Non-obese diabetic or NOD

mice A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...

, like biobreeding rats, are used as an

animal model An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...

for

type 1 diabetes Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for ...

. Diabetes develops in NOD mice as a result of insulitis, a leukocytic infiltrate of the

pancreatic islet The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans. The pancreatic islets constitute 1–2% of ...

s. The onset of

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

is associated with a moderate glycosuria and a non-fasting hyperglycemia. It is recommended to monitor for development of

glycosuria Glycosuria is the excretion of glucose into the urine. Ordinarily, urine contains no glucose because the kidneys are able to reabsorb all of the filtered glucose from the tubular fluid back into the bloodstream. Glycosuria is nearly always caused ...

from 10 weeks of age; this can be carried out using urine glucose

dipsticks A dipstick is one of several measurement devices. Some dipsticks are dipped into a liquid to perform a chemical test or to provide a measure of quantity of the liquid. Since the late 20th century, a flatness/levelness measuring device trademarke ...

. NOD mice will develop spontaneous diabetes when left in a sterile environment. The incidence of spontaneous diabetes in the NOD mouse is 60–80% in females and 20–30% in males. Onset of diabetes also varies between males and females: commonly, onset is delayed in males by several weeks. The mice (as well as

C57BL/6 C57BL/6, often referred to as "C57 black 6", "C57" or "black 6", is a common inbred strain of laboratory mouse. It is the most widely used "genetic background" for genetically modified mice for use as models of human disease. They are the most wid ...

and SJL) are known to carry IgG2c allele.

History

Non-obese diabetic (NOD) mice exhibit a susceptibility to spontaneous development of autoimmune insulin dependent diabetes mellitus (IDDM). The NOD strain and related strains were developed at Shionogi Research Laboratories in Aburahi,

Japan Japan ( ja, 日本, or , and formally , ''Nihonkoku'') is an island country in East Asia. It is situated in the northwest Pacific Ocean, and is bordered on the west by the Sea of Japan, while extending from the Sea of Okhotsk in the north ...

by Makino and colleagues and first reported in 1980. The group developed the NOD strain by an outbreeding of the cataract-prone strain from JcI:ICR mice.

Susceptibility

The susceptibility to IDDM is

polygenic A polygene is a member of a group of non-epistatic genes that interact additively to influence a phenotypic trait, thus contributing to multiple-gene inheritance (polygenic inheritance, multigenic inheritance, quantitative inheritance), a type of ...

and environment exerts a strong effect on

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

penetrances. Environment including housing conditions, health status, and diet all affect development of diabetes in the mice. For instance, NOD mice maintained in different laboratories can have different levels of incidence. The incidence of disease is linked to

Microbiome A microbiome () is the community of microorganisms that can usually be found living together in any given habitat. It was defined more precisely in 1988 by Whipps ''et al.'' as "a characteristic microbial community occupying a reasonably well ...

. NOD mice are also susceptible to developing other

autoimmune In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". P ...

syndromes, including autoimmunine sialitis,

autoimmune thyroiditis Autoimmune thyroiditis, is a chronic disease in which the body interprets the thyroid glands and its hormone products T3, T4 and TSH as threats, therefore producing special antibodies that target the thyroid's cells, thereby destroying it. It may ...

, autoimmune peripheral polyneuropathy etc. Diabetes in these mice can be prevented by a single injection of mycobacterial adjuvants such as complete

Freund's adjuvant Freund's adjuvant is a solution of antigen emulsified in mineral oil and used as an immunopotentiator (booster). The complete form, Freund's Complete Adjuvant (FCA or CFA) is composed of inactivated and dried mycobacteria (usually '' M. tuberculo ...

(FCA) or Bacille de Calmette et Guérin (BCG) vaccine.

Identifying IDDM susceptibility loci

Genetic Loci associated with susceptibility to IDDM have been identified in the NOD mouse strain through the development of congenic mouse strains, which have identified several insulin dependent diabetes (Idd) loci. The most important is idd1 which is the

major histocompatibility complex The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are calle ...

class II loci I-Ag7. NOD mice have polymorphisms in the Idd3 locus which are linked to

IL-2 The Ilyushin Il-2 (Russian: Илью́шин Ил-2) is a ground-attack plane that was produced by the Soviet Union in large numbers during the Second World War. The word ''shturmovík'' ( Cyrillic: штурмовик), the generic Russian term ...

production. IL-2 promotes either immunity or tolerance in a concentration dependent fashion by acting on

T helper cell The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...

s, CTL and

NK cells Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...

. Low amounts of IL-2 may be needed to promote survival of Treg in mice. Loss of IL-2 can thereby contribute to the development of autoimmunity in NOD mice. NOD mice have a mutation in exon 2 of the

CTLA-4 CTLA-4 or CTLA4 (cytotoxic T-lymphocyte-associated protein 4), also known as CD152 (cluster of differentiation 152), is a protein receptor that functions as an immune checkpoint and downregulates immune responses. CTLA-4 is constitutively expres ...

gene, which causes it to be spliced incorrectly.

plays a major role in suppressing the T-cell immune response. Without the proper functioning of

, T-cells attack the insulin producing cells. This results in Type 1 Diabetes.

References

{{Portal bar, Animals, Biology Laboratory mouse strains Diabetes Population genetics