1917-P: Alpha-Cell Function in Patients with Type 1 Diabetes Is Compromised with Different Levels of Residual C-Peptide

Multiple islet autoantibodies (AAb) predict type 1 diabetes (T1D) and hyperglycemia within 10 years. By contrast, T1D develops in just ~15% of single AAb+ (generally against glutamic acid decarboxylase, GADA+) individuals; hence the single GADA+ state may represent an early stage of T1D amenable to interventions. Here, we functionally, histologically, and molecularly phenotype human islets from non-diabetic, GADA+ and T1D donors. Similar to the few remaining beta cells in T1D islets, GADA+ donor islets demonstrated a preserved insulin secretory response. By contrast, alpha cell glucagon secretion was dysregulated in both T1D and GADA+ islets with impaired glucose suppression of glucagon secretion. Single cell RNA sequencing (scRNASeq) of GADA+ alpha cells revealed distinct abnormalities in glycolysis and oxidative phosphorylation pathways and a marked downregulation of PKIB, providing a molecular basis for the loss of glucose suppression and the increased effect of IBMX observed in GADA+ donor islets. The striking observation of a distinct early defect in alpha cell function that precedes beta cell loss in T1D suggests that not only overt disease, but also the progression to T1D itself, is bihormonal in nature.

Download Full-text

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

BMC Pediatrics ◽

10.1186/s12887-020-02339-8 ◽

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.

Download Full-text

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

10.2337/figshare.13516808.v1 ◽

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.

Download Full-text

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.

Download Full-text

Assessment of preservation of beta-cell function in children with long-standing type 1 diabetes with „ultrasensitive c-peptide” method

Pediatric Endocrinology Diabetes and Metabolism ◽

10.18544/pedm-23.03.0084 ◽

2017 ◽

Vol 23 (3) ◽

pp. 130-138 ◽

Cited By ~ 3

Author(s):

Agnieszka Kalinowska ◽

◽

Barbara Orlińska ◽

Mateusz Panasiuk ◽

Milena Jamiołkowska ◽

...

Keyword(s):

Type 1 Diabetes ◽

Beta Cell ◽

Beta Cell Function ◽

Cell Function ◽

C Peptide

Download Full-text

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

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2004-0572 ◽

2004 ◽

Vol 89 (12) ◽

pp. 6305-6309 ◽

Cited By ~ 39

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 < 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.

Download Full-text