Soluble CD93 Is Involved in Metabolic Dysregulation but Does Not Influence Carotid Intima-Media Thickness

Abstract

Type 2 diabetes and cardiovascular disease are complex disorders involving metabolic and inflammatory mechanisms. Here we investigated whether sCD93, a group XIV c-type lectin of the endosialin family, plays a role in metabolic dysregulation or carotid intima-media thickness (IMT). Although no association was observed between sCD93 and IMT, sCD93 levels were significantly lower in subjects with type 2 diabetes (n = 901, mean ± SD 156.6 ± 40.0 ng/mL) compared with subjects without diabetes (n = 2,470, 164.1 ± 44.8 ng/mL, P < 0.0001). Genetic variants associated with diabetes risk (DIAGRAM Consortium) did not influence sCD93 levels (individually or combined in a single nucleotide polymorphism score). In a prospective cohort, lower sCD93 levels preceded the development of diabetes. Consistent with this, a cd93-deficient mouse model (in addition to apoe deficiency) demonstrated no difference in atherosclerotic lesion development compared with apoe(-/-) cd93-sufficient littermates. However, cd93-deficient mice showed impaired glucose clearance and insulin sensitivity (compared with littermate controls) after eating a high-fat diet. The expression of cd93 was observed in pancreatic islets, and leaky vessels were apparent in cd93-deficient pancreases. We further demonstrated that stress-induced release of sCD93 is impaired by hyperglycemia. Therefore, we propose CD93 as an important component in glucometabolic regulation.

Figure 1

Representative image of the descending aorta stained with Sudan IV from apoe^−/−cd93^+/− mice (A) and apoe^−/−cd93^+/+ mice (B). C: Quantification of lesions in the descending aorta of female and male apoe^−/−cd93^+/− (black dots, n = 11 [6 male, 5 female]) or apoe^−/−cd93^+/+ (black squares, n = 9 [5 male, 4 female]) mice.

Figure 2

Glucose metabolism of cd93^+/− male mice compared with cd93^+/+ male mice (black dots and black squares, respectively). A: Glucose tolerance test of cd93^+/− and cd93^+/+ male mice (n = 10–13), 4 months of age, before being fed a Western diet. B: Weight of cd93^+/− and cd93^+/+ male mice (n = 9–12, respectively) after 16 weeks of eating a Western diet. C: Glucose tolerance test of cd93^+/− and cd93^+/+ male mice (n = 9–12, respectively) after 16 weeks of eating a Western diet. D: Insulin tolerance test of cd93^+/− and cd93^+/+ male mice (n = 9–11 respectively) after 16 weeks of eating Western diet. Repeated-measures two-way ANOVA showed statistical significance for C and D with **P ≤ 0.01 or *P ≤ 0.05 statistical significance at a particular time point/s between genotypes using post hoc analysis of Šidák multiple-comparisons test. The error bar indicates SEM.

Figure 3

Immunohistochemistry of pancreas sections demonstrating the location of insulin, sCD93, and VWF in mice with 2, 1, or 0 copies of the cd93 gene (cd93^+/+, cd93^+/−, and cd93^−/−, respectively).

Figure 4

Vascular integrity and endothelial damage in cd93^+/+ and cd93^+/− mice. A: Percentage of VWF-positive islets in pancreata from mice fed for 16 weeks with a Western diet (four of each genotype). B: Quantification of Evans Blue dye in pancreata in cd93^+/− and cd93^+/+ mice (four of each genotype; black and white bars, respectively). *P ≤ 0.05, Student t test. C: Plasma levels of soluble VWF A2 in cd93^+/− and cd93^+/+ mice that were fed for 16 weeks with a Western diet (black and white bars, respectively) or a chow diet (dark and light hashed bars, respectively), n = 9–11 per genotype, *P ≤ 0.05, one-way ANOVA, using Tukey multiple-comparison test between genotypes and diet. D: Plasma levels of e-selectin in cd93^+/− and cd93^+/+ mice that were fed for 16 weeks with a Western diet (black and white bars, respectively) or a chow diet (dark and light hashed bars, respectively), n = 9–11 per genotype. *P ≤ 0.05 Student t test. All error bars indicate the SEM.