Monotonic between last and diagnostic OGTTs (p<0.001). Conversely, the early C-peptide response increased among non-progressors changing from Monophasic to Biphasic (p<0.001). Changes in GRCs were related to changes in GCRCs. <b>Conclusions:</b> Characteristic GRC changes, Biphasic to Monophasic to Monotonic, occur during the progression to type 1 diabetes. These GRC changes correspond to decreasing β-cell function.

scholarly journals Residual β-Cell Function More than Glycemic Control Determines Abnormalities of the Insulin-Like Growth Factor System in Type 1 Diabetes

2004 ◽  
Vol 89 (12) ◽  
pp. 6305-6309 ◽  
Author(s):  
Christina A. Hedman ◽  
Jan Frystyk ◽  
Torbjörn Lindström ◽  
Jian-Wen Chen ◽  
Allan Flyvbjerg ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Glycemic Control ◽  
Cell Function ◽  
Β Cell ◽  
Good Glycemic Control ◽  
C Peptide ◽  
Igf I ◽  
Β Cell Function ◽  
Igfbp 3

Abstract The GH-IGF-I axis is disturbed in patients with type 1 diabetes. Our aim was to investigate whether abnormalities are found in patients in very good glycemic control and, if so, to estimate the role of residual β-cell function. Patients with hemoglobin A1c (HbA1c) less than 6% (reference range, 3.6–5.4%) were selected for the study. Twenty-two men and 24 women, aged 41.3 ± 13.8 yr (mean ± sd), with a diabetes duration of 17.8 ± 14.6 yr participated. Healthy controls (15 women and nine men), aged 41.3 ± 13.0 yr, were also studied. Overnight fasting serum samples were analyzed for HbA1c, C peptide, free and total IGFs, IGF-binding proteins (IGFBPs), GH-binding protein, and IGFBP-3 proteolysis. HbA1c was 5.6 ± 0.5% in patients and 4.4 ± 0.3% in controls. Total IGF-I was 148 ± 7 μg/liter in patients and 178 ± 9 μg/liter in controls (P &lt; 0.001). Free IGF-I, total IGF-II, IGFBP-3, and GH-binding protein were lower, whereas IGFBP-1, IGFBP-1-bound IGF-I, and IGFBP-2 were elevated compared with control values. Patients with detectable C peptide (≥100 pmol/liter) had higher levels of total IGF-I, free IGF-I, and total IGF-II and lower levels of IGFBP-1 and IGFBP-2 than those with an undetectable C peptide level despite having identical average HbA1c. IGFBP-3 proteolysis did not differ between patients and controls. Despite very good glycemic control, patients with type 1 diabetes and no endogenous insulin production have low free and total IGF-I. Residual β-cell function, therefore, seems more important for the disturbances in the IGF system than good metabolic control per se, suggesting that portal insulin delivery is needed to normalize the IGF system.

scholarly journals Effects of delayed gastric emptying on postprandial glucose kinetics, insulin sensitivity, and β-cell function

2014 ◽  
Vol 307 (6) ◽  
pp. E494-E502 ◽  
Author(s):  
Ling Hinshaw ◽  
Michele Schiavon ◽  
Ashwini Mallad ◽  
Chiara Dalla Man ◽  
Rita Basu ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Gastric Emptying ◽  
Insulin Sensitivity ◽  
Delayed Gastric Emptying ◽  
Cell Function ◽  
Postprandial Glucose ◽  
Β Cell ◽  
C Peptide ◽  
Β Cell Function

Controlling meal-related glucose excursions continues to be a therapeutic challenge in diabetes mellitus. Mechanistic reasons for this need to be understood better to develop appropriate therapies. To investigate delayed gastric emptying effects on postprandial glucose turnover, insulin sensitivity, and β-cell responsivity and function, as a feasibility study prior to studying patients with type 1 diabetes, we used the triple tracer technique C-peptide and oral minimal model approach in healthy subjects. A single dose of 30 μg of pramlintide administered at the start of a mixed meal was used to delay gastric emptying rates. With delayed gastric emptying rates, peak rate of meal glucose appearance was delayed, and rate of endogenous glucose production (EGP) was lower. C-peptide and oral minimal models enabled the assessments of β-cell function, insulin sensitivity, and β-cell responsivity simultaneously. Delayed gastric emptying induced by pramlintide improved total insulin sensitivity and decreased total β-cell responsivity. However, β-cell function as measured by total disposition index did not change. The improved whole body insulin sensitivity coupled with lower rate of appearance of EGP with delayed gastric emptying provides experimental proof of the importance of evaluating pramlintide in artificial endocrine pancreas approaches to reduce postprandial blood glucose variability in patients with type 1 diabetes.

