GI - Biochemistry - Diabetes; Other Sugar Metabolism; Bile Acids Flashcards
Of U.S. diabetics, what percentage are type I?
What percentage are type II?
5 - 10%
90 - 95%
What ethnicity is most at-risk for type I diabetes mellitus?
What gender?
What age?
Caucasian > African-American, Hispanic >>> Asian;
men > women;
11 - 13 years of age
What ethnicity is most at-risk for type II diabetes mellitus?
What gender?
What age?
Hispanic, Native American, African-American, Asian > caucasian;
men = women;
> 40
Describe the development of type I diabetes mellitus in terms of cause, timing, and mechanism.
Viral infection induces an autoimmune attack on the pancreatic β-cells (molecular mimicry);
may take up to 10 years post-infection to become a clinical presentation
How is type I diabetes mellitus diagnosed (ADA guidelines)?
(Hint: there are 4 potential tests.)
HbA1c ≥ 6.5%
FPG > 125 mg/dL
OGTT > 200 mg/dL (at 2 hours)
RPG > 200 mg/dL (with classic S/Sy)
What are some of the common signs and symptoms of type I diabetes mellitus?
Polydipsia, polyphagia, polyuria;
unexplained weight loss, lassitude, muscle cramps, blurred vision, peripheral neuropathy, headaches, GI complications
What values for the following tests would indicate prediabetes?
FPG
HbA1c
OGTT
FPG: 110 - 125 mg/dL
HbA1c: 5.6 - 6.4%
OGTT: 140 - 200 mg/dL
What are the normal values for the following tests?
FPG
HbA1c
OGTT
FPG: 70 - 110 mg/dL
HbA1c: < 5.6%
OGTT: < 140 mg/dL
To what conditions is a patient with prediabetes especially predisposed?
Type II diabetes mellitus;
macrovascular disease
Describe the requirements for a patient to be diagnosed with metabolic syndrome.
(I.e. they must have ≥ ____ of which clinical test values?)
Must have ≥3 of the following:
Obesity
Elevated glucose levels (≥ 110 mg/dL FPG)
Dislipidemia (elevated TG and LDL, decreased HDL)
Hypertension
Insulin resistance
Prothrombotic state
Proinflammatory state
To be diagnosed with metabolic syndrome, a patient must have ≥ 3 of what features?
Obesity
Elevated glucose levels (≥ 110 mg/dL FPG)
Dislipidemia (elevated TG and LDL, decreased HDL)
Hypertension
Insulin resistance
Prothrombotic state
Proinflammatory state
Which are the two dominant factors in a patient with metabolic syndrome that especially predispose that individual to T2DM and vascular disease?
Abdominal obesity,
insulin resistance
What percentage of patients with T2DM are obese?
90%
What happens to insulin levels in an individual as they develop T2DM?
An initial compensatory insulin increase;
a steady decrease in insulin production over decades
Describe the changes in serum glucose and insulin in a patient as they develop T2DM.
What are the two features of T2DM development?
Peripheral insulin resistance
+
insufficient insulin-secretory (compensatory) mechanism
What are some of the signs and symptoms of type II diabetes mellitus?
All the S/Sy of T1DM
+
slow-healing sores, itchy skin, frequent yeast infections
Do pregnant women normally develop hyperglycemia or hypoglycemia during pregnancy?
When?
Why?
Hypoglycemia;
intraprandial / during sleep;
fetal glucose need
Does intraprandial hypoglycemia increase or decrease as pregnancy progresses?
Increase
(fetal demand increases)
In non-specific terms, why do some women develop gestational diabetes mellitus?
Susceptible women develop insulin resistance in response to placental steroid and peptide synthesis
A pregnant woman begins to develop insulin resistance in response to the increasing placental steroid and peptide hormone synthesis.
What will occur if her insulin levels are inadequate?
Recurrent postprandial hyperglycemia –>
accelerated fetal growth
What are some of the effects of surging hyperglycemia and hyperinsulinemia (related to gestational diabetes mellitus) on the fetus?
Macrosomia, fetal hypoxia;
hypertension, cardiac remodeling/hypertrophy
What are some of the risk factors for gestational diabetes mellitus?
Consider: age, ethnicity, weight, and medical history.
Age: > 35
Ethnicity: Hispanic, Native American, African-American, Asian > caucasian
Weight: Obesity
Medical History: obstetrical Hx of diabetes or macrosomia; family Hx of DM
How does ethnicity affect a woman’s risk of gestational diabetes mellitus?
What percentage of women with gestational DM will develop overt DM within 5 years of delivery?
