The Deterrence of Rapid Metabolic Decline within 3 Months after Teplizumab Treatment in Individuals at High Risk for Type 1 Diabetes

10.2337/figshare.16640455.v1 ◽

2021 ◽

Author(s):

Emily K. Sims ◽

David Cuthbertson ◽

Kevan C. Herold ◽

Jay M. Sosenko

Keyword(s):

Type 1 Diabetes ◽

High Risk ◽

Oral Glucose ◽

Response Curves ◽

C Peptide ◽

Cell Decline ◽

Glucose Tolerance Tests ◽

Prevention Trials ◽

Mean Glucose

Endpoints that provide an early identification of treatment effects are needed to implement type 1 diabetes prevention trials more efficiently. To this end, we assessed whether metabolic endpoints can be used to detect a teplizumab effect on rapid β-cell decline within 3 months after treatment in high-risk individuals in the TrialNet teplizumab trial. Glucose and C-peptide response curves (GCRCs) were constructed by plotting mean glucose and C-peptide values from 2-hour oral glucose tolerance tests on a 2-dimensional grid. Groups were compared visually for changes in GCRC shape and movement. GCRC changes reflected marked metabolic deterioration in the placebo group within 3 months of randomization. By 6 months, GCRCs resembled typical GCRCs at diagnosis. In contrast, GCRC changes in the teplizumab group suggested metabolic improvement. Quantitative comparisons, including two novel metabolic endpoints that indicate GCRC changes, the Within Quadrant Endpoint (WQE) and the Ordinal Directional Endpoint (ODE), were consistent with visual impressions of an appreciable treatment effect at 3 and 6-month timepoints. In conclusion, an analytic approach combining visual evidence with novel endpoints, demonstrated that Teplizumab delays rapid metabolic decline, and improves the metabolic state within 3 months after treatment; this effect extends for at least 6 months.

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Time-to-Peak C-Peptide and Peak Glucose during an Oral Glucose Tolerance Test (OGTT) Are Independent Risk Factors for Type 1 Diabetes (T1D) in Antibody-Positive (Ab+) Individuals

Diabetes ◽

10.2337/db18-1688-p ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 1688-P

Author(s):

HEBA M. ISMAIL ◽

PING XU ◽

CARMELLA EVANS-MOLINA ◽

JERRY P. PALMER ◽

JAY SOSENKO

Keyword(s):

Risk Factors ◽

Type 1 Diabetes ◽

Glucose Tolerance Test ◽

Tolerance Test ◽

Oral Glucose ◽

Oral Glucose Tolerance ◽

C Peptide ◽

Time To Peak ◽

Independent Risk Factors

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Time to Peak Glucose and Peak C-Peptide During the Progression to Type 1 Diabetes in the Diabetes Prevention Trial and TrialNet Cohorts

10.2337/figshare.14974563.v2 ◽

2021 ◽

Author(s):

Michael G Voss ◽

David D Cuthbertson ◽

Mario M Cleves ◽

Ping Xu ◽

Carmella Evans-Molina ◽

...

Keyword(s):

