HLTH341 - Diabetes (guest lecture

What were the symptoms exhibited by a type 1 diabetic?

Significant recent weight loss, drinking several water bottles each day, presenting with nausea, vomiting, and a fever

Where were the symptoms of a type 2 diabetic?

Hypertension, A1C of 6.7%, denies symptoms of thirst and frequent urinations

What were the symptoms of a gestational diabetic?

Experiencing heart burn but feeling well, routine screening reports 50g of OGTT

Where were the symptoms of a drug-induced diabetic?

Prescribed a drug, routine blood work reports PG of 15 mmol/L but he denies any symptoms of diabetes

Define diabetes mellitus

A heterogenous metabolic disorder characterized by the presence of hyperglycemia due to (a variety of reasons)

What are the frequent signs and symptoms of diabetes?

1. Unusual thirst (polydipsia)

2. Frequent urination (polyuria)

3. Weight change (gain/loss)

4. Blurred vision

5. Recurrent infections

6. Slow healing

7. Tingling/numbness

8. Erectile dysfunction

How do those with type 2 diabetes differ in terms of diabetic symptoms?

No symptoms may be present!

What are the 4 main consequences of hyperglycemia?

1. Heart/brain disease

2. Kidney disease (renal)

3. Eye disease

4. Nerve damage

Is there a life expectancy difference between diabetics and non-diabetics? When does it start?

Yes! Starting at ages 40, no real difference b/w males and females

How common is diabetes?

1 in 9! (And steadily increasing across the country and across Canada!)

How does prevalence of diabetes differ based on age and gender?

Age → prevalence increases with age (highest at 75-79)

Gender → males have a slightly higher prevalence at all stages (7.2% vs 6.4%)

How does prevalence differ based on income, education, identity, and cultural/racial background?

Income → highest in lower incomes

Education → highest in those without high school attainment

Identity → highest in indigenous peoples living off-reserve

Ethnicity → highest in south Asian!

How can the prevalence of diabetes in Ontario and the WWLHIN compare?

WWLHIN (Waterloo Wellington LHIN) reports slightly lower prevalence than all of Ontario (10 vs 12%)

Compare the definitions of type 1 and type 2 diabetes

Type 1 → Pancreatic beta cell destruction, usually leading to absolute insulin deficiency

Type 2 → may be insulin resistance insulin deficiency or secretory defects with insulin resistance

What are the two causes of type 1 diabetes beta cell destruction?

Immune mediated (autoantibodies) and idiopathic (unknown reason for destruction)

Define gestational diabetes

Glucose intolerance with onset or first recognition in pregnancy

What are the 4 main tests used to diagnose diabetes?

1. Fasting plasma glucose

2. A1C test

3. Oral glucose tolerance test

4. Random plasma glucose test

Explain each diagnosis test

Fasting plasma glucose → no caloric intake for 8 hours and the plasma glucose is measured

A1C → measures glycosylation of RBC’s in an assay (not for type 1)

OGTT → patient drinks oral glucose and glucose levels in blood are tracked

Random PG test → plasma glucose is randomly measured throughout the day without relevance to last meal

What are the two main hormones that regulate glucose in the body? When are they released?

1. Insulin (rise in blood glucose)

2. Glucagon (fall in blood glucose)

Compare the action of insulin and glucagon in glucose homeostasis (in a rise or drop of glucose)

Beta cells in pancreas release insulin → insulin triggers liver (store as glycogen) and cells to take up glucose

Alpha cells in pancreas release glucagon → glucagon triggers breakdown of glycogen and release of glucose

What is the homeostatic levels for glucose?

90mg/100mL

What are the 6 main tissues that utilize glucose?

1. Brain

2. Skeletal muscle

3. Kidney

4. Blood cells

5. Splanchnic organs

6. Adipose tissue

Why is glucose so important to the brain?

Glucose is the brain’s main energy source, but it cannot store or synthesize glucose so it is fully dependent on the blood supply!

what is an alternative energy source to glucose in the brain? When does this happen?

Ketone bodies → after prolonged fasting become available to the brain for energy

Why are free fatty acids not an energy source option for the brain?

