Pathophysiology of Type 2 Diabetes and Lifestyle Management

Question 1

How is glucose stored in the body?

Answer 1

• In liver and muscle as glycogen

* Fat (longer-term storage)

Question 2

Mechanism of insulin release?

Answer 2

1. Glucose is transported into the pancreatic β-cell by GLUT2 and is metabolised, to increase ATP conc.
2. ATP binds to the KATP channel and causes closure; K+ can no longer enter the cell so depolarisation occurs, opening the Ca2+ channel
3. Intracellular Ca2+ conc. increases and this stimulates insulin within vesicles to be released

Question 3

Pathophysiology of hyperglycaemia?

Answer 3

Insulin resistance and β-cell dysfunction is caused by:
• Diabetes genes
• Adipokines 
• Inflammation
• Hyperglycaemia
• Free fatty acids 

Pancreas produces more insulin which:
• Regulates lipolysis from fat; also regulates glucose production within the liver, which increases blood glucose
• Stimulates glucose uptake into muscle

Question 4

Core physiological defects in T2DM?

Answer 4

• Insulin resistance

* β-cell dysfunction

Question 5

Explain insulin resistance

Answer 5

Insulin binds to receptor triggering production of glucose transport proteins to allow glucose to enter the cell

In insulin resistance, the receptor is less responsive to the insulin molecule and thus less glucose enters the cell; results in accumulation of glucose in the blood

Question 6

Cause of insulin resistance?

Answer 6

• Ectopic fat accumulation and increase FFA (free fatty acid) circulation; this decreases glucose transport
• Increased inflammatory mediators (CRP)

These both cause inhibition of insulin via serine kinases (responsible for phosphorylation of insulin receptor substrate-1, IRS-1); this results in reduced insulin-stimulated-glycogen synthesis due to reduced glucose transport

Question 7

What is insulin resistance assoc. with?

Answer 7

• Intra-abdominal obesity and inactivity
• Genetics and aging
• Medications
• Smoking
• Fetal malnutrition
• Endothelial disease and dysfunction, PCOS (Polycystic Ovary Syndrome), microalbuminaemia, T2DM, hypertension, non-alcoholic fatty liver disease, dyslipidaemia and macrovascular disease

Question 8

What is β-cell dysfunction?

Answer 8

Reduced ability of β-cells to secrete insulin in response to hyperglycaemia

Initially the β-cells compensate for insulin resistance by increaseing insulin production (i.e: there is impaired glucose tolerance); but pancreatic burnout occurs and insulin production decreases with a rise in blood glucose levels

Question 9

Consequences of insulin resistance?

Answer 9

• Glucotoxicity (hyperglycaemia)
• Lipotoxicity (elevated FFA and triglycerides)

Both cause declining β-cell function

Question 10

Describe β-cell function at the time of diagnosis of T2DM

Answer 10

β-cell dysfunction is already significant (approx. 50% of β-cell function is lost)

Question 11

What is reversal T2DM?

Answer 11

Normalisation of β-cell function in assoc. with decreased pancreas and liver triacylglycerol

This is possible with strict calorie control to ~800 calories per day; there can be normal fat levels in the pancreas and near-normal post-prandial insulin production

Question 12

Presence of insulin resistance pre-diagnosis?

Answer 12

Early defect in T2DM, preceding it by up to 20 years

Question 13

General weight of people with T2DM?

Answer 13

90% are overweight/obese; some are not, but this is atypical

Question 14

Apple vs pear shaped risk?

Answer 14

Apple-shaped patients (weight in the a central distribution) have a higher risk of T2DM and CV disease, compared to pear-shaped patients (weight on the hips)

Apple-shaped people have more intra-abdominal fat, i.e: around their organs as well as subcutaneously

Question 15

What is central-adiposity assoc. with?

Answer 15

• High BP
• High triglycerides
• Low HDL
• Insulin resistance

i.e: the metabolic syndrome

Question 16

Why are T2DM complications often present at diagnosis?

