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177 Cards in this Set

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How does leptin cross the BBB to reach the hypothalamus?
Via a specific carrier
T/F: Insulin and glucocorticoids both increase circulating leptin levels.
True
T/F: Leptin receptor deficiency has been associated with impaired growth hormone secretion
True
T/F: Visceral adipocytes secrete more leptin than their subcutaneous counterparts
False - subcutaneous fat secretes more
T/F: Leptin does not function as a satiety factor in humans
True
What are the immunological effects of leptin?
It appears to help regulate T cell number and function
T/F: Insulin, CCK, neuropeptide Y and glucocorticoids all function as satiety signals.
False - NPY does not - it increases appetite
Which neurotransmitter is especially important in hypothalamic regulation of appetite and eating?
Serotonin
How does sibutramine cause appetite suppression?

What antidepressant causes this as a side effect by the same mechanism?
Sibutramine blocks serotonin reuptake, potentiating its appetite-suppressing role in the hypothalamus.

Fluoxetine has the same effect.
T/F: Insulin's actions on protein synthesis and cell division are manifested in a wider variety of cell types than its effects on glucose metabolism
True - most cells are sensitive to insulin's anabolic and promitotic effects, even if they aren't sensitive to its effects on glucose uptake
Name 3 key enzymes, involved in the synthesis of lipids, which are upregulated by insulin. (3)
Pyruvate dehydrogenase

Acetyl CoA carboxylase

Fatty acid synthetase
What does acetyl CoA carboxylase do?

How does insulin affect it?
It forms the malonyl CoA necessary to form fatty acids from acetyl CoA.

It is upregulated by insulin.
What effect does insulin binding have on intracellular cAMP levels?

How does it do this?
Insulin causes cAMP levels to fall by stimulating phosphodiesterase activity.
What is the most frequent cause of high cholesterol?
Common (polygenic) hypercholesterolaemia
What defect is present in familial hypercholesterolaemia?

What cholesterol levels are found in heterozygotes?
An abnormal LDL receptor is the cause of FH.

Heterozygotes typically have cholesterol levels of 7-14 mmol/L.
What primary hyperlipidamic disorder is suggested by cholesterol-enriched VLDLs and abnormal ApoE lipoproteins?
Remnant (type III) hyperlipidaemia
What is the most common type of hyperlipidaemia?

What apolipoprotein is increased in this disorder?
Familial combined hyperlipidaemia

ApoB levels are elevated
T/F: Chylomicronaemia is associated with a moderately increased risk of CHD
False - the risk of CHD is not raised in this condition.
How much more likely are diabetic people to suffer from periodontitis?
Twice as likely
T/F: The accumulation of advanced glycation end-products leads to collagen crosslinking and free radical formation.
True
T/F: Advanced glycation end-products activate specific receptors on endothelial and immune cells.
True - this is one of the mechanisms by which they cause inflammation and reactive tissue changes.
How do advanced glycation end-products cause impaired delivery of nutrients to tissues? (2 steps)
AGEs cause chronic inflammation via RAGEs (AGE receptors) - these receptors activate NF-κB.

The ensuing inflammation causes thickening of the capillary basement membrane and this impairs exchange of nutrients and waste products.
T/F: Hypoglcaemia causes increased collagen formation and proliferation of fibroblasts and osteoblasts.
False - hyperglycaemia causes these things to be impaired, but they are not increased by hypoglycaemia.
How does hyperglycaemia lead to impaired tissue repair? (2)
Hyperglycaemia:

- inhibits the proliferation and activity of osteoblasts and fibroblasts

- increases collagenase activity
What immune cells are most impaired by hyperglycaemia?
Neutrophils
Name four neutrophil functions which are impaired by hyperglycaemia.
Adherence

