Introduction to Carbohydrates

Introduction to Carbohydrates

• Organisms oxidize complex organic compounds for energy
• The three main sources of energy are lipids (fats), amino acids (proteins), and carbohydrates (sugars, starches)
• Carbohydrates are a major food and energy source
• Carbohydrates are the primary energy source for the brain, erythrocytes, and retinal cells
• Carbohydrates are primarily stored as glycogen in the liver and muscles

Carbohydrate Storage and Synthesis

• Carbohydrates are the main energy producers in the body
• Red blood cells and the brain utilize glucose for energy metabolism
• The brain and RBCs use 80% of the 200g of glucose consumed daily
• Only 10g of glucose is available in plasma, requiring storage
• The Pentose Phosphate Pathway generates ribose for nucleic acid synthesis
• Glycosylation involves carbohydrates modifying proteins, influencing their function

Carbohydrate Breakdown (Digestion)

• In the mouth, salivary amylase breaks down starch into dextrins/maltose
• In the stomach and intestines, pancreatic amylase continues digestion
• Absorption of monosaccharides occurs in the intestinal mucosa and are delivered to the liver
• The ultimate goal of carbohydrate metabolism is to convert glucose into CO₂ and water, producing ATP
• Possible channels for glucose conversion include being converted to liver glycogen for storage, metabolized to CO₂ and H₂O, converted to keto-acids/amino acids/proteins, or converted to fats and stored in adipose tissue
• Other pathways include glycogenesis where glucose is stored as glycogen
• Glycolysis which converts glucose to ATP
• Gluconeogenesis forming glucose from non-carbohydrate sources
• Lipogenesis converts excess glucose into fatty acids
• Lipolysis decomposes fat
• The sum of all processes determines blood glucose level

Types of Carbohydrates

• Important dietary hexoses (six-carbon sugars) include: D-glucose which is most abundant in blood, D-galactose and D-fructose
• Glucose is the primary circulating sugar in the bloodstream
• Disaccharides include lactose, which is made up of glucose and galactose
• Sucrose is also a disaccharide, made up fructose and glucose

Regulation of Plasma Glucose

• Glycogenolysis: The liver releases glucose into the plasma for a quick response
• Gluconeogenesis and lipolysis occur if plasma glucose is increased
• Glycogenesis is the storage of glucose into glycogen by the liver
• Lipogenesis is the formation of lipids
• The liver converts glucose to glycogen and vice versa
• Muscles store glycogen for energy
• The pancreas produces insulin (β-cells) and glucagon (α-cells)
• The pituitary gland produces growth hormone
• The adrenal glands produce epinephrine and cortisol
• The thyroid produces thyroxine

Hormonal Regulation of Glucose Levels

• Insulin lowers blood glucose
• Glucagon, epinephrine, cortisol, growth hormone, thyroxine, and ACTH increase blood glucose
• Gamma cells (1-8%) secrete somatostatin

Key Hormones and Their Actions

Insulin

• Insulin is synthesized and secreted by beta cells in the Islets of Langerhans in the pancreas
• Is a peptide hormone composed of 51 amino acids
• Synthesized as proinsulin, it is cleaved into insulin and C-peptide
• Insulin binds to insulin receptors on target cells like the liver, muscle and adipose tissue, activating intracellular signaling pathways like the PI3K/Akt pathway
• Insulin stimulates glucose uptake by increasing the translocation of GLUT4 glucose transporters to the cell membrane in muscle and adipose tissue
• Promotes glycogenesis by converting glucose to glycogen for storage in the liver and muscles
• Inhibits glycogenolysis by preventing the breakdown of glycogen into glucose
• Promotes lipogenesis by converting glucose to fatty acids and triglycerides
• Inhibits gluconeogenesis by reducing the production of glucose from non-carbohydrate sources
• Decreases blood glucose levels by promoting glucose uptake and storage
• Increases glycogen, lipid, and protein synthesis
• Suppresses ketogenesis preventing the breakdown of fats into ketone bodies
• Insulin secretion is primarily controlled by blood glucose levels
• High blood glucose stimulates insulin release
• Some amino acids and gastrointestinal hormones stimulate insulin secretion
• Somatostatin inhibits insulin secretion

