Physiology

Physiologic States in Carbohydrate Metabolism

Normal State:
- Normoglycemia:
  - Maintained within a tight range by hormones like insulin and glucagon
  - Provides a constant energy supply, especially for the brain
Abnormal States:
- Hyperglycemia: High blood glucose, often due to diabetes (lack of insulin or insulin resistance). Can cause acute (DKA, HHS) and chronic (retinopathy, nephropathy, neuropathy, cardiovascular disease) complications
- Hypoglycemia: Low blood glucose, due to excess insulin, liver/kidney disease, or other factors. Can cause neurological symptoms, seizures, coma, and brain damage
- Insulin Resistance: Cells don’t respond to insulin, leading to high insulin levels and increased risk of type 2 diabetes
- Genetic Disorders:
  - Glycogen Storage Diseases (GSDs): Enzyme deficiencies in glycogen metabolism leading to glycogen accumulation and hypoglycemia
  - Galactosemia: Enzyme deficiencies in galactose metabolism leading to accumulation of galactose and organ damage
  - Fructose Intolerance: Enzyme deficiencies in fructose metabolism leading to accumulation of fructose-1-phosphate and organ damage
  - Pentosuria: Benign condition, deficiency in L-xylulose reductase which is required for the metabolism of L-xylulose

Normal Sate

Normoglycemia

Definition: Normal blood glucose levels
Fasting: 70-99 mg/dL (3.9-5.5 mmol/L)
Postprandial (2 hours after eating): < 140 mg/dL (7.8 mmol/L)
Maintenance: A complex interplay of hormones (insulin, glucagon, epinephrine, cortisol), liver function, and cellular glucose uptake maintains normoglycemia
Importance: Provides a constant supply of glucose for energy, especially for the brain, which relies heavily on glucose

Abnormal States

Hyperglycemia

Definition: Abnormally high blood glucose levels
Causes:
- Diabetes Mellitus (Type 1 and Type 2):
  - Type 1: Autoimmune destruction of pancreatic beta cells, leading to absolute insulin deficiency
  - Type 2: Insulin resistance (cells don’t respond properly to insulin) and relative insulin deficiency (pancreas can’t produce enough insulin to overcome resistance)
- Gestational Diabetes: Insulin resistance during pregnancy
- Other Endocrine Disorders: Cushing’s syndrome (excess cortisol), acromegaly (excess growth hormone), hyperthyroidism
- Pancreatic Diseases: Pancreatitis, cystic fibrosis (affecting pancreatic function)
- Medications: Corticosteroids, some diuretics
- Stress/Illness: Stress hormones (cortisol, epinephrine) can raise blood glucose
Symptoms:
- Classic Symptoms: Polyuria (frequent urination), polydipsia (excessive thirst), polyphagia (increased hunger), unexplained weight loss
- Other Symptoms: Fatigue, blurred vision, slow-healing sores, frequent infections
Complications:
- Acute:
  - Diabetic Ketoacidosis (DKA): Primarily in Type 1 diabetes. Insulin deficiency leads to increased lipolysis, ketone body production, and metabolic acidosis
  - Hyperosmolar Hyperglycemic State (HHS): Primarily in Type 2 diabetes. Severe hyperglycemia leads to dehydration and hyperosmolarity, but less ketosis than DKA
- Chronic:
  - Microvascular Complications:
    - Retinopathy: Damage to blood vessels in the retina, leading to vision loss
    - Nephropathy: Damage to blood vessels in the kidneys, leading to kidney failure
    - Neuropathy: Damage to nerves, leading to pain, numbness, and loss of sensation
  - Macrovascular Complications:
    - Cardiovascular Disease: Increased risk of heart attacks and strokes
    - Peripheral Artery Disease: Reduced blood flow to the limbs, increasing the risk of amputation