Chemotaxis

Phagocytosis

Degranulation

(i.e. everything)
What causes the chronically increased TNF-α and IL-1 levels in diabetes mellitus?
Chronic inflammation due to AGEs and free radicals leading to upregulation of macrophage/monocyte populations.
T/F: Periodontitis worsens insulin sensitivity and glycaemic control in diabetic patients
True
How can periodontitis cause systemic inflammation?
Via bacteraemia and endotoxaemia due to LPS coated causative agents.
leggere (imperf)
leggevo,-i,-a
leggevamo leggevate leggevano
T/F: All diabetic patients should be referred for dental (periodontal) assessment.
True - as glycaemic control is not a reliable predictor of periodontitis, even patients with good control need to be assessed.
T/F: Patients with periodontitis should be assessed for type 2 diabetes.
True
What antibiotic is used to treat periodontitis?

What advantage does this agent have, especially for diabetic periodontitis?
Tetracycline - in addition to its antibiotic effects, it also suppresses collagen breakdown and enhances protein synthesis
T/F: Dietary intervention is significantly more important for type 2 diabetics than for type 1.
True - it is useful for type 1 patients, but is the mainstay of treatment for type 2 patients and can obviate the need for other interventions.
T/F: High dietary levels of saturated fat increase the risk of type 2 diabetes.
True
T/F: Changing the relative proportion of 'good fats' can be more beneficial to a person's serum lipid profile than reducing total fat intake and increasing dietary carbohydrates.
True
What percentage of total energy intake should be provided by saturated fat?
< 10%
What percentage of total fat intake should be in the form of polyunsaturated fat?
< 10%
T/F: Smaller and more frequent carbohydrate intake improves glycaemic control but has no effect on serum cholesterol and triglycerides.
False - it improves all three
T/F: Alcohol, when ingested without food, can trigger hypoglycaemia
True
What effect do saturated fats have on cholesterol production?
They increase LDL production
What effect does monounsaturated fat have on cholesterol levels?
It increases HDL and decreases LDL
Which fatty acid causes the greatest reduction in LDL levels?

Is it an omega-3 or an omega-6 FA?
Linoleic acid - omega-6
T/F: Very long chain omega-3 fatty acids, found in fish oils, reduce thrombosis risk.
True
T/F: Very long chain omega-3 fatty acids, found in fish oils, reduce triglycerides and cholesterol levels
False - they reduce triglycerides but may in fact increase LDL levels at high levels.
What percentage of total energy intake should be contributed by polyunsaturated fats?
< 6%
What effect does excessive consumption (>7% of total energy) of trans fatty acids have on a person's lipid profile?
It increases LDL and decreases HDL levels.
T/F: Dietary cholesterol intake correlates directly with plasma cholesterol.
True - up to 500 mg per day.
What are stanols and plant sterols?

How do they affect cholesterol levels?
Plant sterols and stanols are cholesterol-like substances found in wood pulp, leaves and nuts.

They lower plasma cholesterol by reducing the absorption of cholesterol from food and bile.
T/F: The ingestion of 2-3g of plant sterols or stanols per day reduces LDL cholesterol by 10-15%
True
T/F: Exercise increases HDL and lowers triglycerides but not LDL
False - it improves all three
T/F: Moderate alcohol consumption has a positive effect on HDL levels
True
When does a child's adiposity increase?
Between 4 and 7.
What are the three main side effects of sulfonylureas?
Hypoglycaemia

Allergic reactions

Weight gain
What is the major contraindication for metformin?
Renal failure
What are the two most important side effects of metformin?
Lactic acidosis

Gastric intolerance/diarrhea
T/F: Metformin may assist with weight loss.
True
How does metformin exert its effects on blood sugar level? (4)
- Inhibition of hepatic gluconeogenesis

- Increased insulin sensitivity

- Increased peripheral glucose uptake

- Decreased glucose absorption
Which three classes of oral hypoglycaemic can cause weight gain?
Sulfonylureas

Meglitinides

Thiazolidinediones (glitazones)
Name two effects, other than those directly related to blood glucose levels, which make metformin an ideal drug for obese type 2 diabetics.
Appetite suppression

