Vitamin D binding protein/GC‐globulin: A novel regulator of alpha cell function and glucagon secretion

ABSTRACTVitamin D-binding protein (DBP) or GC-globulin carries vitamin D metabolites from the circulation to target tissues. DBP expression is highly-localized to the liver and pancreatic α-cells. While DBP serum levels, gene polymorphisms and autoantigens have all been associated with diabetes risk, the underlying mechanisms remain unknown. Here, we show that DBP regulates α-cell morphology, α-cell function and glucagon secretion. Deletion of DBP led to smaller and hyperplastic α-cells, altered Na+ channel conductance, impaired α-cell activation by low glucose, and reduced rates of glucagon secretion. Mechanistically, this involved reversible changes in islet microfilament abundance and density, as well as changes in glucagon granule distribution. Defects were also seen in β-cell and δ-cell function. Immunostaining of human pancreata revealed generalized loss of DBP expression as a feature of late-onset and longstanding, but not early-onset type 1 diabetes. Thus, DBP is a critical regulator of α-cell phenotype, with implications for diabetes pathogenesis.HIGHLIGHTSDBP expression is highly-localized to mouse and human α-cellsLoss of DBP increases α-cell number, but decreases α-cell sizeα-cells in DBP knockout islets are dysfunctional and secrete less glucagonDBP expression is decreased in α-cells of donors with late-onset or longstanding type 1 diabetes

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Vitamin D-Binding Protein Clearance Ratio Is Significantly Associated with Glycemic Status and Diabetes Complications in a Predominantly Vitamin D-Deficient Population

Journal of Diabetes Research ◽

10.1155/2018/6239158 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Nabila A. Abdella ◽

Olusegun A. Mojiminiyi

Keyword(s):

Vitamin D ◽

Cell Function ◽

Binding Protein ◽

Area Under The Curve ◽

Significant Negative Correlation ◽

Receiver Operating Curve ◽

Tubular Damage ◽

Vitamin D Binding Protein ◽

Glycemic Status ◽

Clearance Ratio

Introduction. Studies have shown increased urine excretion of vitamin D-binding protein (VDBP) in patients with diabetic nephropathy (DN) resulting from postulated mechanisms linked to renal tubular damage. In this study, we evaluate the utility of VDBP clearance ratio as a novel determinant of glycemic status, DN, and other diabetes-associated complications.Methods. Levels of vitamin D, HbA1c, serum, urine concentrations of VDBP, and creatinine were measured in 309 subjects. The ratio of urine microalbumin to creatinine was determined to categorize subjects as normoalbuminuric (NAO), microalbuminuric (MIA), and macroalbuminuric (MAA). The VDBP clearance ratio was calculated.Results. Mean VDBP clearance ratios in NAO, MIA, and MAA were 0.7, 4, and 15, respectively. Significant positive correlations of VDBP clearance ratio were found with age, WC, SBP, DBP, TG, glucose, HbA1c, urine VDBP, urine microalbumin, and urine microalbumin/creatinine, and a significant negative correlation was found with the steady-state estimate of beta cell function (B%). Receiver operating curve (ROC) analyses of the use of VDBP clearance ratio for detection of albumin status shows a value of 0.81 for the area under the curve.Conclusions. The strong associations of VDBP clearance ratio with glycemic control and diabetes-associated complications suggest that this index could play a wider role in detection and/or pathogenesis and complications of diabetes.

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Vitamin D-binding protein is required for the maintenance of [alpha]-cell identity and function

Endocrine Abstracts ◽

10.1530/endoabs.65.p201 ◽

2019 ◽

Author(s):

Katrina Viloria ◽

Daniela Nasteska ◽

Dean Larner ◽

Nicholas Fine ◽

Fiona Ashford ◽

...

Keyword(s):

Vitamin D ◽

Binding Protein ◽

Alpha Cell ◽

Vitamin D Binding Protein ◽

Cell Identity ◽

And Function

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Alpha cell dysfunction in early type 1 diabetes

10.1101/2021.10.15.464545 ◽

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.

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