APP 8 Diabetes and sex hormones Flashcards
Type 1 diabetes/IDDM genetic basis
Endometrial cancer
- Most common cancer in the female reproductive tract - but least lethal.
- Typically found in older postmenopausal women.
- An early symptom is bleeding which helps with early detection and favorable survival rates.
HbA1c test and risk for complications
Test for glycosylated hemoglobin Goal for patients is 7% As % HbA1c rises, so do risks for retinopathy, nephropathy, neuropathy, and microalbuminuria Though this may only be true in Type I diabetes
Is ketoacidosis common in type I, type II DM?
Type I, not Type II
Salpingitis
Inflammation of the fallopian tubes often caused by pelvic inflammatory disease (particularly chlamydia and gonorrhea infections) but may also be caused by tubal pregnancies or endometriosis.
MODY - Maturity-onset diabetes of youth
Genetic defect in insulin production, release, or utilization. Often misdiagnosed as Type I diabetes because pretty rare (only 2% of young diabetics) Treatment: Oral hypoglycemic drugs, NOT insulin
2 effects of insulin on cells
Insulin binds to a dimeric receptor on body cells and targets two pathways: 1. Insertion of GLUT4 glucose transporter into plasma membrane - allows more glucose to enter the cell 2. Transport of amino acids and potassium into the cell for protein synthesis and Na+/K+ pump respectively
Describe the process of insulin secretion
- Glucose enters Beta pancreatic cells passively through the GLUT2 channel. 2. Glucose metabolism forms ATP. 3. ATP blocks ATP-sensitive K leak channel. 4. Blockage depolarizes membrane, causing influx of Ca. 5. Ca influx causes insulin vesicle release
What happens when blood glucose levels FALL?
Low blood glucose –> sensed by pancreas –> insulin is NOT released –> glucagon released by alpha cells –> decreased glucose uptake and glycogen synthesis; increased gluconeogenesis, lipolysis, ketone production, protein breakdown
Gonadotropes through the ages
-High FSH and LH - in utero and as infant as sex organs develop. -Decreasing FSH and LH during childhood until puberty. -FSH and LH reach a steady level in men and begin to cycle in women. -As a woman ages and depletes her stock of eggs, the basal levels of FSH/LH increase in an effort to get the last good eggs. -Basal FSH and LH increase until menopause, when no more ovulation occurs. -After menopause, weight gain is common and estrogen and progesterone are low.
Progression of cervical cancer
Millions of people per year and exposed to HPV via sexual activity. About 1 million develop an infection (aka cervical intraepithelial neoplasia aka CIN). If the infection doesn’t clear, it can turn into higher grade CIN, but only about 10,500 develop into invasive cancer, and only about 5000 per year metastasize.
Causes of amenorrhea
-Ovarian dysfunction caused by feminizing tumors (act like birth control) -Secondary ovarian failure caused by hyperprolactinemia (mimics constant breastfeeding), HPA disorders -Pregnancy, uterine dysfunction (hysterectomy, adhesions) -Menopause -Congenital/acquired ovarian failure (gonadal dysgenesis, gonadotropin resistance, chemotherapy, autoimmune disease, toxins) -Turner syndrome: primary amenorrhea (45X)
Genetic factors, type I vs type II 1. Concordance rate? 2. HLA linkage?
- 90% 2. Yes; No
What inhibits glucagon secretion?
Insulin
With pre-DM, is it possible to slow down progression of DM?
Yes.
Type 1 diabetes/IDDM clinical presentation
Onset
Breast cancer incidence versus mortality
Breast cancer incidence is rising while mortality is staying the same/slightly declining. Controversy over why.
Name the phases of diabetic retinopathy
- Background 2. Proliferative
Type 2 diabetes/NIDDM pathogenesis
Insulin resistance Relative insulin deficiency
Prostate cancer
Arises in the outer zones of the prostate, usually slow-growing. Not very aggressive, symptoms present later on in life. “Most men die WITH prostate cancer, not OF prostate cancer” Palpate prostate by digital rectal exam.