Reduced LDL and triglycerides
What are the major side effects of the α-glucosidase inhibitors such as acarbose?
Flatulence

Abdominal pain

Abdominal distension
Which two classes of oral hypoglycaemic drugs are most likely to cause hypoglycaemia?
Sulfonylureas

Meglitinides
How do the thiazolidinediones such as rosiglitazone and pioglitazone exert their effects on blood sugar level?
By stimulating the PPAR-γ receptor in fat cells, these drugs improve glucose uptake and insulin sensitivity.
Which two oral hypoglycaemic agents are associated with gastrointestinal side effects?
Metformin

α-glucosidase inhibitors
How do dipeptidyl peptidase IV inhibitors work to lower blood glucose levels?
DPP-IV inhibitors work by decreasing the breakdown of two gut hormones - glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP)

These hormones enhance insulin release after glucose intake.
How does glucagon-like peptide-1 act an anti-diabetic hormone? (3 ways)
After carbohydrate intake, GLP-1:

- enhances insulin release

- inhibits glucagon release

- slows gastric emptying
What kind of drug is sitagliptin?
A DPP-IV inhibitor.
What does dipeptidyl peptidase-IV do?
It breaks downs glucagon-like peptide-1 and gastric inhibitory protein
What is exenatide?

How is it administered?

What are it major side effects?
Exenatide is a GLP-1 analogue that is injected subcutaneously.

Its major side effects are gastrointestinal disturbances such as nausea, vomiting and diarrhea.
Which class of oral hypoglycaemics stimulates insulin release?
The sulfonylureas
T/F: Raised prolactin levels can cause weight gain
True
T/F: Central adiposity in women increases after menopause
True
T/F: Adiponectin is secreted by visceral fat cells in linear proportion to their size and number
False - with increasing central obesity, adiponectin release begins to decline.
Describe the characteristic dyslipidaemia of the metabolic syndrome
High triglycerides

Normal or slightly raised LDL

Low HDL
T/F: The LDL levels seen in metabolic syndrome (normal or mildly raised) are not high enough to cause atheroma in and of themselves.
False - the LDL particles seen in metabolic syndrome are usually smaller and denser than normal, and cause atheroma even at normal levels.
Why are the LDLs typical of metabolic syndrome more atherogenic than usual? (3 reasons)
Smaller and denser

More easily oxidised

Persist in the circulation longer, leading to increased uptake by scavenger receptors on macrophages
T/F: The number of LDLs is more important than their total cholesterol content
True - more LDLs means more competition for LDL receptors. This means more are left to interact with oxidants and scavenger receptors, leading to endothelial inflammation and foam cell formation.
What are the four elements of the metabolic syndrome?
Obesity

Type II diabetes

Hypertension

High triglycerides
T/F: Metabolic syndrome is usually associated with high leptin levels
True
T/F: Metabolic syndrome is usually associated with high fibrinogen levels
True
T/F: Metabolic syndrome is usually associated with decreased PAI-1
False - this inhibitor of fibrin breakdown is elevated, contributed (along with high fibrinogen levels) to increased clotting risk.
T/F: Insulin resistance is a feature of type II but not type I diabetes
False - it is typical in type II, common in poorly controlled type I
T/F: Insulin resistance is associated with hypertension
True - but the reason for the association is not known
T/F: Obese people have lower education levels on average
True - though causality could be in either direction
T/F: Dividing daily calories into smaller, more frequent meals has been shown to improve weight profile
False - there is insufficient evidence to support this assertion. This diet does, however, improve glycaemic control in diabetics.
Name two genetic disorders which are more prevalent in Ashkenazi jews.
Tay-Sachs

Gaucher's
T/F: People of black African descent are more likely to have G6PD deficiency and haemoglobinopathies
True
Name three genetic disorders which are more prevalent in people of mediterranean descent
G6PD deficiency

