Lecture 26: Metabolic syndrome and Diabetes

Question 1

Insulin resistance occurs in…. (tissues)

Answer 1

• Insulin resistance occurs in the liver, muscle and adipose tissue.

Question 2

Define Insulin Resistance

Answer 2

Insulin resistance is for a given concentration of insulin, you get a subnormal glucose response

• High insulin with normal/high glucose (not practical for clinical measure)
• Glucose appear in urine when >10 blood glucose, so there is an asymptomatic window before diabetes due to impaired glucose tolerance (IGT) associated with insulin resistance. Therefore, insulin and glucose are not measured in clinics due to subtle change.

Insulin resistance can occur pre-receptor (Cushing), receptor (rare) or post-receptor (phosphorylation cascade, common).

Question 3

What are the associated diseases with insulin resistance?

Answer 3

1. Obesity
2. Type 2 diabetes (always associated with insulin resistance, can be avoided if remain thin)
3. Endocrine disorders (Cushing, acromegaly)
4. Metabolic syndrome

Question 4

What are the symptoms/signs of an individual with Metabolic syndrome?

Answer 4

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.

Question 5

What is this?

Answer 5

A black pigmentation around back of neck, armpits, knuckles (“dirt doesn’t wash off”) due to growth factor of insulin

Acanthosis Nigricans

Acanthosis nigricans is a fairly common skin pigmentation disorder. The most notable sign of acanthosis nigricans is dark patches of skin with a thick, velvety texture. The affected areas of skin may also itch or have an odor. These patches may appear on skin folds and other areas, such as the: armpits.

Question 6

What is Acanthosis Nigricans

Answer 6

A black pigmentation around back of neck, armpits, knuckles (“dirt doesn’t wash off”) due to growth factor of insulin

Acanthosis nigricans is a fairly common skin pigmentation disorder. The most notable sign of acanthosis nigricans is dark patches of skin with a thick, velvety texture. The affected areas of skin may also itch or have an odor. These patches may appear on skin folds and other areas, such as the: armpits.

Question 7

What may be observed in patients with Insulin Resistance (surface level)?

Answer 7

1) Metabolic Snydrome Cluster
2) Acanthosis Nigricans
3) PCOS

Question 8

What are the causes of insulin resistance?

Answer 8

Causes of Insulin Resistance

• Inherited factors (unknown)
• Environmental factors
• Intrauterine environment (especially for SGA babies)
• Central obesity
  
  • Increased v_isceral fa_t (esp. intraabdominal) thus ↑stored triglyceride, so large adipocytes, which are resistant to insulin (insulin suppress lipolysis)
  • Uncontrolled lipolysis leads to ↑non­‐esterified fatty acids (NEFA) and ↑glycerol (**do not present with ketoacidosis because there is enough insulin around to prevent major ketogenesis)
    
    1. NEFA, glycerol, and inflammatory cytokines released by visceral adipose tissue (TNFα, PAI1, IL6) aggravate insulin resistance in muscle and liver
    2. NEFA, glycerol also accumulates in beta cells of pancreas, which may cause lipotoxicity.
  • ↑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)

Question 9

Fat produces ____ and _____.

Answer 9

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.

• Adiponectin deficiency may play a role in development of insulin resistance and type 2 diabetes
• Resistin overproduction is observed obese mice and decreases adipocyte glucose uptake

Question 10

How does insulin resistance occur IN THE LIVER

Answer 10

Insulin resistance tends to be inside the cell, but the mechanism of how insulin resistance occurs is uncertain. The end result of all processes is insulin resistance in liver, fat and muscle.

Inflammation

• 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.

Fatty Liver

• The fatty liver can cause chronic liver disease, which can lead to liver itself being insulin resistant.
• The fatty liver will also produce cytokines and add to increased adipocyte size.

Increased Adipocyte Size

• Increased adipocyte size leads to reduced adiponectin and increased resistin, also increased free fatty acids.
• The increasing free fatty acids then lead to beta cell toxicity, and adds to the fatty liver.

Question 11

What are the consequences of Insluin Resistance

Answer 11

Insulin has main actions on fat, carbohydrate and protein. In insulin resistance, the effects on carbohydrate metabolism is most important.

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.

1) Glucose

• Increased Hepatic glucose output (not suppressed) (overproduction of glucose in liver)
• IMGU in muscle reduced (reduced glucose uptake and reduced glycogen synthesis)

Therefore, only hyperinsulinaemia (respond to increased glucose) can maintain normal glucose levels (at expense of severe insulin resistance).

2) 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.

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3) 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 reselase, lipotoglucotoxicity, incretin dysfunction)

Poor first phase insulin release leads to post prandial hyperglycaemia.

4) 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).

Question 12

Describe insulin and glucose levels in Lean-normal, Obese-normal, Lean-type 2 and Obese-type 2 individuals

Answer 12

Lean normal

• Produce enough insulin with normal glucose metabolism

Obese normal (insulin resistant)

• Produce a lot more but enough insulin with normal glucose metabolism

Lean type 2 (insulin deficit)

• Produce less insulin than normally needed with glucose load, increased blood glucose.

Obese type 2 (insulin deficit and resistant)

• Produce not enough insulin with glucose load (even though more than lean type 2, less than obese normal) due to beta-cell failure, increased blood glucose.

Therefore, it is only when you become relatively insulin deficient that you’ll develop diabetes.

Note that fasting glucose associated with impaired fasting glucose (IFG), and oral glucose tolerance test (OGTT) after 2 hours associated with impared glucose tolerance (IGT).

Question 13

Draw the OGGT- glucose and OGGT-insulin gluclose-time graphs

Answer 13

Question 14

Define Diabetes Mellitus

Answer 14

One definition is metabolic disorder characterised by presence of hyperglycaemia due to defective insulin secretion, insulin action or both.

Alternative definition is disorder of premature widespread atherosclerosis with hyperglycaemia as an associated feature, therefore diabetes is a disease of blood vessels.

Question 15

Describe the diagnostic criteria for Diabetes Using Glucose Tolerance Test

Answer 15

HbA1c is a measure (in mmol/l) of glycation of haemoglobin to glucose.

• Haemoglobin is made up of different types of sub-fractions, HbA stands for adult haemoglobin.
• 92% HbA carries oxygen. HbA1a and b have no glucose molecules glycated and are not useful for diagnosing diabetes. There are 4-6% HbA attaches to glucose, which is HbA1c.

Therefore, HbA1c 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)

Question 16

What is the difference between Type 1 and Type 2 diabetes (just the definition)

Answer 16

Type 1 is immune-mediated B cell destruction

Type 2 is obesity-related insulin resistance

Question 17

What are the microvascular complications surrounding diabetes?

Answer 17

Microvascular Complications

• 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.

Question 18

What ar ethe macrovascular complications

Answer 18

• 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)

Question 19

What are differences between Type 1 and Type 2 Diabetes

Answer 19

Typical Patient With Type II Diabetes

• Obese with insulin resistance
• Features of metabolic syndrome
• Older and obese
• Family history of type II diabetes
• Don’t need insulin for 5-10 years after diagnosis

Typical Patient With Type I Diabetes

• Autoimmune beta cell destruction
• Abrupt symptoms
• Younger and lean
• No family history
• Ketosis and ketoacidosis prone
• Require insulin (true absolute insulin deficiency) usually from diagnosis and to sustain life

Question 20

How do you manage diabetes?

Answer 20

• _Lifestyle modification (s_moking 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)