Type 2 diabetes/NIDDM genetic basis
>90% concordance in twins because they tend to have similar lifestyle preferences No HLA associations
What is the leading cause of kidney failure?
Diabetes
What is the leading cause of blindness?
Diabetic retinopathy
What happens when blood glucose levels RISE?
High blood glucose –> sensed by pancreas –> insulin released by beta cells (and glucagon secretion is therefore inhibited) –> increased glucose uptake, glycolysis, glycogen synthesis, triglyceride synthesis, AA uptake, protein synthesis
What is the result of increased polyol/sorbitol pathway?
Diabetic neuropathy Cataracts
Preeclampsia symptoms
Characteristic triad: hypertension, proteinuria, edema (due to loss of albumin) Maternal blood pressure increases to deliver gases and nutrients to the starving fetus
What is pre-diabetes?
40% of US adults 40-74 have pre-diabetes About 10% of pre-diabetics graduate to type 2 diabetes
Chronic complications of Diabetes Mellitus
-Hyperglycemia and nonenzymatic glycosylation -Microvascular disease: retinopathy, nephropathy, cardiomyopathy -Macrovascular disease: coronary artery disease, stroke, peripheral arterial disease -Polyol/sorbitol pathway: neuropathy, cataracts -Glaucoma, infection
Acute complications of diabetes mellitus
-Hypoglycemia -Diabetic ketoacidosis -HHNKS/HONKS = Hyperosmolar hyperglycemic nonketotic syndrome
Hydatiform mole (molar pregnancy)
A nonviable egg implants causing swollen chorionic villi Can progress to cancer if not completely removed The mole produces lots of hCG, which you can use to test whether it has been removed/
Clinical diagnosis of diabetes mellitus
- Fasting plasma glucose level > 126 mg/dL and normal levels 200 mg/dL after 2 hours during OGTT
Endometriosis definition, causes, and treatment
Endometrial tissue migrates outside of the endometrium and proliferates and becomes ischemic in response to menstruation hormones. May happen via: -Retrograde movement through the fallopian tubes -migration through the lymph -entry into the bloodstream Treatment - Birth control pills or pregnancy
Diabetic nephropathy
Only ~30% of diabetic patients Treat with ACE inhibitors and/or angiotensin receptor blockers. May require dialysis. -Leakiness of glomerular capillaries: microalbuminuria-proteinuria -Glomerulosclerosis, tubulointerstitial fibrosis -Arteriolar sclerosis -Renal failure, hypertension, CV disease
What causes cervical cancer?
High-risk strains typically destroy the p53 and Rb tumor suppressor proteins. Once these brakes are off, the infected cells can pick up mutations and some of these mutations may cause cancer.
History of diabetes
1st century A.D. - Diabetes is first described 1922 - Insulin extracts first tested on a human (ground up pancreas) 1940s - Links to long-term complications are being made because patients are surviving longer 1959: Type I and Type II identified and described
What percentage of US adults aged 40-74 have pre-DM?
40%
GBM - Gestational diabetes mellitus
Occurs or is identified during pregnancy Often a precursor for developing Type I or Type II diabetes; may or may not go away after women deliver Thought to be caused by chorion somatomammotropin
What are the acute complications of DM? (3)
- Hypoglycemia (TI) 2. Diabetic ketoacidosis (TI) 3. Hyperosmolar hyperglycemic nonketotic syndrome (HONKS; draws water out of cells and the brain, coma)
Menstrual cycle: Ovarian cycle
-Follicular phase: FSH tells follicles to start developing, a Graffian/dominant follicle is selected and secretes lots of estrogen, leading to an LH surge caused by mid-cycle positive feedback switch - triggering the rupture of the follicle/ovulation. -Luteal phase: Corpus luteum is left over from the ruptured Graffian follicle and secretes estrogen and progesterone. Progesterone helps maintain the endometrium among other “pro-pregnancy” actions. If pregnancy does not occur, the CL degenerates into the corpus albicans.
