scholarly journals Alpha cell dysfunction in early type 1 diabetes

2021 ◽  
Author(s):  
Nicolai Doliba ◽  
Andrea Rozo ◽  
Jeffrey Roman ◽  
Wei Qin ◽  
Daniel Traum ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Cell Function ◽  
Early Stage ◽  
Glucagon Secretion ◽  
Cell Loss ◽  
Human Islets ◽  
Alpha Cell ◽  
Acid Decarboxylase ◽  
Alpha Cell Function

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.

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

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1917-P
Author(s):  
LINGYU ZHANG ◽  
YUWEN SHI ◽  
YITING HUANG ◽  
QIZHEN HU ◽  
YAO QIN ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Cell Function ◽  
Alpha Cell ◽  
C Peptide ◽  
Alpha Cell Function ◽  
Different Levels

scholarly journals Alpha cell function in type 1 diabetes

2014 ◽  
Vol 14 (2) ◽  
pp. 45 ◽  
Author(s):  
David Simon Hughes ◽  
Parth Narendran
Keyword(s):  
Type 1 Diabetes ◽  
Cell Function ◽  
Alpha Cell ◽  
Alpha Cell Function

Contribution of Pancreatic Alpha-Cell Function to Insulin Sensitivity and Glucose Variability in Type 1 Diabetes Patients

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 1940-P
Author(s):  
NOBUYUKI TAKAHASHI ◽  
DAISUKE CHUJO ◽  
HIROSHI KAJIO ◽  
KOHJIRO UEKI
Keyword(s):  
Type 1 Diabetes ◽  
Insulin Sensitivity ◽  
Cell Function ◽  
Glucose Variability ◽  
Alpha Cell ◽  
Pancreatic Alpha Cell ◽  
Alpha Cell Function ◽  
Diabetes Patients

235-LB: Time Course of Pancreatic Alpha-Cell Function in Fulminant Type 1 Diabetes

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 235-LB
Author(s):  
LINGYU ZHANG ◽  
YUWEN SHI ◽  
JING WANG ◽  
XING WANG ◽  
YAO QIN ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Time Course ◽  
Cell Function ◽  
Alpha Cell ◽  
Fulminant Type 1 Diabetes ◽  
Pancreatic Alpha Cell ◽  
Alpha Cell Function ◽  
Fulminant Type

scholarly journals Serum miR-204 is an early biomarker of type 1 diabetes-associated pancreatic beta-cell loss

2019 ◽  
Vol 317 (4) ◽  
pp. E723-E730 ◽  
Author(s):  
Guanlan Xu ◽  
Lance A. Thielen ◽  
Junqin Chen ◽  
Truman B. Grayson ◽  
Tiffany Grimes ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Beta Cells ◽  
Cell Function ◽  
Pancreatic Beta Cell ◽  
Cell Loss ◽  
Human Islets ◽  
Serum Samples ◽  
Early Biomarker

Pancreatic beta-cell death is a major factor in the pathogenesis of type 1 diabetes (T1D), but straightforward methods to measure beta-cell loss in humans are lacking, underlining the need for novel biomarkers. Using studies in INS-1 cells, human islets, diabetic mice, and serum samples of subjects with T1D at different stages, we have identified serum miR-204 as an early biomarker of T1D-associated beta-cell loss in humans. MiR-204 is a highly enriched microRNA in human beta-cells, and we found that it is released from dying beta-cells and detectable in human serum. We further discovered that serum miR-204 was elevated in children and adults with T1D and in autoantibody-positive at-risk subjects but not in type 2 diabetes or other autoimmune diseases and was inversely correlated with remaining beta-cell function in recent-onset T1D. Thus, serum miR-204 may provide a much needed novel approach to assess early T1D-associated human beta-cell loss even before onset of overt disease.

scholarly journals Autoantigen Treatment in Type 1 Diabetes: Unsolved Questions on How to Select Autoantigen and Administration Route