β thalassaemia

Familial mediterranean fever
What is measured by λ(s)?
Lambda (sibling) refers to the ratio of risk of a disease for the sibling of an affected person to the risk in the general population.
T/F: Around 1 in 80 single nucleotide polymorphisms cause a change in primary structure of a gene product
False - less than 1 in 220 of known SNPs have any effect on the protein that results
Insulin resistance in type II diabetes is thought to be caused in some cases by a mutation to the gene coding which protein?
PPARγ
T/F: The top seven gene candidates for type II diabetes can only explain 10% of its inheritable component.
True
What lipoproteins predominantly transport triglycerides?
Chylomicrons

VLDLs
What lipoproteins predominantly transport cholesterol esters?
LDLs

HDLs
T/F: Chylomicrons are the smallest and densest type of lipoprotein
False - they are the largest and least dense
T/F: Lipoprotein density correlates with cholesterol content
True - the more cholesterol esters, the denser the particle.
T/F: B48 and B100 apoproteins are not exchangeable
True
T/F: A1, A2, CII and E apoproteins are not exchangeable
False
Name three apoproteins which function as tissue targeting molecules
B48

B100

E
Name two apoproteins which activate enzymes and the enzyme they activate
A1 - lecithin-cholesterol acyl transferase

CII - lipoprotein lipase
What apoproteins on chylomicrons allow them to be taken up by hepatocytes?
B48

E
Where are the apoproteins B48 and B100 produced?
B48 - intestine

B100 - liver
Where are VLDLs synthesised?
In the liver
T/F: Apo CII is present on chylomicrons and VLDLs
True - it is responsible for activating lipoprotein lipase-mediated unloading of triglycerides.
What two fates can VLDL remnants meet?
Degradation in the liver

Conversion to LDL by CETP-mediated cholesterol loading.
Why does inhibition of HMG CoA reductase result in decreased LDL levels specifically?
The liver upregulates LDL receptors to take cholesterol from the blood in order to maintain bile salt production.
T/F: Statins increase the risk of gallstones by limiting the liver's ability to synthesise and secrete bile salts.
False - it appears that statins lower the risk because cholesterol secretion into the bile is decreased more than bile salt secretion.
What apolipoprotein is thought to be particularly atherogenic?
Apo (a)
T/F: Lipoprotein (a) is a modified form of VLDL
False - it is a modified LDL particle
T/F: Lipoprotein (a) levels correlate closely to saturated fat levels in the diet.
False - lipoprotein (a) levels appear to be mainly influenced by genetics.
What apoprotein is uniquely associated with HDL and confers its protective properties regarding atherosclerosis?
Apo A1
How does Apo A1 exert its anti-atheroma effects?

What added property is thought to reduce the risk of IHD?
Apo A1 is the docking molecule which allows HDLs to attach to cholesterol-rich tissue such as atheroma and take up cholesterol.

Apo A1 is also thought to inhibit clot formation by stabilising prostacyclin.
What enzyme is activated by Apo A1?
Lecithin-cholesterol acyl transferase (LCAT)
T/F: In broad terms, LCAT activity is atherogenic and CETP activity is protective
False - it's the other way around. LCAT transfers cholesterol from tissues to HDL's. CETP converts VLDLs into LDLs.
What enzyme is activated by Apo A1?
Lecithin-cholesterol acyl transferase (LCAT)
T/F: In broad terms, LCAT activity is atherogenic and CETP activity is protective
False - it's the other way around. LCAT transfers cholesterol from tissues to HDL's. CETP converts VLDLs into LDLs.
T/F: The liver converts VLDL remnants into LDLs using CETP
False - this happens in the circulation
What apoprotein is a cofactor for lecithin-cholesterol acyl transferase?
Apo A1
What apoprotein is a cofactor for cholesterol ester transfer protein?
CII
What is CETP otherwise known as?
Lipid transfer protein
What two mechanisms are behind the elevation of serum triglycerides in type II diabetes?
- increased hepatic synthesis of VLDLs

