Type 1 Diabetes Mellitus: An Alarming Condition

Diabetes mellitus (DM), a metabolic disorder, is mainly of two types. Type 1 Diabetes Mellitus (T1DM), insulin dependent DM, is an autoimmune reaction to proteins of the islet cells of the pancreas. There is a lack of insulin secretion by β- cells of the pancreas. Type 2 Diabetes Mellitus (T2DM), non-insulin dependent DM, is a combination of genetic factors related to impaired insulin secretion, insulin resistance and environmental factors such as obesity, overeating, lack of exercise, stress, ageing. There is a decreased sensitivity of target tissues to insulin1.


Insulin resistance or lack of insulin prevents effective uptake and utilisation of glucose by the body cells (brain cells being an exception). Therefore, blood glucose concentration increases, cell utilisation of glucose decreases, and utilisation of fats and proteins increases1.

Observations at the onset of overt hyperglycemia are as follows1:
  • A mixture of pseudoatrophic islets with cells producing glycogen, somatostatin, and pancreatic polypeptide
  • Normal islets
  • Islets containing β- cell, infiltrating lymphocytes and monocytes
Neonatal Diabetes Mellitus


Neonatal Diabetes Mellitus (NDM) is a monogenic form of diabetes that appears in the first six months of life. NDM is of two types, viz., permanent neonatal diabetes mellitus (PNDM) and transient neonatal diabetes mellitus (TNDM). Among 50% of those with NDM have PNDM, where the condition remains for lifelong. Whereas, in the remaining NDM patients, the condition is transient and it disappears during infancy but may reappear later in life, which is known as transient neonatal diabetes mellitus (TNDM). The specific genes responsible for NDM have been identified. Glucokinase deficiency, where the glucose-insulin signalling pathway is disturbed, is accountable for PNDM1.

T1DM

Autoimmune destruction of insulin-producing pancreatic β- cells by T cells causes deficiency of insulin secretion. This, in turn, leads to metabolic derangements associated with T1DM1.

Aetiology Of T1DM (IDDM)

Autoimmune reaction to proteins of the islet cells of the pancreas causes T1DM. T1DM is associated with other endocrine autoimmunities. Increased incidence of autoimmune diseases is seen in family members of T1DM patients1.

Types of autoantibodies involved in T1DM:

1. Islet cell cytoplasmic antibodies (ICCA)
o   Primary antibody
o   Found in 90% of T1DM patients
o   Against islet cell cytoplasmic proteins
o   Presence of ICCA is the highly accurate predictor of future development of IDDM

2.      Islet cell surface antibodies (ICSA)
o   Found in 80% of T1DM patients
o   Against islet cell surface antigens

3.      Specific antigen targets of islet cells (Anti-GAD antibodies)
o   Found in 80% of patients newly diagnosed with T1DM
o   Antibodies against glutamic acid decarboxylase (GAD)
o   Anti-GAD antibodies decline over time in T1DM patients
o   Presence of anti-GAD antibodies is the strong predictor of future IDDM in the high-risk population

4.       Anti-insulin antibodies
o   Identified in IDDM patients and in relatives at risk of developing IDDM
o   Detectable even before the onset of insulin therapy
o   Detectable in 40% of young children with IDDM1

Pathogenesis Of T1DM

T1DM is allied with the selective destruction of insulin-producing β-cells in the pancreas. The commencement of clinical disease signifies the end stage of β-cell destruction which leads to T1DM. There is marked heterogeneity of the pancreatic lesions, which makes it difficult to follow the pathogenesis of selective β-cell destruction within the islet in T1DM1.

Following are the features which characterise T1DM as an autoimmune disease:
  1. Presence of accessory and immuno-competent cells in the infiltrated pancreatic islets
  2. Association of the predisposition to disease with the class II genes of the major histocompatibility complex
  3. The existence of islet cell-specific autoantibodies
  4. Alterations of T cell-mediated immunoregulation, in particular in CD4+T cell compartment
  5. The contribution of TH1 cells producing interleukins and monokines in the disease process
  6. Response to immunotherapy
  7. The frequent occurrence of other organs specific autoimmune diseases in affected individuals or in their family members1
Causes Of T1DM
  1. Autoimmunity
  2. Diet (high occurrence in siblings shows malpractice by parents)
  3. Lifestyle (high occurrence in siblings shows malpractice by parents)
  4. History of other autoimmune disorders
  5. Environment2 (location)
  6. Genetic2
  7. Viruses (enterovirus, rotavirus, rubella)2
Role Of Extracellular matrix (ECM) In T1DM

ECM is an important player in T1DM. In T1DM, it has abnormalities, particularly in the extended vascular-ductal pole adjacent to the actual islet. During fetal life and postnatal periods, the vascular-ductal pole is involved in the generation of islets3.

Myeloid cells (which degrade EMC) and macrophages start to accumulate at the vascular-ductal pole as the first sign of insulitis and to encircle the islet later at the islet edges. Myeloid cells and macrophages are involved in normal islet development and for sufficient numbers of insulin-producing cells3.

Autoantigens In T1DM

Two new autoantigens (β-cell proteins) for CD4T cells in T1D4:
  • Chromogranin A (Chg A)
  • Islet amyloid polypeptide (IAPP)
Targets For Preventive Strategies
  1. T cells
  2. Induction of tolerance to the β-cell proteins such as insulin that is inappropriately recognised (HIPs)
  3. β-cell replacement2
Role Of Human Leukocyte Antigen In T1DM

T1D has an association with Human Leukocyte Antigen (HLA). The increase in T1D has been accompanied by a concomitant widening of the HLA risk profile. HLA on chromosome 6 is associated with T1D. This contributes to about half of the familial basis of T1D. There is a combination of HLA genes2:

1. DR4-DQ8 and DR3-DQ2
a.       Present in 90% of children with T1D
b.       Contributes to a greater risk of T1D and is most common in children in whom the disease develops very early in life

2.      DR15-DQ6
a.       Found in less than 1% of children with T1D
bFirst degree relatives of children with DR4-DQ8 and DR3-DQ2 are at greater risk of T1D than are the relatives of children in whom the disease develops later2.

Protective Role Of Vitamin D In T1DM

Some epidemiologic observations support a protective role for vitamin D in T1D2.
  • Maternal intake during pregnancy
  • High doses of vitamin D supplements early in life
(Safety studies of vitamin D doses in pregnancy are required)

References
  1. Ozougwu JC, Obimba KC, et al. The Pathogenesis and Pathophysiology of Type 1 and type 2 Diabetes Mellitus. Journal of Physiology and Pathophysiology. 2013.
  2. Kathleen M. Gillespie. Type 1 diabetes: Pathogenesis and prevention.
  3. Hemmo A. Drexhage, Wim A. Dik, Pieter J. M. Leenen, Marjan A. Versuel. The Immune Pathogenesis of Type 1 Diabetes: Not Only Thinking Outside the Cell but Also Outside the Islet and Out of the Box. Diabetes. 2016;65: 2130-2133. Doi: 10.2337/dbi16-0030.
  4. Thomas Delong, Timothy A. Wiles et al. Pathogenic CD4T cells in type 1 diabetes recognize epitopes formed by peptide fusion. Science. 2016;351(6274).

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Dr. Shivani Desai
Pune, India
Clinical Pharmacologist | Pharmaceutical Sciences Doctorate | Type 1 Diabetes Researcher | Assistant Professor | Basket Ball Player | Gold Medalist Painter