~33%
(higher risk ethnicities nearing 50%)
How is gestational DM diagnosed?
When?
2 steps:
1-hour glucose challenge test (GCT)
2-hour OGTT;
between week 24 and 28
(week 13 for those with risk factors)
What is the major acute complication of T1DM?
What is the major acute complication of T2DM?
Diabetic ketoacidosis (DKA);
hyper(HHNC)
Which has a higher mortality rate, diabetic ketoacidosis (DKA) or hyperosmolar hyperglycemic non-ketotic coma (HHNC)?
HHNC
True/False.
Both DKA and HHNC are characterized by hyperglycemia and dehydration.
True.
What are some causes of DKA in a patient with T1DM?
New onset of DM,
insulin disruption,
infection
What are some causes of HHNC in a patient with T2DM?
Secondary to DM effects:
infection,
fluid loss,
certain drugs
What are the S/Sy of DKA?
1. Serum glucose > 300 mg/dL
2. Acidosis
3. Low HCO3- (< 15 mEq/L)
4. Ketonemia, ketonuria
5. Acetone breath
What are the S/Sy of HHNC?
1. Serum glucose > 600 mg/dL
2. Hyperosmolarity > 320 mOsm/dL
3. Dehydration
4. Na+/K+ loss (via osmotic diuresis)
How is DKA treated?
Fluids
+
Insulin (after 1st hour)
+
Dextrose (eventually, to prevent hypoglycemia)
How is HHNC treated?
Similar to DKA (fluid –> insulin –> glucose)
+ careful electrolyte monitoring
List some of the chronic complications of diabetes.
Neuropathies,
peripheral vascular disease
diabetic nephropathy,
cataracts, glaucoma, retinopathy,
CVD,
skin lesions
Diabetics should be encouraged to aim for a HbA1c of:
< 7%
What are the main sugar- and insulin-related goals of diabetes medication?
HbA1c < 7%
Postprandial glucose of 90 - 130 mg/dL
Increased insulin secretion
Decreased insulin resistance
Why don’t T2 diabetics get DKA?
They have sufficient insulin secretion to prevent ketone production
Other than meglitinides, thiazolidinediones, and incretins, name three categories of drugs often used to treat T2DM.
Biguanides (metformin)
Sulfonylureas (tolbutamide, glipizide, glyburide)
α-glucosidase (miglitol, acarbose) / SGLT-2 inhibitors (
Other than biguanides, sulfonylureas, and α-glucosidase/SGLT inhibitors, name three categories of drugs used to treat T2DM.
Meglitinides (repaglinide)
Thiazolidinediones (rosiglitazone, pioglitazone)
Incretins (DDP-4 inhibitors; glucose-dependent insulinotropic peptide and GLP-1 analogs)
What results occur with virtually all diabetic medications?
A decrease in FPG and a decrease in HbA1c
Name three diabetic drug types that increase insulin secretion.
Sulfonylureas (long-acting);
meglitinides (short-acting);
incretins
Name a diabetic drug type that decreases glucagon secretion.
Incretins
Name two diabetic drug types that increase insulin sensitivity (in the liver, skeletal muscle, and adipose).
Biguanides (e.g. metformin);
glitazones
Name a diabetic drug type that decreases glucose absorption in the gut.
Name a diabetic drug type that decreases glucose absorption in the kidneys.
α-glucosidase inhibitors;
SGLT inhibitors
What is the basic mechanism by which metformin decreases FPG and HbA1c?
What is the basic mechanism by which meglitinides decrease FPG and HbA1c?
What is the basic mechanism by which α-glucosidase (or SGLT-2) inhibitors decrease FPG and HbA1c?
Increased insulin sensitivity;
increased insulin secretion;
decreased gut (or renal) glucose absorption
What is the basic mechanism by which incretins decrease FPG and HbA1c?
What is the basic mechanism by which thiazolidinediones decrease FPG and HbA1c?
What is the basic mechanism by which sulfonylureas decrease FPG and HbA1c?
Increased insulin secretion / decreased glucagon secretion;
decreased renal glucose reabsorption;
increased insulin secretion
Which is long-acting, sulfonylureas or meglitinides?
Sulfonylureas
What is another term for glitazones?
Thiazolidinediones
How do thiazolidinediones (glitazones) affect blood sugar?
PPAR-γ receptor activation –> release of adiponectin
–> increased insulin sensitivity
How do sulfonylureas affect blood sugar?
They depolarize pancreatic β-cells by inhibiting KATP channels
(causing increased insulin secretion)
What enzyme can digest sucrose? What are the products?
Sucrase — glucose + fructose
What enzyme can digest trehalose? What are the products?
