Module 4: Diabetes

Diabetes Mellitus

• A heterogenous metabolic disorder.

• Characterized by the presence of high blood sugar (i.e., hyperglycaemia).

• Chronic hyperglycemia is associated with macrovascular and microvascular complications​.

Signs and Symptoms

• Unusual thirst (i.e., polydipsia).

• Frequent urination (i.e., polyuria).

• Weight change. ​

• Blurred vision.​

• Frequent or recurring infections (e.g., UTI, pneumonia, skin infections). ​

• Cuts and bruises slow to heal.

• Tingling or numbness of the hands or feet.​

• Trouble getting or maintaining an erection.

Can also be entirely asymptomatic for those with Type 2.

Complications of diabetes include an increased risk of…

• Heart disease.

• Brain disease.

• Kidney disease.

• Eye disease.

• Nerve damage.

• Lower limb amputation.

• Ketoacidosis (i.e., high acid in the blood).

• Hyperosmolar syndrome (i.e., high concentration of dissolved substances like sodium, glucose, urea compared to water in the blood).

• Death (i.e., shorter lifespan by 6 years in males and females).

Risk Factors for Diabetes

• Sex: Slightly more males than females.

• Age: Prevalence increases with age, with the sharpest increase around age 40 and highest prevalence around age 76-79.

• SES: Greater in lower SES.

• Education: Greater in lower education.

• Indigenous Identities: Greater in Indigenous peoples living off reserve).

• Ethnicity: Greater in South Asian, Black, and Arab/West Asian communities.​

Type 1 Diabetes

Pancreatic beta cell destruction, usually leading to absolute insulin deficiency (i.e., the pancreas does not produce insulin).

• Formally known as “juvenile” diabetes.

• Caused by genetic predisposition and/or an immune trigger.

• Can be immune mediated or spontaneous.

• Autoimmune markers (i.e., auto-antibodies) present in 85-90% of patients and appears years before beta cell destruction.

• 70% or more of the beta cells in the pancreas must be destroyed before symptoms occur. Therefore, takes time to develop.

• Lack of insulin production (i.e., endogenous insulin) can be measured via the lack of C-peptide in the blood.​

• Endogenous insulin is needed for survival.

• Accounts for 5-10% of diabetes cases.

Type 2 Diabetes

May range from predominantly insulin resistance, to insulin deficiency, to a predominantly secretory defect with insulin resistance.

• i.e., The body doesn't make enough insulin and/or can't use insulin properly. Is typically a mix of these.​

• Causes for development are multi-factorial.

  • Ominous Octet: Used to be 8 biological pathways that cause or lead to diabetes. ​

  • Egregious Eleven: Has been expanded to 11 biological pathways that cause or lead to diabetes.

• Pathogenesis begins years prior to diagnosis.

  • Progressive loss of beta-cell function​.

  • Insulin and glucagon dynamics are abnormal​.

  • Loss of first phase insulin response to glucose.

• Gradual onset, tough may be sudden and severe.

• Associated with obesity or sedentary lifestyle, and family history due to similar lifestyles.

• Most common in older adults (i.e., over 35 years).

  • We are seeing rising rates in children.

• Can be asymptomatic.

• Accounts for 90% of diabetes cases.

Gestational Diabetes

Glucose intolerance that occurs with or is first recognized during the onset of pregnancy.

Other Types of Diabetes

Variety of uncommon diseases, genetic forms, or diabetes associated with drug use.

Diagnostic Tests: FPG

Measures current blood sugar (i.e., glucose) level when you have not eaten or had sugary drinks for at least 8 hours (i.e., fasting).

Diagnostic Tests: Glycated Hemoglobin (A1C)

Measures the average amount of sugar in your blood over the past few months.

Diagnostic Tests: Oral Glucose Tolerance Test (OGTT)

Measures how quickly your body clears sugar from the bloodstream two hours after drinking a sugary drink (i.e., 2hPG, or 2-hour plasma glucose).

Diagnostic Test: Random PG

Measure the amount of plasma glucose (i.e., sugar) circulating in a person's blood at any given time, regardless of when they last ate.

Insulin in Glucose Homeostasis

• A stimulus (e.g., food) causes blood glucose levels to rise.

• Beta cells in the pancreas release insulin into the blood.

• Either…

  • Liver takes up glucose and stores it as glycogen.

  • Body cells take up glucose.

• Blood glucose levels decrease to the homeostatic set point (i.e., 90mg/100mL).