2020 ◽  
Vol 21 (5) ◽  
pp. 1598 ◽  
Author(s):  
Johnny Ludvigsson
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Human Subjects ◽  
Subcutaneous Administration ◽  
Acid Decarboxylase ◽  
Recent Onset ◽  
Prevention Trials

Autoantigen treatment has been tried for the prevention of type 1 diabetes (T1D) and to preserve residual beta-cell function in patients with a recent onset of the disease. In experimental animal models, efficacy was good, but was insufficient in human subjects. Besides the possible minor efficacy of peroral insulin in high-risk individuals to prevent T1D, autoantigen prevention trials have failed. Other studies on autoantigen prevention and intervention at diagnosis are ongoing. One problem is to select autoantigen/s; others are dose and route. Oral administration may be improved by using different vehicles. Proinsulin peptide therapy in patients with T1D has shown possible minor efficacy. In patients with newly diagnosed T1D, subcutaneous injection of glutamic acid decarboxylase (GAD) bound to alum hydroxide (GAD-alum) can likely preserve beta-cell function, but the therapeutic effect needs to be improved. Intra-lymphatic administration may be a better alternative than subcutaneous administration, and combination therapy might improve efficacy. This review elucidates some actual problems of autoantigen therapy in the prevention and/or early intervention of type 1 diabetes.

scholarly journals Characteristics of Slow Progression to Type 1 Diabetes in Children With Increased HLA-Conferred Disease Risk

2019 ◽  
Vol 104 (11) ◽  
pp. 5585-5594 ◽  
Author(s):  
Petra M Pöllänen ◽  
Johanna Lempainen ◽  
Antti-Pekka Laine ◽  
Jorma Toppari ◽  
Riitta Veijola ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Cell Function ◽  
Disease Risk ◽  
Acid Decarboxylase ◽  
Β Cell ◽  
Genetic Characteristics ◽  
Slow Progressors ◽  
Insulin Autoantibody ◽  
Slow Progression

Abstract Context Characterization of slow progression to type 1 diabetes (T1D) may reveal novel means for prevention of T1D. Slow progressors might carry natural immunomodulators that delay β-cell destruction and mediate preservation of β-cell function. Objective To identify demographic, genetic, and immunological characteristics of slow progression from seroconversion to clinical T1D. Design HLA-susceptible children (n = 7410) were observed from birth for islet cell antibody (ICA), insulin autoantibody (IAA), glutamic acid decarboxylase (GADA), and islet antigen-2 autoantibodies (IA-2A), and for clinical T1D. Disease progression that lasted ≥7.26 years (slowest) quartile from initial seroconversion to diagnosis was considered slow. Autoantibody and genetic characteristics including 45 non-HLA single nucleotide polymorphisms (SNPs) predisposing to T1D were analyzed. Results By the end of 2015, 1528 children (21%) had tested autoantibody positive and 247 (16%) had progressed to T1D. The median delay from seroconversion to diagnosis was 8.7 years in slow (n = 62, 25%) and 3.0 years in other progressors. Compared with other progressors, slow progressors were less often multipositive, had lower ICA and IAA titers, and lower frequency of IA-2A at seroconversion. Slow progressors were born more frequently in the fall, whereas other progressors were born more often in the spring. Compared with multipositive nonprogressors, slow progressors were younger, had higher ICA titers, and higher frequency of IAA and multiple autoantibodies at seroconversion. We found no differences in the distributions of non-HLA SNPs between progressors. Conclusions We observed differences in autoantibody characteristics and the season of birth among progressors, but no characteristics present at seroconversion that were specifically predictive for slow progression.

scholarly journals Immunotherapy Strategies for the Prevention and Treatment of Distinct Stages of Type 1 Diabetes: An Overview

2020 ◽  
Vol 21 (6) ◽  
pp. 2103 ◽  
Author(s):  
Novella Rapini ◽  
Riccardo Schiaffini ◽  
Alessandra Fierabracci
Keyword(s):  
Type 1 Diabetes ◽  
Cell Function ◽  
Early Stage ◽  
Β Cell ◽  
Good Glycemic Control ◽  
Autoimmune Attack ◽  
Β Cell Function ◽  
Microvascular And Macrovascular Complications

