N-3 PUFA and Pregnancy Preserve C-Peptide in Women with Type 1 Diabetes Mellitus

Type 1 diabetes (T1DM) is an autoimmune disease characterized by the gradual loss of β-cell function and insulin secretion. In pregnant women with T1DM, endogenous insulin production is absent or minimal, and exogenous insulin is required to control glycemia and prevent ketoacidosis. During pregnancy, there is a partial decrease in the activity of the immune system, and there is a suppression of autoimmune diseases. These changes in pregnant women with T1DM are reflected by Langerhans islet enlargement and improved function compared to pre-pregnancy conditions. N-3 polyunsaturated fatty acids (n-3 PUFA) have a protective effect, affect β-cell preservation, and increase endogenous insulin production. Increased endogenous insulin production results in reduced daily insulin doses, better metabolic control, and adverse effects of insulin therapy, primarily hypoglycemia. Hypoglycemia affects most pregnant women with T1DM and is several times more common than that outside of pregnancy. Strict glycemic control improves the outcome of pregnancy but increases the risk of hypoglycemia and causes maternal complications, including coma and convulsions. The suppression of the immune system during pregnancy increases the concentration of C-peptide in women with T1DM, and n-3 PUFA supplements serve as the additional support for a rise in C-peptide levels through its anti-inflammatory action.

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

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

Effect of Glucagon-Like Peptide-1 on α- and β-Cell Function in C-Peptide-Negative Type 1 Diabetic Patients

Molecular Endocrinology ◽

10.1210/mend.24.4.9999 ◽

2010 ◽

Vol 24 (4) ◽

pp. 875-875

Author(s):

Urd Kielgast ◽

Meena Asmar ◽

Sten Madsbad ◽

Jens J. Holst

Keyword(s):

Insulin Secretion ◽

Cell Function ◽

Glucagon Secretion ◽

Diabetic Patients ◽

Β Cell ◽

C Peptide ◽

Endogenous Insulin Secretion ◽

Endogenous Insulin ◽

Type 1 Diabetic Patients

Abstract Context: The mechanism by which glucagon-like peptide-1 (GLP-1) suppresses glucagon secretion is uncertain, and it is not determined whether endogenous insulin is a necessary factor for this effect. Objective: Our objective was to characterize the α- and β-cell responses to GLP-1 in type 1 diabetic patients without residual β-cell function. Methods: Nine type 1 diabetic patients, classified as C-peptide negative by a glucagon test, were clamped at plasma glucose of 20 mmol/liter for 90 min with arginine infusion at time 45 min and concomitant infusion of GLP-1 (1.2 pmol/kg · min) or saline. Results: Infusion with GLP-1 increased C-peptide concentration just above the detection limit of 33 pmol/liter in one patient, but C-peptide remained immeasurable in all other patients. In the eight remaining patients, total area under the curve of glucagon was significantly decreased with GLP-1 compared with saline: 485 ± 72 vs. 760 ± 97 pmol/liter · min (P < 0.001). In addition, GLP-1 decreased the arginine-stimulated glucagon release (incremental AUC of 103 ± 21 and 137 ± 16 pmol/liter · min, with GLP-1 and saline, respectively, P < 0.05). Conclusions: In type 1 diabetic patients without endogenous insulin secretion, GLP-1 decreases the glucagon secretion as well as the arginine-induced glucagon response during hyperglycemia. GLP-1 induced endogenous insulin secretion in one of nine type 1 diabetic patients previously classified as being without endogenous insulin secretion.

Download Full-text

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00199.2014 ◽

2014 ◽

Vol 307 (6) ◽

pp. E494-E502 ◽

Cited By ~ 17

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.

Download Full-text

Rapid Point-of-Care Test for Determination of C-Peptide Levels

Journal of Diabetes Science and Technology ◽

10.1177/1932296821995557 ◽

2021 ◽

pp. 193229682199555

Author(s):

Paturi V. Rao ◽

Eric Bean ◽

Dhanalakshmi Nair-Schaef ◽

Siting Chen ◽

Steven C. Kazmierczak ◽

...

Keyword(s):

Type 1 Diabetes ◽

Cell Function ◽

Late Onset ◽

Autoimmune Diabetes ◽

Point Of Care ◽

Cell Mass ◽

Hepatic Clearance ◽

Β Cell ◽

C Peptide

C-peptide is co-secreted with insulin and is not subject to hepatic clearance and thus reflects functional β-cell mass. Assessment of C-peptide levels can identify individuals at risk for or with type 1 diabetes with residual β-cell function in whom β cell-sparing interventions can be evaluated, and can aid in distinguishing type 2 diabetes from Latent Autoimmune Diabetes in Adults and late-onset type 1 diabetes. To facilitate C-peptide testing, we describe a quantitative point-of-care C-peptide test. C-peptide levels as low as 0.2 ng/ml were measurable in a fingerstick sample, and the test was accurate over a range of 0.17 to 12.0 ng/ml. This test exhibited a correlation of r = 0.98 with a high-sensitivity commercial ELISA assay and a correlation of r = 0.90 between matched serum and fingerstick samples.

Download Full-text

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

Journal of International Medical Research ◽

10.1177/03000605211066306 ◽

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.

Download Full-text

Effect of Glucagon-Like Peptide-1 on α- and β-Cell Function in C-Peptide-Negative Type 1 Diabetic Patients

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-2440 ◽

2010 ◽

Vol 95 (5) ◽

pp. 2492-2496 ◽

Cited By ~ 37

Author(s):

Urd Kielgast ◽

Meena Asmar ◽

Sten Madsbad ◽

Jens J. Holst

Keyword(s):

Insulin Secretion ◽

Cell Function ◽

Glucagon Secretion ◽

Diabetic Patients ◽

Β Cell ◽

C Peptide ◽

Endogenous Insulin Secretion ◽

Endogenous Insulin ◽

Type 1 Diabetic Patients

Abstract Context: The mechanism by which glucagon-like peptide-1 (GLP-1) suppresses glucagon secretion is uncertain, and it is not determined whether endogenous insulin is a necessary factor for this effect. Objective: To characterize the α- and β-cell responses to GLP-1 in type 1 diabetic patients without residual β-cell function. Methods: Nine type 1 diabetic patients, classified as C-peptide negative by a glucagon test, were clamped at plasma glucose of 20 mmol/liter for 90 min with arginine infusion at time 45 min and concomitant infusion of GLP-1 (1.2 pmol/kg · min) or saline. Results: Infusion with GLP-1 increased C-peptide concentration just above the detection limit of 33 pmol/liter in one patient, but C-peptide remained immeasurable in all other patients. In the eight remaining patients, total area under the curve of glucagon was significantly decreased with GLP-1 compared with saline: 485 ± 72 vs. 760 ± 97 pmol/liter · min (P < 0.001). In addition, GLP-1 decreased the arginine-stimulated glucagon release (incremental AUC of 103 ± 21 and 137 ± 16 pmol/liter · min, with GLP-1 and saline, respectively, P < 0.05). Conclusions: In type 1 diabetic patients without endogenous insulin secretion, GLP-1 decreases the glucagon secretion as well as the arginine-induced glucagon response during hyperglycemia. GLP-1 induced endogenous insulin secretion in one of nine type 1 diabetic patients previously classified as being without endogenous insulin secretion.

Download Full-text