Diagnostic criteria for DM
- Fasting plasma glucose level
- 2 hours post oral glucose tolerance test
- > 126 mg/dL
- > 200 mg/dL
Diabetes insipidus
A defect in water reabsorption in the kidney
Type 2 diabetes/NIDDM clinical presentation
Onset > 30 years old (usually) Associated with obesity Increased blood insulin No anti-islet cell antibodies Ketoacidosis is rare
Menstrual cycle: Endometrial cycle
-Menstruation: Bleeding. :( -Proliferative phase: pre-ovulatory uterus is thickening its endometrium -Secretory phase: Post-ovulatory uterus. Corresponds to the Luteal phase of the ovarian cycle, endometrium is maintained by CL’s progesterone.
What is a treatment of hyperkalemia? Why?
Insulin. It increases ATPase activity, thus putting K into the cells.
Frequency of diabetes types: 1. Type I 2. Type II 3. Maturity-onset diabetes of youth 4. Gestational diabetes
- 10% 2. 90% 3.
Which has higher risk for retinopathy, TI or TII?
TI (40%) > TII (20%)
Pancreas structure/functions
Exocrine function: to produce digestive enzymes and bicarbonate, which are delivered to the small intestine via the pancreatic duct. Endocrine functions: Islets of Langerhan secrete insulin/C peptide (beta cells), glucagon (alpha cells), and somatostatin (delta cells) to help regulate blood glucose levels.
Peripheral diabetic neuropathy
Causes either pain or loss of feeling in the toes, feet, legs, hands, arms “Diabetic foot” - Blisters and sores may appear on numb areas of foot because pressure/injury goes unnoticed May require amputation
PID
Pelvic inflammatory disease - inflammation of either or both the ovary and fallopian tube
What is believed to be the cause of gestational diabetes?
Chorionic somatommamotropin
Ectopic pregnancy
Embryo implants outside of the uterus. Cannot go to term due to insufficient trophic support. Most commonly in the fallopian tubes because scar tissue impedes egg movement. Risk of exsanguination of tube ruptures. *Always test for ectopic pregnancy if a woman presents with LRQ pain
Is glucose in a high or low concentration in the cell? Why?
Low. It is immediately phosphorylated, keeping concentration low.
Clinical diagnosis of pre-diabetes
Also called impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) IFG: Fasting plasma glucose levels are above 99 mg/dL and below 126 mg/dL – not high enough to be classified as diabetes IGT: blood glucose is 140-199 mg/dL after a 2-hr OGTT – not high enough to be classified as diabetes
How many pre-diabetics “graduate” to TII DM each year?
10%
What does autonomic neuropathy effect?
- Sexual response, digestion, bowel and bladder function, perspiration, heart and BP.
Levels of hormones/molecules over the first 12 hours of starvation
-Insulin drops -Glucagon rises -Free fatty acids rise a LOT -Blood glucose drops -Liver glycogen drops a LOT after a slight initial rise -Blood ketone bodies rise a LOT LOT
Energy cost of menstrual cycle
The menstrual cycle is energy costly and inefficient. Women burn calories equivalent to about a pound of fat each month. The entire endometrium of the uterus thickens to prepare for potential implantation, even though only a tiny area is actually needed for a fertilized egg to implant.
Type 1 diabetes/IDDM pathogenesis
Autoimmunity, immunopathic mechanisms, severe insulin deficiency
Where do fluids tend to gather in the female peritoneum?
Anterior and posterior cul-de-sacs Aka vesicouterine pouch and rectouterine pouch/pouch of douglas.
Leiomyomas
Tumors of smooth muscle with well-defined borders most commonly found in the uterus. Can asymptomatic but may be very painful. Operable. NOT CANCER.
What stimulates insulin secretion?
Glucose
Preeclampsia pathology
Shallow egg implantation limits nutrient diffusion to the growing fetus Usually subclinical until the end of the 2nd or beginning of the 3rd trimester when growth rate is the highest and the fetus feel starved
Complete vs partial hydatiform mole
Complete: All vesicular villi, no embryonic tissue, diploid paternal DNA Partial: some vesicular villi, deformed (nonviable) fetus, triploid DNA (2 paternal 1 maternal)
How many oocytes is a baby girl born with?