scholarly journals Effects of incretin-based therapies on β-cell function in type 1 diabetes mellitus: a systematic review and meta-analysis

2021 ◽  
Vol 49 (12) ◽  
pp. 030006052110663
Author(s):  
Yucheng Wu ◽  
Yu Lu ◽  
Shufang Yang ◽  
Qingqing Zhang
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Plasma Glucose ◽  
Fasting Plasma Glucose ◽  
Cell Function ◽  
Meta Analysis ◽  
Β Cell ◽  
C Peptide ◽  
Β Cell Function

Aim To assess the effects of incretin-based therapies on β-cell function in patients with type 1 diabetes mellitus (T1DM). Methods We searched the PubMed, Cochrane Library, Embase, and Web of Knowledge databases for eligible randomized clinical trials published up to July 2021. The inclusion criteria were patients with T1DM or latent autoimmune diabetes in adults, patients treated with dipeptidyl peptidase-4 inhibitors or glucagon like peptide-1 receptor agonists, and outcomes included one of the following: fasting plasma glucose, fasting C-peptide, postprandial C-peptide, C-peptide area under the curve (AUC), homeostasis model assessment for β cell function, and insulin resistance. The effects were analyzed using a random effect model with STATA 11.0. Results Eight trials including 427 participants were included in the final analysis. A pooled analysis found no significant difference in fasting plasma glucose, fasting C-peptide, postprandial C-peptide, or C-peptide AUC between patients treated with incretin-based therapies and placebo. The two trials that reported changes in 2-hour postprandial C-peptide and two of the four trials that reported changes in C-peptide AUC reported increases after incretin-based therapies. Conclusion This meta-analysis showed that incretin-based therapies did not preserve β-cell function in patients with T1DM.

scholarly journals Stimulated urine C-peptide creatinine ratio vs serum C-peptide level for monitoring of β-cell function in the first year after diagnosis of Type 1 diabetes

2016 ◽  
Vol 33 (11) ◽  
pp. 1564-1568 ◽  
Author(s):  
D. Tatovic ◽  
S. Luzio ◽  
G. Dunseath ◽  
Y. Liu ◽  
M. Alhadj Ali ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Cell Function ◽  
First Year ◽  
Creatinine Ratio ◽  
Β Cell ◽  
C Peptide ◽  
Peptide Level ◽  
Β Cell Function

scholarly journals Residual β-Cell Function and the Insulin-Like Growth Factor System in Danish Children and Adolescents With Type 1 Diabetes

2015 ◽  
Vol 100 (3) ◽  
pp. 1053-1061 ◽  
Author(s):  
Jesper S. Sorensen ◽  
Niels H. Birkebaek ◽  
Mette Bjerre ◽  
Flemming Pociot ◽  
Kurt Kristensen ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Cell Function ◽  
Β Cell ◽  
Cross Sectional ◽  
Prepubertal Children ◽  
C Peptide ◽  
Pubertal Status ◽  
Igf System ◽  
Β Cell Function

Context: C-peptide-positive adults with type 1 diabetes (T1D) have higher circulating total and free IGF-1 and lower IGF binding protein 1 (IGFBP-1) than C-peptide-negative patients. Whether this is also the case in children remains unknown. Objective: The objective of the study was to examine the IGF system in children/adolescents with and without residual β-cell function (RBF). Design and Patients: This was a cross-sectional study containing 136 prepubertal (hereof 15 RBF positive) and 206 pubertal (hereof 42 RBF positive) children/adolescents with T1D for 3–6 years as well as 40 prepubertal and 30 pubertal healthy controls. RBF was evaluated by meal-stimulated C-peptide. Main Outcome Measures: Fasting serum levels of bioactive IGF (ie, the ability of serum to activate the IGF-1 receptor in vitro), total IGF-1, total IGF-2, and IGFBP-1 and -3. Results: Irrespective of pubertal status, patients with T1D showed lower bioactive IGF and total IGF-1, but higher IGFBP-1 as compared with controls (P &lt; .05). When stratified according to RBF status, a positive RBF was associated with normalization of all IGF-related peptides but IGFBP-1 in prepubertal children (P &lt; .05), whereas none of the IGF components were normalized in prepubertal, RBF-negative children. In pubertal children, total IGF-1 and bioactive IGF remained subnormal and IGFBP-1 supranormal, irrespective of RBF status (P &lt; .05). Conclusion: Independent of pubertal status, T1D was associated with an abnormal IGF system. However, a positive RBF status appeared important but only in prepubertal children, in whom all IGF components but IGFBP-1 were normalized. We speculate that the pubertal GH surge induces insulin resistance, which overrides the stimulatory effect that an RBF may exert on the liver-derived IGF system.

