TCF7L2 Genetic Variants do not Influence Insulin Sensitivity or Secretion Indices in Autoantibody-positive Individuals at Risk for Type 1 Diabetes

Objective: We aimed to test whether type 2 diabetes (T2D)-associated TCF7L2 genetic variants affect insulin sensitivity or secretion in autoantibody-positive relatives at risk for type 1 diabetes (T1D). Research Design and Methods: We studied autoantibody-positive TrialNet Pathway to Prevention study participants (n=1,061; mean age=16.3 years) with TCF7L2 SNP information and baseline oral glucose tolerance test (OGTT) to calculate indices of insulin sensitivity and secretion. With Bonferroni correction for multiple comparisons, p-values <0.0086 were considered statistically significant. Results: None, one and two T2D-linked TCF7L2 alleles were present, respectively, in 48.1%, 43.9% and 8.0% of the participants. Insulin sensitivity (as reflected by 1/IF) decreased with increasing BMI-Z-score and was lower in Hispanics. Insulin secretion (as measured by 30-min C-peptide index) positively correlated with age and BMI-Z-score. Oral disposition index was negatively correlated with age, BMI-Z-score and Hispanic ethnicity. None of the indices were associated with TCF7L2 SNPs. In multivariate analysis models with age, BMI Z-score, ethnicity, sex and TCF7L2 alleles as independent variables, C-peptide index increased with age, while BMI Z-score was associated with higher insulin secretion (C-peptide index), lower insulin sensitivity (1/IF) and lower disposition index; there was no significant effect of the TCF7L2 SNPs on any of these indices. When restricting the analyses to participants with normal OGTT (n=743, 70%), the results were similar. Conclusions: In non-diabetic autoantibody-positive individuals, TCF7L2 SNPs were not related to insulin sensitivity or secretion indices after accounting for BMI-Z-score, age, sex and ethnicity.

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110-OR: Type 2 Diabetes (T2D)–Associated TCF7L2 Genetic Variants and Indices of Insulin Secretion and Sensitivity in Individuals at Risk for Type 1 Diabetes (T1D)

Diabetes ◽

10.2337/db20-110-or ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 110-OR

Author(s):

MARIA J. REDONDO ◽

MEGAN V. WARNOCK ◽

LAURA E. BOCCHINO ◽

SUSAN GEYER ◽

ALBERTO PUGLIESE ◽

...

Keyword(s):

Type 2 Diabetes ◽

At Risk ◽

Type 1 Diabetes ◽

Insulin Secretion ◽

Genetic Variants

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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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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 ◽

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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TCF7L2 Genetic Variants Do Not Influence Insulin Sensitivity or Secretion Indices in Autoantibody-Positive Individuals at Risk for Type 1 Diabetes

Diabetes Care ◽

10.2337/dc21-0531 ◽

2021 ◽

pp. dc210531

Author(s):

Maria J. Redondo ◽

Megan V. Warnock ◽

Ingrid M. Libman ◽

Laura E. Bocchino ◽

David Cuthbertson ◽

...

Keyword(s):

At Risk ◽

Type 1 Diabetes ◽

Insulin Sensitivity ◽

Genetic Variants

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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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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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The Effect of Ethnicity in the Rate of Beta-Cell Functional Loss in the First 3 Years After Type 1 Diabetes Diagnosis

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa348 ◽

2020 ◽

Vol 105 (12) ◽

pp. e4393-e4406 ◽

Cited By ~ 1

Author(s):

Mustafa Tosur ◽

Mario A Cleves ◽

Jay M Sosenko ◽

Ingrid Libman ◽

David A Baidal ◽

...

Keyword(s):

Type 1 Diabetes ◽

Beta Cell ◽

Clinical Diagnosis ◽

Area Under The Curve ◽

Diabetes Diagnosis ◽

Z Score ◽

C Peptide ◽

Functional Loss ◽

Intervention Trials

Abstract Objective We set forth to compare ethnicities for metabolic and immunological characteristics at the clinical diagnosis of type 1 diabetes (T1D) and assess the effect of ethnicity on beta-cell functional loss within 3 years after clinical diagnosis. Research Methods and Design We studied participants in TrialNet New Onset Intervention Trials (n = 624, median age = 14.4 years, 58% male, 8.7% Hispanic) and followed them prospectively for 3 years. Mixed meal tolerance tests (MMTT) were performed within 6 months following clinical diagnosis and repeated semiannually. Unless otherwise indicated, analyses were adjusted for age, sex, BMI Z-score, and diabetes duration. Results At T1D clinical diagnosis, Hispanics, compared with non-Hispanic whites (NHW), had a higher frequency of diabetic ketoacidosis (DKA) (44.7% vs 25.3%, OR = 2.36, P = 0.01), lower fasting glucose (97 vs 109 mg/dL, P = 0.02) and higher fasting C-peptide (1.23 vs 0.94 ng/mL, P = 0.02) on the first MMTT, and higher frequency of ZnT8 autoantibody positivity (n = 201, 94.1% vs 64%, OR = 7.98, P = 0.05). After exclusion of participants in experimental arms of positive clinical trials, C-peptide area under the curve (AUC) trajectories during the first 3 years after clinical diagnosis were not significantly different between Hispanics and NHW after adjusting for age, sex, BMI-z score, and DKA (n = 413, P = 0.14). Conclusion Despite differences in the metabolic and immunological characteristics at clinical diagnosis of T1D between Hispanics and NHW, C-peptide trajectories did not differ significantly in the first 3 years following clinical diagnosis after adjustment for body mass index and other confounders. These findings may inform the design of observational studies and intervention trials in T1D.