Glucagon

• Glucagon is synthesized and secreted by alpha cells in the Islets of Langerhans in the pancreas
• It is a 29-amino acid peptide hormone
• Binds to glucagon receptors on liver cells, activating adenylate cyclase, increasing cAMP levels, and activating protein kinase A (PKA)
• Stimulates glycogenolysis by breaking down glycogen into glucose in the liver
• Promotes gluconeogenesis, converting amino acids, lactate, and glycerol into glucose in the liver
• Inhibits glycogenesis by preventing the storage of glucose as glycogen
• Promotes lipolysis, breaking down fats into fatty acids and glycerol in adipose tissue
• Increases blood glucose levels by releasing glucose from the liver
• Provides energy during fasting or stress, mobilizing stored glycogen and fats
• Glucagon secretion is primarily controlled by low blood glucose levels
• High amino acid levels also stimulate glucagon release
• Somatostatin inhibits glucagon secretion

Epinephrine (Adrenaline)

• Secreted by the adrenal medulla in response to stress, exercise, or low blood glucose
• Binds to beta-adrenergic receptors, activating adenylate cyclase, increasing cAMP levels, and activating protein kinase A (PKA)
• Stimulates glycogenolysis by breaking down glycogen into glucose in the liver and muscles
• Inhibits insulin secretion, reducing glucose uptake by cells
• Promotes lipolysis, breaking down fats into fatty acids and glycerol in adipose tissue
• Increases blood glucose levels rapidly during stress or exercise
• Provides immediate energy by mobilizing glucose and fatty acids
• Epinephrine secretion is controlled by the sympathetic nervous system in response to stress, exercise, or low blood glucose

Cortisol

• Secreted by the adrenal cortex in response to stress
• It is a steroid hormone that acts on the liver, muscles, and adipose tissue
• increases the expression of enzymes involved in gluconeogenesis and lipolysis
• Promotes gluconeogenesis, converting amino acids, lactate, and glycerol into glucose in the liver
• Inhibits glucose uptake by muscle and adipose tissue
• Promotes lipolysis, breaking down fats into fatty acids and glycerol in adipose tissue
• Cortisol secretion is controlled by the hypothalamic-pituitary-adrenal (HPA) axis
• Adrenocorticotropic hormone (ACTH) stimulates cortisol release from the pituitary
• Increases blood glucose levels during prolonged stress or fasting
• Provides energy by mobilizing stored fuels (proteins and fats)

Growth Hormone (GH)

• Secreted by the anterior pituitary gland
• Acts on the liver, muscles, and adipose tissue
• Stimulates the production of insulin-like growth factor 1 (IGF-1), which mediates many of its effects
• Inhibits glucose uptake by muscle and adipose tissue
• Promotes lipolysis, breaking down fats into fatty acids and glycerol in adipose tissue
• Stimulates gluconeogenesis, increasing glucose production in the liver
• Increases blood glucose levels by reducing glucose uptake and promoting gluconeogenesis
• Provides energy during fasting or stress
• GH secretion is controlled by growth hormone-releasing hormone (GHRH) and somatostatin from the hypothalamus

Thyroxine (T4)

• Secreted by the thyroid gland
• Increases the basal metabolic rate (BMR) and enhances the effects of related hormones
• Promotes glycogenolysis, breaking down glycogen into glucose in the liver
• Increases glucose absorption from the intestines
• Enhances gluconeogenesis by increasing glucose production in the liver
• Increases blood glucose levels by promoting glycogenolysis and gluconeogenesis
• Increases energy by increasing metabolic activity
• Is controlled by thyroid-stimulating hormone (TSH) from the pituitary gland

Somatostatin

• Secreted by delta cells of the Islets of Langerhans
• It is a peptide hormone that inhibits insulin and glucagon secretion
• Regulates the balance between glucose storage and mobilization
• Slows down digestion and reduces absorption of glucose from the intestines
• Modulates blood glucose levels by regulating insulin and glucagon secretion
• Prevents rapid fluctuations in blood glucose
• Somatostatin secretion is controlled by high blood glucose levels and certain amino acids