Trehalase — glucose
What enzyme can digest lactose? What are the products?
Lactase — glucose + galactose
What enzyme can digest α-1,6 glycosidic linkages in the gut? What is the product?
isomaltase (α-dextrinose) — glucose
Why can infants absorb some oligosacharrides?
(Hint: it is the same reason they can absorb their mothers’ IgA without breaking them down.)
Leaky tight junctions
(not yet fully formed enterocyte connections)
True/False.
Adults can only take up monosacharrides, but infants can take up oligosacharrides.
True.
(Due to infantile ‘leaky’ tight junctions)
What is inulin?
A non-digestible fructose polymer
What is sucralose?
(Splenda) A non-digestible sucrose that is chlorinated
Which hexokinase cannot phosphorylate fructose to F6P?
Glucokinase (hexokinase IV)
What monosacharrides can be phosphorylated by hexokinase I?
(Are there Km differences?)
Glucose, fructose
(lower Km for glucose)
What two hepatic enzymes are the main factors controlling fructose metabolism?
Fructokinase,
aldolase B
What happens to a fructose molecule after entering a hepatocyte?
Fructokinase converts it to F1P;
aldolase B then converts it to glyceraldehyde and DHAP
(then glyceraldehyde 3-P, a glycolytic intermediate)
What happens if a person is deficient in fructokinase?
Fructosuria
(fructose is never converted to F1P, and so it accumulates in the urine)
What happens if a person is deficient in aldolase B?
Essential fructosemia (hereditary fructose intolerance)
–> F1P builds up, inhibiting glycogen phosphorylase and damaging the liver
What enzyme is deficient in essential fructosemia?
What enzyme is deficient in fructosuria?
Aldolase B;
fructokinase
Name the respective buildup products for the following two diseases:
Fructosuria
Essential fructosemia
Fructose (in urine)
F1P (in liver)
Which of the following damages the liver, fructosuria or essential fructosemia?
Essential fructosemia
A parent brings their 3-year-old child into the clinic with complaints of vomiting, lethargy, irritability, and convulsions. The child has met all their milestones and been otherwise healthy. The S/Sy began recently when the child was first introduced to fruit juices.
What inborn error of metabolism comes to mind?
Essential fructosuria
Will essential fructosuria cause hyperglycemia or hypoglycemia?
Hypoglycemia
(due to glycogen phosphorlyase inhibition by F1P)
Patients with essential fructosuria are advised to avoid ingesting what sugar(s)?
Fructose,
sucrose,
sorbitol (converted to fructose via sorbitol dehydrogenase)
What enzyme can interconvert glucose and sorbitol?
Where is it found?
Aldose reductase;
the lens, retina, and Schwann cells
(the cause of some diabetic complications)
What is the purpose of pyrophosphorylases?
To activate monosacharrides by attaching UDP to them
True/False.
UDP-galactose can be formed by transfering UDP from UDP-glucose to a Gal-1P.
True.
What is galactosemia?
What enzyme(s) is(are) deficient?
Galactose buildup;
galactokinase OR galactose 1-phosphate uridyl transferase
Which shows up right away at birth and is more severe,
galactosemia or essential fructosemia?
Galactosemia
What are some of the S/Sy of galactosemia?
S/Sy begin shortly after birth;
mental retardation, liver disease, cataract formation
What is the underlying mechanism that explains diabetic retinopathy, cataract formation, and peripheral vascular disease?
Sorbitol accumulation in the lens, retina, and Schwann cells
(via aldose reductase conversion of glucose to sorbitol)
How is galactosemia managed?
Simple removal of galactose from the diet
Expression of what lactation protein is upregulated by prolactin?
α-lactalbumin
What enzyme and modifying protein are responsible for lactose formation in the mammary glands?
What substance increases expression of the modifying protein?
Galactosyl transferase, α-lactalbumin;
prolactin
Via what mechanism does prolactin affect lactose production in breast milk?
Upregulation of α-lactalbumin
(galactosyl transferase switches from glycoprotein synthesis to lactose synthesis)
Why are many compounds synthesized in the body (or drugs metabolized in the body) attached to uronic acids?
To increase solubility
(and make for easier transport)
If a patient with lactose intolerance ingests a substance containing only lactose, what effect will the substance have on their blood glucose levels?
No effect
(the lactose is not absorbed)
(The child did not improve with a switch to formula and eventually developed cataracts and liver damage.)
Galactosemia (check via blood test);
remove galactose and lactose from the diet
What class of enzyme converts cholesterol into its derivatives such as bile acids, steroid hormones, and calcitriol?
