Exam 2: Endocrine Flashcards
what are the two hormones pancreas makes for glycemic control?
- insulin
- glucagon
what kind of hormone is insulin? and describe the basic function of it
- it is a anabolic hormone
function: it drives sugar into cells and storage, increasing the production of energy proteins glycogen and fat
- the energy helps the cells carry out their purpose and their functions
what kind of hormone is glucagon? and describe its function
- it is a catabolic hormone
function: it drives the release of energy from storage molecules when blood sugar is lower
what is a decrease in insulin caused by? (3)
- defects in the beta cell of the pancreas
-the insulin molecule itself - the insulin receptors of all of these
what are the two types of T1DM?
- autoimmune
- non-immune
describe T1DM in immune mediated
autoimmune destruction of pancreatic beta cells, insulitis
unknown environmental trigger in genetically predisposed individual triggers pancreatic cell destruction
diagnostic criteria for DM (4)
- HbA1C >6.5%
- FPG >126 mg/dL; fasting is defined as no caloric intake for at least 8 hrs
- 2-h plasma glucose >200 mg/dL during OGTT
- in an individual with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose >200
**if just using 4: need both clinical prsentation paired with elevated BG
** if using criteria 1-3 : we need two of these from one sample or two
why is hgb A1C useful for both diagnosing and monitoring glycemic control
because theres a tendency for glucose to bind to the hgb in RBC
-the RBC last about 120 days–> so this gives us a good idea of the average blood glucose levels over the last 4 month
what are the big influencers for T1DM?
-autoimmune
-genetic
what are the big influencers for T2DM
-genetic
- environmental factors–> races and obesity being the biggest influences
what triggers T1DM?
- need both the genetic susceptibility and then exposure to something in the environment that kind of trigger it
–this is why often times children develop T1DM or get the diagnosis after they had some kind of viral infection
what is the genetic susceptibility of DM 1?
- first degree relative (parent or sibling) with type 1 DM
- strongest association with major histocompatibility complex (MHC)
what are environmental factors of DM 1? (4)
- viral infection
- h. pylori
- exposure to cows milk proteins
- relative lack of vitamin D (also implicated)
what is autoimmunity type 1 DM?
a slowly progressive autoimmune T-cell mediated disease that destroys beta cells of the pancreas and occurs in genetically susceptible individuals
the cell mediate immune process of T1DM
o Destruction of beta cells mediated by cytokines, produced by cells such as lymphocytes
- beta cells will slowly be destroyed and insulin levels will drop while the glucagon levels rise, leading to increase BS
what happens when beta cells are destroyed and insulin levels drop causing BS to rise in T1DM?
this causes a lot of catabolic breakdown, an increase in serum osmolarity and resulting in weight loss, low energy, ketone production and since cells cant use the blood sugar thats how the ketones break down and go into ketosis
-then the three polys happen–>polydipsia, polyuria, polyphagia
what are the classifications and treatments of T1DM?
Can occur at any time in life
10% of the diabetic population are T1DM
Treatment- exercise, diet, insulin
what is the asymptomatic phase of T2DM? (3)
- decreasing insulin sensitivity
- hyperinsulinemia
- mild increased postprandial blood glucose and FPG
describe insulin resistance
insulin binds to cell surface receptors and;
* the binding may be impaired
* there may be less receptors
* there may be post-receptor defects
o what normally should happen is- when insulin binds to cell surface receptors, the glucose follows into cells through facilitated glucose transporters
-> insulin can’t do its job in getting glucose into cell
describe the pathophysiology of T2DM
Overall Summary-
* Initially we see people have peripheral insulin resistance
o Some defect in the binding
* then what happens glucose can’t enter the cell effectively
* in response to the resistance beta cells put out a lot of insulin, to try to overcome that (hyperinsulinemia, high levels of insulin in blood)
* eventually you get impaired glucose tolerance
o You will see after eating your glucose is higher than what it should be OR during fasting glucose is higher
o SOME DEFECT IS OCCURING “defective gluco-recognition”
* you will see “early diabetes”
o Problems with BOTH fasting and after eating, glucose is high
* then causes beta cell failure, “late diabetes”
o beta cells can’t produce enough insulin to overcome the resistance
what happens in decrease insulin sensitivity in T2DM?
at some point the body becomes less sensitive to insulin so the body tries to counter this by increasing insulin secretion and glycemic control begins to be affected as evidenced by changes in postprandial and the fasting BG levels
what are the organs that involved that will have defects in T2DM?
