Week 3: Disorders Of Carbohydrate Metabolism

Front 1

What are the 3 categories of carbohydrate metabolic disorders?

Back 1

1. underproduction/utilization of glucose (disorders of glycogenolysis and gluconeogenesis)
2. overutlization of glucose (hyperinsulinsm)
3. defective insulin action (diabetes)

Front 2

Underproduction of glucose disorders (4 categories)

Back 2

1. glycogenolysis
2. gluconeogenesis
3. inhibition of gluconeogenesis
4. ketotic hypoglycemia

Front 3

Disorders of glycogenolysis

Back 3

glycogen storage diseases (GSDs)

Front 4

GSD 1

Back 4

von Gierke's disease
1:100,000 incidence
no G6Pase from glucose-6-P to glucose

Tx: IV dextrose, correct acidosis, frequent 3 hr feeds avoiding lactose/fructose. NG feeds with only glucose formula

Front 5

GSD II

Back 5

Pompe's disease
deficiency of alpha-1,4-glucosidase enzyme (lysosomal acid maltase)
-glycogen accumulation in lysosome due to this deficiency, damage to heart, skeletal, muscle (hypotonia), liver, nervous system

-1:14,000 - 1:50,000
-Tx: high protein, low carbohydrate, synthetic alpha glucosidase

Front 6

GSD III

Back 6

IIa, c- affect liver, muscles
IIIb, d affect only liver
GSD III- deficiency of amylo-1,6 glucosidase or debrancher enzyme

-infancy, early childhood- hepatomegally, elevated liver enzymes, ketotic hypoglycemia, hyperlipidemia
-adolescent, adult- less prominent liver disease, hypertrophic cardiomyopathy
-1:100,000
-myopathy
-Tx: discouraging prolonged exercise, high protein diet. synthetic ketone bodies

Front 7

Disorders of gluconeogenesis

Back 7

-fructose 1,6-biphosphatase deficiency
-pyruvate carboxylase deficiency
-phosphoenolpyruvate carboxykinase (PEPCK) deficiency
-pyruvate dehydrogenase deficiency

Front 8

F 1,6-biphosphatase deficiency

Back 8

-present with irritability, poor feeding neonate, fasting hypoglycemia evolves, lethargy/poor tone, irritability, poor milestones developmental delay, prolonged- abd distension
- fatty liver, 3 carbon molecules cannot be used, shunted to make pyruvate, lactic acid, lactic acidosis, ketoacidosis
-Tx: eat frequently, avoid gluconeogenesis, not fasting for long periods, high carb foods, NG feeds, avoid fructose

Front 9

Inhibition of gluconeogenesis by accumulation of metabolic products

Back 9

-galactosemia
-galactokinase deficiency
-UDPgalactose epimerase deficiency
-hereditary fructose intolerance

Front 10

Hereditary fructose intolerance

Back 10

-aldolase B def- AR
-hepatomegaly, failure to thrive, emesis
-avoid fructose. not as severe/deadly as other GSDs

Front 11

Galactosemia

Back 11

-galactose-1-phosphate uridyltransferase (GALT) deficiency. 1:30 to 1:60,000. neonatal screen
-infants develop feeding difficulties, lethargy, hypoglycemia, failure to thrive, jaundice, bleeding, sepsis, shock from infections, delayed development, cataract, ovarian failure
Tx: avoid lactose

Front 12

Ketotic hypoglycemia

Back 12

-substrate limited gluconeogenesis, "accelerated starvation"
-0.5-1.0% incidence
-dominant in apperance, 1-5 year olds, due to low alanine availability for GN

Front 13

Underproduction of glucose

Back 13

- endocrine hormone deficiencies
-drugs: ethanol, salicylates, beta blockers, pentamidine
-other: fatty acid oxidation defects, disorders of ketogenesis, mitochondrial disorders

Front 14

what endocrine deficiencies can lead to underproduction of glucose

Back 14

-GH def
-cortisol, primary addisons, primary adrenal and secondary adrenal
-glucagon def (very rare)
-insulin deficiency- diabetes

Front 15

How do endocrine hormones respond to hypoglycemia

Back 15

-decr insulin
-incr glucagon
-incr epinephrine
-incr cortisol
-incr GH

Front 16

insulin

Back 16

-insulin decr--> glycogenolysis to produce glucose.
-decreased insuli--> glycagon secretion by direct stimulation in pancreatic alpha cells- further increases hepatic glucose production
-insulin normally restrains glucagon secretion

Front 17

glucagon

Back 17

-increased in hypoglycemia
-falling below 65-70 mg/dl
-glucagon acts only on liver, increasing glucose production via glycogenolysis, gluconeogenesis from alanine, amino acids, glycerol

Front 18

epinephrine

Back 18

-b-2-adrenergic receptors, stimulates hepatic glycogen breakdown. increases delivery of gluconeogenic substrates from periphery
-inhibits glucose utilization by tissues
-via a-2receptors, inhibits insulin secretion
-65-70 threshold

Front 19

cortisol and GH

Back 19

last line defenses following insulin decline and increases in glucagon and epinephrine
-limit glucose utilization, enhance hepatic glucose production via gluconeogensis, require intact HPA

Front 20

What are some drugs and substances that cause hypoglycemia?

