Flashcards in Pathology of Diabetes and Diabetes-Related Pathologies Deck (45)
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.
What is GLUCAGON?
- 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?
*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).
2. OSMOTIC DAMAGE
**** 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