diabetes and CVD risk
- risk of mortality: diabetes without prior MI ~ non-diabetes with prior MI
- diabetes + prior MI –> much higher risk
mediators of diabetes –> atherosclerosis
hyperglycemia, hyperinsulinemia, endothelial dysfuction, hypercoagulability, obesity, lipid profile
macrovascular complications of diabetes
CVD
Tx to reduce risk of CV complications in diabetes
- for type 1: intensive glycemic control (A1C 7.0%) in early stages of disease is preventative over long term (even if control worsens after). improves microvascular Sx in short term
- for type 2: same!
BUT tight control in patients with long-standing diabetes is not necessarily beneficial
Screening in diabetes
PLAGUE-F:
- Pressure (bp < 100)
- Aspirin (Secondary prevention, 10-year risk >10%)
- Glycemia (A1C < 7%)
- Urine (Microalbumin, Creatinine annually)
- Eyes (dilated eye exam annually)
- Feet (Annual foot exam, neuropathy screening)
first-line Tx for T2DM
lifestyle + metformin
sites of action for glucose-lowering drugs
- liver (glucose output)
- skeletal muscle (glucose uptake)
- Gut (glucose absorption and incretin secretion)
- pancreas (insulin/glucagon secretion)
advantageous characteristics for T2DM drugs
- weight neutral or weight loss
- no hypoglycemia
- freq of administration
- PO vs injectable
disadvantageous characteristics for T2DM drugs
- weight gain (reversal of osmotic diuresis, reversal of starvation/normalization of glucose, fluid retention)
- hypoglycemia
- frequency
- injectable vs PO
metformin (biguanide). Action, mechanism, effect, weight, metabolism, adverse effects, hypoglycemia, contraindications, efficacy
- reduces hepatic gluconeogenesis and lipid synth, sensitizes liver and muscle to insulin
- activation/phosphorylation of AMPK
- improves pre-meal glucose with modest effect on post-prandial glucose
- weight neutral/weight loss
- not metabolized. renally excreted
- anorexia, nausea, dirrhea, lactic acidosis (must ramp dose slowly)
- no hypoglycemia
- contra: prone to acidosis, hypoxic states, renal failure, MI, T1DM
- lowers A1C by as much as 2% (higher start point –> bigger effect)
sulfonylureas Action, mechanism, effect, weight, metabolism, adverse effects, hypoglycemia, contraindications, efficacy
- stimulates pancreatic insulin secretion 12-24 hrs
- binds to sulfonyl R in beta cells resulting in depolarization via ATP-dependent K+ channels
- mostly effects pre-meal glucose
- hepatic metabolism, excreted by kidney. active metabolites. caution in renal impairment
- contra: T1DM, DKA, sulfa allergy
- adverse: hypoglycemia, weight gain, hunger
- A1C reduction up to 1.5% Higher start point–> bigger effect
meglitinides/glinides. Action, mechanism, onset, effect, weight, metabolism, adverse effects, hypoglycemia, contraindications, efficacy
- Stimulates pancreatic insulin secretion for 3-4 hrs
- Binds Sul 1 R on beta cells, depolarization via ATP-dependent K+ cahnnels
- Fast onset
- Adverse: hypoglycemia 2-4 hrs after a meal, weight gain, patient adherence (take with every meal
- metabolism: hepatic P450, GI excretion
- contra: T1DM, liver failure, DKA, sulfa allergy
- lowers A1c ~0.4%
Thiazolidinediones (PPAR-gamma agonists) Action, mechanism, effect, weight, metabolism, adverse effects, hypoglycemia, contraindications, efficacy, controversy
- decreases peripheral insulin resistance in muscle, liver, adipose
- binds to nuclear PPAR-gamma, increasing GLUT4 expression
- PO 1-2x daily
- lowers pre-meal and post-meal glucose
- adverse: weight gain due to improved glycemic control and intravascular colume expansion. hepatocellular injury
- contra: active liver disease, heart failure, renal insufficiency. Reduces TGs but increases LDL/HDL
- no hypoglycemia
- lowers A1c up to 1.8%
- controversy: link to bladder cancer. Risk of CVD (?)
