Type 1 Diabetes Pathophysiology

Type 1 Diabetes Pathophysiology

Type 1 diabetes (T1D) is a chronic autoimmune disorder that occurs in genetically susceptible individuals and that may be precipitated by environmental factors. In a susceptible individual, the immune system is triggered to develop an autoimmune response against altered pancreatic beta cell antigens, or molecules in beta cells that resemble a viral protein. Approximately 85% of T1D patients have circulating islet cell antibodies, and the majority of patients also have detectable anti-insulin antibodies. Most islet cell antibodies are directed against glutamic acid decarboxylase (GAD) within pancreatic beta cells (1).

Several scenarios for development of T1D have been put forth. In one model, an environmental trigger induces islet autoimmunity and beta-cell death in genetically susceptible individuals, leading to a sequence of prediabetic stages and eventually clinical onset of T1D (2). Other scenarios have been proposed to account for wide variations in the time between initiation of autoimmunity and clinical onset of T1D. For example, interactions between genetic factors and environmental challenges such as viral infections might contribute to fluctuations in beta-cell mass observed before onset of T1D (3). Alternatively, T1D could be a relapsing-remitting disease, dependent on cyclical disruption and restoration of the balance between effector and regulatory T cells (4,5). Finally, the fertile field hypothesis postulates the existence of a time window following viral infection during which at-risk individuals may develop autoimmunity (1,6).

Clinical Course
T1D is a catabolic disorder wherein circulating insulin is very low or absent, plasma glucagon is elevated, and the pancreatic beta cells fail to respond to all insulin-secretory stimuli. The pancreas shows lymphocytic infiltration and destruction of insulin-secreting cells of the islets of Langerhans, causing insulin deficiency (1).
Absolute insulin deficiency has many physiologic consequences, including the disruption of glucose uptake into muscle and adipose cells and the absence of an inhibitory effect on hepatic glucose production, lipolysis, and ketogenesis. Extreme insulin deficiency leads to osmotic diuresis and dehydration as well as elevated free fatty acid levels and diabetic ketoacidosis (DKA), which may be life-threatening. Muscle wasting observed in patients with uncontrolled T1D results from the failure to stimulate amino acid uptake and protein synthesis and inhibit protein degradation (7).

References

  1. van Belle TL, Coppieters KT, von Herrath MG. Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev. 2011;91:79-118.
  2. Eisenbarth GS. Type I diabetes mellitus. A chronic autoimmune disease. N Engl J Med. 1986;314:1360-8.
  3. Chatenoud L, Bluestone JA. CD3-specific antibodies: a portal to the treatment of autoimmunity. Nat Rev Immunol. 2007;7:622-32.
  4. Thorsby E, Ronningen KS. Particular HLA-DQ molecules play a dominant role in determining susceptibility or resistance to type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1993;36:371-7.
  5. Gomez-Tourino I, Arif S, Eichmann M, Peakman M. T cells in type 1 diabetes: Instructors, regulators and effectors: A comprehensive review. J Autoimmun. 2015.
  6. Jaberi-Douraki M, Liu SW, Pietropaolo M, Khadra A. Autoimmune responses in T1DM: quantitative methods to understand onset, progression, and prevention of disease. Pediatr Diabetes. 2014;15:162-74.
  7. Newsholme EA, Dimitriadis G. Integration of biochemical and physiologic effects of insulin on glucose metabolism. Exp Clin Endocrinol Diabetes. 2001;109 Suppl 2:S122-34.