Diabetes Mellitus: Glucose Transport & Classifications

Diabetes Mellitus Pathophysiology/Epidemiology/Etiology

• Diabetes mellitus is a chronic disease characterized by insulin deficiency or resistance.
• This leads to disturbances in carbohydrate, fat, and protein metabolism, resulting in hyperglycemia (elevated blood glucose levels).
• Other types of diabetes exist, such as diabetes insipidus, which is characterized by excessive water loss due to a hypertonic blood volume.
• Beta cells in the islets of Langerhans secrete insulin, while alpha cells secrete glucagon and delta cells secrete somatostatin.

What Insulin Does

• Insulin facilitates glucose transport from the bloodstream into muscle and fat cells.
• It inhibits the breakdown of glycogen into glucose (glycogenolysis) and the production of glucose from fat and protein (gluconeogenesis).
• It promotes the storage of energy in the form of glycogen and fat, and the building of body tissues (proteins). It is considered an anabolic hormone.

What Glucagon Does

• Glucagon promotes glycogenolysis and gluconeogenesis.
• It inhibits energy storage (glycogen and fat) and tissue building (proteins). It is considered a catabolic hormone.

Sugar Transport by GLUT Transporters

• GLUT1: Glucose uptake in red blood cells and the brain.
• GLUT2: Glucose, fructose, and galactose uptake in the liver.
• GLUT3: Glucose uptake in the brain.
• GLUT4: Insulin-mediated glucose uptake in muscles and adipose tissue.
• GLUT5: Fructose transporter, primarily in the intestines.

Which GLUT is Involved in Glucose Transport

• GLUT4 glucose transport is insulin-dependent.
• Signal transduction, gene expression, and growth regulation are also involved in this transport mechanism.
• GLUT4 moves glucose into target cells following the activation of insulin receptors.

Not All Glucose Transport is Insulin-Dependent

• Brain, blood cells, and liver use transporters that are NOT insulin-dependent.
• Other hormones influence glucose metabolism.

Classifications of Diabetes Mellitus (DM)

• Prediabetes: Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT).
• Type 1 DM: Starts usually before 20 years of age, characterized by absolute insulin deficiency.
• Type 2 DM: Disease of aging and obesity, characterized by insulin resistance then insulin deficiency.
• Pre-existing DM in pregnancy: Gestational diabetes (GDM).

Cost of Diabetes in Canada

• People with diabetes access healthcare services more often and spend more time in hospitals.
• Medical costs for people with diabetes are 2-3 times higher than for those without.
• Canada has high spending on diabetes-related healthcare, totaling 17 billion US dollars in 2015.

Impaired Fasting Glucose

• New intermediate designation.
• Fasting glucose increased (6.1-6.9 mmol/L, or 110-124 mg/dL).
• No clinical signs, but increased risk of diabetes and CVD.

Impaired Glucose Tolerance

• More established intermediate designation.
• 20-25% of those with IGT develop advanced stages of diabetes mellitus.
• No clinical signs but increased risk of CVD. Hyperglycemia (7.8-11.0 mmol/L post-feeding, or 140-198 mg/dL).

Overview of Type 1 Diabetes Mellitus

• About 10-15% of diabetes cases.
• Starts typically before 20 years of age.
• Characterized by absolute insulin deficiency.
• Peak incidence at 5 years and puberty.

Type 1 Diabetes Mellitus Etiology

• Strong genetic component.
• Immune system susceptibility (e.g., autoimmune disease).
• Transmissible agents hypothesis ("Hygiene" and "Overload" hypotheses).
• Relationship to type 2 DM.

Type 1 Diabetes Mellitus: Antibodies

• 85-90% of type 1 diabetics have circulating antibodies against beta cells, insulin, or other beta cell antigens.
• These antibodies attach to insulin and beta cells, leading to their destruction.

Natural History of Type 1 Diabetes Mellitus

• Genetic 'prodrome'.
• Environmental-genetic interaction affects autoantibody development (peaks around 2 years of age), influencing later-life diabetes development.
• Once 80-90% of beta cells are lost, minimal insulin is secreted.

Natural History of Type 1 Diabetes Mellitus (Graph)

• A graph shows the relationship between insulin secretory capacity, age, and the development of type 1 diabetes linked to a trigger (possibly enterovirus infection) and genetic predisposition, with a period of asymptomatic progression.