alpha-glucosidase inhibitors Action, mechanism, effect, weight, metabolism, adverse effects, hypoglycemia, contraindications, efficacy
- competitively inhibit oligosaccharide breakdown enzymes in small intestine brush border
- Delay gut carbo absorption, increases GLP-1
- post-prandial glucose only
- pills taken with meals
- side-effects: flatulance, bloating
- no hypoglycemia
- contra: GI disorders esp IBD
- not metabolized; renally excreted
- lowers A1c ~0.4%
exenatide/liraglutide. Action, mechanism, effect, weight, metabolism, adverse effects, hypoglycemia, contraindications, efficacy
- GLP-1 R agonists
- potent glucose-dependent insulin secretion, slows gastric emptying
- peptides –> sub-cut admin 2x day
- adverse: nausea, bloating
- no hypoglycemia (effect declines as glucose level declines)
- contra: gastroparesis
- increases satiety –> weight loss
- A1C ~1% but some people lose a lot
incretin system
- secreted by gut in response to food.
- Increases I/G ratio, slows gut motility, induces satiety
- inactivated by DPP-4 in 1-7 minutes
gliptins. Action, mechanism, effect, weight, metabolism, adverse effects, hypoglycemia, contraindications, efficacy
- increase duration of action of GLP-1
- inhibit DPP-4
- immediate effect, mostly on post-meal glucose
- not metabolized, excreted renally
- PO once daily
- contra: no
- adverse: GI
- no hypglycemia and weight neutral
- reduces A1c ~1%
Canagliflozin (sodium-glucose transport inhibitor). Action, mechanism, effect, weight, metabolism, adverse effects, hypoglycemia, contraindications, efficacy
- inhibits SGLT2, decreases glucose reabsorption
- hepatic metabolism
- contra: severe renal impairment, ESRD, dialysis
- adverse: vulvovaginal candidiasis/mycotic infection, UTIs, polyuria
- lowers A1c ~1% and weight loss ~2.2%
insulin mechanism and effect
binds to insulin and IGF-1 Rs resulting in phosphorylation/2nd messenger cascade and GLUT translocation
Anabolic: TG synth/storage in adipose, glycogen and protein synth in muscle, glycogen synth and reduced glucose output in liver.
metabolism of insulin
endogenous: 60% degraded in first-pass of liver. remaining 40% degraded in kidneys
Exogenous: 60% kidney, 40% liver
indications for insulin Tx
- T1DM
- inadequately controlled T2DM
- temporary use: hospitalization, pregnancy, renal disease, initial control in severe T2DM
bolus insulin
- used for coverage of food intake or correction of hyperglycemia.
- Short acting: regular
- Rapid acting: aspart, lispro, glulisine
aspart/lispro
- AA substitution decreases formation of hexamer. monamers exert action much faster.
- faster absorption, higher peak concentration, shorter duration than regular insulin
basal insulin
- maintain euglycemia in the fasting state
- intermediate: NPH (1-2x daily)
- long acting: glargine, detemir
glargine
long-acting insulin. packaged at acidic pH. forms crystals once injected –> slow release
Detemir
long-acting insulin modified so it binds albumin, released slowly
split/mixed insulin regimen
combination of lispro/NPH injected once in the morning and once in the evening
requires regimented eating and can result in peaks/valleys
lispro pump regimen
pump delivers basal level, injections for meals
basal-bolus regimen
lispro injected for meals, glargine injected at night for basal levels
disadvantages of insulin pump
requires carb counting and frequent blood glucose checking. can go into DKA quickly if don’t monitor blood glucose
factors determining insulin dose
provider: weight, blood glucose, insulin sensitivity
patient: carb intake (ideally ratio), blood glucose, physical activity
complications of insulin
hypoglycemia, lipatrophy/lipohypertrophy locally, allergy (rare), resistance
ileus
cessation of GI motility due to non-mechanical causes (can be due to electrolyte imbalance i.e. from DKA)
Kussmaul’s breathing
rapid, shallow breathing (i.e. to breathe off acetone in DKA)
main tissues utilizing glucose
brain, muscle, red and white cells, renal medulla.