- Liver- will have an increase glucose production, in spite that the glucose is already high
- Pancreas- becomes impaired, not making enough insulin
o Pancreas still makes insulin, just not enough to what you need - Muscle/Peripheral tissues- there is insulin resistance, glucose can’t enter the muscle due to receptor defects
stage 1 of T2DM
o Insulin resistance is dictated by; environment and genetics
- muscle fat and liver start to struggle to respond to insulin
-The pancreas works harder to compensate by making more insulin
Food, activity, obesity, family hx of T2DM
o hyperinsulinemia
Making a lot of insulin to overcome glucose
o temporary restoration of normal glucose homeostasis
stage 2 T2DM
-sometimes called impaired glucose tolerance
-Prediabetes is when glucose levels become higher than usual, yet are not considered high enough for a type two diabetes diagnosis
o You are making insulin, but it is not enough to suppress fat lipolysis (breakdown of fat)
o -> decrease suppression of visceral fat lipolysis
o As a result, there is an increase release of fatty acids
o Which also increases insulin resistance
–More increase resistance due to a lot of mobilization of fats now
o there is impairment in glucose uptake in insulin sensitive tissues, primarily the muscles
o hyperinsulinemia continues to rise, but still NOT enough to overcome
o you start to see some issues in genetics that will start -> unmasking beta cell secretory defect causing beta cells to get exhausted
o You will start to see higher glucose levels after eating, than what it should be. There is NORMAL fasting glucose levels
stage 3 of T2DM
o MORE INCREASE in free fatty acids
o MORE INCREASE in insulin resistance
o body continue to increase insulin production, hyperinsulinemia
o there is a decrease suppression of hepatic glucose production (liver makes glucose, in spite high glucose levels)
o You will see high glucose levels BOTH fasting and after eating
o as a result, there is down regulation of insulin receptors and impairment of post receptor events
o HIGH GLUCOSE LEVELS, HYPERGLYECEMIA
o REALLY DECREASE IN INSULIN SECRETION
Because that high glucose level is toxic to the beta cells
o diagnosed with T2DM
classifications of T1DM
-beta cell destruction leading to absolute insulin deficency; immune mediated DM is most common form (90%)
idiopathic (10%)
classification of T2DM
progressive loss of b-cell insulin secretion frequency on the background of insulin resistance
characteristics of T1DM (6)
- cellular mediated autoimmune destruction of pancreatic beta cells
-individual prone to ketoacidosis - little to no insulin secretion
-insulin dependent
-75% of individuals develop before 30 years of age; can occur up to tenth decade
-usually not obese
characteristics of T2DM (5)
- usually not insulin dependent but may be requiring insulin
- individual not ketosis prone (but may form ketones under stress)
- generally occurs in those older than 40 y.o, but frequently is rapidly increasing in children
- strong genetic predisposition
- often associated with HTN and dyslipidemia
clinical manifestation and rationale: polydipsia
because of elevated BG levels, water is osmotically attracted from body cells, resulting in intracellular dehydration and hypothalamic stimulation of thirst
clinical manifestation and rationale: polyuria
hyperglycemia acts as an osmotic diuretic; the amt of glucose filtered by the glomeruli of the kidneys exceeds the amt that can be reabsorbed by the renal tubules; glycosuria results, accompanied by large amt of water lost in the urine
clinical manifestation and rationale: polyphagia
depletion of cellular stores of carbs, fats, and protein results in cellular starvation and a corresponding increase in hunger
clinical manifestation and rationale: weight loss
occurs because of fluid loss in osmotic diuresis and the loss of body tissue as fat and proteins are used for energy as a result of the effects of insulin deficiency
clinical manifestation and rationale: fatigue
metabolic changes result in poor use of food products contributing to lethargy and fatigue; sleep loss from severe nocturia also contributes to fatigue