Acute Effects of Insulin Deficiency

• Hyperglycemia High amounts of glucose in the bloodstream.
• Glucosuria: Glucose spills into urine.
• Polyuria: Increased urine volume due to osmotic diuresis.
• Polydipsia: Excessive thirst.
• Dehydration.
• Polyphagia: Increased hunger and food intake.

Other Acute Symptoms

• Fatigue.
• Weight loss despite increased appetite, due to body wasting from protein and fat breakdown for energy.

When Lack of Glucose is Severe

• Lipids are used for fuel, causing ketone production.
• Ketosis: Ketone accumulation in the blood.
• Ketoacidosis: Uncontrolled ketosis resulting in lowered blood pH.
• Diabetic ketoacidosis (DKA): Severe form of ketoacidosis.

Diabetes Keto-Acidosis

• Primarily occurs in type 1 diabetes due to complete insulin deficiency.
• Hyperpnea: Exaggerated deep, rapid, or labored breathing.
• Stupor: State of near-unconsciousness or insensibility.
• Coma: Loss of consciousness and responsiveness.

Can We Prevent/Treat Type 1 Diabetes?

• Current research focuses on prevention and treatment strategies for type 1 diabetes.

Overview of Type 2 Diabetes Mellitus

• 85-90% of diabetes cases.
• Disease of aging and obesity.
• Insulin resistance initially, then progressing to insulin insufficiency (relative, rather than absolute, deficiency).

Type 2 Diabetes Mellitus Etiology

• Genetic predisposition.
• Obesity (60-80% of type 2 cases with BMI > 30).
• Insulin resistance (common).
• Metabolic syndrome preceding type 2 development.
• Diet and related factors (saturated fat, complex food matrix, glycemic load/index.

Natural History of Type 2 Diabetes Mellitus

• Genetic Predisposition.
• Large Environmental Influence.
• Cell receptors are resistant to insulin.
• Hyperinsulinemia results.
• Pancreatic decline with loss of insulin secretion.
• Loss of insulin secretion relative to current needs is evident.

Natural History of Type 2 Diabetes (Flow Chart)

• A graphical representation shows the progression from insulin resistance to hyperinsulinemia and ultimately type 2 diabetes, encompassing prediabetes stages.

Insulin Sensitivity vs. Resistance (Two Figures)

• A comparison showing the differing insulin requirements for maintaining normal glucose levels between an insulin-sensitive (e.g., endurance athlete) and an insulin-resistant individual (e.g., person with excess body fat).

Short-Term Effects of Diabetes

• Classic symptoms (e.g., increased urination, thirst, hunger) may or may not be present.
• Mild fatigue.
• Mild or no weight loss.
• Mild ketosis, no ketoacidosis.

Etiological Classification of Diabetes Mellitus (Table)

• Type 1 is primarily due to pancreatic beta cell destruction, typically leading to ketoacidosis.
• Type 2 ranges from predominant insulin resistance to predominant secretory defect with possible ketoacidosis.
• Gestational diabetes involves glucose intolerance first recognized during pregnancy.
• Other types include genetically defined conditions.

Hypoglycemia

• Low blood glucose levels.
• Two types:
  • Fasting/spontaneous (e.g., tumors, liver disease, alcoholism; lack of insulin or counter-regulatory hormones).
  • Reactive/functional (e.g., post-prandial, administering too much insulin; occurs in type 2 prior to diagnosis; eating too little food).

Hypoglycemia Symptoms

• Dizziness, weakness, tremors, heart palpitations, sweating, hunger, nervousness.
• Headaches, confusion, visual disturbances, motor weakness, palsy, ataxia, personality changes.
• Can progress to insulin shock, coma, or death.

Hypoglycemia in Diabetes Mellitus

• Strict glycemic control may increase likelihood of hypoglycemia.
• Episodic hypoglycemia is difficult to control (brittle type 1 DM).
• Can result in brain damage.

Test your knowledge of diabetes mellitus with these questions. These questions cover insulin-mediated glucose uptake, diabetes classifications (IFG/IGT), glucose transporters (GLUT4, GLUT5), healthcare costs, and Type 1 Diabetes etiology.