brain can adapt to ketones
sources of glucose
ingestion, glycogenolysis (liver) 24-36hrs fast (12 hrs in children). Gluconeogenesis (liver)
hormonal control of fasting systems
fasting systems: glycogenolysis, gluconeogenesis, lipolysis, ketogenesis
insulin: inhibits all
glucagon: stimulates gylcogenolysis, gluconeogenesis
Epinephrine: stimulates gylcogenolysis, lipolysis, ketogenesis
Cortison: stimulates gluconeogenesis
Growth hormone: stimulates lipolysis
normal glucose range
60-100 mg/dL
glucose range for Sx, activation of glucose counterregulatory hormones, diagnostic threshold, therapeutic threshold
activation of hormones: 65-70 mg/dL
Sx: 50-55
Cognitive dysfuction: 45-50
Diagnostic: 70
Diagnosis of hypoglycemia
whipple’s triad
- Sx of hypoglycemia
- measured low glucose at time of Sx
- correction with food or glucose
neurogenic Sx of hypoglycemia
perception of physiological changes cause by CNS-mediated sympathetic discharge (adrenergic and cholinergic
Previous episodes of hypogylcemia may blunt, especially adrenergic response (HAAF)
neuroglycopenic Sx of hypoglycemia
brain dysfunction (dizziness, fatigue, blurred vision, headache…death)
post-prandial hypoglycemia
rare “reactive” hypoglycemia
- Late Dumping Syndrome (hyperinsulinemic hypoglycemia). occurs in ppl w/ abdominal surgery
- Early diabetes (dysregulation of insulin)
- idiopathic
- congenital metabolic disorders (galactosemia, hereditary fructose intolerance)
Fasting hypoglycemia mechanisms
- insulin-mediated (insulinoma, congenital hyperinsulinism, exogenous insulin)
- failure of counter-regulation
- congenital metabolic defects
insulin-induced hypoglycemia labs
increased glucose utilization -hyperinsulinemia, high C-peptide hypo FFAs hypo ketones glycemic response to glucagon
insulinoma
usually benign, solitary, but can have multiple ectopic
increased pro-insulin/insulin ratio.
can be small: must localize and resect!
congenital hyperinsulinemia
dysregulation of beta-cell secretion. defects change ATP level regulation (ATP is trigger for membrane depol)
eg dominant GOF for glucokinase or Glutamate dehydrogenase
mutations to ATP-dep K channel (most severe)
Tx congenital hyperinsulinemia
diazoxide: stimulates ATP-dependent K channels
somatostatin: inhibits Ca++ release in beta cells
octreotide: multiple effects, including K-ATP channel activation
for focal: surgical
immune-mediated hypoglycemia
can have activating antibodies or antibodies to insulin itself
hypoglycemia in GH/cortisol deficiency
shortened fasting (impairment of gluconeogenesis, lipolysis), midline defect or microphallus, ketotic hypoglycemia (can mimic hyperinsulinism) Tx: replace hormones.
G6Pase deficiency (problem, Sx, labs, Tx, complications)
can’t release glucose from liver.
