Glycemic states Flashcards
Stimulants of insulin release
glucose (major)
amino acids (arginine, leucine)
PSNS, GIP, GLP, glucagon
inhibitors of insulin release
SNS
somatostatin
effects of insulin - general
facilitates glucose (GLUT4) and amino acid uptake into cells
inhibits gluconeogenesis, glycogenolysis, lipolysis
increases rate of protein synthesis and decreases rate of degradation
Effects of insulin - muscle
stimulates glycogenesis
Effects of insulin - adipocyte
stimulates conversion of FFAs ans glucose –> TGs
Effects of insulin - liver
- stimulates glycogenesis by activation of glycogen snthase
- stimulates glycolysis by activation of glucokinase, phosphofructokinase, pyruvate kinase
- inhibits glycogenolysis by inactivation of glycogen phosphorylase
- inhibits gluconeogenesis by inhibition of pyruvate carboxylase, phosphenol pyruvate carboxykinase (PEPCK) and fructose 1,6 diphosphatase
Stimulants of glucagon release
SNS, PSNS, GIP, CCK, amino acids (arginine and alanine)
Inhibitors of glucagon release
insulin, somatostatin, GLP, glucose, Islet amyloid polypeptide (secreted with insulin from B-cells, acts to retard gastric emptying and glucagon secretion, helps to control blood glucose sparing insulin)
Glucagon effects on metabolism
Inhibits glycogenesis, TG synthesis, hepatic protein synthesis
Stimulates gluconeogenesis via increased uptake of gluconeogenic amino acids; inhibition of pyruvate kinase, and stimulation of PEPCK and pyruvate carboxylase
Stimulates glycogenolysis via glycogen phosphorylase
Stimulates fat breakdown and hepatic (NOT MUSCLE) protein breakdown
enhances ketogenesis
Epinephrine effects on metabolism
Stimulates glycogenolysis, gluconeogenesis, glucagon release, lipolysis
Inhibits insulin release
Effects of cortisol on metabolism
stimulates gluconeogenesis, lipolysis, protein degradation
inhibits glucose uptake by muscle and adipose tissue
Effects of GH on metabolism
stimulates lipolysis and promotes protein synthesis
inhibits glucose uptake by muscle and decreases rate of protein degradation
GH stimulant
Ghrelin
Causes of hyperglycemia
Endocrine: - diabetes - acromegaly - Cushing's - glucagonoma - somatostatinoma - pheochromocytoma Pancreatic insufficiency - chronic pancreatitis, hemochromatosis, subtotal pancreatectomy Drugs: GCs, thiazides, phenytoin, niacin, OCP Others: gestational diabetes, cirrhosis
Hypoglycemia causes
Reactive/postprandial/functional hypoglycemia
- can be normal or due to post gastrectomy, galactosemia, hereditary fructose intolerance
Excess use of insulin/sulfonylurea
Acute alcohol intoxication - suppress gluconeogenesis
Drugs: salicylates, quinine, propoxyphene, disopyramide, propanolol, MAOIs
Hyperinsulinism: insulinoma, hyperplasia of beta cells, inherited defects of Katp channels
Endocrine: adrenal failure, panhypopituitarism, isolated ACTH/GH deficiency
Liver failure
Renal failure
Non-pancreatic neoplasms: increased IGF2
Neonatal disorders (glycogen storage, etc)
Septicema
Insulin synthesis and processing
1) Proinsulin synthesized in beta cells
- A and B chains linked by -S-S-
- C-peptide
2) Proinsulin processed efficiently in granules by prohormone convertase enzymes (PC1/3 and PC2), and carboxypeptidase E –> Insulin and C-peptide
3) Insulin crystallizes with Zinc in granule centre; C peptide in granule halo
- C-peptide no known function, but a good marker for endogenous insulin secretion
Insulin receptor
Tyrosine kinase enzyme (glycoprotein)
on muscle, adipose, and liver tissue
2 alpha - extracellular, linked by -S-S-
2 beta - transmembrane, dip into cytoplasm, each linked to alpha by -S-S-
1) Binds insulin –> conformational change
2) stimulates TK activity in beta units
3) autophosphorylation of receptor
4) phosphorylation of other intracellular proteins
5) various actions - e.g. translocation of GLUT4 onto surface
Consequences of insulin deficiency
Hyperglycemia
Increased FA in blood
Protein catabolism
Consequences of insulin excess
Reverse metabolic changes
First symptoms:
- palpitations, sweating, nervousness
Lower plasma glucose levels: confusion, other cognitive abilities
Even lower: lethargy, coma, convulsions, eventually death
Newborn hypoglycemia
Common in critically ill or extremely low birthweight infants
Most cases - multifactorial, transient and easily supported.
