Metabolic Pathophys: Diabetes, Inborn Errors Flashcards
hereditary fructose intolerance
- aldolase B defect –> toxic accumulation of fructose-1-phosphate in hepatocytes
- hypoglycemia
- convulsions
- eventual liver failure
essential fructosuria
- fructokinase defect
- benign
- incomplete metabolism of fructose in liver –> fructose in urine
galactokinase deficiency
- accumulation of non-phosphorylated galactose / can’t be broken down through typical pathway
- converted to galactitol
- galactitol accumulation
- early bilateral cataracts
less severe than classic galactosemia as there is no accumulation of 1P-gal
classic galactosemia
- galactose-1p-uridyltransferase (GALT) deficiency
- autosomal recessive
- phosphorylated galactose can’t be converted to glucose
- toxic accumulation of phosphorylated galactose, galactitol, other alternative metabolites in hepatocytes
- liver disease
- infantile bilateral cataracts
- sepsis risk
- premature ovarian failure
- neurocognitive defects, speech
ketogenic amino acids
leucine
lysine
result in ketones when metabolized
glucogenic amino acids
alanine
glutamate
aspartate
can be used for gluconeogenesis
phenylketonuria (PKU)
- phenylalanine hydroxylase (PAH) defect
- autosomal recessive
mx:
- Phe not converted to Tyr
- buildup of Phe, phenyl acetate, and other derivatives
sx:
- severe neurodevelopmental disease w/ seizures if untreated
- “musty” odor in urine d/t phenyl acetate
- pale skin, hair, eyes (relatively) d/t reduced melanin synthesis (from Tyr)
tx:
- phenylalanine free diet
- initiate ASAP, newborn screening
hyperammonemia w/o metabolic acidosis
- genetic defects in urea cycle
- low BUN
- seizures
- coma
- hyperventilation
- lethargy, irritability
- vomiting
hyperammonemia w/ metabolic acidosis
- defects in metabolism of specific organic acids, such as methyl malonate
- seizures
- coma
- hyperventilation
- lethargy, irritability
- vomiting
hyperammonemia w/ hyperbilirubinemia
- liver failure/cirrhosis
- diminished LFTs
- seizures
- coma
- hyperventilation
- lethargy, irritability
- vomiting
- jaundice
- other sx of liver failure
hypOketotic hypOglycemia
- fatty acid oxidation disorders (FAOD), when fasting
- d/t genetic defects in fat metabolism (beta-oxidation/acyl-dehydrogenases or carnitine shuttlers)
- when fasting, don’t have enough blood glucose (hence hypOglycemia), but also now can’t break down fatty acids (which would generate ketones and, via 3-C stubs, induce gluconeogenesis)
- energy defecits
- organ damage
- neuro damage
key intermediate in cholesterol synthesis
HMG-CoA
M6P tag
- tags lysosomal enzymes at Golgi for shuttling to lysosomes (i.e. proteins that are supposed to function in the lysosome, not things being marked for degradation)
- important in enzyme-replacement therapy for lysosomal storage diseases - therapeutics must contain M6P tag
GSD type I
- G6PD deficiency
- glycogen storage disease
- essentially a liver disease because G6PD only functions in glycogen storage in the liver (not heart or muscle)
- accumulation of glucose-6-phosphate –> increased production/decreased consumption of lactate, triglycerides, uric acid
- can’t release glucose from glycogen on fasting (glycogenolysis) AND can’t complete gluconeogenesis –> hypoglycemia
- severe hypoglycemia on fasting
- hepatomegaly
- elevated lactate, triglycerides, and uric acid
GSD type 2
- deficiency in lysosomal degradation of glycogen
- liver, heart, muscle manifestations
- death w/in 5 years of life
GSD type 3
- deficiency in glycogen debranching enzyme
- liver, muscle manifestations
- mild hypoglycemia (no problem with gluoconeogenesis)
- overal milder
GSD type 5
- deficiency in muscle-specific form of glycogen phosphorylase
- muscle-specific manifestations (weakness, wasting)
- myoglobinuria
- second-wind phenomenon
X-linked adrenoleukodystrophy
- classic peroxisomal disease
- mutations in peroxisomal transporter for very long chain fatty acids (VLCFAs)
- VLCFAs then accumulate in cells because they can’t be degraded in mitochondria
- progressive loss of myelin
refeeding syndrome
deficiency of:
- phosphate
- magnesium
- potassium (hypO-K)
- vitamin B1
d/t prolonged starvation followed by refeeding
- phosphate, Mg++, K+, and B1 all reached equilibrium during starvation
- suddenly making a bunch of new cells –> deficiency.