Monooxygenases
(oxygenating cholesterol)
What are some of the potential fates of hepatic cholesterol?
- Synthesis of plasma membranes
- Export to peripheral tissues via VLDL
- Secretion as bile acids/salts
- Synthesis of calcitriol or other steroid hormones
What do hepatic monooxygenase enzymes do to cholesterol?
What cofactors are needed?
Add hydroxyl groups to them;
NADPH, O2
The hepatic monooxygenase enzymes are part of what system?
What nomenclature can be used to indicate 7α-hydroxylase?
Cytochrome P450;
CYP7A1
Describe the basic structure of cholesterol.
4 rings + hydrocarbon tail
How is cholic acid (a bile acid) modified from normal cholesterol (shown below)?
Addition of hydroxyl groups + a carboxyl group
What portion of a bile acid is conjugated to glycine or taurine?
The carboxyl group
What is the most common bile acid?
Is it primary (liver-synthesized) or secondary (gut-modified)?
Cholic acid;
primary
What is the rate-limiting step of bile acid synthesis?
What provides negative feedback to this enzyme?
7α-hydroxylase;
cholic acid
What are the two main bile acids?
Which is a triol (3x -OH) and a better detergent than the corresponding diol (2x -OH)?
Cholic acid, chenodeoxycholic acid;
cholic acid
What percentage of bile acids are reabsorbed in the gut and recirculated into bile?
90%
How does cholestyramine (a medication) lower plasma cholesterol?
What dietary substance has the same effect?
By sequestering gut bile acids and increasing their excretion
(more cholesterol then needed to resynthesize the bile acids);
dietary fiber
What medication is here described: sequesters gut bile acids to increased their excretion.
What is the overall effect?
Cholestryamine;
decreased plasma cholesterol
Which is a better emulsifer, bile acids or bile salts?
Which is secreted into the bile?
Which is more easily reabsorbed in the gut?
Bile salts;
bile salts;
bile salts
How is a bile acid turned into a bile salt?
Via conjugation of its carboxyl group with either glycine or taurine
How do the gut flora interact with bile acids/salts?
Via conversion of 1° acids/salts into 2° acids/salts (removal of the 7α-OH);
via deconjugation (removal of glycine or taurine)
Which is more soluble and more easily reabsorbed in the gut, primary or secondary bile acids/salts?
Primary (conjugated + one more hydroxyl group)
Describe the enterohepatic circulation of bile salts.
What term indicates gallstone formation due to bile salt deficiency?
Cholelithiasis
(more cholesterol than bile salts –> the cholesterol precipitates)
Define cholelithiasis.
How is it treated (give surgical and non-surgical options)?
Gallstone formation (due to bile salt deficiency);
laparoscopic cholecystectomy,
oral chenodeoxycholic acid
How does oral chenodeoxycholic acid treat gallstones?
How quick acting are its effects?
By substituting the missing bile salts –> emulsifies / dissolves the gallstone cholesterol back into bile;
takes months-to-years
What are some conditions/situations that can decrease [bile salt] and increase risk of cholelithiasis?
Ileal disease,
biliary obstruction (enterohepatic circulation interrupted),
hepatic dysfunction,
fibrates
What does CYP7A1 indicate?
What is CYP2E1?
Cytochrome P450 7α-1 hydroxylase
(rate-limiting enzyme for bile acid synthesis);
cytochrome P450 2E1 (alcohol dehydrogenase)
True/False.
In the absence of prolactin, α-lactalbumin is a galactosyl transferase for glycoprotein synthesis.
True.
(With prolactin, it begins lactose synthesis)
A 12 year old patient comes in after fainting during a long boy scouts trip. History reveals that father’s brother has ‘some troubles with sugars’ and maternal grandmother had died young of liver failure. Physical examination shows liver tenderness and moderate hepatomegaly, while blood tests reveal low blood sugar. Urine does not contain any free sugars.
What tentative diagnosis do you give; what recommendations do you have for the family?
Fructosemia;
advise parents to keep fructose out of diet.
Imagine 2 molecules of glucose, one from the blood stream and the other stored in glycogen.
Which molecule will have a higher net energy yield after completing glycolysis?
The glucose molecule mobilized from glycogen stores
(it is already phosphorylated)
The typical patient has had T2DM for __-__ years at the time a first diagnosis is made.
4, 7
How does EtOH abuse cause thiamine deficiencies?
- Inadequate nutrition
- Decreased enterocyte active transport
- Decreased thiamine stores (hepatic steatosis / fibrosis)
- Decreased Mg+ (required for thiamine utilization)