- decreased clearance due to lower expression of lipoprotein lipase
How do fibrates lower serum triglyceride levels? (2 ways)
Fibrates:

- suppress hepatic VLDL production

- increase the expression of lipoprotein lipase, increasing VLDL clearance.
T/F: Weight loss in an obese person will increase their HDL levels
True
What quantitative improvement in total cholesterol, LDL cholesterol and triglycerides would be typical in an obese person who lost 10kg?
Total: 10% decrease

LDL: 15% decrease

Trigs: 30% decrease
T/F: 10kg of weight loss in an obese person will decrease their fasting blood glucose by up to 30%
False - more like 50%
T/F: 10kg of weight loss in an obese person will decrease their chance of dying due to any cause by around 20%
True
T/F: Weight loss in an obese person will affect their diastolic BP more than their systolic
True - diastolic will fall by about twice as much.
T/F: Subclinical hypothyroidism is a common cause of obesity
False - it rarely causes weight gain as such, but can make it difficult to lose weight if untreated.
T/F: Dietary cholesterol is a stronger influence on serum LDL levels than saturated fats
False
T/F: Dietary cholesterol consumption has no demonstrable effect on cardiovascular risk
True
T/F: The primary reason for increasing physical activity in a person with metabolic syndrome is weight loss
False - the activity itself is if anything more important than any weight loss it may cause because of its metabolic effects
What benefits does physical activity have for someone with metabolic syndrome even if they don't lose weight? (4)
Activity:

- reduces BP
- improves glycaemic control
- reduces insulin resistance
- improves lipid profile

even in the absence of any weight loss.
T/F: Lifestyle changes are as effective as metformin in preventing the onset of diabetes in insulin resistant patients
False - lifestyle changes are almost twice as effective (58% vs 31% risk reduction)
Name 4 indications for a very low energy diet.
Morbid obesity

Preparation for surgery

Oral agent failure in type II DM

Severe OSA
T/F: Weight loss in obese patients cannot be achieved without lifestyle changes
True
What kind of drug are phentermine and diethylpropion?

What are their side effects? (4)
Phentermine and diethylpropion are noradrenergic agonists which are used as appetite suppressants.

Their side-effects include:

- raised blood pressure
- insomnia
- nervousness/irritability
- angina exacerbation
What is sibutramine?

How does it work? (two ways)
Sibutramine (Reductil) is a weight loss medication that blocks the reuptake of serotonin and noradrenaline.

It works by:

- increasing RMR
- enhancing satiety
T/F: Sibutramine is less effective than lifestyle modification when used in isolation
True
T/F: Sibutramine improves lipid profile and glycaemic control by a variety of mechanisms
False - these all occur due to weight loss, and are absent if weight loss does not occur
T/F: Sibutramine reduces the positive impact of weight loss on blood pressure
True - BP will fall but not as much as would be expected for a given amount of weight loss.
What is orlistat (Xenical)?

What is it used for?

What is its major side effect?
Orlistat is an inhibitor of pancreatic lipases used for weight loss in obese people.