The blood-brain barrier (BBB) blocks free fatty acids!

What are the 3 metabolic states?

Fed state (4 hours after a meal), fasting state (post 4-hours), and starvation state

Compare the hormones active in a fed state vs fasting state

Fed → high insulin, low glucagon

Fasting → low insulin, high glucagon

What two processes does insulin inhibit during the fed state?

Lipolysis and gluconeogenesis!

Compare the effects of insulin in the liver vs the kidney during fed state

Liver → endogenous glucose release is rapidly suppressed (80%!)

Kidney → endogenous glucose release by the kidney is not suppressed

What two processes does glucagon stimulate during a fasted state?

Glycogenolysis (breakdown of glycogen) and later gluconeogenesis (create new glucose)

How does the balance between glycogenolysis and gluconeogenesis change as a fasting state increases?

Gluconeogenesis increases with duration of fasting as glycogen stores are depleted:

Starts at 50% glycocenolysis and 30% gluconeogenesis, but decreases

24hr = 70% gluconeogenesis

48hr = 90% gluconeogenesis

How long until glycogen stores are completely depleted? What is this point called?

60 hours! → prolonged fasting / starvation state

Define a prolonged fasting / starvation state, what is it also referred to?

Occurs when the body is deprived of glucose for a prolonged duration (2-3 days!) → survival mode

Since glycogen levels are depleted, how does the body get its energy?

Body relies on fat and protein for energy through gluconeogenesis (AA and FFA)

Why is the starvation state bad for the brain?

Brain cannot use fat for energy, so it starts using ketones as an energy source

What are ketones?

Byproducts of breaking down FFA (free-fatty acids) for energy

What are 4 glucose regulators that are not insulin/glucagon?

1. Catecholamines

2. Growth hormones and cortisol

3. Free fatty acids (FFA)

4. Incretins / endocannabinoids

What are the 2 functions of the pancreas?

1. Produce and secrete digestive enzymes (digestion)

2. Produce and secrete hormones for glucose regulation (endocrine)

What four tissues does insulin bind to? What is the function?

Binds to liver, kidney, muscle, and adipose tissue

Liver + kidney → suppresses glucose release

Muscle + adipose tissue → increases glucose uptake

How does insulin inhibit the release of FFA into circulation? How does this reduce plasma glucose?

Inhibits lipases and increases FFA clearance → FFA stimulate gluconeogenesis and reduce glucose transport (so not there = reduce plasma glucose)

How does insulin promote glucose storage?

Inhibits glycogenolysis enzymes and stimulates glycogen synthease

How does insulin signalling exactly increase glucose uptake in muscle/adipose tissue?

The binding of insulin causes Glut4 receptors stored in a vesicle to fuse with the plasma membrane → allows glucose to enter the cell

Why is glucagon considered a counterregulatory hormone to insulin?

It increases plasma glucose by stimulating hepatic glycogenolysis (enzymes…)

How do catecholamines affect glucose metabolism? Which two have an effect?

Fast-acting way to increase glucose via glycogenolysis, gluconeogenesis, lipolysis! → epinephrine and norepinephrine

How do growth hormones and cortisol affect glucose metabolism?

Slow-acting way to increase glucose via gluconeogenic enzymes and reducing GLUT4 transporters

(+ cortisol impairs insulin secretion)

How do FFA’s regulate glucose metabolism?

Stimulate glucose production in liver / kidney and inhibit glucose transport into muscle tissue (opposite of insulin!)

Why is FFA so integral to glucose metabolism? What are the three exceptions?

They are the predominant fuel used by most organs EXCEPT brain, renal medulla, and blood cells

Define incretins. What are the two main ones?

Hormones secreted by the gut that stimulate insulin release from the pancreas → GIP and GLP-1

What is the additional function of GLP-1 in glucose metabolism? What happens if it is deficient?

Inhibits glucagon secretion, delays gastric emptying, and promotes satiety → deficiency = type 2 diabetes

What is the pathogenesis of type 1 diabetes?

Pre-clinical period of autoimmune destruction of beta cells in the pancreas

When will symptoms occur in type 1 diabetes?