clinical manifestation and rationale: recurrent infections (e.g. boils and carbuncle; skin infections) and prolonged wound healing (T2DM)
growth of microorganisms is stimulated by increase glucose levels; impaired blood supply hinders healing; decline in immune protection
clinical manifestation and rationale: genital pruritus (T2DM)
hyperglycemia and glycosuria favor fungal growth; candidal infections; resulting in pruritus are common presenting symptoms in women
clinical manifestation and rationale (T2DM): visual changes
blurred vision occurs as water balance in the eye fluctuates because of elevated BG levels; diabetic retinopathy is another cause of visual loss
clinical manifestation and rationale (T2DM): paresthesias
common manifestations of diabetic neuropathies
clinical manifestation and rationale (T2DM): acanthosis nigricans
brown to black pigmentation in body folds associated with insulin resistance
define insulin resistance
-is defined as a suboptimal response of insulin-sensitive tissues, liver, muscle, adipose tissue
* The binding may be impaired, may be fewer receptors, may be post-receptor defects
o Abnormal insulin molecule, high amounts of insulin antagonist, downregulation of insulin molecule, decreased or abnormal activation of post-receptor kinases and alteration of glucose transporter (GLU) proteins.
* Insulin cannot get an appropriate amount of glucose inside the cell which leads to acute and chronic problems if not properly treated
what is a universal characteristic of T2DM?
insulin resistance
what is believed to be a major risk factor for insulin resistance and T2DM
obesity because adipose tissue produces substances that causes inflammation
obesity and insulin resistance: adipose tissue release/produces (4)
- fatty acids, glycerol, hormones, and pro-inflammatory cytokines (adipokines)
**all participates in decreasing insulin sensitivity
obesity and insulin resistance: inflammation and adipokines
- decreases insulin receptor density
- impairs insulin receptor binding
- causes defects in responses to insulin binding
-mitochondrial dysfunction (decreased activity):Alterations in oxidative phosphorylation in cellular mitochondria have been documented, resulting in reduced insulin-stimulated mitochondrial activity and insulin resistance, especially in skeletal muscle and hepatocytes.
-cytotoxic to beta cells
what are ghrelin hormones?
hormone produced in stomach and pancreatic islets
o Regulates food intake, energy balance, hormonal secretion
o Decreased levels of ghrelin are also associated to insulin resistance, increases fasting insulin levels
DESCRIBE THE USE AND SIGNIFICANCE OF THE GLYCOSYLATED HEMOGLOBIN LEVEL.
- A1C looks at average glucose control over last 3 months, counts receptors on RBCs
- Refers to the glucose attachment to hemoglobin molecules and reflects the average plasma glucose exposure over the life of a red blood cell ~120 days
- Used to diagnosed DM
glucose tolerance test to diagnose DM
glucose challenge over two hours, the patient glucose will be 140-200s. glucose is not being cleared effectively
EXPLAIN THE DIFFERENCE IN IMPAIRED GLUCOSE TOLERANCE AND IMPAIRED FASTING GLUCOSE IN PRE-DIABETES STATES
- Fasting glucose should be no more than 80-100.
o In prediabetes the fasting glucose is 100-125 - Impaired glucose tolerance is when 75g of sugar is consumed and blood sugar is not decreasing appropriately at the 2 hour mark.
o In pre diabetes the 2 hour fasting is 140-200 - A1C is 5.7-6.4%
what are the three GI hormones that are low in individuals with DM
- amylin
- incretin
- ghrelin
function of amylin
another hormone produced by the beta cells in the pancreas
- its job is to slow down the gastric emptying and decrease hunger and also help stabilize postprandial glucose
function of incretin
released by the GI tract
- stimulate glucose dependent insulin release from the pancreas and inhibit glucagon release
function of ghrelin
-produced in the stomach and the pancreatic islet cells
-they reduce insulin secretion, especially during periods of fasting
what does microvascular changes cause damage to?