Principles of Clinical Tests

Glucose Measurement

• Used to measure blood glucose levels for diagnosing and managing diabetes and other metabolic disorders
• Whole blood contains both plasma and cellular components; glucose levels are lower than in plasma
• Plasma/serum: preferred for measurement because provides accurate and consistent results
• Plasma glucose levels are 10-15% higher than whole blood glucose levels

Specimen Collection

• Sodium Fluoride Tubes: Used to inhibit glycolysis in blood samples, preserving glucose levels for accurate measurement
• Plasma should be separated from cells within one hour of collection to prevent glucose utilization by red blood cells

Methods

• Glucose Oxidase Method: Glucose is oxidized by the enzyme glucose oxidase, producing gluconic acid and hydrogen peroxide (H₂O₂)
• H₂O₂ reacts with a chromogen in the presence of peroxidase, producing a colored product that is measured spectrophotometrically
• Glucose + O₂ + H₂O → Gluconic acid + H₂O₂ H₂O₂ + Chromogen → Oxidized chromogen + H₂O
• Specific for glucose, widely used in automated analyzers
• Susceptible to interference from substances like ascorbic acid, bilirubin, and uric acid
• Hexokinase Method: Glucose is phosphorylated by hexokinase in the presence of ATP, forming glucose-6-phosphate (G6P)
• G6P is then oxidized by glucose-6-phosphate dehydrogenase (G6PD), producing NADPH, which is measured spectrophotometrically
• Glucose + ATP → Glucose-6-phosphate + ADP Glucose-6-phosphate + NADP⁺ → 6-Phosphogluconate + NADPH + H⁺
• Highly accurate and specific, it is considered the reference method
• More time-consuming and expensive than the glucose oxidase method

Fasting Blood Sugar (FBS)

• Measures blood glucose levels after an overnight fast (8-12 hours)
• Normal Range: 74-106 mg/dL (4.1-5.9 mmol/L)
• Impaired Fasting Glucose (IFG): 110-125 mg/dL (6.1-6.9 mmol/L)
• Diabetes Mellitus: Fasting glucose ≥ 126 mg/dL (7.0 mmol/L) on two separate occasions
• Patient fasts for 8-12 hours
• Blood is drawn, and glucose levels are measured using the glucose oxidase or hexokinase method

Oral Glucose Tolerance Test (OGTT)

• Assesses the body's ability to metabolize glucose after a glucose load
• Used to diagnose diabetes mellitus, impaired glucose tolerance (IGT), and gestational diabetes.
• Normal Response: Blood glucose returns to fasting levels within 2 hours
• Diabetes Mellitus: 2-hour glucose ≥ 200 mg/dL (11.1 mmol/L)
• Impaired Glucose Tolerance (IGT): 2-hour glucose 140-199 mg/dL (7.8-11.0 mmol/L)
• Patient fasts overnight
• Fasting blood glucose is measured
• Patient drinks a 75g glucose solution
• Blood glucose is measured at 1-hour and 2-hour intervals
• Normal: Fasting < 100 mg/dL, 2-hour < 140 mg/dL
• Prediabetes: Fasting 100-125 mg/dL, 2-hour 140-199 mg/dL
• Diabetes: Fasting ≥ 126 mg/dL, 2-hour ≥ 200 mg/dL

Glycated Hemoglobin (HbA1c)

• Measures long-term glucose control over the past 2-3 months
• Glucose non-enzymatically attaches to the valine residue of the hemoglobin beta chain, forming HbA1c
• The amount of HbA1c is proportional to the average blood glucose levels over the lifespan of red blood cells (120 days)
• Normal Range: 4.0-6.0%
• Prediabetes: 5.7-6.4%
• Diabetes Mellitus: ≥ 6.5%