It reduces absorption of excess lipids in the diet

Its main side effects are steatorrhea-related (diarrhea, rectal incontinence etc)
T/F; Patients on warfarin should not take orlistat
False - but their coagulation times should be monitored just in case
T/F: Free fatty acids directly affect insulin sensitivity
True
T/F: Orlistat has a positive effect on LDL levels, but this is the same as in weight loss due to other causes
False - orlistat improves LDL levels above and beyond what would be expected from the weight loss it causes.
T/F: Orlistat reduces the risk of progression from insulin resistance to type II diabetes by more than metformin but less than lifestyle modification.
True - 31% for metformin, 45% for orlistat, and 58% for lifestyle modificiation
What oral hypoglycaemic is also useful in treating PCOS and infertility?
Metformin
In what subgroup of overweight/obese patients is the use of antidepressants particularly useful?
Those with a binge-eating disorder
T/F: Exenatide can cause weight loss
True - but it's expensive
T/F: Procedures such as the biliopancreatic diversion with duodenal switch, gastric bypass and gastric banding are very effective for weight loss.
True - but malabsorption and surgical morbidity is very high
T/F: All bariatric surgical procedures can result in nutrient deficiencies
True - but to varying degrees
What effect does bariatric surgery have on the incidence of type II diabetes in the morbidly obese?
It reduces it by around 70%
Which has the biggest effect on weight: gastric bypass, gastric banding or vertical banded gastroplasty?
Gastric bypass
Which has the highest failure and reoperation rate: gastric bypass, gastric banding or vertical banded gastroplasty?
Gastric bypass
What is the estimated prevalence of type II DM in Australia?
5-10%
T/F: Insulin resistance correlates closely to the amount of visceral fat a person has
True
What serum lipids are raised in the metabolic syndrome? (2)
Triglycerides

LDL
T/F: Type II diabetes does not have to involve insulin deficiency
False - at the very least, a relative insulin deficiency is present (defined as insufficient insulin to normalise blood sugar)
Name two theories for why the pancreas fails in type II diabetes
Glucose toxicity, causing blunting of insulin release

Amylin toxicity
T/F: Concordance for type II DM in identical twins is around 75%
False - its over 90%
T/F: Paternal type II DM confers greater risk than maternal
False - maternal DM confers greater risk
T/F: A person's risk of type II DM, unlike type I, has no relationship to HLA type.
True
Name 5 gene products implicated in type II diabetes.
Glucokinase

Insulin

Insulin receptor

Insulin receptor substrate (IRS-1)

Mitochondrial proteins
What eponymous glomerular aggregates are indicative of diabetic nephropathy?
Kimmelstein-Wilson nodules
T/F: Macroalbuminuria in diabetics is almost always associated with an elevated serum creatinine
False - creatinine is often normal in the early phase
What sensory modality is usually the last to be affected by diabetic neuropathy?
Light touch
What is diabetic amyotrophy?
Painful muscle wasting in the distribution of a large nerve, such as the femoral nerve.
T/F: The mononeuritis associated with diabetic neuropathy commonly affects a facial nerve
True
Name 7 manifestations of diabetes-associated autonomic neuropathy
Gastroparesis

Gustatory sweating

Orthostatic hypotension

Impotence

Hypoglycaemia unawareness

Bladder dysfunction

Diarrhea
T/F: Type II diabetics are more prone to both micro and macrovascular disease than type I diabetics
False - microvascular disease affects type I diabetics more often than type II
T/F: Type II diabetics can get ketoacidosis, but type I diabetics don't develop hyperosmolar non-ketogenic coma.
False - both types of patient can experience either, but their predisposition is opposite.
What blood glucose level is typical of a hyperosmolar non-ketotic state?
Over 35 mmol/L
What are the three components of immediate management for hyperosmolar nonketotic coma?
Rehydration

Careful infusion of insulin

Potassium
T/F: Both diabetic ketoacidosis and non-ketotic hyperosmolar hyperglycaemia usually present with hypokalemia.
False - DKA can be normo- or even hyperkalemic due to acidotic effects on transcellular K+ transport.

Both states will deplete total body potassium however and this should be supplemented when insulin is administered to prevent catastrophic hypokalemia.
Name two oral hypoglycaemic drug classes which increase insulin release.
Sulfonylureas

Meglitinides
Name two oral hypoglycaemic drug classes which increase insulin sensitivity.
Metformin

Thiazolidinediones (glitazones)
What is the HbA1c target for diabetics?

What is the normal range?
Diabetics: 7-7.5%

Non-diabetics: 3.5-6%
How are the diabetic macrovascular complications best avoided?
By minimising risk factors:

- smoking
- lipids
- BP
- obesity
- kidney disease