Pathogenesis

Diabetes mellitus type 1 (DM1) is a disease that is subdivided into two groups: immune system mediated (type 1A) and idiopathic (type 1B). Those with DM type 1B have permanent insulin secretion deficiency by the pancreas, but no development of autoimmunity (Ichinose, Kawasaki, & Eguchi, 2007). Since more than 80% of patients with DM1 have the immune system mediated form, the following physiological changes refer to type 1A (Skyler, 2011).

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).
Mechanism of beta cell destruction in DM1:


Roncarolo, M.G., & Battagliam, M. (2007). Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans. Nature Reviews, 7(8), 585-598 

  • 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).
Pathogenesis of DM1 is related to the imbalance between Tregs cells and Teff cells (Bluestone, Herold, & Eisenbarth, 2010).

3. Onset of clinical disease
  • Refer to Clinical Manifestations.
4. Transient remission
  • 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).
5. Established disease
  • Almost all beta-cell function is lost → patient is totally dependent on exogenous insulin.
6. Acute and chronic complications of DM1:
Short-term complications
Hyperglycemia: result of excess glucose and/or insufficient 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.
Hypoglycemia: result of insufficient glucose and/or an excess of insulin.

Long-term complications
Microcirculation and macrocirculation
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.

MICROCIRCULATION:
Microcirculation refers to the capillaries. Capillaries are most abundant in the periphery of the body (fingers and toes) and at the interface of various organs such as the eyes and kidneys. The four pathological processes above in turn affect the capillaries as they are more vulnerable in terms of fragility and size. The main effects of this peripheral capillary damage are found in these pathologies: retinopathy, nephropathy and neuropathy.
Retinopathy:
Diabetic retinopathy is the leading cause of blindness in the world (Huether et al., 2012, p. 467). In a 2003 study cited in A.D.A.M. (accredited medical information web site), 40% of young DM1 adults had developed retinopathy within 10 years.
The consistently high BG levels eventually weakens the capillaries in the eye causing rupture, leakage of blood and waxy formation in areas of the retina and lens of the eye. Vision problems are evident at this stage. As the problem progresses, the capillaries become further blocked and eventually the blood flow to the eye is cut off. At this point, a major hemorrhage or retinal detachment can also occur causing blindness (Huether et al., 2012, p. 467).
Nephropathy:
The microcirculation of the kidney becomes affected in stages similar to those in the eye. Decreased kidney function is a result of the breakdown in integrity of the microcirculation from the above four processes. Microalbuminuria is the first sign of dysfunction of the kidneys. If left untreated, diabetic patients with microalbuminuria will progress to proteinuria. Continuously decreased glomerular filtration rates lead to overt diabetic nephropathy (Huether et al., 2012, p. 467). Eventually, uncontrollable nephropathy can result in the need for kidney dialysis if the kidney loses its function completely.
Neuropathies:
Diabetic neuropathy is considered the most common complication of diabetes and the most common cause of neuropathy in the Western countries (Huether et al., 2012, p. 467). Neuropathies tend to be mostly sensory based and include the loss of pain expressed as numbness, the sense of vibration and the sense of temperature. In DM1 patients, foot neuropathies are very common (Huether et al., 2012, p.467). All of these sensory losses put a diabetic at risk for foot ulcerations as a diabetic may not realize they have injured themselves without the usual feedback mechanisms. There are many other types of neuropathies including autonomic neuropathy, which affects internal processes such as diarrhea,  bladder function and impotence.  Although it is related to hyperglycemia, the exact mechanism of injury to the peripheral nerves is not known, however, it is likely to be related to the above pathways, specifically polyol accumulation, formation of AGEs and oxidative stress (Fowler, 2008). Neuropathies generally get progressively worse however, sometimes the process can be reversed although there is not always obvious connections to the reasons for the reversal (Huether et al., 2012, p. 467).

MACROCIRCULATION
Macrocirculation refers to medium- and large-sized arteries. Macrovascular complications such as coronary artery disease, stroke and peripheral vascular disease arise due to these four altered pathways and hyperglycemia. Arteriosclerosis and atherosclerosis are the central pathological mechanisms in macrovascular disease. Arteriosclerosis refers to stiffening of arteries related to loss of elasticity. Over time, high blood pressure causes the arteries to become progressively hardened by fibrous tissue and calcification (Huether et al., 2012, p. 594). Atherosclerosis is characterized by narrowing of an arterial wall, and is thought to result from chronic inflammation and injury to the wall itself. This leads to oxidized lipids from low-density lipoprotein (LDL) particles and macrophages to accumulate and form an atherosclerotic lesion called a plaque (Fowler, 2008). Atherosclerosis is often present in those with insulin resistance and impaired glucose tolerance, and is not related to severity of diabetes.
Both arteriosclerosis and atherosclerosis are accelerated by DM1. A diabetic patient with arteriosclerosis may not have atherosclerosis, but a patient with atherosclerosis does have arteriosclerosis. There are many stages of atherosclerotic plaque development that  aspects of DM1 pathophysiology affects including; endothelial damage (the 1st stage), thickening of the vessel wall, increased inflammation and thrombosis (clot formation), glycation of vascular proteins, dyslipidemia (elevated LDL and reduced HDL), and decreased production of nitric oxide and other endothelial vasodilators (Huether, et al., 2012, p.599).  As a result the progression of macrocirculation complications is accelerated. Although the exact mechanism through which DM1 increases the likelihood of these cardiovascular diseases (arterial wall hardening and plaque formation) is unknown, a strong association is found to exist. In fact, CVD is the primary cause of death in patients with either type 1 or type 2 DM (Fowler, 2008).
Coronary artery disease (CAD):
CAD, also called ischemic heart disease, is caused by hardening and thickening (arteriosclerosis) of the walls of the blood vessels that go into your heart (National Diabetes Information Clearinghouse). These vessels not only become narrow (arteriosclerosis), but may also be blocked (atherosclerosis) by plaque. Studies have shown that patients with DM1 have a higher mortality from CAD at all ages compared to the general population (Fowler, 2008). 60% of deaths in all diabetics are a result of heart attacks (A.D.A.M., 2004). 
Stroke:
As a cerebral vascular disease, stroke results when the blood supply to the brain is suddenly cut off due to narrowing or blocking of those blood vessels (National Diabetes Information Clearinghouse). Compared to non-diabetic patients, stroke is twice as common in those with diabetes. Additionally, the survival rate after a massive stroke for those with diabetes is generally shorter (Huether et al., 2012, p.468). Strokes account for 25% of deaths in all diabetics (A.D.A.M., 2004).
Peripheral vascular disease (PVD):
In PVD, the blood vessels of the legs are narrowed or blocked by plaque deposits, which decreases blood flow to the legs and feet (National Diabetes Information Clearinghouse). PVD in those with diabetes often involves arteries below the knee. Occlusions of the blood vessels initially result in lesions beginning as ulcers, and then continue to progress to gangrene formation requiring amputation (Huether et al., 2012, p.468).
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). 

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