Glucagon in Glucose Homeostasis

• A stimulus (e.g., not eating) causes blood glucose levels to fall.

• Alpha cells in the pancreas release glucagon.

• The liver breaks down glycogen and releases glucose.

• Blood glucose levels rise to the homeostatic set point (i.e., 90mg/100mL).

Glycogenolysis

The metabolic process of breaking down stored glycogen into glucose, providing the body with quick energy during fasting, exercise, or stress.

• Done by the liver.

Glucogeogenesis

The metabolic process where the body creates new glucose from non-carbohydrate sources like lactate, glycerol (from fats), and amino acids.

• Done by the liver and kidneys.

Six Main Tissues that Utilize Glucose

• Brain.

• Skeletal muscle.

• Kidneys.

• Blood cells.

• Splanchnic organs (e.g., stomach, small and large intestines, spleen).

• Adipose tissue and skin.

Glucose is the _____’s main energy source.

Brain.

• Dependant on glucose supply from plasma, since it cannot store or synthesize glucose. ​

• Blood-brain barrier blocks free fatty acids.

• Glucose concentrations less than 3.0 mmol/L can impair cerebral function. ​

• After prolonged fasting, ketone bodies are produced and available to the brain for energy. ​

Fed (Post-Prandial or Absorptive) State

• Occurs after a meal, and lasts for approximately 4 hours.

• High insulin, low glucagon.

• Glucose is supplied by the meal​.

• Insulin is released and inhibits lipolysis and gluconeogenesis.

• Endogenous glucose release by the liver is rapidly suppressed by ~80% during the 5 hour postprandial period​.

• Endogenous glucose release by the kidney is not suppressed.​

Fasting (Post-Absorptive) State

• Occurs after food has been digested, absorbed, and stored.

  • e.g., Overnight fast, skipping meals during the day, etc.

• Low insulin, high glucagon.

• Glucose levels fall, insulin levels decrease, glucagon released​.

• Glucagon stimulates process called glycogenolysis​.

• Glycogen stores are depleted over time, and the body relies more on gluconeogenesis​.

Prolonged Fasting or Starvation State

• Occurs when the body is deprived of glucose for a prolonged duration (i.e., 2-3 days without food)​.

• The body enters “survival mode”.

• Glycogen levels have been depleted (for approximately 60 hours)​.

• Body starts to rely on fats and protein for energy​.

• Gluconeogenesis from amino acids and FFA​.

In the prolonged fasting or starvation state, the brain cannot use fat for energy, which means that…

• The body starts to use ketones for an energy source​.

• Ketones are a byproduct of breaking down FFA for energy​.

• Ketone bodies supply 2 to 6% of the body’s energy requirements after overnight fast and 30 to 40% of energy need after a 3-day fast​.

Functions of the Pancreas

• Produce and secrete digestive enzymes.

• Produce and secrete hormones for glucose regulation.

Regulation of Glucose Metabolism: Insulin

Increases glucose uptake in muscle and adipose tissue​.

• Regulates glucose via direct and indirect mechanisms​.

• Binds to receptors in liver, kidney, muscle, and adipose tissue​.

• Supresses glucose release from liver and kidney​.

• Inhibits release of free fatty acids (FFA) into the circulation via suppression of lipase and increased FFA clearance.

  • This indirectly reduces plasma glucose as FFA stimulate gluconeogenesis and reduce glucose transport into cells​.

• Promotes glucose storage (i.e. glycogen) via inhibition of glycogenolysis enzymes and stimulating of glycogen synthase​.

Secretion of the compound itself is regulated by plasma glucose concentration.

Insulin Signalling

• Insulin binds to an insulin receptor on the outside of a cell.

• Sets off an insulin signalling pathway.

• Causes a GLUT4 vesicle inside the cell to fuse with the plasma membrane.

• The newly positioned GLUT4 transporter allows glucose to enter the cell.

Regulation of Glucose Metabolism: Glucagon

Increases plasma glucose production via stimulation of hepatic glycogenolysis​.

• Major counter-regulator hormone to insulin.

• Secretion of the compound itself is stimulated by hypoglycemia and inhibited by hyperglycemia.

Regulation of Glucose Metabolism: Catecholamines

Increases glucose via glycogenolysis, gluconeogenesis, and lipolysis.

• Includes epinephrine and norepinephrine.

• Fast-acing.

• Counter-regulatory to insulin.

