Lecture 18 Metabolic syndrome and Diabetes Flashcards
Define Insulin resistance - how does this affect blood insulin concentrations over time
Problems before the receptor, at the receptor or post receptor which leads to a subnormal glucose intake with same concentration of insulin given.
This drives higher insulin concentrations to maintain normal glucose which gets higher as it production can’t keep up.
Metabolic syndrome = (central obesity + 2 other associated signs)
What are the factors that contribute to the central/truncal obesity
- Central obesity caused by
- Lifestyle factors of excess energy intake and decreased physical activity contribute mainly
- Intrauterine environment (GED, hypertension, nutrient deprived) and genetic predisposition do play a part also
What are all the associated signs of metabolic syndrome (central obesity + 2 other associated signs)
- Hypertension
- Raised glucose - glucose intolerance, but not diabetes
- High triglycerides: Fatty liver and Dyslipidemia
- Low HDL cholesterol (usually protective)
- Endothelial dysfunction: inflammatory markers and procoagulant state
What is the starting event that causes insulin resistance in the fat, muscle, liver
- Increased visceral fat -truncal obesity, makes adipocytes with large stores of triglyceride.
- Large adipocytes are resistant to the ability of insulin to suppress lipolysis
- Increased lipolysis leads to increased release of Non Esterified FA and glycerol
- NEFA, glycerol as well as inflammatory cytokines released by visceral adipose tissue (eg. Tnf-a, IL6) aggravate insulin resistance in muscle and liver:
Insulin signaling is blocked by the inhibition of phosphorylation of insulin receptor substrate proteins
- May also cause lipotoxicity in beta cell - blocking insulin production
What is the downstream effect of insulin resistance in Fat, muscle, and liver (in that order)
1a. Insulin resistance in Fat enhances lipolysis and release of non-esterified fatty acids, contributes to Muscle and Liver insulin resistance.
b) Rise in FFA and triglycerides cause dyslipidaemia - atherosclerosis risk
c. Glycerol released increases gluconeogenesis
d) Glycerol is lipotoxic to beta cell (and liver and muscle) so further increases insulin release
2. Insulin resistance in Muscle leads to reduced uptake of glucose so reduced glycogen synthesis
- Insulin resistance in the Liver results in
a) increased hepatic glucose output - increased glycogenolysis, gluconeogenesis
b) increased triglyceride synthesis -> leading to fatty liver disease
What are the 3 signs that help to identify a patient with Insulin resistance
- Metabolic syndrome cluster
- Ancanthosis nigricans - hyperkeratosis (darkening skin) at base of neck/axilla
- PCOS - male pattern hair growth/acne, 19+ follicles on USS, anovulation
What is the key step in the pathogenesis of Type 2 diabetes while developing insulin resistance and what other ways can this come about
Progressive beta cell dysfunction leads to less pulses of insulin so
1. poor first phase insulin release post prandial -> hyperglycaemia
- Alpha cell dysregulation and hyperglucagonaemia
B-cell dysfunction caused by
- Reduced bcell mass - genetic/intrauterine
- lipo and glucotoxicity (increased triglycerides)
- Incretin dysfunction
What is the key test diagnostic values for diabetes
- HbA1c: glucose binding site on Hb which is stable for 3 months.
=/> 50 mmol is Diabetes: risk of complications start - Fasting glucose >/= 7 mmol/L
for a person with no symptoms want 2 abnormal tests over 2 months.
At what values of fasting glucose can progression to diabetes be reversed and how
between 5.5- 7 mmol/L there is a period of increased glucose tolerance where lifestyle inventions - diet and exercise can help reverse the progression
Compare the post prandial insulin curve between lean normal, obese normal, lean type 2 and obese type 2 including their problems
- lean normal: steady rise and fall of curve
- obese normal: higher spike of insulin to maintain same glucose
- lean type 2: very low insulin, not much increase - insulin secretion problem due to lipo/glucotoxicity, has visceral adiposity
- obese type 2: rising insulin but reaches a threshold 1/3 below the peak of normal: insulin resistance problem and can’t make enough insulin to overcome
What are main differences between type 1 and type 2 diabetes
Type 1: autoimmune destruction of b cells with absolute insulin deficiency.
Leads to rapid progression of hyperglycaemia, greater risk of DKA
- young, lean patients, insulin for survival
Type 2: Progressive b cell dysfunction leads to reducing capacity to secrete insulin over time and coupled with loss of incretin response, hyperglycaemia develops.
- old, central obesity, insulin for control 5-10yrs after diagnosis- prevent longterm complications
What are Microvascular complications of diabetes, and the cause
Through hyperglycaemia causing endothelial dysfunction
- Retinopathy
- Peripheral neuropathy: (mono= glove and stocking or autonomic= postural hypotension/erectile dysfunction)
- Nephropathy: Proteinuria
What are the macrovascular complications of diabetes
High prevalence of CVD:
Ischaemic heart disease, Peripheral vascular disease, Cerebrovascular disease
because of the endothelial dysfunction caused by hyperglycaemia there is accelerated development of atherosclerosis,
Which is helped by the dyslipidaemia, hypertension and obesity found in metabolic syndrome
What are some symptoms of early presentation of type 2 diabetes
- Fatigue
- Blurred vision due to accumulation of glucose in the lens of eye with osmotic effects
- Polyuria, and Polydipsia (thirst): glucose exceeds renal threshold for reabsorption
What are the 5 types of drugs used to control glucose
- Insulin in type 1 and also in 50% of type 2
- Metformin: improves insulin sensitivity by inhibiting hepatic gluconeogenesis
- Sulphonylurea (eg. Glipizide): stimulate B cell K+ channel to close, letting more ca2+, more insulin release
- Incretin therapy: GLP1 agonist or DPP4 (glp1 breakdown enzyme) blocker to increase insulin and decrease glucagon
- SGLT2 inhibitors (empagliflozin): stop reabsorption of glucose in the kidney
