Metabolic syndrome and diabetes Flashcards
What is type 2 diabetes?
Metabolic disorder characterised by presence of hyperglycaemia due to glucose receptor insensitivity.
Caused by insulin resistance in the liver, muscle and adipose tissue. You get a suboptimal glucose response from a given amount of insulin.
The insulin resistance, progressive beta cell dysfunction and alpha cell dysfunction all lead to the blood glucose to rise and the patient presents with type 2 diabetes
Type 1 diabetes is an auto immune disease and requires insulin to control hyperglycaemia.
impaired fasting glucose (IFG), and oral glucose tolerance test (OGTT) after 2 hours associated with impared glucose tolerance (IGT).
How do you identify type 2 diabetes?
High insulin with normal/high glucose (not practical for clinical measure)
Glucose appear in urine when >10 mmol/L blood glucose, so there is an asymptomatic window before diabetes due to impaired glucose tolerance (IGT) associated with insulin resistance.
Insulin resistance can occur pre-receptor (Cushing, caused by cortisol excess), receptor (rare) or post-receptor (phosphorylation cascade, common).
What disease are associated with type 2 diabetes?
Endocrine disorders (cushings)
Metabolic syndrom
obesity
What is a metabolic disorder
Caused by excess energy intake and decreased physical activity.
A person with metabolic syndrome is defined as someone with central obesity (intra-abdominal fat around organs) (waist >94 men, >80 women) and at least two of risk factors of obesity (caused by increased insulin):
• Hypertension (>130/85 or medication) (salt and water retention by kidney; also gout due to reduced uric acid excretion so more accumulation)
• Abnormal glucose (IGT, IFG) (reduced glucose uptake and so reduced gluconeogenesis in muscle)
• High triglycerides (>1.7)
• Low HDL (<0.9 men, <1.1 women) (unable to produce healthy high density lipoproteins in liver)
Manage weight can reduce insulin resistance hence reduce all other symptoms.
PCOS and insulin resistance?
Almost all women with PCOS are insulin resistant.
What are the causes of insulin resistance?
Inherited factors (unknown)
Environmental factors
Intrauterine environment (especially for SGA babies)
Central obesity
Central obesity causes insulin resistance in multiple ways.
Fat is an endocrine organ and releases hormones. Fat produces adiponectin (insulin sensitivity) and resistin (insulin resistance), which may provide a link between obesity and insulin resistance.
Development of obesity is a pro-inflammatory state, it produces a lot of cytokines that will cause inflammation. This inflammation can lead to development of a fatty liver. The fatty liver can cause chronic liver disease, which can lead to liver itself being insulin resistant. Increased visceral fat means they have higher triglyceride stores so large adipocytes that undergo uncontrolled lipolysis (insulin suppresses lipolysis). The fatty liver will also produce cytokines and add to increased adipocyte size. Increased adipocyte size leads to reduced adiponectin and increased resistin, also increased free fatty acids. Uncontrolled lipolysis leads to free fatty acids and increased glycerol (do not present with ketoacidosis because there is enough insulin around to prevent major ketogenesis). The increasing free fatty acids then lead to beta cell toxicity, and adds to the fatty liver.
- FFA, glycerol, and inflammatory cytokines released by visceral adipose tissue (TNFα, IL6) aggravate insulin resistance in muscle and liver
-FFA, glycerol also accumulates in beta cells of pancreas, which may cause lipotoxicity.
Increased glycerol turns into glucose, so patient produces more insulin to counteract, which creates viscous cycle with ↑↑↑insulin in pancreas (trying to keep blood sugar normal)
What happens because of insulin resistance?
Hepatic glucose output is not suppressed -> overproduction of glucose in the liver.
Insulin-mediated glucose uptake is reduced (reduced glucose uptake and reduced glycogen stimulation).
Therefore, hyperinsulinaemia (in respond to increased glucose) can maintain normal glucose levels (at expense of severe insulin resistance).
Fat
For metabolic effect, more substrate for glucose production, enhance lipolysis results in raised FFA and triglycerides (TG)
For hormonal effect, adipoctyokines leads to inflammation and develop vascular disease.
Beta cell dysfunction:
Glucose rises due to increased insulin resistance, eventually develops glucose toxicity in beta cell.
Increased FFA due to insulin resistance leads to lipotoxicity in beta cell, liver and muscle. Cells are filled with fat.
Now beta cell starts to fail progressively. Beta cell dysfunction is a critical step in pathogenesis of type 2 diabetes.
• ↓ beta cell mass (genetic or maternal)
• ↓ beta cell function (less pulses of insulin release, lipotoglucotoxicity, incretin dysfunction)
Poor first phase insulin release leads to post prandial hyperglycaemia.
Alpha Cell Dyregulation
After the beta cell stops working, eventually alpha cells will stop working.
• Normally when you eat, glucagon production by alpha cells are switched off rapidly because blood glucose is rapidly rising.
• When this glucagon release is dysregulated, you get excess secretion of glucagon (hyperglucagonaemia).
What does a measure of HbA1C indicate?
HbA1c is the glycation of haemoglobin to glucose. 4-6% of HbA attaches to glucose. It measures average blood glucose for last 120 days (red blood cell survival) and it is used as a diagnostic test.
• Normal ≤40mmol/mol
• Abnormal 41-49mmol/mol
• Diabetes ≥50mmol/mol (or/and fasting glucose ≥7mmol/l)
What are some microvascular complications of diabetes?
Retinopathy
Silent complication, usually no symptoms until they become blind.
Blurred vision due to the accumulation of glucose in the lens of the eye with resulting osmotic effects.
Haemorrhage and exudate in the retina, threatens patient’s vision.
Peripheral neuropathy (mono and autonomic) Mono: burning, numbness sensation; can cause ulcers and foot infection, if left untreated lead to amputation Autonomic: when the person stands up, they faint and fall down because they don’t vasoconstrict; when they eat, stomach doesn’t empty properly and they can get vomiting; can get excessive sweating; erectile dysfunction in men.
Nephropathy
Patients may present with tiredness, polydipsia, polyuria, glycosuria.
If undetected, most common cause of end stage renal failure (high mortality).
There is reduction in glomerular filtration rate, leading to protein in the urine.
What are some macrovascular complications of diabetes?
Ischemic heart disease (IHD) (e.g. atherosclerosis, myocardial infarct, left ventricular failure, death)
Peripheral vascular disease (PVD)
Further complicates neuropathy, e.g. nerve damage to feet combined with poor blood circulation, often amputation.
Cerebral vascular accident (CVA) (e.g. stroke)
How is diabetes managed?
Lifestyle modification (smoking cessation, diet and exercise is paramount)
• Medication to control glucose
Insulin for all type 1 and half type 2 diabetes (e.g. reusable insulin injection pen, insulin pump, continuous glucose monitor)
Metformin (improve insulin resistance)
Sulphonylurea (stimulates the pancreas to produce more insulin)
Insulin incretin therapy
SGLT2 inhibitors
Attend to BP, lipids, smoking etc.
Hypertensive medication
Statin (dyslipidaemia) and aspirin (platelet aggregation)
