In DM type 1A, a genetically susceptible host develops autoimmunity against his or her own beta cells. In some (but not all) patients, this autoimmune process results in progressive destruction of beta cells until a critical mass of beta cells is lost and insulin deficiency develops (Ali, 2010).
Since those with evidence of autoimmunity do not necessarily progress to DM1, this indicates that there are "checkpoints" when the autoimmune process can be stopped or reversed (Ziegler & Nepom, 2010).
DM1 involves some or all of the following stages (Ali, 2010):
1. Initiation of autoimmunity
- DM1 is believed to result from the combination of genetic and environmental factors (see Etiology/Risk Factors) that trigger an autoimmune response (Ichinose, Kawasaki, & Eguchi, 2007).
- Appearance of several autoantibodies: insulin-associated antibodies (IAA) followed by glutamic acid decarboxylase 65 kDa (GAD65) and tyrosine phosphatase insulinoma-associated 2 (IA-2) antibodies (Ali, 2010)
2. Preclinical autoimmunity with progressive loss of beta cell function
- The above antibodies representing the humoral immune response do not mediate ß-cell destruction, but serve as markers for the presence of autoimmunity. The actual damage to the ß-cells is primarily T-lymphocyte cell-mediated immune response (Skyler, 2011).
- The risk of developing DM1 is related to the number of antibodies present. For example, 30% of children with one antibody will progress to diabetes, 70% when two antibodies are present and 90% when three are present. The risk of developing DM1 also varies with the intensity of the antibody titres (Ali, 2010).
- In non-diabetic patients - immature dendritic cells (iDCs) activate regulatory T-lymphocytes (Tregs), which induce central tolerance → no ß-cell death (not shown on diagram) (Csorba, Lyon, & Hollenberg, 2010).
- In DM1 patients - DCs bind the ß-cell antigens released from islets of Langerhans, and express major histocompatibility complex (MHC)/human leukocyte antigen (HLA) class I molecules. These MHC molecules are recognized by CD8+T-cells → release of cytotoxic cytokines (IFN-gamma and granzymes).
- iDCs internalize modified islet ß-cell antigens, and migrate to pancreatic lymph nodes. DCs mature during migration and express MHC Class II molecules. The antigens are presented to CD4+ T-cells, which then differentiate into CD4+ effector T-cells (Teff) (Summers, Marleau, Stephens, Mahon, & Singh, 2004).
- The activated CD4+Teff release pro-inflammatory cytokines, such as IL-2, IL-12, IFN-gamma and TNF-alpha → inflammatory response (insulitis). Pancreatic ß-cell apoptosis is mainly mediated by IL-1 and tumor necrosis factor (TNF) cytokines (Roncarolo & Battagliam, 2007).
- Refer to Clinical Manifestations.
- Also known as honeymoon period or a decrease in exogenous insulin requirement as a result of viable beta cells recovering some function .
- This natural remission is temporary and insulin requirements increase gradually or abruptly within few months (Ali, 2010).
- Almost all beta-cell function is lost → patient is totally dependent on exogenous insulin.
- If hyperglycemia goes untreated and the body cannot utilize glucose, there is a breakdown of fats to generate energy. This condition is called diabetic ketoacidosis (DKA), which develops when there is not enough insulin. Insulin deficiency leads to increased activity of lipase → breakdown of triglyceride into glycerol and free fatty acids (FFA).
In liver, FFA's are oxidized to ketone bodies. The body cannot excrete all the ketones, and they build up in the blood leading to ketoacidosis (Huether et al., 2012, p. 465). See Clinical Manifestations for DKA symptoms.
DM1 along with its long-term complications reduces the normal life span by about 5-8 years. Generally, survival rates are increasing in both genders and all ethnic groups, which is most likely related to improvements in blood glucose monitoring (A.D.A.M., 2004). Most of the long term complications of DM1 are a result of hyperglycemia. This constant state leads to four known different pathologic metabolic pathways and resultant products that affect the body chronically in many different ways.
I) POLYOL pathway:
One of the errent metabolic pathways is the polyol pathway. Unlike muscle and other body cells, certain cells do not need insulin to assist glucose into the cells (nerves, RBC's, eye lens and kidneys). These four tissues and organs can not block an excess of sugar from entering, nor can they eliminate the excess sugar. As a result, in DM1 the excess blood sugar ends up being shunted through the polyol pathway in these organs, producing two results. The first result is the production of sorbitol, a polyol, or 6 carbon sugar alcohol. The second is a reduced production of glutathione, a very important instrinsic antioxidant. The excess of sorbitol accumulates in these tissues and attracts water to the area causing increased osmotic pressure. Some examples of these problems are visual changes and cataract formation due to an excess of sorbitol in the lens of the eyes. In the nerve tissue, there is disruption to ion pumps and conduction and Schwann cells are damaged. Red blood cell perfusion (delivery of blood to the capillary bed) is affected due to increased size and reduced flexibility of the cells due to swelling from sorbitol. Our intrinsic antioxidants, such as glutathione are constantly dealing with tissue injury and repair. These two products negatively affect the microcirculation (Huether et al., 2012, p.466).
II) PROTEIN KINASE C (PKC):
PKC is a family of intracellular signalling proteins. They are inappropriately activated with hyperglycemia. The pathological production of inflammatory cytokines, extra extracellular matrix and increased insulin resistance are results of this errent function. In addition, other factors that affect the long-term microvascular complications are enhanced contractility, increased permeability and endothelial proliferation of the vasculature (Huether et al., 2012, p.466).
III) ADVANCED GLYCATION END PRODUCTS:
Glucose normally binds to lipids, proteins and nucleic acids and can remove itself without enzymes. With a constant state of hyperglycemia, this process of attachment becomes irreversible and is called glycation. The end products of this process involve glucose attaching, not just to free floating macromolecules, but to the protein in blood vessel walls, cells and interstitial walls. The end products are called AGE's: advanced glycation end products. AGE's attach to their receptor or act independently. There has been much research on how these products cause tissue injury and pathological conditions which would be in part responsible for the long term compications of DM1. The five areas that are known to be affected by AGE's are; the inactivation of nitric oxide (which is responsible for vasodilation), increased platelet adhesion and procoagulant changes of the endothelial cells (increased "stickiness"),the cross linking and trapping of proteins (LDL's, IgG's, complement) and thickening of the basement membrane, lipid oxidation, inflammation and oxidative stress, increasing the release of cytokines and growth factors through the binding to macrophages and other cell receptors. These factors trigger cell proliferation in the smooth muscle of blood vessels and glomerulus (Huether et al., 2012, p. 466).
One of the main indicators utilized for determination of DM1 disease, as well as changes in management of blood glucose levels as mentioned in the Clinical Manifestations section, is the HbA1C levels. This indicator is a glycosylation end product generated through one of the pathological or errent pathways as discussed in this section. It is the irreversible glycosylation of the red blood cell by the excess blood glucose (Huether et al., 2012, p.467) .
IV) HEXOSAMINE PATHWAY:
Within cells, continuous elevated levels of blood sugar are made into "O"(oligosaccharides) linked glycosylation (sugars attached to proteins) of certain enzymes and proteins. This happens when the excess sugar is shunted to these specific pathways. This process causes oxidative stress and alters signal transduction pathways (Huether et al., 2012, p.467).
All of the above four processes are associated with the advanced cardiovascular complications of DM1.
Coronary artery disease (CAD):
Peripheral vascular disease (PVD):
To help prevent vascular and nerve damage complications, it is essential to control blood glucose and keep glycosylated hemoglobin (HbA1c) levels below 7.0 (A.D.A.M., 2004).