Sx: failure to thrive, hepatomegaly
Labs: hyperlacticacidemia, hyperTGs, hyperuricemia, lack of glycemic response to glucagon
Tx: frequent CHO
Late complications: liver tumors, nephropathy
F16Pase deficiency
gluconeogenic defect
Sx: attacks of acidemia, hyperuricemia
triggers: fasting or fructose
Tx: limit fasting, no fructose/sucrose
GSD type 3 (defect, clinical, labs, Tx, complications)
defect in glycogenolysis (debranching enzyme)
clinical: failure to thrive, hepatomegaly, muscle weaksness
Labs: hyperketonemia, inc LFT
Tx: frequent low CHO feed
Late complications: cardiomypoathy, mypoathy
Tfs in pituitary development
Prop-1, Plt-1
Deficiency –> hypopituitaryism for some/all hormones
Ant pituitary hormone
- Glycoproteins: (TSH, LH, FSH)–share alpha subunit, different beta-subunit
- ACTH (from large molecule POMC)
- GH/PRL (structural homology and affinity for PRLR)
ant pituitary cell types
somatotrope (GH), thyrotrope (TSH), lactotrope (PRL), gonadotrope (LH/FSH), Corticotrope (ACTH)
ACTH (synthesis, function, stimuli, inhibitors, rhythm)
- POMC cleaved to form ACTH and melanotropin
- induces secretion of cortisol, stimulates lipolysis, and increases skin pigmentation.
- stimuli: CRH, Stress, hypoglycemia, anxiety, depression
- inhibitor: cortisol
- diurnal: peaks in morning
GH axis
hypothal: GHRH (+) and somatostatin (-)
GHRH: episodic release, stimulated by hypoglycemia, dietary protein, exercise
somatotropes: GH –> liver
liver: IGF1 –| pit, hypothal
somatostatin: inhibitory, extra-pituitary receptors (GIT), pharm application
GH ( release, regulation, lab)
pulsatile release, regulated by age, sex, nutrition, sleep, stress, exercise. stimulates post-natal grown via IGF-1.
lab: measure IGF1–integrated measure of GH’s effects
PRL axis
- normally suppressed by DA from hypothal
- neural stimulus (e.g. suckling) acts on hypothal
- “PRFs” induce PRL secretion.
- PRL acts on mammary gland
- PRL feeds back on hypothal (-) and suppresses gonadotropins via GnRH
stimulators: breast stimulation, stress, estrogen, sleep, DA antagonists, TRH
Inhibitors: DA and DA agonists
H-P-G axis
hypothal: GnRH
GnRH: FSH/LH
estrogens/ testosterone/progesterone feedback on hypothal and pituitary
GnRH
pulsatility and pulse freq are critical
greater freq and amplitude of pulses in puberty
H-P-T axis
hypothal: TRH –> TSH/PRL
Pit: TSH
TSH: T4–>T3
T3 feeds back on pituitary. When intracellular T3 reaches certain level, TRH-Rs are removed from membrane
MCAD deficiency
- Hypoketotic hypoglycemia
- Mimics Reye’s
- Newborn screening
- Tx: limit fasting
Iatrogenic Hypoglycemia
- Sulfonylureas
- Salicylate OD (esp children)
- Beta blockers (blocks adrenergic warning cells, hypoketotic hypoglycemia pattern– impaired lipolysis)
- exogenous insulin (high insulin, low C peptide)
- Pentamide (for pneum carnii)
Alcohol induced hypoglycemia
Oxidation of EtOH –> NADH –| gluconeogenesis
- occurs in absence of glyocgen (starvation)
- can be lethal in children
non-islet cell tumor hypoglycemia (types, mechanism of hypoglycemia)
- Mesenchymal, epithelial, leukemia/lymphoma
- Poor nutrition w/ advanced malignancy, tumor consumption of glucose, reduced hepatic gluconeogenesis (metastatic disease involving liver)
Critical sample in hypoglycemia
Must be done at time of hypoglycemia
- counter regulation: insulin/C-peptide, GH, cortisol
- metabolites (ketones, FFAs, etc)
- tox and drug screen
Diagnostic tree hypoglycemia
Acidmia: high lactate (gluconeogenic eg EtOH) vs high ketones (glycogenolysis, defect of counter-regulation)
No acidemia: Low ketones/high FFA –> FAO defects vs low ketones/low FFA –> hyperinsulinemic
General DDx hypoglycemia
- counter-regulation
- glycogenolysis
- gluconeogenesis
- ketogenesis
glycogen metabolism in muscle vs liver
muscle glycogen is available only for muscle
leptin system
secreted by adipose, binds to Mc4R in brain
effect of fat location on risk
central/visceral obesity much worse than peripheral: Diabetes, NAFLD, sleep apnea, CVD, Cancer
sarcopenia in thighs –> no bueno!
