Consequences of Both Coxsackievirus B4 and Type 1 Diabetes on Female Non-Obese Diabetic Mouse Kidneys

Half of the mortality in diabetes is seen in individuals <50 years of age and commonly predicted by the early onset of kidney disease (DKD). In Type 1 diabetes, increased uACR (urinary albumin-creatinine ratio) during adolescence defines this risk, but the pathological factors responsible remain unknown. We postulated that early in diabetes, glucose variations contribute to kidney injury molecule- 1 (KIM-1) release from circulating T cells, elevating uACR and DKD risk. DKD risk was assigned in youth with type 1 diabetes [n=100; 20.0±2.8 yrs; M:F-54:46, HbA1C-66.1(12.3) mmol/mol; diabetes duration-10.7±5.2 yrs; BMI-24.5(5.3) kg.m-2] and 10 year historical uACR, HbA1C and random blood glucose concentrations collected retrospectively. Glucose fluctuations in the absence of diabetes were also compared to streptozotocin diabetes in Apolipoprotein E-/- mice. Kidney biopsies were used to examine infiltration of KIM-1 expressing T cells in DKD and compared with other chronic kidney disease. Individuals at high risk for DKD had persistent elevations in uACR (uACRAUC0-10yrs, 29.7±8.8 vs 4.5±0.5; P<0.01 vs low risk) and early kidney dysfunction including ~8.3ml.min-1.1.73m-2 higher estimated glomerular filtration rates (eGFRSCHWARTZ; Padj <0.031 vs low risk) and plasma KIM-1 concentrations (~15% higher vs low risk; P<0.034). High risk individuals had greater glycemic variability and increased peripheral blood T cell KIM-1 expression, particularly on CD8+ T cells. These findings were confirmed in a murine model of glycemic variability both in the presence and absence of diabetes. KIM-1+ T cells were also infiltrating kidney biopsies from individuals with DKD. Healthy primary human proximal tubule epithelial cells exposed to plasma from high risk youth with diabetes showed elevated collagen IV and SGLT2 expression, alleviated with KIM-1 blockade. Taken together, these studies suggest that glycemic variations confer risk for DKD in diabetes via increased CD8+ T cell production of KIM-1.

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T Cell Expression and Release of Kidney Injury Molecule-1 in Response to Glucose Variations Initiates Kidney Injury in Early Diabetes

10.2337/figshare.14186459 ◽

2021 ◽

Author(s):

Josephine M. Forbes ◽

Domenica A. McCarthy ◽

Andrew J. Kassianos ◽

Tracey Baskerville ◽

Amelia J. Fotheringham ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

T Cell ◽

High Risk ◽

Kidney Disease ◽

Kidney Injury ◽

Glycemic Variability ◽

Low Risk ◽

Kidney Injury Molecule 1

Half of the mortality in diabetes is seen in individuals <50 years of age and commonly predicted by the early onset of kidney disease (DKD). In Type 1 diabetes, increased uACR (urinary albumin-creatinine ratio) during adolescence defines this risk, but the pathological factors responsible remain unknown. We postulated that early in diabetes, glucose variations contribute to kidney injury molecule- 1 (KIM-1) release from circulating T cells, elevating uACR and DKD risk. DKD risk was assigned in youth with type 1 diabetes [n=100; 20.0±2.8 yrs; M:F-54:46, HbA1C-66.1(12.3) mmol/mol; diabetes duration-10.7±5.2 yrs; BMI-24.5(5.3) kg.m-2] and 10 year historical uACR, HbA1C and random blood glucose concentrations collected retrospectively. Glucose fluctuations in the absence of diabetes were also compared to streptozotocin diabetes in Apolipoprotein E-/- mice. Kidney biopsies were used to examine infiltration of KIM-1 expressing T cells in DKD and compared with other chronic kidney disease. Individuals at high risk for DKD had persistent elevations in uACR (uACRAUC0-10yrs, 29.7±8.8 vs 4.5±0.5; P<0.01 vs low risk) and early kidney dysfunction including ~8.3ml.min-1.1.73m-2 higher estimated glomerular filtration rates (eGFRSCHWARTZ; Padj <0.031 vs low risk) and plasma KIM-1 concentrations (~15% higher vs low risk; P<0.034). High risk individuals had greater glycemic variability and increased peripheral blood T cell KIM-1 expression, particularly on CD8+ T cells. These findings were confirmed in a murine model of glycemic variability both in the presence and absence of diabetes. KIM-1+ T cells were also infiltrating kidney biopsies from individuals with DKD. Healthy primary human proximal tubule epithelial cells exposed to plasma from high risk youth with diabetes showed elevated collagen IV and SGLT2 expression, alleviated with KIM-1 blockade. Taken together, these studies suggest that glycemic variations confer risk for DKD in diabetes via increased CD8+ T cell production of KIM-1.