Methods

• Ion-Exchange Chromatography: Separates HbA1c from other hemoglobin variants based on charge differences
• Immunoassays use antibodies specific to the glycated portion of hemoglobin
• Affinity Chromatography uses boronic acid to bind glycated hemoglobin
• Reflects long-term glucose control and is not affected by short-term fluctuations in blood glucose
• Is affected by conditions that alter red blood cell turnover (e.g., anemia, hemoglobinopathies)

Urine Glucose Tests

• Detects glucose in the urine, which occurs when blood glucose levels exceed the renal threshold (160-180 mg/dL)

Methods

• Copper Reduction (Benedict's Test): Glucose reduces copper ions (Cu²⁺) to cuprous oxide (Cu⁺), producing a color change from blue to green, yellow, orange, or red
• Not specific for glucose; detects all reducing sugars (e.g., galactose, fructose)
• Glucose Oxidase Dipstick: Uses glucose oxidase to produce H₂O₂, which reacts with a chromogen to produce a color change
• Specific for glucose and more accurate than Benedict's test
• Glucosuria indicates hyperglycemia (e.g., diabetes mellitus)

Ketone Tests

• Detects ketone bodies (acetoacetate, acetone, β-hydroxybutyrate) in blood or urine, produced during fat metabolism
• Ketosis is elevated ketone levels, often seen in diabetic ketoacidosis (DKA), starvation, or prolonged fasting

Methods

• Nitroprusside Test: Detects acetoacetate and acetone in urine or serum, reacting with nitroprusside to produce a purple color

• But does not detect β-hydroxybutyrate, the predominant ketone in DKA.

• Enzymatic Method: Measures β-hydroxybutyrate using β-hydroxybutyrate dehydrogenase (β-HBD), producing NADH, which is measured spectrophotometrically

• Specific for β-hydroxybutyrate, the most clinically relevant ketone in DKA

Microalbuminuria Test

• Detects small amounts of albumin in the urine, an early indicator of diabetic nephropathy
• Normal: < 30 mg albumin/24 hours or < 30 µg albumin/mg creatinine
• Microalbuminuria: 30-300 mg albumin/24 hours or 30-300 µg albumin/mg creatinine Macroalbuminuria: > 300 mg albumin/24 hours or > 300 µg albumin/mg creatinine.
• Immunoassays use antibodies specific to albumin for precise measurement
• Dipstick Tests are semi-quantitative methods for screening

Self-Monitoring of Blood Glucose (SMBG)

• Allows patients to monitor their blood glucose levels at home
• Uses glucose oxidase or hexokinase immobilized on test strips
• Glucose in a drop of capillary blood reacts with the enzyme, producing an electrical current or color change measured by a glucose meter
• Provides real-time glucose levels
• Helps patients adjust insulin doses and dietary intake

Carbohydrate Diseases and Pathophysiology

• Hyperglycemia is elevated blood glucose levels, typically above the normal range (fasting glucose > 126 mg/dL or random glucose > 200 mg/dL)

Causes

• Diabetes Mellitus is characterized for type 1, autoimmune destruction of beta cells, leading to absolute insulin deficiency
• Type 2 Diabetes is characterized for insulin resistance, other causes include endocrine disorders (Cushing's, acromegaly, pheochromocytoma), drug-induced (corticosteroids, thiazide diuretics), and stress-induced (surgery, trauma, infection)

Pathophysiology

• Insulin Deficiency includes decreased glucose uptake by muscle and adipose tissue
• Increased glycogenolysis and gluconeogenesis in the liver
• Increased lipolysis, leading to elevated free fatty acids and ketone bodies
• Insulin Resistance includes reduced sensitivity of target tissues to insulin, and compensatory hyperinsulinemia

Clinical Manifestations

• Acute Symptoms include polyuria (excessive urination), polydipsia (excessive thirst), polyphagia (excessive hunger), weight loss, fatigue, and blurred vision
• Chronic Complications include microvascular as diabetic retinopathy, nephropathy, neuropathy Macrovascular as coronary artery disease, stroke, and peripheral vascular disease