Answer 16

Many patients have T2DM 9-12 years pre-diagnosis and chronic damage may occur in this time and presentation with life-threatening metabolic problems can occur, e.g:
• Hyperglycaemia, hyperosmolar, non-ketotic coma (HONK)

Other complications:
• Retinopathy
• Neuropathy
• Nephropathy
• Erectile dysfunction

Question 17

Typical features of TD2M presentation?

Answer 17

Age (uncommon <50 years and certainly <40 years; may still occur but atypical)

Obesity is common

Other metabolic features:
• Dyslipidaemia
• Hypertension

Often a strong FH

Question 18

Differential diagnoses to consider alongside T2DM?

Answer 18

Red flags for:
• T1DM (young age, usually ~12 years old)
• Pancreatic disease
• LADA (similar presentation to T1DM but later in life, usually 35-40 years)
• Medication-induced

Question 19

How to determine if it is safe to treat T2DM with lifestyle changes alone?

Answer 19

Consider:
• HbA1c level
• Osmotic symptoms
• Weight loss

Question 20

Therapy staircase of T2DM?

Answer 20

1. Diet and exercise (lifestyle changes)
2. Oral monotherapy
3. Oral combination
4. Injectable (exogenous insulin) and oral combination

Question 21

Presenting features of T2DM?

Answer 21

Insidious onset of symptoms, which may include:
• Thirst (polydipsia)
• Polyuria
• Fatigue
• Thrush

There is NO weight loss, generally, and most people are obese

Question 22

Conditions in the FH that may indicate T2DM?

Answer 22

FH of T2DM or gestation diabetes

Question 23

Conditions in the PMH that may indicate T2DM?

Answer 23

• Gestational diabetes
• PCOS (Polycystic Ovarian Syndrome)
• Pancreatitis
• Cystic Fibrosis or myotonic dystrophy

Question 24

Drugs that can cause T2DM or signs that indicate it?

Answer 24

Steroids, statins, thiazides

Question 25

SH to consider in potential T2DM presentation?

Answer 25

Alcohol intake (consider pancreatic issues, e.g: pancreatitis)

Smoking

Question 26

Signs on examination of T2DM?

Answer 26

Acanthosis nigricans (thickening and hyperpigmentation of the skin, often in skin folds, due to INSULIN RESISTANCE)

No signs of other endocrine disease, e.g: Cushing’s disease

Question 27

Lifestyle advice to help control T2DM?

Answer 27

• Weight loss (improves survival and reduces risk of diabetes-related death)
• Exercise
• Smoking cessation
• Improve diet

Question 28

Relationship between obesity and relative risk in T2DM of mortality?

Answer 28

As BMI increase, past 25, relative risk of mortality increases

However, this can be adjusted, e.g: in the South-East Asian population, BMI cut-off can be 22

Question 29

Consequences of obesity?

Answer 29

Increased risk of diabetes and CV disease

Question 30

Guidelines for physical activity in older adults?

Answer 30

Some physical activity is better than none and more activity provides greater health benefits

Older adults at risk of falls should incorporate physical activity to improve balance and coordination on at least 2 days of the week

Question 31

Factors that affect self-management of T2DM?

Answer 31

• Health literacy, education/knowledge
• Motivation, e.g: wearable technology, like pedometers, apps, activity monitors
• Competing priorities, time
• Other health issues
• Social and mood problems

Question 32

Methods of aiding patient self-management?

Answer 32

• Education, e.g: structured education programmes (should be offered to all T2DM patients)
• Motivational interviewing
• Personal info sharing
• Behaviour changing

Question 33

Low health literacy levels are assoc. with?

Answer 33

• Increased rate of chronic condition, e.g: diabetes, obesity and hypertension
• Poor disease Mx, poor glycaemic control,
• Complications
• Hypoglycaemia
• Higher risk of death

Question 34

What is House of Care for diabetes?

Answer 34

Motivation interviewing that involves:
• Goal setting, e.g: target HbA1c
• Behaviour change
• Information sharing
• Education