Regulation of Glucose Metabolism: Growth Hormone and Cortisol

Increase glucose via stimulation of gluconeogenic enzymes and reduction of glucose transport​.

• Slow-acting (i.e., can take hours).

• Counter-regulatory to insulin.

  • The latter impairs insulin secretion.

Regulation of Glucose Metabolism: Free Fatty Acids (FFA)

Stimulate glucose production in liver and kidney via gluconeogenesis​.

• Impair glucose transport into muscle tissue​.

• Predominant fuel used by most organs (brain, renal medulla, and blood cells are exceptions)​.

• Regulators of the compound itself includes sympathetic nervous system, growth hormone, insulin, and hyperglycemia​.

Regulation of Glucose Metabolism: Incretins

Stimulates insulin release from the pancreas.

• Is a hormone secreted by the gut (i.e., intestinal mucosa).

• Includes gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1).

  • GLP-1 also inhibits glucagon secretion, delays gastric emptying and promotes satiety​.

  • GLP-1 is deficient in type 2 diabetes.

Incretins are released by the gut, which means that…

More insulin is produced when a patient receives oral glucose compared to IV glucose.

Islet Auto-Antibody Testing

Used to distinguish between type 1 diabetes (immune) and type 2 diabetes or monogenic diabetes (non-immune)​.

• Antibodies include…

  • GADA = glutamic acid decarboxylase autoantibodies​.

  • IAA = insulin autoantibodies​.

  • 1A-2A = insulinoma-associated-2 autoantibodies​.

  • ICA = islet cell cytoplasmic autoantibodies​.

  • TzT8Ab = zinc transporter 8.

C-Peptide

A measure of endogenous insulin secretion.

• Most useful 3-5 years after diagnosis.

• High levels suggest Type 2 diabetes.

• Low or absent levels confirm absolute insulin requirement (i.e., Type 1 diabetes).

Latent Auto-Immune Diabetes in Adults (LADA)

A slow, slow form of Type 1 diabetes, where beta-cells fail after many, many years.​

• Considered “Type 1.5” diabetes.

• Commonly misdiagnosed as non-obese type 2 diabetes​.

• Occurs most often in those 30 years of age​ or older.

• Slower progression of autoimmune beta cell failure​.

• Islet antibodies present at diagnosis​.

Risk Factors for Type 1 Diabetes

• Genetics.

  • Parent or sibling with type 1 diabetes slightly increases risk​.

  • No family history = 0.4%​.

  • Father with type 1 diabetes = 3 to 8%​.

  • Mother with type 1 diabetes = 1 to 4%​.

  • Both parents with type 1 diabetes = up to 30%​.

  • Sibling (non-twin) with type 1 diabetes = 3 to 6%​.

  • Dizygotic twin with type 1 diabetes = 8%.

  • Monozygotic twin with type 1 diabetes = up to 30%

• Environmental factors.

  • Appears to trigger immune response​.

  • Potential triggers include viral infections, diet, etc.

Overall, not well established.

A _____ in pancreatic beta-cell function and mass leads to a _____ in insulin. This is the final common denominator in all of the egregious eleven.

Decrease; decrease.

In patients with Type 2 diabetes, after a meal, there is a _____ insulin response.

Delayed or depressed.

• It takes longer to “kick-in” or the levels do not increase.

In patients with Type 2 diabetes, after a meal, there is a _____ glucagon response.

Non-suppressed (i.e., high).

• The levels rise significantly and takes much longer to go back down.

Goals of Diabetes Therapy

• Avoid symptoms of hyperglycaemia.

• Avoid or minimize the risk of acute complications.

  • Hypoglycaemia (i.e., abnormally low glucose).

  • Hyperglycaemic emergencies (e.g., diabetic keto-acidosis, hyperosmolar hyperglycaemic state).

• Reduce the risk of chronic complications.

  • Microvascular complications (e.g., neuropathy, retinopathy, nephropathy).

  • Microvascular complications (e.g., cerebrovascular disease, coronary heart disease, peripheral vascular disease).

ABCDES³ of Diabetes Care

A framework for managing diabetes by reducing heart/stroke risk (since death associated with diabetes is due to cardiovascular causes), by…

• Focusing on A1C (blood sugar).

• Blood pressure.

• Cholesterol.

• Drugs (for heart protection).

• Exercise & Eating healthy.

• Stopping smoking.

• Stress management.

• Screening for complications.