Management of obesity
Lifestyle (10k steps)
Diet (reduce calories)
Exercise (if possible)
Treat related illnesses
Rx in obesity
not a lot of good drugs. Sympathetic side-effects
Olistat (Alli) inhibits pancreatic lipase (–> steatorrhea)
Bariatric surgery
- Adjustable gastric banding
- Vertical Sleeve Gastrectomy
- Roux-en-Y (most invasive, greatest reduction in weight, decreases weight and fat, sleep apnea, risk of cancer. long-term can have deficiencies, dumping syndrome (Vagal overload after big meals), recurrent severe hypoglycemia)
anabolic pathways for muscle
follistatin, IGF-1, androgens
interest in these to counteract cachexia in cancer
Tx cachexia
controlled refeeding
Diagnose and Tx underlying disease (anorexia, cancer)
Anabolic Rx: megesterol, THC
common features in endocrine tissues
ductless (vs exocrine), vascular, organization (blocks, cords, plates), epithelial (except in gonads–mesenchymal and post pet/adrenal medulla–neural), polyhedral, numerous organelles
- specialized secretory cells
- proximity to blood vessels (fenestrated endothelium)
- individual endocrine cells (enteroendocrine, juxtaglomerular)
histologic cell types in ant pituitary
acidophils (somatotropes, lactotropes)
basophils (corticotropes, gonadotropes, thyrotropes)
Chromophobes (unknown function)
histology of post pit
unmyelinated nerve axons and pituicytes (supportive cells), with capillaries Herring bodies (granules at axon terminals storing hormones)
histology/function of thyroid
- characteristic follicle with large lumen surrounded by simple cuboidal epithelium
- Extracellular thyroglobulin called colloid accumulates in the follicles (UNIQUE TO THYROID)
- Follicular cells use thyroglobulin to produce T3/T4
- parafollicular cells (C cells) produce calcitonin
parathyroid glands hist/function
- usually 4
- regulate calcium
- lobules of cells with fine capillary network
- fat cells common (inc with age)
- principle (chief cells) secrete PTH
- oxyphil cells–larger and pink (unknown function, lots of mitochondria)
Adrenal hist and function
cortex (90% weight): cords of steroid-secreting cells, sperated by sinusoids
- Z Glomerulosa (Mineralcorticoids)
- Z Fasciculata (Glucocorticoids)–clear foamy cells
- Z Reticularis (Gonadocorticoids)
medulla (neuralectoderm origin): innervated by symp nerve fibers.
-chromaffin arranged in groups or cords clustered around capillaries and venules (“post synaptic w/o axons)
Large dense core vesicles: norepinephrine
Small less dense core vesicles: epinephrine
pheochromocytoma
often benign tumor of adrenal medulla (makes NE or E)
pancreas (hist/function)
acini: exocrine islets (more numerous in tail--1-2% overall): endocrine -A cells: glucagon (periphery of islets) -B cells: insulin -D cells: somatostatin -minor types
severe hypoglycemia in T1DM (causes, complications)
insulin OD. with greater # of episodes, Sx go down, so can be unaware
-QT prolongation –> sudden cardiac death
Strategies for transplantation in T1DM
- pancreas with kidney
- pancreas after kidney
- experimental: islets with/after kidney
-pancreas with kidney is most successful because come from same donor so will be rejected at the same rate…serum creatinine is much more sensitive marker of function and rejection than is hypoglycemia)
good indicators for pancreas transplant
- recipient <50
- donor not obese
islet cell transplant
- infused directly into portal vein, engraft on liver
- OK for preventing hypoglycemia (fasting)