Diagnosis

• Fasting Plasma Glucose (FPG) ≥ 126 mg/dL
• Oral Glucose Tolerance Test (OGTT) 2-hour glucose ≥ 200 mg/dL
• HbA1c > 6.5%
• Random Plasma Glucose ≥ 200 mg/dL with symptoms

Hypoglycemia

• Low blood glucose levels, typically < 50 mg/dL (2.8 mmol/L)

Causes

• Reactive Hypoglycemia when occurs after meals, often due to excessive insulin secretion, and common after gastrointestinal surgery
• Spontaneous Hypoglycemia when Occurs during fasting, often due to underlying disease, and include insulinoma, liver disease, adrenal insufficiency
• Drug-Induced like the use of insulin or sulfonylurea overdose, as well as alcohol ingestion

Pathophysiology

• Excess Insulin promotes glucose uptake by tissues, leading to low blood glucose with inhibited glycogenolysis and gluconeogenesis
• Counterregulatory Hormone Deficiency has lack of glucagon, cortisol, or growth hormone impairs glucose production
• Neurogenic Symptoms (due to adrenaline release): Sweating, trembling, palpitations, hunger
• Neuroglycopenic Symptoms (due to brain glucose deprivation): Confusion, drowsiness, seizures, coma

Diagnosis

• Plasma Glucose: < 50 mg/dL
• Insulin Levels: Elevated in insulinoma
• C-Peptide: Differentiates endogenous vs. exogenous insulin
• Insulin Tolerance Test: Assesses insulin sensitivity

Inborn Errors of Carbohydrate Metabolism

• These are genetic disorders caused by deficiencies in enzymes involved in carbohydrate metabolism
• Often present in infancy or childhood, can lead to metabolic disturbances

Glycogen Storage Diseases (GSD)

• A group of disorders caused by defects in glycogen metabolism, leading to abnormal glycogen accumulation in tissues

Types

• Type I (Von Gierke Disease) which leads to hypoglycemia and lactic acidosis
• Clinical manifestations include hypoglycemia, growth retardation, hepatomegaly, and hyperlipidemia
• Type II (Pompe Disease) which leads to muscle weakness and cardiomyopathy

Types

• Deficiency: Lysosomal alpha-glucosidase.
• Deficiency: Glucose-6-phosphatase
• Enzyme Assays: Measure enzyme activity in liver or muscle tissue
• Genetic Testing: Identifies specific mutations

Galactosemia

• A disorder of galactose metabolism due to a deficiency of galactose-1-phosphate uridyltransferase (GALT)

• Accumulation of galactose-1-phosphate, leading to liver damage, cataracts, and intellectual disability

• Clinical manifestations include jaundice, hepatomegaly, failure to thrive, and cataracts

• Urine Galactose: Elevated galactose in urine with Elevated galactose in urine

• Genetic Testing: Identifies GALT gene mutations

Hereditary Fructose Intolerance

• A disorder of fructose metabolism due to deficiency of aldolase B
• Accumulation of fructose-1-phosphate, leading to inhibition of glycolysis and gluconeogenesis
• Clinical manifestations include vomiting, hypoglycemia, hepatomegaly, failure to thrive
• Fructose Tolerance Test: No increase in blood glucose after fructose administration
• Enzyme Assays: Measure aldolase B activity in liver tissue

Mucopolysaccharidoses (MPS)

• A group of lysosomal storage disorders caused by deficiencies in enzymes that break down glycosaminoglycans (GAGs)
• Accumulation of GAGs in tissues, leading to progressive damage to bones, joints, and organs
• Features include coarse facial features, skeletal abnormalities, developmental delay, and organomegaly
• Urine: Elevated GAGs in urine and measure specific lysosomal enzyme activity as well as identify specific gene mutations

Gestational Diabetes Mellitus (GDM)

• Glucose intolerance that develops during pregnancy
• Hormonal changes include an increase in human placental lactogen that can lead to insulin resistance
• Inadequate insulin secretion results in hyperglycemia
• Often asymptomatic, but can lead to complications such as macrosomia (large baby), neonatal hypoglycemia, and preeclampsia