c peptide
cleaved from insulin precursor (1:1)
indirect measurement of blood glucose
random and fasting glucose in diabetes
Fasting:
>126
<100 is normal
100-125 is prediabetic
Random:
> 200 if symptomatic (polyuria, polydipsia, polyphagia, weight loss)
oral glucose tolerance test (OGGT) in diabetes
glucose >200 2 hours after glucose challenge
HgbA1c in diabetes
> 6.5
MODY
autosomal dominant defect in insulin production or function
several possible gene mutations, generally single defect in a given patient
generally presents in non obese patients <25 y/o
exocrine pancreatic disorders
include pancreatitis, trauma, pancreatectomy, CF, hemochromocytosis
damage pancreas –> diabetes
somatostatinoma
decreased insulin secretion –> diabetes
drugs associated with insulin deficient diabetes
beta cell toxicity:
- alcohol
- pentamidine
- cyclosporine
beta cell autoimmunity:
- IFN-alpha
- anti-PD-1
- anti-CTLA-4
beta cell dysfunction:
- thiazide diuretics
- diaxozide
drugs associated with insulin resistant diabetes
- gluococorticoids
- progesterone
- atypical antipsychotics
- ARV protease inhibitors
- tacromilus
infections associated with insulin deficient diabetes
- congenital rubella
- CMV
gestational diabetes
- 2nd to 3rd tri
- IR d/t hormones, weight gain
- inadequate compensatory insulin secretion
- high risk for future non-G diabetes
stages of T1DM
1
- autoimmunity
- multiple antibodies
- normoglycemia
2
- autoimmunity
- prediabetes on testing/progressive dysglycemia
3
- symptomatic
- hyperglycemia
- progressive loss of measurable C-peptide
antibodies associated with T1DM
GAD
ICA
IAA
ZnT8
preventative medication T2DM
metformin if <60, obese, and very high risk
emergent complications of diabetes
hypERglycemia :
- DKA
- hypER-osmolar state
hypOglycemia
absolute insulin deficiency
no insulin at all
–> DKA
hypERglycemic hypERosmotic state (HHS)
osmotic diuresis –> excessive water/lyte loss
- -> dehydration –> hypERosmolarity
- -> impaired renal function
- hypERglycemic emergency
- absent or minimal ketogenesis
- relative rather than absolute insulin deficiency
- glycogenolysis
sx:
- dehydration
- AMS
- polys
- ± weight loss
diabetic ketoacidosis (DKA)
absolute insulin deficiency –> lipolysis, ketogenesis –> depleted alkali reserve –> *metabolic acidosis
lipolysis –> increased free fatty acids to liver –> *hyperlipidemia
hyperglycemia –> *HHS –> impaired renal function
sx:
- nausea, vomiting
- abdominal pain
- fruity breath
- Kussmaul respirations (rapid and deep)
- polys
- ± weight loss
- dehydration
precipitants of hypERglycemic crisis
- infection
- insulin omission
- CVA/MI
- alcohol or drug abuse
- meds (steroids, antipsychotics, SGLT2i)
- previously undiagnosed diabetes
excessive stress –> increase in counter regulatory hormones (cortisol, catecholamines, glucagon) –> gluconeogenesis
PLUS
absolute or relative insulin deficiency/insufficient compensatory insulin secretion
classes of hypOglycemia
1: glucose 54-70
2: <54
“severe:” requires help
tx hypOglycemia
if able: “rapid” carbs (no fat, which would slow absorption)
- 15-30 g
- 15 g = 4 lifesavers, 4 glucose tabs, 4 oz juice, 8 oz skim milk
- note chocolate and ice cream have too much fat to be as effective
else, IV dextrose ± glucagon
hypOglycemia sx
- sweating
- shakiness
- anxiety
- palpitations
- AMS
or asymptomatic (hypoglycemic unawareness) - most common in patients w/ frequent hypOglycemia
most common cause of hypOglycemia
mismatch meds to food/exercise
- too much med to not enough food or too much exercise
long term complications of diabetes
microvascular:
- retinopathy
- nephropathy
- neuropathy
macrovascular:
- CVD
- pulmonary artery disease (PAD)
diabetic retinopathy pathogenesis
hyperglycemia –>
- accumulation of sorbitol in retinal cells
- accumulation of AGEs in extracellular fluid (advanced glycosylation end products)
- impaired auto regulation of retinal blood flow
- -> capillary leakage –> macular edema, distortion
- -> capillary dropout and retinal ischemia
- -> VEGF –> neovascularization –> leakage, bleeding, tractional retinal detachment