-eyes
-kidneys
-peripheral nerves
what does macrovascular changes cause damage to?
- heart
-peripheral vessels
-brain
describe microvascular complications
o cells do not need insulin to get into specific cells
o Occlusion of capillaries with thickening of the capillary basement membrane, endothelial cell hyperplasia, thrombosis, and pericyte degeneration.
o Hypoxia and ischemia
what are microvascular complications
-retinopathy
-neuropathy
-nephropathy
macrovascular complications
o Larger vessel disease, such as arteries
o cardiovascular disease, stroke, peripheral vascular disease
HTN, CVD, MI
* HTN associated with metabolic syndrome
* HTN leads to CAD and stroke
o Occlusion of small arteries/arterioles amputation
Dyslipidemia, HIGH levels of LDL
the most common complication in DM
diabetic neuropathy
the primary cause of death in individuals with DM
cardiovascular disease
when does hypoglycemia occur?
when glucose levels are less than <70
o When on PO/insulin medication; Insulin levels in body do not appropriately decrease, glucagon and other hormones increase but not enough to what the patient needs,
causes of hypoglycemia
o Exogenous-
Medications, alcohol, exercise
o Endogenous-
Tumors of the pancreas, or inherited disorders
o Functional-
Hyperalimentation, spontaneous, liver disease
* Risk for hypoglycemia T1DM»_space; T2DM
symptoms of hypoglycemia
result either from activation of the sympathetic nervous system (neurogenic adrenergic symptoms) or from an abrupt cessation of glucose delivery to the brain (neuroglycopenic symptoms), or both.
o Neuroglycopenic Symptoms- (later symptoms)
RAPID DROP in glucose
Irritability, confusion, drowsiness, weakness, difficulty speaking, unconsciousness, seizures, and coma.
o Autonomic SS
tachycardia, palpitations, diaphoresis, tremors, pallor, huger, anxiety
what is hypoglycemia unawareness
o a phenomenon that occurs in individuals without appropriate autonomic warning symptoms
o recovery from hypoglycemia may be delayed because of impaired glycogenolysis and hampered delivery of gluconeogenic substrates to the liver.
what is DKA
o Serious complication related to a deficiency of insulin and an increase in the levels of insulin counter regulatory hormones
Catecholamines, cortisol, glucagon, growth hormone
o Dehydration, fluid/electrolyte imbalance, metabolic acidosis, hyperglycemia
precipitating factors for DKA
Illness, infection, trauma, surgery, MI, poor adherence, interruption of insulin administration
Slow onset
pathophysiology of DKA
DKA is the effect of lack of CHO, fat, and protein metabolism (THESE ALL HAPPEN AT THE SAME TIME)
clinical symptoms of DKA
Kussmaul respirations, central nervous system depression, ketonuria, anorexia, nausea, vomiting, abdominal pain, acetone odor on breath, dehydration, thirst, polyuria
Glucose levels >250, low bicarb, increased anion gap, ketones+
describe HHS
o Uncommon, but significant complication for T2DM
o No metabolic acidosis**
o Can occur over a very long period of time
o DEHYDATION, HIGH OSMO LEVELS
precipitating factors for HHS
Infection, medications, undiagnosed DM
Occurs with stressful events that increase glucocorticoids
Also happen with burns
Steroid administration
pathophysiology for HHS
decreased glucose use> increased gluconeogenesis and glycogenolysis > osmotic diuresis> dehydration
there is an increased level of counter-regulatory/stress hormones, catecholamines, glucagon, cortisol, growth hormone
* Catecholamines decrease glucose utilization even further