~2 million… this is all the eggs she will ever have
Focal diabetic neuropathy
Results in sudden weakness of one nerve or a group of nerves causing muscle weakness or pain. Any nerve in the body may be affected.
Autonomic diabetic neuropathy
Changes in digestion, bowel/bladder function, sexual response, perspiration, heart rate, blood pressure
Diabetic retinopathy
Diabetes is the leading cause of blindness - retinal damage Early phase: background diabetic retinopathy - arteries in the retina becomes weakened and leak, forming small hemorrhages Later phase: Proliferative diabetic retinopathy - Poor circulation causes areas of the retina to become ischemic. Neovascularization occurs, developing new fragile vessels to develop in an attempt to maintain oxygen levels in the retina. But these baby vessels hemorrhages easily, worsening the problem.
PCOS symptoms and treatment
Symptoms: -Amenorrhea/irregular menstruation -Excess androgen & masculinization -Enlarged ovaries with multiple cysts (unruptured follicles) Treatment: Birth control pills to regulate hormone levels (and other things)
Type 1 diabetes/IDDM islet cell presentation
Early insulitis Marked atrophy and fibrosis Beta-cell depletion
What are the values for pre-diabetes? 1. Fasting glucose 2. 2 hours post OGGT
- 100-125 mg/dL 2. 140-199
What is the most effective treatment for nephropathy?
ACE inhibitors
How does glucose cause insulin release from the beta cells?
Glucose enters beta cells via GLUT2 transporters. Glucose levels rise, causing ATP/ADP levels to rise, resulting in gating of the ATP-sensitive potassium channels. K+ builds up, leading to depolarization of the beta cells, causing voltage-gated Ca++ channels to open. Influx of Ca++ causes release of insulin by exocytosis of storage granules.
Type 2 diabetes/NIDDM islet cell presentation
No insulitis Focal atrophy and amyloid deposits Mild beta cell depletion
What is used to supply energy to brain if glucose is not available?
Ketones
Benign Prostatic Hyperplasia
Normal growth of prostate tissue as men age, usually in the central zone. Becomes a problem as it compresses the urethra Treatment: Catheterization or surgery to reduce the tissue
Teratoma
Germ cell tumor Because germ cells are pluripotent, teratomas contain all sorts of tissues (skin, hair, teeth, bones, etc). Usually not malignant
What percentage of DM patients develop nephropathy?
30%
PCOS pathology
Polycystic ovarian syndrome HIGH levels of LH - theca cells makes lots of androstenedione which normally gets converted to estradiol in the granulosa cells by FSH – but is not in PCOS due to LOW FSH levels. Androstenedione circulates systemically and is converted to estrone by peripheral adipose tissue, which further decreases FSH levels by negative feedback. So now we have even lower estradiol levels. In summary… HIGH LH and HIGH ANDROGEN –> LOW FSH –> LOW ESTROGEN
HPV infection types
HPV 6 and 11 cause low-risk episomal infections –> condylomas. High-risk HPV infections are caused by 16, 18 and others and use viral integration to attack the cells of the squamocolumnar junctions where the vagina meets the endometrium.
Ovarian cancer of surface epithelial cells
Surface epithelial-stromal cell tumors 65-70% of all ovarian cancers 90% of MALIGNANT tumors Affects ages 20+ years Dismal survival rate because very few symptoms Once there’s a visible lump its probably already metastasized **Women with BRCA1 mutation have a lifetime risk of 30%, compared with 2% for “normal” women
What is the cause of pain and numbness in neuropathy?
Schwann cells compress the axons
the __ cell produces glucagon
alpha
what does diabetes do to basement membranes?