Some cases: due to hyperinsulinism, hypopituitarism, or an inborn error of metabolism
Causes of transient newborn hypoglycemia
Prematurity, intrauterine growth retardation, perinatal asphyxia
Maternal hyperglycemia due to diabetes or iatrogenic glucose administration
Sepsis
prolonged fasting
Hypoglycemia in young children
Gastroenteritis/fasting
Recurrent - inborn error of metabolism, congenital hypopituitarism, or congenital hyperinsulinism
Hypoglycemia in young adults
Most common: injected insulin for type 1 diabetes
Congenital causes would have manifested before this age
Body mass large enough - starvation/idiopathic ketotic hypoglycemia less common
Addison’s disease
Sepsis
Hypoglycemia in older adults
Complex drug interactions Insulinoma, other tumours Acquired adrenal insufficiency Acquired hypopituitarism Immunopathologic hypoglycemia
Carinitine level during hypoglycemia
Should be increased due to increased lipolysis and ferrying of FFAs to the mitochondria
may be low in FA oxidation disorders
Amino acid levels during hypoglycemia
should be decreased due to increased gluconeogenesis (esp essential amino acids)
Abnormal: suggests certain inborn errors of amino acid metabolism or gluconeogenesis
Somatostatin indication
suppression of hormones or transmitters in:
- islet cell tumours (insulinoma, glucagonoma)
- acromegaly
- symptomatic VIP/carcinoid tumours
Somatostatin MOA
secreted by delta cells of the pancreatic islet
inhibits release of: insulin (via inhibition of CaV), glucagon, GH, gastrin, VIP
causes v/c leading to reduced portal venous flow
Glucagon indication
refractory hypoglycemia (not corrected by glucose)
Glucagon MOA
endogenous peptide hormone , counter regulatory
Main effects on the liver: increase glycogenolysis, decrease glycogenesis, increase glycolysis, increase ketogenesis
Positive ionotropic and chronotropic effect on cardiac tissue
Stimulates endogenous insulin secretion
Inhibited by insulin and somatostatin
Diazoxide MOA
prolongs opening of ATP sensing K+ channel in beta cells, inhibits pancreatic secretion of insulin
Diazoxide indications
parenteral use as an antihypertensive
orally antihypoglycemic agent secondary to hyperinsulinemia
Glucokinase mutation
dominant inheritance
regulatory mutation
leads to hyperinsulinism
Glutamate dehydrogenase mutation
dominant
leads to hypoglycemia and hyperinsulinism and hyperammonemia
G6phosphatase deficiency
Glycogen storage disease, gluconeogenesis disorder
critical enzyme in the generation of all new glucose from within the straight chains of glycogen
Can get hepatomegaly, high levels of serum triglycerides
elevated plasma lactate can also lead to metabolic acidosis
Can get hypophosphatemia
Minimal ketosis compared to lactic acid buildup
Amino 1,6 glucosidase deficiency
Glycogen storage disease
hepatomegaly
hypoglycemia
have capacity to undergo gluconeogenesis
Liver phosphorylase and phosphorylase kinase deficiency
Glycogen storage disease
Phosphorylase complex
ultimately results in teh degradation of the straight chains of liver glycogen
Glycogen synthase deficiency
Glycogen storage disease
Fructose 1,6 diphosphatase deficiency
gluconeogenesis disorder
results in a block of gluconeogenesis from all possible precursors below the level of fructose 1,6 diphosphate
results in lactic acidosis
glycogenolysis remains intact
PEP carboxykinase deficiency
gluconeogenesis disorder
Galactosemia
Galactose –> phosphorylated –> conjugated + uridine –> UDP galactose –> epimerization to UDP glucose
Galactose restricted diet
Deficiencies: galactose-1-phosphate uridyl rtansferase
UDP-galactose-4-epimerase
Fructose-1-phosphate aldolase
results in hereditary fructose intolerance
Newborn short hypoglycemia management
take critical blood sample
then glucagon 1 mg im/iv
Cause of neonatal fasting hypoglycemia with lactic acidosis
Can be normal
G6Pase, FDPase, Pyruvate carboxylase deficiency
Test for gluconeogenic precursors
Glucagon stimulation test
Causes of neonatal fasting hypoglycemia with ketoacidosis
Normal
GH deficiency
Cortisol deficiency
Test for adrenal and pituitary function
glucagon stimulationt est
Causes of fasting hypoglycemia with no ketosis
Elevated FFA: FA oxidation disorders, normal
do acyl-carinitine profile
Low FFA: hyperinsulinism, panhypopituitarism, SGA, birth asphyxia
- glucagon stimulation test
- pituitary, adrenal and thyroid function
- insulin assay
- other tests for HI
Infant glucose requirement
6-8 mg/kg /min - larger requirement, high brain-to-body ratio
Prone to hypoglycemia due to small stores
mobilization of glycogen stores initiated at cutting of umbilical cord
Adult glucose requirement
3.4 mg /kg /min
Insulin secretion mechanism
1) glucose uptake via GLUT 2
2) metabolized, ATP produced
3) increased ATP/ADP –> K-ATP channel closes, depolarization
4) CaV opens, Ca influx –> insulin granule exocytosis
5) Ca also activates gene expression via CREB
Acute symptomatic neonatal/infant hypoglycemia treatment
iv D10W infusion, then continuous glucose infusion
If hypoglycemic seizures present –> more D10W bolus
Management of persistent neonatal/infantile hypoglycemia
Increase rate of iv glucose to 10-15 mg/kg/min or more if needed
Hyperinsulinemia –> diazoxide, then octreotide
Hypoglycemia unresonposive to glucose + diazoxide/octreotide –> consider partial/near-total pancreatectomy
Continued prolonged medical therapy without pancreactic resection if hypoglycemia is favourable, due to spontaneous recovery in some cases
Total pancreatectomy not optimal: risk of surgery, permanent DM, exocrine pancreatic insufficiency