Back 20

-alcohol
-bactrim (ABx)
-beta blockers
-haloperidol
-insulin
-MAO inhibitors
-metformin when used with sulfonylureas
-pentamidine
-quinidine
-quinine
-sulfonylureas

Front 21

Non ketotic hypoglycemias

Back 21

-fatty acid oxidation disorders
-hyperinsulinism (too much insulin, forced caloric ingestion/infusion, hospital acquired)

Front 22

MCAD

Back 22

-medium chain acyl CoA dehydrogenase deficiency
-acyl-CoA dehydrogenase catalyzes oxidation of fatty acid moiety of acyl-CoA to produce double bond between carbons 2 & 3.
-in mitochondrial matrix
-MCAD most potent for inducing hypoglycemia

Front 23

B oxidation

Back 23

Front 24

What happens during fasting (chemical pathway)

Back 24

Fasting: oxaloacetate depleted in lever due to gluconeogenesis. This impedes acetyl-CoA entry into Krebs. Then this acetyl CoA in liver mitochondria converted to ketone bodies, acetoacetate, B-hydrobutyrate

Front 25

MCAD treatment

Back 25

MCAD is AR, prevealent in individuals of northern european caucasian descent.
-treatment is frequent feeds, avoidance of fasting-carnitine supplementation

Front 26

What tumors can lead to hyperinsulinism?

Back 26

1. insulin-secreting tumors-pancreatic
2. non-islet cell, IGF-II secreting tumors
3. myeloma, lymphoma, leukemia
4. metastatic cancers

Front 27

PHHI- pathogenesis

Back 27

persistent hyperinsulinemic hypoglycemia of infancy
-AR mutation in gene encoding K-ATP channel
-inactivating mutations reduce open channels, depolarization of beta cells and hypersecretion of insulin
-aberrant secretion is diffuse

Front 28

PHHI presenting symptoms

Back 28

-pallor
-hypothermia
-tremors/seizures
-rapid breathing (tachypnea)
-rapid heart rate (tachycardia)

Front 29

PHHI lab findings

Back 29

hypoglycemia
decreased free fatty acids
no ketones
elevated cortisol and growth hormone
elevated insuln, c-peptide

Front 30

PHHI treatment

Back 30

IV glucose to maintain levels >80
diazoxide-block sulfonylurea receptors on beta cells, opening KATP channels and decreasing insulin release
IV glucagon
somatostatic analogues (octreotide)
CCBs

Front 31

PHHI - when surgical treatment

Back 31

-diazoxide unresponsive patients or those who have complications of treatment
-90% pancreatectemy

Front 32

PHHI- complications

Back 32

-heart failure, poor nutrition, liver enlargement, obesity, hirsutism
-long term: seizures, neurological delay, diabetes post op

Front 33

Types of diabetes

Back 33

Type I
Type II
Gestational diabetes
steroid induced diabetes
other types of diabetes

Front 34

caused by autoimmune destruction,
of the pancreatic beta cell, leading to decreased
insulin secretion.

Back 34

Type I diabetes

Front 35

caused by insulin resistance due to
ineffective insulin cellular action; beta cell insulin
secretion is usually preserved.

Back 35

Type II diabetes

Front 36

Autoimmunity in diabetes?

Back 36

-associated with Type I
-MHC-chr 6- >90% pts carry HLA DR3, DQB1*0201, HLA DR4,DQB1*0302
-anti-islet cell Ab, anti-GAD Ab

Front 37

typical incidence of diabetes, age of presentation

Back 37

8-16 yrs

Front 38

What happens in absence of insulin?

Back 38

increased FFA, glycerol production (fat cell) leading to ketogenesis and gluconeogenesis (liver) and proteolysis (muscle)
-increased glucagon, glycogenolysis
-increased cortisol, gluconeogenesis
-incrs epinephrine, FFA and glycogenolysis, gluconeogenesis

Front 39

COMMON SIGNS OF DIABETES?

Back 39

-incr thirst, urination
-weight loss (due to catabolic state)
-vomiting (episodic, continuous)
-fatigue and irritability
-rapid breathing in absence of pulmonary disease

Front 40

How does diabetes affect kidney

Back 40

-elevated serum glucose is filtered, much of which does not get reabsorbed and is excreted. this causes incr water excretion (polyuria), Na and K losses, promotes incr thirst (polydypsia) and dehydration

Front 41

acute presentation diabetes

Back 41

-Vomiting, dehydrated, air hunger, abd pain, rapid breathing (kussmaul), cyanosis.
-symptoms can mimic appendicitis, stomach virus, asthma
-acidosis, hyperglycemia
-treatment is ICU for fluids, IV insulin, close monitoring

Front 42

sub-acute presentation diabetes

Back 42

-incr thirst, urination about 2-3 weeks duration. weight loss, incr or decr appetite, intermittent nausea, appear nearly well
-ketosis maay be present, no acidosis, mild hyperglycemia.
-positive anti-islet cell and anti GAD Ab
-treatment is insulin and education

Front 43

What is the best regimen of insulin

Back 43

combination of long acting to cover basal needs, short acting to cover meal needs

Front 44

Each meal insulin dose=

Back 44

carb factor + premeal glucose factor

Front 45

How do we monitor the long term glucose control of a patient?

Back 45

-Hemoglobin A1C- irreversible non enzymatic association of glucose on the A1C subset of hemoglobin

Front 46

Ideal HgA1C

Back 46

5.5-6.9%

Front 47

Acute diabetic complications

Back 47

cerebral edema/thrombosis, arrhythmias/arrest

Front 48

Chronic diabetic complications

Back 48

1.retinopathy
2. nephropathy
3. neuropathy
4. psychological
5. cardiovascular
6. economic

Front 49

Relationship of HbA1C to risk of microvascular complications

Back 49