Type I Diabetes

Type I Diabetes Mellitus (TIDM) is a chronic, autoimmune disease where pancreatic beta cells are destroyed, thus little to no insulin is produced.

This renders the patient unable to use glucose at the cellular level. There is no cure available, with the gold standard of treatment being lifelong insulin therapy. TIDM accounts for 10% of all diabetes cases globally (1), and is the most common type of diabetes in children. Incidence of TIDM worldwide has been increasing by 2-5%, with prevalence at 1 in 300 by 18 years of age (2). In the United States, the costs due to TIDM are estimated to be $14.4 billion annually.

The classical presentation of type 1 diabetes includes polyuria polydipsia, xerostomia, polyphagia, fatigue, and weight loss (3)(4), with the strongest association being with IDDM1, the gene encoding the major histocompatibility complex type 2 (MHCII) on chromosome 6. Certain variants of this gene seem to be associated with increased risk, while others may be protective (5). Although certain chemicals are known to destroy the insulin producing beta cells in the pancreas, no environmental factors have been convincing linked to T1DM. The development of autoantibodies to a number of antigens found on beta cells is associated with increasing risk of T1DM. Not all individuals with antibodies to beta-islet cells, insulin, glutamate decarboxylase, IA-2 or ZnT8 will develop T1DM, but as the number of these proteins to which an individual produces antibodies increases, so their risk of T1DM increases, though the time interval is highly variable (6).

T1DM is not currently preventable, and does not have the same association with obesity that type 2 diabetes has. T1DM does respond to insulin, unlike type 2 diabetes, and individuals with T1DM are generally dependent on insulin. There are currently no approved treatments for T1DM, and potential treatments are focused on transplantation (pancreas, beta-islet cells, stem cells) or vaccines designed to induce tolerance. The complications of T1DM are largely due to excessive glycosylation of proteins due to the elevated levels of blood glucose. While the impact of poorly controlled blood glucose is monitored by the glycosylation of hemoglobin, the pathological impact is seen on basement membrane proteins in the kidney (diabetic nephropathy), the retina (diabetic retinopathy), and blood vessels generally (cardiovascular disease, diabetic ulcer, diabetic vascular dementia, diabetic neuropathy) (7, 8).

Animal Models of Type 1 Diabetes

Pharma Models LLC offers a variety of different models of Type 1 Diabetes. The NOD mouse strain is the most frequently used spontaneous model of preclinical diabetes research due to its similarities to human autoimmune diabetes. For chemically induced models of Type 1 Diabetes, alloxan or streptozotocin (STZ) are the most commonly used drugs in producing the disease.

NOD mouse model of Type 1 Diabetes

The NOD mouse strain has a genetic predisposition to developing diabetes and thus is an ideal model with which to study human autoimmune diabetes. Diabetes development starts at five weeks of age, with mice developing diabetes by 40 weeks. Females are most prone to developing diabetes, while the incidence is much lower in male NOD mice.

Streptozotocin model of Type 1 Diabetes

Streptozotocin (STZ) is a synthetic nitrosoureido glucopyranose derivative that taken up preferentially by the pancreatic ß-cells via the GLUT2 glucose transporter. Delivered intraperitoneally, STZ in high doses selectively kill insulin-producing ß-cells, while low doses will generate hydrogen peroxide and induces expression of glutamic acid decarboxylase (GAD) autoantigens. Low dose protocols call for a daily injection of STZ solution intraperitoneally for five days in order to develop Type 1 Diabetes.

Alloxan model of Type 1 Diabetes

Alloxan (AX) is a well known diabetogenic urea agent that causes selective necrosis of the islet ß-cells. It is also possible to produce different grades of diabetes by varying the dose of alloxan. A single dose of alloxan delivered intraperitoneally is recommended, after which the mouse is allowed a rest period for 12 days.

Bibliography

  1. “Type 1 Diabetes”. American Diabetes Association. American Diabetes Association.
  2. Kasper, Dennis L; Braunwald, Eugene; Fauci, Anthony; et al. (2005). Harrison’s Principles of Internal Medicine (16th ed.). New York: McGraw-Hill.
  3. Cooke DW, Plotnick L (November 2008). “Type 1 diabetes mellitus in pediatrics”. Pediatr Rev 29 (11): 374–84.
  4. Ionescu-Tîrgovişte, Constantin; Gagniuc, Paul Aurelian; Guja, Cristian. “Structural Properties of Gene Promoters Highlight More than Two Phenotypes of Diabetes”. PLOS ONE 10 (9).
  5. Bluestone JA, Herold K, Eisenbarth G (2010). “Genetics, pathogenesis and clinical interventions in type 1 diabetes”. Nature 464 (7293): 1293–1300.
  6. Knip M, Veijola R, Virtanen SM, Hyöty H, Vaarala O, Akerblom HK (2005). “Environmental Triggers and Determinants of Type 1 Diabetes”. Diabetes 54: S125–S136.
  7. Huxley, Rachel R; Peters, Sanne A E; Mishra, Gita D; Woodward, Mark (February 2015). “Risk of all-cause mortality and vascular events in women versus men with type 1 diabetes: a systematic review and meta-analysis”. The Lancet Diabetes & Endocrinology.
  8. Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev. 2013 Jan;93(1):137-88.
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