T1DM: more likely to progress to ischemia, detachment, vision loss
T2DM: more likely to progress to macular edema (distorted central vision)
diabetic eye disease sx and screening
early stages asymptomatic
- screen in T1DM starting @ 5 yr after dx
- in T2DM @ dx
- both f/u yearly
sx:
- blurred vision
- scotomas
- visual field cuts
- acute visual loss
tx diabetic eye disease
anti-VEGF
- most effective tx for macular edema and preventing proliferative retinopathy (neovascularization)
- less helpful once damage is already progressed to ischemia, detachment, vision loss
pan-retinal photocoagulation (laser therapy) may also help
diabetic nephropathy prevention and tx
screening
- yearly
- asymptomatic in early stages
prevention
- glycemic and bp control
- ACEi or ARB
tx - slow progression in T2DM
- SGLT2i
- GLP-1R agonists
- finerenone (mineralocorticoid aNTagonist)
leptin
adipokine more fat = more leptin "energy sufficiency" signal reduces appetite long term - doesn't do much meal-to-meal
obesity is associated with leptin resistance
adiponectin
protective adipokine
inversely correlated with fat (less fat = more adiponectin)
less inflammation, IR, atherosclerosis
resistin
adipokine
more fat = more resistin
promotes IR, hepatic gluconeogenesis
RAAS and obesity
RAAS (all of those peptides) produced by adipocytes
links obesity to htn
PAI-1 and obesity
prothrombophilin
inhibits fibrinolysis (promotes thrombosis)
produced by adipocytes (among other tissues)
links obesity to atherosclerosis
ghrelin
released by stomach
signals hunger
highest when fasting, suppressed by food ingestion
obesity linked to increased ghrelin sensitivity (increased hunger response to lower ghrelin levels)
GLP-1
secreted by L cells of SI following nutrient uptake
promote satiety
inhibits gastric emptying and intestinal motility
promotes glucose-mediated insulin release
antagonized by somatostatin
PYY
secreted by L cells of intestine co-secreted with GLP-1 signals satiety at hypothalamus inhibits gastric emptying and intestinal mobility no effect on glucose
weight loss and ghrelin
increase in baseline and post-prandial ghrelin for 1+ years following/during weight loss
(increases hunger during this time)
weight loss and PYY
decreased baseline and post-prandial PYY for 1+ years following/during weight loss
(decreases satiety/increases hunger during this time)
POMC
cells of melanocortin system in arcuate nucleus of hypothalamus
reduces food intake when activated
NPY/AgRP
cells of melanocortin system in arcuate nucleus of hypothalamus
increases food intake when activated
beta-endorphins
inhibit POMC
increases food intake
obesity pharmacotherapy
gastric/pancreatic lipase inhibitor
- induces fat maldigestion/malabsorption
- binds lipases in intestinal lumen
sympathomimetic amines
- e.g. amphetamines
- NE (and dopamine, serotonin) release in ht to induce satiety
GLP-1 analogues
- stimulate POMC (satiety)
- reduce gastric transit/emptying (satiety)
- reduce glucose-mediated insulin release
roux en Y gastric bypass
stapling or transecting stomach
make 10-30 ml proximal gastric pouch
anastomose pouch to jejunum via “roux en Y limb”
- bypasses duodenum, maldigestion
- decreases food intake
- reduced ghrelin (hunger), increased PYY and GLP-1 (satiety, glycemic improvement)
complications:
- vitamin and mineral deficiencies
- B1, B2, B6, B12, B9 (folate)
- iron
- zinc
- vitamin A
- vitamin D
sleeve gastrectomy
vertical resection of a portion of the stomach
- decreases food intake
- reduced ghrelin (hunger), increased PYY and GLP-1 (satiety, insulin sensitivity)
alpha cells
glucagon
beta cells
insulin
delta cells
somatostatin
pp cells
pancreatic polypeptide
distinguishing islet cell types
requires IHC
insulinoma
usually non-malignant, sx (hypoglycemia) arise from insulin production
- may be overt hypOglycemia
- may be more subtle, e.g. diarrhea or weight loss
on histology look like an exceptionally large islet (up to 7-10 cm) surrounded by a capsule
IHC can distinguish them from other endocrinomas of pancreas
