Srikal Dhar - Diabetes Flashcards
How is insulin involved in glucose metabolism
- Insulin binds to insulin receptor
- Triggers signalling cascade that causes translocation of GLUT4 into plasma membrane
- GLUT4 goes to surface
- Glucose enters cell via GLUT4
- Glucose is converted to pyruvate via glycolysis
- Pyruvate is converted to acetyl CoA via pyruvate oxidation
What is the primary distribution of the GLUT 1 transporter (Where is it usually found)
Endothelium, erythrocytes
What is the primary distribution of the GLUT 2 transporter?
Kidney, small intestine, liver, pancreatic beta cells
What is the primary distribution of the GLUT 3 transporter?
Neurones, placenta
What is the primary distribution of the GLUT 4 transporter?
Skeletal muscle, adipose tissue
Which glucose transporters are insulin independent
GLUT 1, 2 & 3
Which glucose transporters have a high affinity for glucose?
GLUT 3 & 4
Which glucose transporters have a low affinity for glucose?
GLUT 2
What is the affinity for glucose of GLUT 1?
Baseline
How does SGLT1 and SGLT2 transport glucose?
- Active transport of glucose into luminal epithelial cells in the kidney and small intestine
What are the core defects in T2DM?
- Insulin resistance in muscle and the liver
- Impaired insulin secretion by the pancreatic β-cells
What contributes to progressive failure in the function of β-cells?
β-cell resistance to the incretin ‘glucagon-like peptide 1’ (GLP1)
What is prediabetes?
When blood sugar is higher than usual but not high enough to be diagnosed with Type 2 diabetes however are at high risk of developing it
Is prediabetes reversible?
Yes
What does trending mean in terms of T2DM?
When there is higher than usual blood sugar.
What are other names for prediabetes?
- Borderline diabetes
- Impaired Glucose Regulation (IGR)
- Non-diabetic hyperglycaemia
- Impaired fasting glucose (IFG) WITH Impaired Glucose Tolerance
What are the symptoms of prediabetes?
There are none, if there are T2DM has already developed
What modifiable factors increase the risk of diabetes
- Smoking
- History of high BP
- Being overweight (especially centripetal obesity)
- Sedentary lifestyle
- Alcohol
What non-modifiable factors increase the risk of diabetes?
- Older age
- White and over 40
- Afro- caribbean, black african, south asian and over 25
- Having relative with diabetes
- Gestational diabetes
- PCOS
- Mental health conditions
- Anti-psychotic medications
Why has the NHS diabetes prevention programme been implemented?
- Many cases of Type 2 diabetes are preventable through behavioural interventions
- Diabetes treatment currently accounts for 10% of the annual NHS budget
What are the aims of the NHS diabetes prevention programme?
- Reduce the incidences of T2DM
- Reduce the incidence of complications associated with diabetes
- Reduce health inequalities associated with the incidence of diabetes
What are the complications associated with diabetes?
Heart, stroke, kidney, eye and foot problems
What are the 3 core goals of the NHS DPP?
- Achieving a healthy weight
- Achievement of dietary recommendations
- Achievement of CMO physical activity recommendations
Who is eligible for the programme?
- Those with non diabetic hyperglycaemia (Hba1c 42-47 or fasting plasma glucose of 5.5-6.9)
- NDH within last 12 monts
- Most recent blood reading used
- 18 years and over
List the causes of hyperglycaemia (RULING HIVE)
- Increased Reabsorption
- Decreased glucose Uptake
- Increased Lipolysis
-
Inflammation
-Neurotransmitter dysfunction - Increased Glucagon secretion
- Increased Hepatic glucose production
- Decreased Insulin secretion
-Vascular insulin resistance - Decreased incretin Effect
How does increased glucose reabsorption cause hyperglycaemia
Increased renal glucose reabsorption by the sodium/glucose co transporter 2 (SGLT2) and increased threshold for glucose spillage in the urine contribute to the maintenance of hyperglycaemia
How does decreased glucose uptake cause hyperglycaemia
- Beta cell failure therefore less insulin secreted therefore hyperglycaemia
How does increased lipolysis cause hyperglycaemia
Insulin resistance in adipocytes results in accelerated lipolysis and increased plasma free fatty acid levels, both of which aggravate the insulin resistance in muscle and the liver and contribute to beta cell failure
How does inflammation cause hyperglycaemia?
Inflammation activates and increases the expression of several proteins that suppress insulin signalling pathways, making the human body less responsive to insulin and increasing the risk for insulin resistance
How does neurotransmitter dysfunction cause hyperglycaemia?
Resistance to the appetite suppressive effects of a number of hormones as well as low brain dopamine and increased brain serotonin levels contribute to weight gain, which exacerbates the underlying resistance
How does increased glucagon secretion cause hyperglycaemia
Over time after lots of insulin is being produced, alpha cells become insulin resistant, glucagon secretion increases and blood glucose increases
How does increased hepatic glucose production cause hyperglycaemia?