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Insulin-Like Growth Factor-1 at Diagnosis and during Subsequent Years in Adolescents with Type 1 Diabetes

Journal of Diabetes Research ◽

10.1155/2018/8623560 ◽

2018 ◽

Vol 2018 ◽

pp. 1-6 ◽

Cited By ~ 4

Author(s):

Simona I. Chisalita ◽

J. Ludvigsson

Keyword(s):

Type 1 Diabetes ◽

Insulin Secretion ◽

Insulin Treatment ◽

Insulin Dose ◽

Newly Diagnosed ◽

Blood Samples ◽

C Peptide ◽

Endogenous Insulin ◽

High Hba1c

Background. Type 1 diabetes (T1D) in adolescents is associated with alterations in the insulin-like factor system probably caused both by a deranged metabolism and insulinopenia in the portal vein. Objective. To study how the circulating IGF-1 is affected at diagnosis and during subsequent years in adolescents with T1D. Methods. Ten girls and ten boys with type 1 diabetes (T1D), aged 13.0 ± 1.4 (mean ± SD) years at diagnosis, took part in the study. Blood samples were drawn at diagnosis and after 3, 9, 18, and 48 months. HbA1c, total IGF-1, and C-peptide were measured. Results. At diagnosis, the patients had high HbA1c, low IGF-1, and measurable C-peptide. After the start of insulin treatment, maximal improvement in glycemic control and IGF-1 occurred within 3 months and then both tended to deteriorate, that is, HbA1c to increase and IGF-1 to decrease. C-peptide decreased with time, and after 4 years, half of the patients were C-peptide negative. At diagnosis, C-peptide correlated positively to IGF-1 (r=0.50; p<0.03). C-peptide correlated negatively with insulin dose (U/kg) after 18 and 48 months from diagnosis (r=−0.48; p<0.03 and r=−0.72; p<0.001, resp.). Conclusions. In conclusion, our results show that in newly diagnosed adolescents with type 1 diabetes and deranged metabolism, the IGF-1 level is low and rapidly improves with insulin treatment but later tends to decrease concomitantly with declining endogenous insulin secretion.

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Type 1 diabetes can present before the age of 6 months and is characterised by autoimmunity and rapid loss of beta cells

Diabetologia ◽

10.1007/s00125-020-05276-4 ◽

2020 ◽

Vol 63 (12) ◽

pp. 2605-2615 ◽

Cited By ~ 1

Author(s):

Matthew B. Johnson ◽

◽

Kashyap A. Patel ◽

Elisa De Franco ◽

William Hagopian ◽

...

Keyword(s):

Type 1 Diabetes ◽

Insulin Secretion ◽

Genetic Risk ◽

Early Onset ◽

Genetic Risk Score ◽

Neonatal Diabetes ◽

Pathogenic Variant ◽

Rapid Loss ◽

C Peptide

Abstract Aims/hypothesis Diabetes diagnosed at <6 months of age is usually monogenic. However, 10–15% of affected infants do not have a pathogenic variant in one of the 26 known neonatal diabetes genes. We characterised infants diagnosed at <6 months of age without a pathogenic variant to assess whether polygenic type 1 diabetes could arise at early ages. Methods We studied 166 infants diagnosed with type 1 diabetes at <6 months of age in whom pathogenic variants in all 26 known genes had been excluded and compared them with infants with monogenic neonatal diabetes (n = 164) or children with type 1 diabetes diagnosed at 6–24 months of age (n = 152). We assessed the type 1 diabetes genetic risk score (T1D-GRS), islet autoantibodies, C-peptide and clinical features. Results We found an excess of infants with high T1D-GRS: 38% (63/166) had a T1D-GRS >95th centile of healthy individuals, whereas 5% (8/166) would be expected if all were monogenic (p < 0.0001). Individuals with a high T1D-GRS had a similar rate of autoantibody positivity to that seen in individuals with type 1 diabetes diagnosed at 6–24 months of age (41% vs 58%, p = 0.2), and had markedly reduced C-peptide levels (median <3 pmol/l within 1 year of diagnosis), reflecting rapid loss of insulin secretion. These individuals also had reduced birthweights (median z score −0.89), which were lowest in those diagnosed with type 1 diabetes at <3 months of age (median z score −1.98). Conclusions/interpretation We provide strong evidence that type 1 diabetes can present before the age of 6 months based on individuals with this extremely early-onset diabetes subtype having the classic features of childhood type 1 diabetes: high genetic risk, autoimmunity and rapid beta cell loss. The early-onset association with reduced birthweight raises the possibility that for some individuals there was reduced insulin secretion in utero. Comprehensive genetic testing for all neonatal diabetes genes remains essential for all individuals diagnosed with diabetes at <6 months of age.

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