- lower function with glucose challenge (need insulin)
- newer protocols improve efficiency
- can reverse HAAF
pituitary adenomas
- any kind of ant pit cell
- protein hormones tend to be efficient in secretion and cause recognizable clinical Sx more often
somatotroph adenoma (signs, latency, Dx, consequences, Tx)
- acromegaly: nose, jaw, fingers, lips swell
- latency to diagnosis ~10 yrs
- Dx: measure IGF-1, failure to suppress GH on oral glucose load
- arthritis, colon cancer, CVD, neuropathy, sleep apnea, mortality
- Tx: surgical, pharm (DA agonists, somatostatin analogs, GH antagonists), radiation
lactotroph ademona (Sx, Tx)
-Premenopausal: amenorrhea/oligomenorrhea, sometimes galactorrhea
postmenopausal: neurological
Men: decreased libido, fertility, potency
-Tx: DA agonist–> tumor regression
DDx high PRL
- physiologic: pregnancy, nursing, exercise, stress
- pathologic: adenoma, DA antagonists, catecholamine inhibitors, estrogens, opiates H2 antagonists
thyrotroph adenoma (Sx, Tx)
-usually inefficient–hyperthyroidism uncommon
Tx: somatostatin analog (inhibits TSH)
Gonadotroph adenomas (Sx,
-usually very inefficient–neuro Sx most common, hormonal abnormality (premature puberty, ovarian hyperstim) uncommon
Hypercortisolism (Chushingoid) causes
-bilateral hyperplasia 80% (pit ACTH, ectopic ACTH (e.g. lung cancer), primary hyperplasia, idopathic/iatrogenic)
-Adenoma 10%
-Carcinoma 10%
In CHILDREN:
-carcinomas much more common (50%), adenoma more common, hyperplasia 35%
adrenocortical carcinoma (gross characteristics, Sx, prognosis, syndromes
gross: large size, necrosis, hemorrhage, invasion
micro: cellular pleomorphism, capsular invasion, vascular invasion, metastases, mitosis
Sx: (don’t necessarily have to do with hormone secretion) weigh gain/loss, fever, anorexia, hormone secretion (commonly cortisol but could be anything)
Prognosis: poor
Syndromes: (Li-Fraumeni syndrom (p53), Beckman-Wiedemann, Familial adenomatous polypsis coli, multiple endocrine neoplasia type I)
Definitive criteria for malignancy of adrenocortex
- distant metastasis
- local invasion
hyperaldosteronism causes
- adenoma (65%)
- bilateral hyperplasia (35%)
- carcinoma (v rare)
hypofunction (Addison’s) of adrenal cortex causes
- autoimmune destruction
- replacement (TB, fungi, amyloid, tumor)
- need 90% of both cortices destroyed for Sx
hyperfunction of medulla causes
- neoplasm (pheochromocytoma)
- hyperplasia
- neuroblastoma (rare)
pheochromocytoma clinical triad
paroxysmal HTN
headaches
diapheresis
characteristic of familial-syndrome pheochromocytoma
multi-centered!
criteria for malignant pheochromocytoma
most reliable is presence of metastases.
PASS score is pretty predictive (>4)
NOT necrosis, mitoses, vasc invasion
MEN syndromes
genetically defined, familial syndromes with multiple endocrine organ involvement. signs and symptoms vary. Also have lesions in non-endocrine systems
MEN 1
3 Ps:
hyperplasia and neoplasia of pituitary, parathyroid, pancreatic
-prognosis related to lesions of pancreas (can develop into malignancies
-mutation in MENIN – multiple sites
MEN 2A/2B
MEN2A: Neoplasia/hyperplasia of Thyroid C cells, Adrenal medulla, parathyroids (15-25%)
- Men2B: same lesions, no parathyroid + neural tissue of oral/GI systems and eye abnormalities. 50% familial, 50% sporadic
- mutations in ret
causes of hypercortisolism by age
Adults: hyperplasia (80%) > adenoma (10%)/carcinoma (10%)
Children: carcinoma (50%) > hyperplasia (35%) > adenoma (14%)