6 An Introduction To Diabetes Mellitus Flashcards
Q: How does insulin affect glucose? (2)
A: Decrease hepatic glucose output
Increase uptake of glucose by muscles
Q: How does insulin affect protein?
A: Decreased proteolysis
Q: How does insulin affect lipids? ketones? Reason?
A: Decrease lipolysis
Decrease ketogenesis
once we’ve eaten there is no need to make ketones/lipids
Q: What are the 3 molecules that insulin affects (metabolic effects)?
A: glucose
protein
lipid
Q: Describe glucose uptake through GLUT4. Where is it particularly abundant? (2) What stimulates it? What is its structure? How much does it increase glucose uptake?
A: Glucose is mainly taken up by Glucose Transporter 4 (GLUT-4)
GLUT-4 is particularly abundant in muscle and adipose tissue
Insulin stimulates glucose transporter 4
It has hydrophobic elements on the outside embedded in the membrane and a hydrophilic core which allows glucose into the cell - it is insulin responsive
GLUT-4 sits in vesicles within the cytoplasm - insulin recruits them to the membrane thus causing up to 7-fold increase in glucose uptake
Q: Which cells don’t have insulin sensitive glucose transporters? (2) What variations exist?
A: brain since glucose must get into brain cells regardless or RBC
pancreas has GLUT2 (beta cells)
Q: Using a muscle cell as an example, show how insulin affects protein. Include other hormones.
A: \_\_\_\_\_\_\_\_\_\_\_\_\_
| |
| protein |
| | / \ |
| \ / | | O2 in
protein -> aa (proteolysis)
(- insulin) (+ cortisol)
Insulin stops proteolysis
Cortisol increases proteolysis when we’re stressed
aa -> protein (protein synthesis)
(+ insulin) (+ IGF 1 : growth hormone)
aa out are gluconeogenic eg alanine = go to liver to make glucose (fuel source)
Amino acids could be oxidised in the muscle cell
(- insulin)
Q: Where does most glucose present in our blood come from?
A: made by us
Q: What is a short term energy store? Long term?
A: glycogen (keep us going 6-8hrs between meals)
fat
Q: What should glucose concentration be in blood?
A: 4-7mmol/L
Q: Explain gluconeogenesis in liver cells including the effect of insulin and other hormones (diagram).
A: liver cell
Gluconeogenic amino acids enter the liver via specific transporter channels (Glucagon increases the uptake of amino acids by the liver)
In the liver, protein synthesis where aa becomes protein (stimulated by insulin)
proteolysis in opposite direction can occur (stimulated by protein defic and glcg)
The amino acids can be used to make glucose - GLUCONEOGENESIS (insulin inhibits gluconeogenesis while Somatotrophin, Cortisol, Catecholamines and Glucagon increase gluconeogenesis)
The glucose produced from gluconeogenesis can then enter the circulation as HEPATIC GLUCOSE OUTPUT (HGO)- helps maintain sugar levels
Q: Recall the fuel stores in a normal man.
STORE: CHO (liver + muscle), protein, fat
WEIGHT (Kg), ENERGY (KJ/g), TIME
A: CHO= 0.5, 16, 16 hrs
protein= 8-9, 17, 15 days
fat= 9-10, 37, 30-40 days
Q: Explain how insulin and other hormones affect adipocytes.
A: adipocyte and a blood vessel next to it
Triglycerides come in the vasculature and are too big to enter the adipocyte directly
Triglycerides have to be broken down by LIPOPROTEIN LIPASE before it can enter the adipocyte (Lipoprotein Lipase is stimulated by insulin)
Triglyceride is broken down into glycerol and non-esterified fatty acids which are absorbed into the adipocyte
Glucose also enters the adipocyte (GLUT4 which is stimulated by insulin) and can be used to make NEFA
Glucose can also be chopped up to make two glycerols and the fatty acids can be stuck to the glycerol to make triglycerides (insulin promotes)
TGs can be broken back down
- production of glycerol is reduced by insulin
- production of NEFA is encouraged by cortisol, GH, Catecholamines (fight/flight) -> released back into circulation
Q: What is lipoprotein lipase?