o hormones made by adrenal glands; dopamine, epi, nor-epi
catecholamines are sent out in blood when there is stress, therefore it decreases glucose utilization
clinical symptoms for HHS
Polyuria, polydipsia, hypovolemia, dehydration, parched lips, poor skin turgor, hypotension, tachycardia, hypoperfusion, weight loss, weakness, nausea/vomiting, abdominal pain, hypothermia, stupor, coma, seizures
Glucose levels >600, lack of ketones, serum osmo >320, elevated BUN/creat; larger fluid deficit b/c BG higher
what is hypothyroidism
-deficient production of TH by the thyroid gland
-most common for thyroid dysfunction
-most common in women and elderly
etiology for hypothyroidism
congenital defects, idiopathic, radioactive iodine, surgery, radiation, iodine deficiency, drugs (lithium), chronic thyroiditis (hashimoto’s- starts hyper>hypo), suprathyroidial
* suprathyroidial- failure to secrete TSH
o secondary to postpartum necrosis, tumor, or granulomatous tissue
o anterior pituitary removed
o very rare
what is primary hypothyroidism
- Decreased production of TH and increased secretion of TSH and TRH
- insufficient production/release of T3 and T4 by thyroid gland
what is secondary hypothyroidism
- Caused by the pituitary’s failure to synthesize adequate amounts of TSH or a lack of TRH
o Example- Pituitary tumors that compress or their treatment
clinical/diagnostic manifestations of hypothyroidism
The extent of symptoms is closely related to the degree of TH deficiency
* Decrease in TH, lowers energy metabolism and heat production
Low basal metabolic rate, cold intolerance, lethargy, tiredness, diastolic HTN, constipation, weight gain, arthralgias, deep hoarse voice, weakness, dry hair with tendency to fall out, cool/tough skin, obesity, diminished auditory acuity, cardiomegaly, prolonged relaxation phase of deep tendon reflexes
two common causes of primary hypothyroidism
-hashimoto disease (autoimmune thyroiditis)
–most common type in the US
–lab reveal either or both elevated TPO and TG antibodies
-iodine deficiency aka endemic goiter
–most common worldwide
**also tx for hyperthyroidism: removal, destruction, suppression
function of thyroid peroxidase (TPO) enzyme
an enzyme that is involved in the three important steps in the formation of t3 and t4
1) oxidation of iodine itself into I2
2) takes I2 and is in charge of iodination of the tyrosine portion of the thyroid globulin protein
–sometimes two iodine are place and sometimes one
-when theres only one its called monoiodotyrosine
-when there is two its called diiodotyrosine (MIT or DIT)
3)conjugation of these iodinated tyrosine
-if put two of the DIT together –t4
–if put one DIT and one MIT–t3
complications of hypothyroidism
Severe long-standing hypothyroidism, MYXEDEMA
* Altered composition of the dermis and other tissues
o Connective fibers are separated by an increased amount of protein and mucopolysaccharides. Which binds to water, producing non pitting boggy edema
Tongue, laryngeal, pharyngeal mucous membranes thicken slurred speech and hoarsness
MYXEDEMA COMA, medical emergency
* Decreased LOC and severe hypothyroidism
* Precipitating Factors-
o infections, discontinuing thyroid meds, overuse of narcotics
* Symptoms-
o Hypothermia without shivering, hypoventilation, hypotension, hypoglycemia, lactic acidosis, coma
in fetuses-
* brain development and skeletal function impaired, decreased cardiac output, decreased sensitivity to heat, decreased O2 demand> decreased production of erythropoietin
what is hyperthyroidsm?