Type 1 diabetes mellitus is a heterogeneous disorder characterized by destruction of pancreatic β cells, culminating in absolute insulin deficiency. The goals of Type 1 diabetes care, established by the Diabetes Control and Complications Trial (DCCT), are to achieve good glycemic control, to prevent hyperglycaemia (which is associated with long-term microvascular and macrovascular complications) and to avoid recurrent episodes of hypoglycaemia (which may have adverse effects on cognitive function). However, despite continuing optimization of insulin therapy regimes, the actual hormonal substitutive administration acts only to treat the symptoms without an effect on disease pathology and etiopathogenesis. In recent decades, a great deal of interest has been focused on prevention approaches in high-risk individuals, based on the hypothesis that a therapeutic intervention, if applied at the early stage of disease, might contribute to maintaining endogenous β cell function by preserving the residual β cell reservoir from autoimmune attack. This manuscript provides an overview of the most important immunotherapeutic interventions established so far for Type 1 diabetes treatment at different stages of disease that have reached an advanced stage of assessment.

scholarly journals Vildagliptin Reduces Glucagon during Hyperglycemia and Sustains Glucagon Counterregulation during Hypoglycemia in Type 1 Diabetes

2012 ◽  
Vol 97 (10) ◽  
pp. 3799-3806 ◽  
Author(s):  
Johan Farngren ◽  
Margaretha Persson ◽  
Anja Schweizer ◽  
James E. Foley ◽  
Bo Ahrén
Keyword(s):  
Type 1 Diabetes ◽  
Treatment Period ◽  
Cell Function ◽  
Glycosylated Hemoglobin ◽  
Glucagon Secretion ◽  
Double Blind ◽  
Dipeptidyl Peptidase 4 ◽  
Dipeptidyl Peptidase 4 Inhibitor ◽  
Respective Treatment

Abstract Context: The dipeptidyl peptidase-4 inhibitor, vildagliptin, inhibits glucagon secretion at hyperglycemia but appears to enhance glucagon counterregulation during hypoglycemia in type 2 diabetes. Objective: The objective of the investigation was to study whether vildagliptin also improves α-cell function in type 1 diabetes (T1D). Patients and Methods: The study was a single-center, double-blind, randomized, placebo-controlled crossover study involving 28 patients with C-peptide negative and antibody positive T1D [21 males, seven females, glycosylated hemoglobin 57.9 mmol/mol (7.5%)]. Patients received vildagliptin (50 mg twice a day) or placebo as an add-on to their insulin therapy for 4 wk each. On d 28 of the respective treatment period, patients were served a standard meal (500 kcal) to raise the circulating incretin hormone levels followed by a hyperinsulinemic hypoglycemic clamp at 2.5 mmol/liter. Main Outcome Measure: The increase in plasma glucagon levels during the 30-min hypoglycemic clamp (min 165–195 of the test) was measured. Results: During the meal, glucagon levels were lower with vildagliptin than with placebo (120 min area under the curveglucagon 2.4 ± 0.2 vs. 2.6 ± 0.2 nmol/liter × minutes, P = 0.022 for between group difference). In contrast, during hypoglycemia, the glucagon counterregulation was not reduced by vildagliptin (increase in glucagon 1.5 ± 1.0 pmol/liter with vildagliptin vs. 1.7 ± 0.8 pmol/liter with placebo, P = NS). In addition, the counterregulatory responses in epinephrine, norepinephrine, cortisol, and pancreatic polypeptide were not different between the treatments. During the 4-wk treatment period, vildagliptin reduced the mean glycosylated hemoglobin, whereas there was no change with placebo [between group difference was −3.4 ± 1.0 mmol/mol (−0.32 ± 0.09%; P = 0.002)] from baseline of 57.9 mmol/mol (7.5%). Conclusions: Vildagliptin, although inhibiting glucagon secretion during hyperglycemia, does not compromise the glucagon counterregulatory response during hypoglycemia in T1D.

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