A: hormone sensitive lipase particular to capillary beds
Q: What are the 2 effects insulin has on fat depending on where it acts?
A: Blood - breaks down the fats so that it can enter the adipocyte
Adipocyte - promotes formation of triglyceride and storage of fat and inhibits lipolysis
Q: Draw a simple diagram for circulation and explain.
A: lungs // heart // liver // gut // all tissues
Blood reaches the gut and there is a portal system connecting the intestines to the liver (has its own circulation)
The blood passes through the liver for the absorbed food to be processed
Q: What is a simple indicator of an individual’s risk of ischaemic heart disease?
A: omental fat/waist circumference
Q: Explain the use of glycerol by the liver?
A: Glycerol coming from adipocytes and food enters the liver (particularly come from omental circulation since omental adipocytes have a more profound effect metabolism than adipocytes in arm/leg)
then : glycerol -> glycerol 3 phosphate -> triglycerides
Glycerol could also be used to make glucose - form of gluconeogenesis (Two glycerols can be stuck together)= supports HEPATIC GLUCOSE OUTPUT
Q: After a fast of 10 hours, what percentage of our hepatic glucose output is supported by new glucose production?
A: 25
Q: Where can the brain get energy? Where can it not get it from?
A: Brain CAN use: Glucose + Ketone Bodies
Brain CAN NOT use: Fatty Acids (no ability to do lipolysis since no enzymes present to facilitate)
Q: How does insulin and other hormones affect ketone body synthesis in the liver?
A: Fatty acids (some generated from lipolysis) can enter the liver and be used to make ketone bodies
NEFA -> FA acyl CoA
FA acyl CoA -> acetyl CoA -> acetoacetate -> acetone + 3 OH-B
Insulin INHIBITS the conversion of Fatty Acyl CoA to Ketone Bodies
Glucagon PROMOTES the conversion of Fatty Acyl CoA to Ketone Bodies
Ketone bodies will enter the circulation and mainly be used by the muscles
Q: When should there be high ketone bodies present and when should there not be? Why is this clinically useful?
A: If someone has high insulin then they should stop making ketone bodies
High Blood Glucose + High Ketone Bodies = INSULIN DEFICIENT (abnormal)
testing sugars and ketones is useful when determining a person does not have enough insulin
Q: Explain the effect of insulin and other hormones on hepatic glycogenolysis (in liver).
A: glycogenolysis- no new synthesis, just liberating
Glucose enters the liver and is converted to Glucose-6-Phosphate
G6P -> stored glycogen (Insulin promotes)
glycogen -> G6P (glucagon and Catecholamines promote)
G6P can be converted back into glucose to support HGO
Q: Name 2 processes that support hepatic glucose output.
A: Gluconeogenesis
Glycogenolysis
Q: Explain the effect of insulin and other hormones on glucose uptake by muscle cells.
A: Glucose enters muscle through GLUT-4 (Insulin PROMOTES)
Stress hormones tend to INHIBIT uptake of glucose by GLUT-4 (GH, catecholamines, cortisol)
Glucose can then be stored as glycogen in the muscle but is mainly used as a fuel source
muscle cell doesn’t release the glucose into circulation- glucose can just be used in the muscle cell
Q: Describe the fasted state. Insulin:glycogen ratio? Blood glucose concentration and why? Muscle uses? Brain uses? Increase in (5)? Decrease in?
A: Low Insulin:Glycogen ratio
Blood glucose concentration is NORMAL (3-5.5mmol/L)because the change in Insulin: Glucagon ratio maintains a normal blood glucose concentration
Muscle use lipids
Brain uses glucose and then, at a later stage, ketone bodies
INCREASE IN:
Concentration of NEFA (released by lipolysis and used except by brain)
Proteolysis
Lipolysis
Hepatic Glucose Output (from glycogenolysis and gluconeogensis)
ketogenesis when prolonged
DECREASE IN:
Amino Acid Concentration (when prolonged)
Q: Describe the fed state. Insulin:Glucagon ratio? What happens to stored insulin? What stops? Increase in (3)? Decrease in (2)?