excess amt of TH are secreted from thyroid gland
- TH are regulated by negative feedback loop
etiology of hyperthyroidism
Grave’s disease (TSH receptor antibodies)
Toxic multinodular goiter (aka plummers disease)
* Goiter in past, certain areas are nodular acting independently and secreting thyroid hormone on its own
Thyroid adenoma, one tumor
Thyroiditis, inflammation
describe Graves disease
50-80% of hyperthyroidism cases
Consist of one or more of the following;
* Hyperthyroidism
* Diffuse goiter
* Exophthalmos
* Dermopathy, shins look like an orange peel, RARE
autoimmune disease, results from a form of type II hypersensitivity
Body produces thyroid stimulating immunoglobulins with act like TSH and bind to receptors on thyroid cell which causes the release of thyroid hormone outside of negative feedback loop
* Antibodies that stimulate thyroid gland continuously
diagnostic manifestation of hyperthyroidism
Blood levels, elevated T3/T4, low TSH
Iodide uptake test
* GRAVES- shows uptake in all of thyroid (diffuse release)
* TOXIC MULTINODULAR GOITER/THYROID ADENOMA- iodine uptake is suppressed on some spots
symptoms of hyperthyroidism
tachycardia, palpitations, wide pulse pressure, arrhythmia, systolic murmurs, palmer erythema, vitiligo (loss of pigmentation), hair changes (fine or bald), eye changes (prominent stare, lid lag, failure to wrinkle brow on upward gaze), tremor, excessive sweating, heat intolerance, hyperreflexia, weight loss, proximal muscle weakness, emotional lability, anorexia, N/V, diarrhea, menstrual abnormalities (increased blood flow), goiter!
* amplify effects of catecholamines, stimulating the SNS
complications of hyperthyroidism
Thyroid Storm/Thyrotoxic crisis
* Rare, but dangerous.
* Death can occur within 48 hrs without treatment
* May develop spontaneously, usually occurs in individuals who have undiagnosed or partially treated severe hyperthyroidism, and who are subjective to excessive stress;
o Infection, resp/cv disorders, trauma, burns, seizures, surgery especially thyroid surgery, emotional stress
hashimoto disease clinical manifestion
- myxedema
-slow metabolic rate
-decreased CO
-weight gain
-lethargy
-cold intolerance
-decreased mental acuity
lab results for hyperthyroidism
-low TSH
-high T3/T4
lab results for hypothyroidism
- high TSH
-low T3/T4
what are free T4 and free T3
free portion, the small amt thats not bound to proteins that can be biologically active and make it to the tissues
what is T3 and what protein does it mostly bind to?
the active hormone (most important for regulation of thyroid hormone)
-it is three to four times more potent than T4–so the tissues to be effective will tend to convert T4 into T3
-thyroxine binding protein
what is T4 and what protein does it mostly bind to?
a major secretory product of the thyroid, metabolized by deiodination
-T4 binding globulin
most made is T4!
what is metabolic syndrome
- A cluster of conditions that increase the risk of heart disease, stroke, DM-
criteria for dx: three of five traits must be present:
o Central obesity
o Dyslipidemia (plasma triglycerides and plasma HDL)
o Pre hypertension
o Elevated fasting glucose
describe Aldose Reductase and the Polyol Pathway
- The polyol pathway is a biochemical pathway, aldose reductase is one of its primary enzymes
o Normally-
allows for the metabolism of a small amount of glucose
aldose reductase Reduce toxic aldehydes (highly reactive organic compounds) in the cell to inactive alcohols
o During Hyperglycemia-
more glucose enters this pathway
When the glucose concentration in the cell becomes too high, aldose reductase reduces glucose to sorbitol, which is later oxidized to fructose.
In this process, aldose reductase consumes a cofactor (NADPH) which is used for regenerating a critical intracellular antioxidant, reduced glutathione.
This inability to regenerate reduced glutathione increases susceptibility to intracellular oxidative stress
describe Advanced Glycation End-products (AGEs)
- Result of chronic hyperglycemia
o Glycation refers binding of a sugar molecule, such as fructose or glucose, to a protein or lipid molecule.
o results in alterations in the protein structure
o the development of irreversible AGEs that interfere with structure and function
describe Protein Kinase C (effects of hyperglycemia)
- Protein kinase C’s are a family of protein kinases, most of which are activated by the lipid second messenger system diacylglycerol (DAG).
- When PKC is activated by intracellular hyperglycemia, it appears to initiate a variety of effects on gene expression leading to abnormalities;
o basement membrane thickening, blood flow abnormalities, increased vascular permeability, angiogenesis, decreased fibrinolysis, vascular occlusion
