Hyperglycemia and Salivary Gland Dysfunction in the Non-obese Diabetic Mouse: Caveats for Preclinical Studies in Sjögren’s Syndrome

Abstract

the non-obese Diabetic (noD) mouse model for type i diabetes also develops some features of Sjögren's syndrome (SS). Since the source of the mice and the environment exert a strong influence on diabetes, this study investigated SS development in noD mice obtained from two vendors. female noD mice from the Jackson Laboratory (JAX) and taconic Biosciences were monitored for blood glucose and pilocarpine-induced salivation. The gut microbiome was analyzed by 16S rRNA sequencing of stool DnA. At euthanasia, serum cytokines and sialoadenitis severity were evaluated. the onset of diabetes was significantly accelerated in JAX mice compared to Taconic mice. Although the gut microbiome between the two groups was distinct, both groups developed sialoadenitis. there was no correlation between the severity of sialoadenitis and reduced saliva production. instead, salivary gland dysfunction was associated with hyperglycemia and elevation of serum IL1β, IL16, and CXCL13. Our data suggest that inflammatory pathways linked with hyperglycemia are confounding factors for salivary gland dysfunction in female noD mice, and might not be representative of the mechanisms operative in SS patients. considering that noD mice have been used to test numerous experimental therapies for SS, caution needs to be exerted before advancing these therapeutics for human trials. Reduced fluid secretion by the exocrine salivary and lacrimal glands is a major cause of dry mouth and dry eyes in Sjögren's syndrome (SS) 1. Multiple factors like intrinsic glandular defects, innate immune activation, and adaptive autoimmune responses contribute to the development of glandular dysfunction in SS. The Non-obese Diabetic (NOD) mouse model, primarily developed to study type I diabetes, is extensively used to investigate the pathogenic mechanisms in SS 2. Although under a robust genetic control, environmental factors also significantly affect the development of diabetes in the NOD mouse 3. The environmental influence is exemplified by studies showing differences in the incidence of hyperglycemia in NOD mice obtained from two different commercial sources, The Jackson Laboratory (JAX) and Taconic Biosciences 4. The NOD mice have been used for several preclinical drug studies for SS 5-11. Since the mice are obtained from different commercial sources or are bred within the investigator's facility, they are exposed to distinct housing conditions. Thus, it is not surprising to note considerable variations in the incidence, severity, and kinetics of SS in NOD mice. We undertook this study to investigate whether the commercial source of the mice influences the development of SS in NOD mice housed under the same environment. Our results demonstrate that the NOD mice from JAX had an accelerated onset of diabetes; in contrast, the Taconic mice had a significantly (p = 0.0289) higher severity of salivary gland inflammation. Regardless of the commercial source, mice showed evidence for salivary gland dysfunction, which was strongly associated with hyperglycemia.

Polydatin Alleviates Diabetes-Induced Hyposalivation through Anti-Glycation Activity in db/db Mouse

“…Hyperglycemia due to high blood glucose levels is a characteristic of diabetes, which causes many changes in the body through damage to various organs. Hyposalivation and submandibular gland dysfunction have been reported in in vivo models, especially in type 2 diabetic mice [26], non-obese diabetic mice [27], streptozotocin (STZ)-induced type 1 diabetic rats [28], and this study confirmed the improvement effect of polydatin on diabetes-induced hyposalivation in a type 2 diabetic db/db mice model.…”

Transcriptomic and Single-Cell Analysis Reveals Regulatory Networks and Cellular Heterogeneity in Mouse Primary Sjögren’s Syndrome Salivary Glands

“…Although the initial NOD inbred (NOD/ShiLt) strain displayed symptoms resembling SS including the presence of inflammatory cell infiltrates and impaired salivary and lacrimal secretion, these animals also developed type I diabetes (T1D) (19,21). To circumvent the difficulties of studying SS in the background of T1D (27), we utilized a mouse model in which the NOD/ShiLt major histocompatibility complex was replaced with that of a healthy C57BL/10 strain, resulting in a congenic strain of mice (NOD.B10Sn-H2 b /J or NOD.B10) that develop pSS but are protected from T1D (16). Indeed, these animals share many clinical features associated with pSS including a female disease predilection, focal lymphocytic infiltration of the SMG and lacrimal glands, reduced salivary flow and systemic disease manifestations affecting the kidney and lung (17,(28)(29)(30).…”

Protocols for Experimental Sjögren's Syndrome

“…The quantitative method measures the disease severity either as the area fraction covered by lymphocytic infiltrates (Allushi, Bagavant, Papinska, & Deshmukh, 2019) or as a focus score per 4 mm 2 salivary gland tissue (Fisher et al, 2017).…”

“…They also develop salivary and lacrimal gland inflammation, show a drop in saliva production with increasing age, and are used as a SS model (Hu et al., 1992). However, glandular dysfunction in NOD mice correlates strongly with the level of hyperglycemia, a characteristic not common in patients with SS (Allushi et al., 2019). Thus, while glandular inflammation in NOD mouse may mimic that seen in patients, NOD mouse utility in investigating salivary gland dysfunction is open to debate.…”