Pathology of Diabetes and Diabetes-Related Pathologies Flashcards Preview

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Flashcards in Pathology of Diabetes and Diabetes-Related Pathologies Deck (45)
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Of what is the endocrine pancreas composed?

- clusters of cells termed islets of Langerhans.
- a single islet consists of multiple cell types, each producing one type of hormone.
- INSULIN is secreted by BETA cells; lie in the CENTER of islets.


What is INSULIN?

- the major anabolic hormone, which up-regulates insulin-dependent GLUT4 on skeletal muscle and adipose tissue (decreasing serum glucose).
*increased glucose uptake by tissues leads to increased glycogen synthesis, protein synthesis, and lipogenesis.



- hormone secreted by ALPHA cells, which opposes insulin in order to increase blood glucose (e.g. states of fasting) via glycogenolysis and lipolysis.


**** What is Type 1 Diabetes Mellitus (T1DM)?

- AUTOIMMUNE DESTRUCTION of BETA cells by T LYMPHOCYTES (type IV hypersensitivity) causing an insulin deficiency, which leads to a metabolic disorder characterized by hyperglycemia.
- characterized by INFLAMMATION of ISLETS.
- INSULINITIS= necrosis of islets and lymphocytic infiltration.


With what HLAs is T1DM associated?

- HLA-DR3 and DR4


In T1DM, can autoantibodies against insulin be present years before clinical disease develops?

- YES often.


When does T1DM manifest?

- in CHILDHOOD with features of insulin deficiency.


**** What are the clinical signs of T1DM?

- high serum glucose (lack of insulin leads to decreased glucose uptake by fat and skeletal muscle).
- weight loss, low muscle mass, and polyphagia (unopposed glucagon leads to gluconeogenesis, glycogenolysis, and lipolysis, which further exacerbates hyperglycemia).
- polyuria, polydispsia, and glycosuria (hyperglycemia exceeds renal ability to resorb glucose; excess filtered glucose leads to osmotic diuresis).


How do you treat T1DM?

- life long insulin


What is a feared complication of T1DM?

- diabetic ketoacidosis (DKA)


**** What is diabetic ketoacidosis (DKA)?

- excessive serum ketones that often arises with stress (e.g. infection); epinephrine stimulates GLUCAGON secretion, increasing lipolysis, along with gluconeogenesis and glycogenolysis.


What happens in DKA with increased lipolysis?

- increased FFAs, which the liver converts to KETONE BODIES (B-hydroxybutyric acid and acetoacetic acid).


**** What are the clinical features of DKA?

- HYPERGLYCEMIA (greater than 300 mg/dL) due to stimulation of gluconeogenesis and glycogenolysis.
- anion gap METABOLIC ACIDOSIS (due to excess ketones in the blood)
- HYPERKALEMIA bc insulin is required for driving K+ into cells, and the body tries to buffer the acidic blood by driving H+ into the cells in exchange for K+ out into the blood; note much of the K+ will be lost in the urine.
- KUSSMAUL RESPIRATIONS (trying to blow off the acidosis), dehydration, nausea, vomiting, mental status changes, and FRUITY SMELLING BREATH


*** How do you treat DKA?

- FLUIDS (corrects dehydration from plyuria)
- ELECTROLYTES (potassium)


**** What is type 2 Diabetes Mellitus (T2DM)?

- end-organ INSULIN RESISTANCE leading to metabolic disorder characterized by HYPERGLYCEMIA.


Is T1DM or T2DM more common?

- T2DM by FAR
*incidence is rising!


In whom does T2DM arise?

- OBESE middle-aged adults.
- Obesity leads to DECREASED numbers of insulin-RECEPTORS.


Is there a genetic predisposition for T2DM?

- YES, higher than T1DM


Will insulin levels be high or low, in the early stages of T2DM?

- HIGH bc the islet cells of the pancreas are producing more in an attempt to overcome the insulin resistance of the cells.


What happens to insulin later in T2DM?

- insulin deficiency due to BETA cell EXHAUSTION.


**** What will you see on histology of the pancreas in T2DM?

- AMYLOID deposition in islets.


**** What are the clinical features of T2DM?

- polyuria
- polydipsia
- hyperglycemia
*often clinically silent


How do you diagnose T2DM?

- random glucose greater than 200 mg/dL
- fasting glucose greater than 126 mg/dL
- glucose tolerance test greater than 200 mg/dL 2 hours after glucose load.


How do you treat T2DM?

- weight loss
- drug therapy to counter insulin resistance
- insulin in later stages of disease


What is hyperosmolar non-ketotic coma? (risk of T2DM)

- high glucose (greater than 500 mg/dL) leads to life-threatening diuresis (due to overwhelming glucose in the filtrate, pulling water along with it) with hypotension and coma.
*ketones are absent due to small amounts of circulating insulin.


**** What are the 2 long-term consequences of diabetes?

1. NONENZYMATIC GLYCOSYLATION (NEG) of vascular basement membranes (aka you are just sticking sugar to the vessel walls).


**** What complications can arise from nonenzymatic glycosylation (NEG) caused by diabetes?

- NEG of large and medium sized vessels MACROvascular disease= ATHEROSCLEROSIS; CVD is the leading cause of death among diabetics and PVD is the leading cause of nontraumatic amputations in diabetics.
- NEG of small vessels (MICROvascular disease)= HYALINE ARTERIOLOSCLEROSIS.
- NEG of hemoglobin= HbA1c


**** What complications can arise in the kidneys due to NEG of small vessels (MICROvascular disease) in diabetes causing hyaline arteriolosclerosis (thickening of basement membrane; mostly type IV collagen)?

- small scarred kidneys with a granular surface
- preferential involvement of the EFFERENT arterioles leads to glomerular hyperfiltration injury with microalbuminuria that eventually progresses to NEPHROTIC syndrome (characterized by KIMMELSTIEL-WILSON nodules in glomeruli).
*can eventually lead to chronic renal failure.


What is important about HbA1c?

- it is an important marker of glycemic control


**** How does osmotic damage occur as a long-term consequences of diabetes? (VERY HIGH YIELD)

- glucose freely enters into Schwann cells (which myelinate peripheral nerves), pericytes of retinal blood vessels, and the lens.
- ALDOSE REDUCTASE converts glucose to SORBITOL, resulting in osmotic damage.
- this leads to PERIPHERAL NEUROPATHY (can lead to infections), IMPOTENCE, BLINDNESS, AND CATARACTS.