-diffuse thickening -can lead to leaky capillaries
treatment for DKA
-restore volume -give insulin
what is the cause of Kussmaul respirations?
lungs are trying to blow of CO2 to compensate for the acidosis
the __ cell produces insulin
beta
genetics of Type I diabetes
many/variable HLA genes on chromosome 6 DR3, DR4
what does diabetes do to the small vessels?
hyaline arteriosclerosis
what is the progression of neuropathy in diabetics?
-loss of vibration sense, light touch and thermal sensitivity -numbness tingling, pain -wasting of muscles, sensory ataxia
why do diabetics get retinopathy?
-increased VEGF -osmotic damage to pericytes of retinal blood vessels -osmotic damage to the lens
what is the most common cause of death in diabetics?
MI
hyperosmolar hyperglycemic syndrome
-more common in type II diabetes -severe dehydration secondary to sustained osmotic diuresis -signs of dehydration, neuro abnormalities (seizure, aphasia)
why is central (intraabdominal fat) a risk factor for type II diabetes?
-it has a higher lipolytic rate than peripheral fat and is more resistant to insulin -results in more circulating free fatty acids allowing for greater gluconeogenesis, leading to higher glucose levels
in DKA, patients become ___kalemic because: Body stores of potassium are ___
hyper- -cells activate the hydrogen/potassium exchanger to get rid of acidosis, taking up hydrogen and putting out potassium -low
how does the histology of the pancreas differ in type I and type II diabetes?
type I: insulinitis (inflammation) type II: amyloid deposition (beta cells burning out)
where is neuropathy typically seen in diabetes?
hands and feet
why do patients with type I diabetes get very hungry?
-catabolism of muscle leads to a negative nitrogen balance
what happens in the polyol pathway?
-glucose is converted to sorbitol by aldose reductase -this uses up NADPH, which is also needed by glutathione reductase -sorbitol is converted to fructose -this creates NADH which can lead to the formation of free radicals
in what organ is glucose uptake independent of insulin?
brain
explain the production of ketones in type I diabetes
-lack of insulin leads to increased lipolysis -free fatty acids go to the liver where they are converted to ketone bodies
why is non-enzymatic glycosylation a problem?
-glycosylation of hemoglobin, collagen, laminin makes them resistant to degradation -they accumulate and cause damage: -cytokines -reactive oxygen species -vascular permeability -procoagulant activity -increased ECM protein depositin
what is the other problem with sorbitol accumulation in the cell?
-it exerts an osmotic force which damages the cell
the ___ cell produces somatostatin
somatostatin
what is the treatment of hyperosmolar hyperglycemic syndrome
-volume resuscitation and insulin administration
how is diabetes diagnosed?
-random glucose > 200 mg/dL -fasting glucose > 126 mg/dL -abnormal glucose tolerance test: >200 2 hours after a standard carbohydrate load -HbA1c level > 6.5
findings in DKA
-weakness, lethargy, nausea, vomiting -peri-umbilical pain -advancing polyuria and polydipsia -Kussmaul respirations -fruity odor
what is the progression of kidney findings seen in diabetes?
-hyperfiltration -microalbuminemia -macroalbuminemia -nephrotic syndrome
what are precipitants of DKA?
-inadequate insulin therapy -infection -thrombotic episode -alcohol intoxication
presentation of type I diabetes
-abrupt onset -polyuria -polydipsia -polyphagia -paradoxical weight loss
what is the feared complication of DKA?
coma (brain runs out of full)
what are the problems caused by PKC activation?
-enhanced VEGF production -stimulation of growth factors which enhance extracellular matrix deposition and thicken basement membranes -stimulation of pro-inflammatory cytokines
why are diabetics at increased risk of papillary necrosis?
they are at increased risk of infection, leading to acute pylonephritis
what does diabetes do to the large and medium sized vessels?
atherosclerosis via non-enzymatic glycosylation
the polyol pathway occurs in what tissues?
tissues that are insulin-independent for glucose transport (nerves, lens, kidneys, blood vessels)
how does diabetes cause protein kinase C activation?
metabolism of glucose creates diacylglycerol which activates PKC