Diagnosis

• One-Step OGTT: Fasting: ≥ 92 mg/dL, 1-hour: ≥ 180 mg/dL, 2-hour: ≥ 153 mg/dL
• Initial 50g glucose challenge test, followed by a 100g OGTT if positive

Hyperglycemia Manifestations and Clinical Correlations

Acute Manifestations

• Polyuria (Excessive Urination): High blood glucose levels exceed the renal threshold (160-180 mg/dL), leading to glucose spilling into the urine (glucosuria), and leading to increased urine
• Clinical Correlation: Patients experience frequent urination, leads to dehydration and electrolyte imbalances
• Polydipsia caused by dehydration from polyuria triggers the thirst mechanism, leading to increased fluid intake
• Clinical Correlation: Patients report intense thirst and may consume fluids
• Polyphagia: Despite high blood glucose levels, cells are still unable to take up glucose or resist insulin, leading to the starvation of required cells and increased hunger to compensate
• Clinical Correlation: Patients may experience constant hunger and increased food intake, yet still lose weight
• Weight Loss: Occurs when the body cant absorb glucose and breaks down fats for energy, leading to loss of weight
• Clinical Correlation: Causes symptoms, especially in type 1 diabetes

Chronic Manifestations

• Inability to utilize glucose for its energy for cells, leading to fatigue and weakness
• Clinical Correlation: Patients often report feeling tired and lethargic

Blurred Vision

• High glucose levels cause osmotic changes in the lens of the eye, leading to temporary vision changes
• Clinical Correlation: Patients that experience normalization of blood glucose levels

Microvascular Complications

• High glucose leads to long-term complications due to glycation of proteins, oxidative stress, and vascular damage
• Chronic hyperglycemia causes damage to the small blood vessels in the retina, leading to leakage, hemorrhage, and eventually blindness Patients may experience vision loss in many cases of untreated blood glucose
• Chronic hyperglycemia damages the glomerular capillaries in the kidneys, leading to proteinuria, reduced glomerular filtration rate

Macrovascular Complications

• High glucose accelerates atherosclerosis, increased risk of myocardial infarction
• Patients may experience chest pain in some, shortness of breath, or sudden cardiac death.

Cerebrovascular Disease

• Atherosclerosis increases the risk of stroke

Peripheral Artery Disease

• Atherosclerosis, leads to reduces blood flow to limbs and pain

Diabetic Ketoacidosis (DKA)

• The body cant handle insulin, body breaks down fat for energy, leads to a high production of ketone bodies , leading to metabolic acidosis

Clinical Manifestations

• Symptoms include Blood glucose levels > 250 mg/dL, elevated ketone levels in blood and urine as well as acidiosis

Hyperosmolar Hyperglycemic State (HHS)

• Severe hyperglycemia , leads to extreme dehydration and hyperosmolarity Clinical Manifestations:
• Fasting leads to dehydration. Blood levels > 600mg/dL , leads into seizures and coma

Glycation of Proteins and Advanced Glycation End Products (AGEs)

Leads to diabetic complications

Laboratory Findings in Hyperglycemia

• Leads to a low Urine Glucose

Diabetes in the urine.

Leaks to high Electrolyte inbalance , as well as low Acidosis in blood.

Types of Diabetes Mellitus

• Type 1 Diabetes Mellitus (T1DM): Autoimmune destruction , is caused by a autoimmune beta of T1DM. Is the leading cause of Insuline deficiency to genetic predisposition related to it

Mangagment

Lifelong insuline related replacement will be required. Requires daily exercise to maintain function , as well as to maintain insulin levels in the body.

Types of Diabetes

• Metabolic - Genetics like defects during gestation A maternal and genetics predisposition, leads genetics defects.
• Enocrine, Pancreatic and drug intake and all leads to insulin resistance

Insulin resistance (IR)

Deffinition

• Leads to the condition where the body becomes low receptive to insulin

Pahtophysiology

• Leads to obesity

Types of diabetes

• Contributes to the intake of aging and lifestyle. Doesnt have known clinical testing to confirm or prove