Pathophysiology
Summary
Type 1 diabetes mellitus (T1DM) characterized by autoimmune destruction of the islets of Langerhans in pancreatic beta cells, leading to an absolute insulin deficiency. T1DM usually appears in the autoimmune process, both adaptive and innate immune systems are involved. Specifically, CD8+ T-cells attack pancreatic beta cells after losing their "self-tolerance," while B-cells produce autoantibodies, aided by CD4+ helper T cells. Common autoantibodies in T1DM include anti-glutamic acid decarboxylase and anti-insulin antibodies. Genetic predispositions feature polymorphisms in MHC class 2 molecules, particularly haplotypes HLA-DR3 and DR4, which are more likely to present self-antigens to helper T cells. T1DM often coexists with other autoimmune diseases like Grave's disease, Hashimoto's thyroiditis, and celiac disease.
In T1DM, histological examination reveals lymphocytic infiltrate within the pancreatic tissue. mostly comprised of T-cells. This infiltration leads to a reduction in both the number and size of islets of Langerhans. The pathophysiology of T1DM centers on metabolic alterations stemming from insulin deficiency. When insulin is deficient, glucose can't enter peripheral cells, leading to a catabolic state. This activates glycogenolysis and gluconeogenesis in the liver and muscle and subsequent hyperglycemia. Clinically, this results in glucosuria, as the kidneys' capacity to reabsorb glucose is surpassed, and polyuria due to increased urinary water loss. The resultant increased plasma osmolality triggers polydipsia through hypothalamic osmoreceptors. Additional symptoms include weight loss and excessive hunger, arising from the breakdown of fat and muscle and the inability of tissues to absorb glucose.
Treatment of T1DM relies on exogenous insulin to replace the deficient endogenous hormone. Management aims to control hyperglycemia and prevent acute and long-term complications.
Type 2 diabetes mellitus (T2DM) is an endocrine disorder characterized by a relative insulin deficiency due to a combination of insulin resistance and pancreatic beta cell dysfunction. Important risk factors for T2DM include family history & obesity.
In the setting of obesity, adipocytes release cytokines (adipokines) that also contribute to insulin resistance. Additionally, intracellular triglycerides and free fatty acids inhibit insulin signaling, further exacerbating insulin resistance. Free fatty acids within macrophages and beta cells lead to cytokine release, which also contributes to insulin resistance and beta cell dysfunction.
Pancreatic beta cells initially respond to insulin resistance by increasing insulin production. However, over time, beta cells are unable to sustain this excessive insulin production, leading to ‘beta cell burnout’ and relative insulin deficiency. Excessive glucose and free fatty acids can accumulate in beta cells, triggering cytokine release that exacerbates beta cell dysfunction. GLP secreted by the intestines may also inadequately stimulate beta cells and contribute dysfunction. Amylin, a polypeptide co-secreted with insulin, forms aggregates of amyloid inside beta cell secretory granules, which can also play a role.
Acute complications of T2DM include the hyperosmolar hyperglycemic state (HHS), which is characterized by extreme hyperglycemia, hyperosmolality, and dehydration. Chronic complications arise due to nonenzymatic glycation, resulting microvascular & macrovascular diseases and neuropathy.
Diagnosis can be made based on various criteria, including random or fasting serum glucose levels, glucose tolerance tests, or hemoglobin A1c (HbA1c) levels, which reflect glycemic control over the preceding three months due to the 3-month lifespan of red blood cells. Treatment involves lifestyle modifications, often in conjunction with oral medications.
Metabolic syndrome (syndrome X) is a constellation of symptoms that includes obesity, hyperglycemia, hypertension, and dyslipidemia. It is a significant risk factor for T2DM and cardiovascular disease. Diagnosis requires at least three of the five findings: elevated fasting glucose, hypertension, hypertriglyceridemia, hypercholesterolemia, and increased waist circumference. Abdominal obesity, as measured by waist circumference, contributes to insulin resistance in both metabolic syndrome and T2DM.
Lastly, mature-onset diabetes of youth (MODY) is an autosomal dominant syndrome characterized by non-insulin-dependent diabetes at a young age. MODY presents similarly to T2DM, with insulin resistance being a prominent feature in both conditions.
Lesson Outline
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FAQs
T1DM is an autoimmune disorder where the immune system mistakenly targets and destroys pancreatic beta cells located in the islets of Langerhans. This autoimmune response is primarily mediated by CD8+ killer T-cells that have lost self-tolerance, and is further facilitated by B-cells that produce autoantibodies against beta cells following activation by CD4+ helper T-cells. Common targets for these autoantibodies include glutamic acid decarboxylase and insulin. The autoimmune destruction, often linked to specific polymorphisms in MHC class 2 molecules like HLA-DR3 and DR4, results in an absolute deficiency of insulin due to the loss of functional beta cells.
The immediate clinical manifestations of T1DM are diverse and stem from an absolute insulin deficiency. This deficiency leads to increased glycogenolysis and gluconeogenesis, resulting in hyperglycemia and glucosuria. The condition also triggers polyuria and polydipsia due to elevated plasma osmolality. Additional symptoms include weight loss from the breakdown of fat and muscle, excessive hunger despite losing weight, and the risk of severe hyperglycemic crises like diabetic ketoacidosis. These symptoms occur because the body cannot effectively transport glucose into peripheral cells for energy.
In T1DM, the pancreatic tissue often exhibits lymphocytic infiltration, appearing as a dense collection of blue cells primarily composed of T-cells. This autoimmune attack leads to a reduction in both the size and number of the pancreatic islets of Langerhans. In histological examinations, these endocrine cells within the islets appear paler compared to the surrounding exocrine acinar cells, which remain largely unaffected by the autoimmune process.
In T2DM, pancreatic beta cells initially increase insulin production to compensate for insulin resistance. Over time, they fail to maintain this elevated output, leading to 'beta-cell burnout.' This dysfunction is influenced by intracellular accumulation of glucose and free fatty acids, which induce cytokine release. Additionally, amylin aggregation, co-secreted with insulin, may also be involved in or result from this beta-cell dysfunction.
Metabolic syndrome is a significant risk factor for the development of T2DM. It is characterized by a constellation of symptoms including abdominal obesity, hyperglycemia, hypertension, and dyslipidemia. Insulin resistance is a common feature in both conditions, often exacerbated by excessive visceral abdominal adipose tissue. A diagnosis of metabolic syndrome requires at least three of five of the findings: elevated fasting glucose, hypertension, hypertriglyceridemia, hypercholesterolemia, increased waist circumference. Metabolic syndrome significantly increases the likelihood of developing T2DM (3-5x) and cardiovascular disease (2x).