Increased glucagon levels and enhanced hepatic sensitivity to glucagon contribute to the excessive glucose production by the liver
How does decreased insulin secretion cause hyperglycaemia?
Beta cell failure due to GLP1 resistance and/or insulin resistant adipose muscle and liver tissue.
How does vascular insulin resistance cause hyperglycaemia
Prolonged exposure to high levels of insulin causes increased vasculature resistance
How does decreased incretin effect cause hyperglycaemia
GLP1 stimulates beta cells to secrete insulin
What are the functional effects of insulin on the liver?
- INCREASED glucose uptake
- INCREASED glycogenesis
- DECREASED glycogenolysis
- DECREASED gluconeogenesis
- DECREASED lipolysis
What are the functional effects of insulin on fat?
- INCREASED glucose uptake
- DECREASED lipolysis
- INCREASED lipogenesis
What are the functional effects of insulin on muscle?
- INCREASED glucose uptake
- INCREASED glycogenesis
- INCREASED protein synthesis
- DECREASED protein catabolism
What is the difference in pathogenesis between T1DM and T2DM?
Type 1 - Very little/no insulin produced at all
Type 2 - Little insulin produced AND insulin resistant cells
When in a fasting glucose state what is the range of blood sugar which indicates normal metabolism?
<5.5 mmol/L
When in a fasting glucose state what is the range of blood sugar which indicates impaired fasting glucose?
5.5-6.9 mmol/L
When in a fasting glucose state what is the range of blood sugar which indicates impaired glucose tolerance?
<7mmol/L
When in a fasting glucose state what is the range of blood sugar which indicates diabetes?
≥ 7 mmol/L
When in a post prandial glucose state what is the range of blood sugar which indicates normal metabolism?
<7.8 mmol/L
When in a post prandial glucose state what is the range of blood sugar which indicates impaired glucose tolerance?
7.8-11.1mmol/L
When in a post prandial glucose state what is the range of blood sugar which indicates diabetes?
≥ 11.1mmol/L
When a random blood glucose is taken what is the range of blood sugar which indicates diabetes?
≥ 11.1 mmol/L
What does impaired fasting glucose indicate?
Predominantly hepatic insulin resistance that leads to continuous glucose output from the liver
What does impaired glucose tolerance indicate?
Predominantly muscle insulin resistance plus impaired post prandial insulin release results in poor cellular glucose uptake
What are the 3 main diabetes symptoms?
Polydipsia
Polyuria
Polyphagia
What is polydipsia and what is it caused by?
An INCREASE in thirst
- When blood glucose levels get high, your kidneys produce more urine to remove excess glucose, resulting in thirst.
What is polyuria and what is it caused by?
FREQUENT URINATION
- When blood glucose levels get high, your kidneys produce more urine to remove excess glucose, resulting in more water filtered out therefore increased need to urinate
What is polyuria and what is it caused by?
INCREASE IN APPETITE
- When glucose can’t enter cells to be used for energy causing hunger
- Can either be due to low insulin levels or insulin resistance.
What is needed for a diabetes diagnosis?
- Symptoms + 1 positive blood glucose test
- No symptoms + multiple postive blood glucose tests
What is the renal threshold for glucose?
When the blood glucose level exceeds 160-180 mg/dL, the proximal tubule cannot reabsorb more glucose and begins to excrete glucose in the urine
What is a HbA1c?
A haemoglobin that has become glycosylated (chemically linked to a sugar)
Are enzymes needed for the formation of HbA1c?
No
What sugars can formation of HbA1c involve?
Glucose, fructose, galactose
Why can HbA1c levels be used to diagnose and monitor diabetes?
Formation of HbA1c occurs proportionately to plasma glucose levels
What are the advantages of using HbA1c as a diagnostic tool for diabetes?
- Takes into account blood glucose levels for 2-3 months
- Easy to measure as fasting not needed and isnt affected by stress, diet or exercise
- Cheap
What are the disadvantages of using HbA1c as a diagnostic tool for diabetes?
- Only approximate
- Not reliable in certain conditions (eg. pregnancy, renal failure, sickle cell)
How does metformin work
Reduces amount of sugar liver releases into blood
- Suppresses enzymatic reactions of gluconeogenesis
- Inhibition of glucagon action
- Downregulation of gluconeogenic genes
- Makes body respons better to insulin by stimulating GLUT 4 translocation
What are the advantages of taking metformin?
- Broad targets (AMPK)
- Cheap
- Lower risk of hypoglycaemia
- No weight gain, possible weight loss
- Associated w/ lower BP
- Associated w/ lower LDL cholesterol level
- May have protective effect against kidney and pancreatic cancer
What are the side effects of taking metformin?
- Vomiting
- Diarrhoea
- Stomach-ache
- Lack of appetite
What is the EAST framework for behavioural change?
