Endocrine - Diabetes Flashcards
Pancreatic Islet of Langerhands
(inner portion of pancreas) – endocrine portion
o Alpha cell – glucagon – secretion is inhibited by insulin – NOT controlled by glucose
o Beta cell – insulin and C peptide
o Delta cell – somatostatin
Effects of Insulin
o Decreased: appetite, glucagon, decrease extracellular potassium levels
o Increased: glucose uptake, glycolysis, glycogen synthesis, triglyceride synthesis, amino acid uptake, protein synthesis
Effects of Lack of Insulin
- primarily mediated by glucagon
o Decreased: glucose uptake, protein synthesis
o Increased: appetite, glucagon, blood glucose, gluconeogenesis, lipolysis, protein breakdown, glycogenolysis, ketone body production (ketoacidosis)
Insulin Effect Mechanism
o Binds to dimeric receptor resulting in intracellular events
o GLUT4 glucose transporter inserted into plasma membrane
Insulin Secretion Mechanism
o Secretion triggered by rising blood glucose levels
o Glucose uptake by GLUT2 transporter leading to increase in cellular ATP ATP binds to ATP-potassium channel preventing K+ from leaking out cell depolarization Ca+ influx exocytotic release of insulin from storage granules
Type 1 Diabetes
(10%) – autoimmune destruction of beta-cells (no insulin = HIGH glucagon)
o Clinical: onset < 20 years old, normal weight, decreased blood insulin, anti-islet cell antibodies, ketoacidosis is common
o Genetics: <50% concordance in twins; HLA-D linked
o Islet Cells: insulitis early, marked atrophy and fibrosis, beta-cell depletion
o Clinical symptoms do not arise until sufficient destruction (50%) has occurred
Type 2 Diabetes
(90%) – insulin resistance
o Clinical: onset > 30 years old, obese, increase blood insulin, ketoacidosis is RARE
o Genetics: >90% concordance in twins; NO HLA associations
o Pathogenesis: insulin resistance, relative insulin deficiency
o Islet Cells: no insulitis, focal atrophy and amyloid deposits, mild beta-cell depletion
o Progressive loss of insulin sensitivity, resulting in progressive increase in insulin production
Maintains normal serum glucose but results in hyperinsulinemia
As insulin insensitivity falls, hyperinsulinemia is not sufficient to maintain normal glycemia and hyperglycemia results
Chronic hyperglycemia (glucose toxicity) results in beta-cell destruction and loss of insulin production; typically requires more than 10 years
Other Types of Diabetes
(<1%)
o Maturity-onset diabetes of youth – 2% of diabetics under age of 15
Genetic defect in insulin production or release
Often misdiagnosed for Type I diabetes
Treatment: oral hypoglycemic drug
o Gestational Diabetes Mellitus – diabetes identified during pregnancy
Most likely pre-diabetic prior to birth
Possibly caused by chorionic somatomammotropin
o Various other endocrine disorders – Cushing’s, acromegaly, pheochromocytoma, etc.
Oral Glucose Test
o Normal fasting plasma glucose levels < 100mg/dl
o Fasting plasma glucose level > 126mg/dl
o OR Plasma glucose levels in excess >200mg/dl after 2 hours during tests
Pre-Diabetes
o Also called impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) depending on test used to diagnose it (some people have both)
o IFG – blood glucose level is 100-125mg/dl after an overnight fast
o IGT – blood glucose level is 140-199 after 2 hour oral glucose tolerance test
o 40% of adults between 40-75 have pre-diabetes
o 10% of pre-diabetics develop into type 2 diabetes
Acute Complications
o Acute Complications – hypoglycemia, diabetic ketoacidosis, hyperosmolar hyperglycemic nonketotic syndrome, glucosuria/polyuria
Hyperosmolar Hyperglycemic Nonketotic Syndrome – only affects Type II diabetics
• Result of glucose in blood drawing water out of cells
Chronic Complications
Hyperglycemia & Nonenzymatic glycosylation-advanced glycosylation end-products
• Glucose binds to and damages proteins (ex: HbA1c – glycosylated hemoglobin)
o Higher levels of HbA1c = higher risk of retinopathy, nephropathy, neuropathy, microalbuminuria
Associated with Type 1 diabetics and NOT Type 2 diabetics
Microvascular disease – diabetic retinopathy, nephropathy, cardiomyopathy
Macrovascular disease – coronary artery disease, stroke, peripheral arterial disease
Increase activity of polyol/sorbitol pathway - diabetic neuropathy, cataracts
Other – glaucoma, infection
Ketogenesis
– generation of ketone bodies from acetyl-CoA,
o Increased urine output leads to dehydration and hypovolemic shock
o Enzymes involved are unique to hepatocytes
o Mitochondrial HMG-CoA is essential intermediate
o Initial product acetoacetic acid can decompose to beta-hydroxybutyrate or acetone
Diabetic Retinopathy
o Diabetes causes retinal damage and leads to blindness
o Prevalence is higher in Type 1 (40%) than in Type 2 (20%)
o Earliest Phase of Disease – background diabetic retinopathy – arteries in retina become weakened and leak, forming small, dot-like hemorrhages
o Later Stage – proliferative diabetic retinopathy – circulation problems cause areas of retina to become oxygen-deprived (ischemic) – new fragile vessels develop as circulatory system attempts to maintain adequate oxygen levels within retina BUT the vessels will hemorrhage easily
Diabetic Nephropathy
o Leakiness of glomerular capillaries: microalbuminuria-proteinuria
o Glomerulosclerosis, tubulointerstitial fibrosis, arteriolar sclerosis
o Renal failure, hypertension, cardiovascular disease
o Kidney disease – granular surface, decreased function, smaller size, high urine protein
Diabetic Nephropathy Characteristics
o 30% of diabetics will develop diabetic nephropathy
o Diabetes (type 1 and 2) is leading cause of kidney failure
o Greatest rate of progression seen in patients with poor control of their blood pressure
o Main treatment (once proteinuria is diagnosed) – keep blood pressure under control
o Treatment: angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers
o Uncontrolled diabetes often requires dialysis diabetic patients do worse
Diabetic Neuropathy
o Peripheral Neuropathy – causes pain or loss of feeling in toes, feet, legs, hands, and arms
o Diabetic Foot – blisters/sores appear on numb areas of foot b/z pressure or injury goes unnoticed
If untreated – infection may spread to bone and foot may need to be amputated
o Autonomic Neuropathy – causes changes in digestion, bowel and bladder function, sexual response, and perspiration
Can also affect nerves that serve the heart and control blood pressure
o Focal Neuropathy – sudden weakness of one nerve or group of nerves, causing weakness or pain
Any nerve in body may be affected
Gestational Diabetes
o During pregnancy, hormonal changes can cause impaired insulin sensitivity
o Glucose levels are normally lower during pregnancy so cutoff levels for diagnosis of diabetes in pregnancy are lower
Fasting blood glucose = 95mg/dl, 1-hour level = 180mg/dl, 2-hour level = 155mg/dl, 3-hour level = 40mg/dl
o Usually occurs between 24-28 weeks of pregnancy
o If poorly controlled, can cross the placenta and give the baby hyperglycemia
o Babies from mothers with gestational diabetes have higher risk for developing hypertension and cardiovascular disease
o Resolves itself following childbirth
o Once you’ve had gestational diabetes, chances are it will return in future pregnancies