A: High Insulin:Glucagon ratio
Stored insulin is released then you get 2nd phase insulin release (2/3hrs)
Stop Hepatic Glucose Output
INCREASE IN:
Glycogen
Protein Synthesis (store aa)
Lipogenesis (fat store)
DECREASE IN:
Gluconeogenesis
Proteolysis
Q: What is the sequence of events when you eat a meal? (7)
A: 1 eat meal
2 L cells in gut sense
3 get high insulin concentration
4 switches off HGO
5 insulin in systemic circulation
6 glucose and aa driven into muscle cells
7 glycerol and fatty acids driven into fat cells to make TGs
Q: Why does having diabetes increase urine output?
A: sugars leaks into urine and takes water with it
Q: How do you describe the difference between the different DM types?
A: one is insulin sensitive and the other is insulin insensitive
Q: When is hypoglycaemia inevitable? What does it cause an increase in? (4) Decrease in?
A: hypoglycaemia is inevitable in T1- insulin induced hypoglycaemia (when you get injection)
INCREASE IN:
- (Insulin (leaking out from injection site))
- Glucagon
- Catecholamines
- Cortisol
- Somatotrophin
- HGO (later with glycogenolysis and glyconeogenesis)
- lipolysis
Q: How is T1DM presented? (4) Define.
A: =Absolute insulin deficiency
Proteolysis with weight loss
Hyperglycaemia (high plasma glucose)
Glycosuria with osmotic symptoms (polyuria and polydipsia)
Ketonuria
Q: How do you treat a patient with hypoglycaemia?
A: if conscious- get sugary drink
if not- given glucagon injection -> intramuscular glucagon -> enters liver -> glucose made
Q: In T2DM where does insulin resistance lie?
A: liver, muscle, adipose tissue
all metabolic sites and all arms of intermediary metabolism
Q: In T2DM there is still enough insulin to suppress certain processes. What are these?
A: ketogenesis
proteolysis (don’t lose muscle bulk/fat cells)
Q: What are the 2 pathways affected by insulin? Draw a diagram representing this.
A: Mitogenic Pathway (MAPK- insulin resistance does not lie in this pathway) Metabolic Pathway (PI3K-Akt)
insulin receptor
Shc IRS
Grb2 | (where insulin
Sos \ /resistance lies)
ras PI3K-Akt pathway
| |
\ / \/ MAPK pathway metabolic actions
|
\ / growth, proliferation
Q: What is the feedback loop for insulin production mainly through?
A: blood glucose concentration
Q: How does someone with insulin resistance maintain normal blood glucose levels? Why doesn’t this solve everything?
A: compensatory hyperinsulinaemia
high insulin still harms bodies
-has an increased effect on the mitogenic pathway (MAPK) = increases dyslipidaemia and smooth muscle hypertrophy in arteries = increases blood pressure
Q: What are the features of insulin resistance measured in clinic?
A: HYPERTENSION (BP > 135/80)
High Triglyceride + Low HDL + high LDL (= dyslipidaemia)
Fasting Blood Glucose > 6.0mmol/l
High Omental Fat (hence large waist circumference)
Q: How is T2DM presented? (6)
A: =insulin resistance
60-80% OBESE (central- omental circulation)
Dyslipidaemia (damages arteries and causes premature atheroma)
Later insulin deficiency (because of exhaustion of beta cells) (years later)
Hyperglycaemia
Fewer osmotic symptoms
T2DM presents with complications whereas T1DM hardly ever presents with complications
Q: How is T2DM controlled? (5)
A: Control of total calorie intake
REDUCE:
Fat
calories as refined Carbohydrate
Sodium (to lower the risk of hypertension)
INCREASE:
Calories as complex Carbohydrates
Soluble Fibre (prolongs absorption of glucose)