Type 1 Diabetes ◽

Diabetes Prevention ◽

Prevention Trial ◽

Oral Glucose ◽

Z Score ◽

C Peptide ◽

Time To Peak ◽

Diabetes Progression ◽

Diabetes Development

Objective: To assess the progression of type 1 diabetes using time to peak glucose or C-peptide during oral glucose tolerance tests (OGTTs) in autoantibody positive (Ab+) relatives of people with type 1 diabetes. Methods: We examined 2-hour OGTTs of participants in the Diabetes Prevention Trial Type 1 (DPT-1) and TrialNet Pathway to Prevention (PTP) studies. We included 706 DPT-1 participants (Mean±SD age: 13.84±9.53 years; BMI-Z-Score: 0.33±1.07; 56.1% male) and 3,720 PTP participants (age: 16.01±12.33 Years, BMI-Z-Score 0.66±1.3; 49.7% male). Log-rank testing and Cox regression analyses with adjustments (age, sex, race, BMI Z-Score, HOMA-IR and peak Glucose/C-peptide levels, respectively) were performed. Results: In each of DPT-1 and PTP, higher 5-year diabetes progression risk was seen in those with time to peak glucose >30 min and time to peak C-peptide >60 min (p<0.001 for all groups), before and after adjustments. In models examining strength of association with diabetes development, associations were greater for time to peak C-peptide versus peak C-peptide value (DPT-1: X2 = 25.76 vs. X2 = 8.62 and PTP: X2 = 149.19 vs. X2 = 79.98; all p<0.001). Changes in the percentage of individuals with delayed glucose and/or C-peptide peaks were noted over time. Conclusions: In two independent at risk populations, we show that those with delayed OGTT peak times for glucose or C-peptide are at higher risk of diabetes development within 5 years, independent of peak levels. Moreover, time to peak C-peptide appears more predictive than the peak level, suggesting its potential use as a specific biomarker for diabetes progression.

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Exocrine pancreas function is impaired in adult relatives of patients with type 1 diabetes

Acta Diabetologica ◽

10.1007/s00592-021-01819-2 ◽

2021 ◽

Author(s):

Anna Giovenzana ◽

Federica Vecchio ◽

Federica Cugnata ◽

Alessandro Nonis ◽

Alessandra Mandelli ◽

...

Keyword(s):

At Risk ◽

Type 1 Diabetes ◽

High Risk ◽

Exocrine Pancreas ◽

Pancreatic Enzyme ◽

Low Risk ◽

C Peptide ◽

Hla Genotypes ◽

Pancreas Function

Abstract Aims Alterations of the exocrine pancreas have been reported in type 1 diabetes, but their contribution to the pathogenesis of the disease is poorly understood. Here, we investigated markers of exocrine pancreas dysfunction in individuals at-risk of developing type 1 diabetes. Methods Serum P-amylase and lipase levels were assessed in samples obtained from healthy controls, patients with new onset type 1 diabetes, relatives participating to the TrialNet Pathway to Prevention who were, at blood collection, autoantibody negative or positive for a single autoantibody (low-risk individuals), and positive for multiple autoantibodies (high-risk individuals). Linear mixed models were adopted to estimate variation of pancreatic enzymes among the groups and to evaluate the influence of high-risk HLA genotypes and residual beta cell function on exocrine pancreas function. Results In adults, but not children, reduced levels of P-amylase and lipase were shown in at-risk individuals, including (for P-amylase levels only) those at low-risk, and in T1Dnew. Furthermore, while high-risk HLA genotypes negatively affected P-amylase levels in autoantibody negative adult individuals, fasting C-peptide levels did not correlate with pancreatic enzyme levels. Conclusions Exocrine pancreas dysfunction precedes the onset of type 1 diabetes in adult at-risk individuals and may be unrelated to fasting C-peptide levels.

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Associations of HbA1c with the timing of C‐peptide responses during the oral glucose tolerance test at the diagnosis of type 1 diabetes

Pediatric Diabetes ◽

10.1111/pedi.12845 ◽

2019 ◽

Vol 20 (4) ◽

pp. 408-413

Author(s):

Heba M. Ismail ◽

Carmella Evans‐Molina ◽

Linda A. DiMeglio ◽

Dorothy J. Becker ◽

Ingrid Libman ◽

...

Keyword(s):

Type 1 Diabetes ◽

Glucose Tolerance ◽

Oral Glucose Tolerance Test ◽

Glucose Tolerance Test ◽

Tolerance Test ◽

Oral Glucose ◽

Oral Glucose Tolerance ◽

C Peptide

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

10.2337/figshare.12753662.v2 ◽

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

Objective: 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. Research Design and Methods: 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. Results: 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. Conclusions: 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.

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