Once 70% of beta cells in pancreas are destroyed!

Describe the change in beta cells starting at birth in a type 1 diabetic individual

At birth → 80% of beta cells, increases to 100%

Genetic predisposition and immune cell abnormalities trigger a progressive decline in insulin release and beta cell % until diabetes is diagnosed

What are the typical characteristics of type 1 diabetes?

• destruction of pancreatic beta cells (usually rapid)

• Absolute insulin deficiency, need exogenous insulin for survival

• 5-10% of total diabetes cases

• Autoimmune markers present (i.e. autoantibodies in 85-90% of patients!)

What is islet autoantibody testing used for?

Distinguishing between type 1 diabetes (immune) and type 2 diabetes or monogenic diabetes (non-immune)

What is C-peptide? When is it most useful?

A measure of endogenous insulin secretion → used 3 to 5 years after diagnosis

Compare the results of a high and low C-peptide concentration

High → suggests type 2 diabetes

Low/absent → absolute insulin requirement

How is C-peptide generated? How does this relate to the concentrations of C-peptide in disease?

In preproinsulin, the A and B-chains are separated by C-peptide which must be removed for insulin function

(Thus lack of C-peptide means no insulin is produced, and too much means resistance to insulin is occurring)

what is LADA?

Latent autoimmune diabetes in adults

What type of diabetes is LADA? What is it misdiagnosed as?

“Type 1.5” → misdiagnosed was non-obese type 2 diabetes typically

What happens in LADA?

A slower progression of autoimmune beta cell failure, happening >30 years of age → islet antibodies are still present!!

Compare the genetic vs environmental risk factors of type 1 diabetes

Genetics → parents or siblings with type 1 slightly increases the risk and also twinning?

Environmental factors → can trigger an immune response, could also include viral infections?

What are two common auto-antibodies present in type 1 diabetes?

glutamic acid decarboyylase (GAD) or insulin auto-antibodies (IAA)

What are the two predominant types of type 2 diabetes

Either relative insulin deficiency (impaired secretion) or insulin resistance (impaired response) or both!

Why is type 2 diabetes considered multifactorial?

It involves and is dependent on a number of different factors / causes (ominous octet or egregious eleven1!)

When does pathogenesis of type 2 diabetes begin? What is it characterized by?

Years before diagnosis → a progressive loss of beta cel function causing abnormal insulin and glucagon dynamics

Why is the beta cells of the pancreas considered the final common denominator in the egregious eleven?

A decrease in B-cell function or mass leads to a decrease in insulin that ultimately causes all eleven of the pathologies related to type two diabetes

Describe the progression of beta cell function loss and the point of diagnosis in type 2 diabetes

Diagnosis typically occurs at ~60% beta function, having experienced years of hyperglycemia (after eating a meal)

Compare the insulin and glucagon dynamics in response to a meal between type 2 diabetics and normal subjects

Insulin → the insulin spike is far smaller, and has a delayed response

Glucagon → the spike is far greater (not suppressed), when it should be decreasing

Overall blood glucose → 2-3x higher after eating!

Describe the first-phase insulin response. How does this change in type 2 diabetes?

First-phase insulin response = rapid burst of insulin from the pancreas within minutes of glucose rising

In type 2 diabetes → burst is much weaker and delayed.

How are the typical characteristics/causes of type 2 diabetes different than that of type 1?

• onset is far more gradual

• Caused by obesity or sedentary lifestyles (not genetic)

• Seen in older men/women (>35 years)

• Family history increases the odds

• Symptoms may not appear!

What are the 3 goals of diabetes therapy?

1. Avoid symptoms of hyperglycemia

2. Avoid or minimize risk of acute complications

3. Reduce risk of chronic complications

Compare possible acute vs chronic complications with diabetes therapy

Acute → hypoglycemia or hyperglycemic emergencies

chronic → microvascular (neuropathy) or macrovascular (cerebrovascular disease)

What is the ABCDES³ of diabetes care?

A = A1C targets

B = Blood pressure targets

C = cholesterol targets

D = drugs for CVD risk reduction

E = exercise

S³ = screening, smoking (cessation), and self-management (stress)