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
**** 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.
What is the leading cause of blindness in the developed world?
What are pancreatic endocrine tumors?
- tumors of the islet cells of the pancreas
Of what are pancreatic tumors often a component?
- MEN1 (along with parathyroid hyperplasia and pituitary adenoma).
*REMEMBER THE 3 P's
What is an insulinoma?
- tumor that produces insulin causing episodic hypoglycemia with mental status changes that are relieved by glucose.
What lab studies will you see with insulinoma?
- increased insulin
- decreased glucose
- increased C-peptide (produced along with insulin)
What if insulin is high but C-peptide is low?
- pt is likely injecting them-self with insulin to seek the attention of medical professionals.
What is a gastrinoma?
- tumor that produces gastrin (goes to the parietal cells of the stomach, causing them to produce HCl via proton pumps).
- will see treatment-resistant peptic ulcers (ZE syndrome)
- ulcers may be multiple and can extend into the jejunum.
What is a somatostatinoma?
- tumor that produces somatostain (inhibits gastrin causing ACHLORHYDRIA, and also inhibits cholecystokinin leading to cholelithiasis and steatorrhea due to lack of gallbladder contraction).
What is a VIPoma?
- tumor that produces vasoactive intestinal peptide (VIP) resulting in watery diarrhea, achlorhydria (due to inhibition of gastric acid secretion), and hypokalemia.
In T1DM, what may be a target of autoantibodies?
- glutamic acid decarboxylase (GAD) in the islets of langerhans
What cytokines can induce BETA cell apoptosis in T1DM?
- IFN, TNF, and IL-1
In T1DM, is there a linkage to MHC Class II HLA genes?
*not in T2DM
**** What are the 3 metabolic pathways by which damage occurs in diabetes?
1. advanced glycation end products= formed from reaction between intracellular glucose derived dicarbonyl precursors with amino group of intracellular and extracellular proteins, leading to cross linking between peptides of the ECM (decreasing elastin, contribute to endothelial injury, trap LDL, increase endothelial permeability, and increase procoagulant activity).
2. activation of protein kinase C= intracellular hyperglycemia causes synthesis of diacylglycerol and activation of PKC, producing VEGF (leads to neovascularaiztion in diabetic retinopathy), increases activity of vasoconstrictor endothelin 1, and decreases vasodilator endothelin nitric oxide synthase.
3. disturbance in polyol pathways= increases cell response to oxidative injury as glucose is converted to fructose, which requires NADPH as a cofactor; NADPH is also a cofactor in the production of glutathione, an antioxidant. Thus you are depleting this important cofactor.
What is the major cause of death in DM?
- MI from atherosclerosis