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Toll-Like Receptor 3 Is Critical for Coxsackievirus B4-Induced Type 1 Diabetes in Female NOD Mice

Endocrinology ◽

10.1210/en.2013-2006 ◽

2014 ◽

Vol 156 (2) ◽

pp. 453-461 ◽

Cited By ~ 16

Author(s):

Kelly D. McCall ◽

Jean R. Thuma ◽

Maria C. Courreges ◽

Fabian Benencia ◽

Calvin B.L. James ◽

...

Keyword(s):

Type 1 Diabetes ◽

Knockout Mice ◽

Nod Mice ◽

Toll Like Receptor ◽

Wild Type ◽

Infected Female ◽

Coxsackievirus B4 ◽

Nonobese Diabetic ◽

Group B

Group B coxsackieviruses (CVBs) are involved in triggering some cases of type 1 diabetes mellitus (T1DM). However, the molecular mechanism(s) responsible for this remain elusive. Toll-like receptor 3 (TLR3), a receptor that recognizes viral double-stranded RNA, is hypothesized to play a role in virus-induced T1DM, although this hypothesis is yet to be substantiated. The objective of this study was to directly investigate the role of TLR3 in CVB-triggered T1DM in nonobese diabetic (NOD) mice, a mouse model of human T1DM that is widely used to study both spontaneous autoimmune and viral-induced T1DM. As such, we infected female wild-type (TLR3+/+) and TLR3 knockout (TLR3−/−) NOD mice with CVB4 and compared the incidence of diabetes in CVB4-infected mice with that of uninfected counterparts. We also evaluated the islets of uninfected and CVB4-infected wild-type and TLR3 knockout NOD mice by immunohistochemistry and insulitis scoring. TLR3 knockout mice were markedly protected from CVB4-induced diabetes compared with CVB4-infected wild-type mice. CVB4-induced T-lymphocyte-mediated insulitis was also significantly less severe in TLR3 knockout mice compared with wild-type mice. No differences in insulitis were observed between uninfected animals, either wild-type or TLR3 knockout mice. These data demonstrate for the first time that TLR3 is 1) critical for CVB4-induced T1DM, and 2) modulates CVB4-induced insulitis in genetically prone NOD mice.

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Advances in our understanding of the pathophysiology of Type 1 diabetes: lessons from the NOD mouse

Clinical Science ◽

10.1042/cs20120627 ◽

2013 ◽

Vol 126 (1) ◽

pp. 1-18 ◽

Cited By ~ 37

Author(s):

Abhirup Jayasimhan ◽

Kristy P. Mansour ◽

Robyn M. Slattery

Keyword(s):

Type 1 Diabetes ◽

Cell Mass ◽

Nod Mice ◽

Diabetic Mouse ◽

Nod Mouse ◽

Β Cells ◽

Autoimmune Destruction ◽

Immune Mediated ◽

And Function

T1D (Type 1 diabetes) is an autoimmune disease caused by the immune-mediated destruction of pancreatic β-cells. Studies in T1D patients have been limited by the availability of pancreatic samples, a protracted pre-diabetic phase and limitations in markers that reflect β-cell mass and function. The NOD (non-obese diabetic) mouse is currently the best available animal model of T1D, since it develops disease spontaneously and shares many genetic and immunopathogenic features with human T1D. Consequently, the NOD mouse has been extensively studied and has made a tremendous contribution to our understanding of human T1D. The present review summarizes the key lessons from NOD mouse studies concerning the genetic susceptibility, aetiology and immunopathogenic mechanisms that contribute to autoimmune destruction of β-cells. Finally, we summarize the potential and limitations of immunotherapeutic strategies, successful in NOD mice, now being trialled in T1D patients and individuals at risk of developing T1D.

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