Hypoglycemia

Definition: Abnormally low blood glucose levels
Threshold: Generally defined as < 70 mg/dL (3.9 mmol/L), but symptoms can vary
Causes:
- Excess Insulin:
  - Insulin Overdose: In diabetic patients
  - Insulinoma: Insulin-secreting tumor of the pancreas
- Reactive Hypoglycemia: Exaggerated insulin release after a meal
- Fasting Hypoglycemia:
  - Liver Disease: Impaired gluconeogenesis and glycogen storage
  - Kidney Disease: Impaired gluconeogenesis
  - Hormone Deficiencies: Adrenal insufficiency (low cortisol), growth hormone deficiency
  - Certain Tumors: Non-islet cell tumors can secrete insulin-like substances
- Alcohol Consumption: Inhibits gluconeogenesis
- Intense Exercise: Can deplete glycogen stores
Symptoms:
- Adrenergic Symptoms (Early): Sweating, shakiness, anxiety, palpitations, hunger
- Neuroglycopenic Symptoms (Later): Confusion, dizziness, blurred vision, difficulty speaking, seizures, loss of consciousness
Complications:
- Brain Damage: Prolonged or severe hypoglycemia can lead to irreversible brain damage
- Seizures
- Coma
- Death

Insulin Resistance

Definition: Cells don’t respond normally to insulin, requiring higher levels of insulin to achieve the same effect on glucose uptake
Causes:
- Obesity: Excess adipose tissue releases factors that interfere with insulin signaling
- Genetics: Some individuals are genetically predisposed to insulin resistance
- Physical Inactivity
- Inflammation
- Aging
Consequences:
- Hyperinsulinemia: Elevated insulin levels as the pancreas tries to compensate for resistance
- Prediabetes: Impaired fasting glucose or impaired glucose tolerance
- Type 2 Diabetes: Eventually, the pancreas may not be able to produce enough insulin to overcome resistance
- Metabolic Syndrome: A cluster of conditions including insulin resistance, abdominal obesity, high blood pressure, high triglycerides, and low HDL cholesterol, increasing the risk of cardiovascular disease and type 2 diabetes

Genetic Defects in Glycogen Metabolism

Glycogen Storage Diseases (GSDs)

Definition: A group of inherited disorders caused by deficiencies in enzymes involved in glycogen synthesis or breakdown
Types:
- Von Gierke Disease (Type Ia): Deficiency in glucose-6-phosphatase. Causes severe hypoglycemia, hepatomegaly, lactic acidosis, hyperlipidemia
- Pompe Disease (Type II): Deficiency in lysosomal α-glucosidase (acid maltase). Causes glycogen accumulation in lysosomes, affecting various organs, especially the heart and muscles
- Cori Disease (Type III): Deficiency in debranching enzyme. Causes milder hypoglycemia and hepatomegaly than Von Gierke disease
- McArdle Disease (Type V): Deficiency in muscle glycogen phosphorylase. Causes muscle cramps and fatigue during exercise
Symptoms: Depend on the specific enzyme deficiency and the tissues affected

Galactosemia

Definition: An inherited disorder caused by deficiency in enzymes needed to convert galactose to glucose
Cause: Most commonly a deficiency in galactose-1-phosphate uridyltransferase (GALT)
Symptoms:
- Early: Feeding difficulties, vomiting, diarrhea, lethargy, jaundice, hepatomegaly
- Later: Cataracts, intellectual disability, liver damage, kidney damage
Treatment: Strict galactose-free diet

Fructose Intolerance

Definition: Impaired Fructose Metabolism
- Hereditary Fructose Intolerance (HFI): Deficiency in aldolase B. Causes accumulation of fructose-1-phosphate, inhibiting gluconeogenesis and glycogenolysis
- Fructose Malabsorption: Impaired absorption of fructose in the small intestine
Symptoms:
- HFI: Vomiting, abdominal pain, hypoglycemia, liver damage, kidney damage
- Fructose Malabsorption: Bloating, gas, diarrhea
Treatment:
- HFI: Strict fructose-free and sucrose-free diet
- Fructose Malabsorption: Limiting fructose intake

Pentosuria

Definition: Excess excretion of pentoses in the urine
- Essential Pentosuria: Deficiency in L-xylulose reductase which is required for the metabolism of L-xylulose, a pentose sugar
Symptoms:
- Essential Pentosuria: Benign condition where L-xylulose accumulates and is excreted in urine, thus there are no clinical symptoms

Key Terms

Normoglycemia: Normal blood glucose levels
Hyperglycemia: Elevated blood glucose levels
Hypoglycemia: Reduced blood glucose levels
Insulin Resistance: Impaired cellular response to insulin
Glycogen Storage Diseases (GSDs): Genetic defects in glycogen metabolism
Galactosemia: Impaired galactose metabolism
Fructose Intolerance: Impaired fructose metabolism
Pentosuria: Excess excretion of pentoses in the urine

Metabolic

Properties