scholarly journals The Pathological Evolution of Glucose Response Curves During the Progression to Type 1 Diabetes in the TrialNet Pathway to Prevention Study

2020 ◽  
Author(s):  
Heba M. Ismail ◽  
Mario A. Cleves ◽  
Ping Xu ◽  
Ingrid M. Libman ◽  
Dorothy J. Becker ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Cell Function ◽  
Prevention Study ◽  
Β Cell ◽  
Response Curves ◽  
Glucose Response ◽  
Continuous Increase ◽  
C Peptide ◽  
Β Cell Function

<b>Objective: </b>Glucose response curves (GRCs) during oral glucose tolerance tests (OGTTs) are predictive of type 1 diabetes. We performed a longitudinal analysis in pancreatic autoantibody positive (Ab+) individuals to assess: 1) characteristic GRC changes during progression to type 1 diabetes, and 2) GRC changes in relation to β-cell function changes and to combined glucose and C-peptide response curve (GCRC) changes. <b>Research Design and Methods:</b> Among Ab+ individuals with serial OGTTs in the TrialNet Pathway to Prevention study, GRC changes from first to last OGTTs were compared between progressors (n=298) to type 1 diabetes and non-progressors (n=2216). GRC changes from last before diagnosis to diagnostic OGTTs were studied in progressors. <b>Results:</b> GRCs changed more frequently from Biphasic (2 peaks) to Monophasic (1 peak) GRCs between first and last OGTTs in progressors than in non-progressors [75.4% vs. 51.0%; p<0.001]. In contrast, progressors changed less frequently from Monophasic to Biphasic than non-progressors [12.6% vs. 30.6%; p <0.001]. Monotonic (continuous increase) GRCs were present in 47.7% of progressors at diagnosis. The early (30-0 min) C-peptide response decreased in progressors changing from Biphasic to Monophasic between first and last OGTTs (p<0.001) and from Monophasic to Monotonic between last and diagnostic OGTTs (p<0.001). Conversely, the early C-peptide response increased among non-progressors changing from Monophasic to Biphasic (p<0.001). Changes in GRCs were related to changes in GCRCs. <b>Conclusions:</b> Characteristic GRC changes, Biphasic to Monophasic to Monotonic, occur during the progression to type 1 diabetes. These GRC changes correspond to decreasing β-cell function.

scholarly journals BMI is an important driver of β-cell loss in type 1 diabetes upon diagnosis in 10 to 18-year-old children

2015 ◽  
Vol 172 (2) ◽  
pp. 107-113 ◽  
Author(s):  
A Lauria ◽  
A Barker ◽  
N Schloot ◽  
N Hosszufalusi ◽  
J Ludvigsson ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Body Weight ◽  
Cell Function ◽  
Independent Predictor ◽  
Insulin Dose ◽  
Cell Loss ◽  
Β Cell ◽  
C Peptide ◽  
Β Cell Function

ObjectiveBody weight-related insulin resistance probably plays a role in progression to type 1 diabetes, but has an uncertain impact following diagnosis. In this study, we investigated whether BMI measured at diagnosis was an independent predictor of C-peptide decline 1-year post-diagnosis.DesignMulticentre longitudinal study carried out at diagnosis and up to 1-year follow-up.MethodsData on C-peptide were collected from seven diabetes centres in Europe. Patients were grouped according to age at diagnosis (<5 years, n=126; >5 years <10 years, n=295; >10 years <18 years, n=421; >18 years, n=410). Linear regression was used to investigate whether BMI was an independent predictor of change in fasting C-peptide over 1 year. Models were additionally adjusted for baseline insulin dose and HbA1c.ResultsIn individuals diagnosed between 0 and 5 years, 5 and 10 years and those diagnosed >18 years, we found no association between BMI and C-peptide decline. In patients aged 10–18 years, higher BMI at baseline was associated with a greater decline in fasting C-peptide over 1 year with a decrease (β 95% CI; P value) of 0.025 (0.010, 0.041) nM/kg per m2 higher baseline BMI (P=0.001). This association remained significant after adjusting for gender and differences in HbA1c and insulin dose (β=0.026, 95% CI=0.0097, 0.042; P=0.002).ConclusionsThese observations indicate that increased body weight and increased insulin demand are associated with more rapid disease progression after diagnosis of type 1 diabetes in an age group 10–18 years. This should be considered in studies of β-cell function in type 1 diabetes.

Sign in / Sign up

Export Citation Format

Share Document