Blood Glucose Regulation

• Blood glucose levels are tightly regulated to ensure a continuous glucose supply to the brain, which relies heavily on it.
• Red blood cells and the kidney medulla also require glucose for fuel.

Factors Maintaining Blood Glucose

• Plasma glucose at any moment balances glucose entering and exiting extracellular fluid.
• Hormones, hyperglycemic and hypoglycemic help maintain this balance.
• Glucose enters the blood through intestinal absorption, glycogen breakdown (glycogenolysis), the production of glucose from non-carbohydrate sources (gluconeogenesis), and hyperglycemic hormones.
• Glucose exits the blood via tissue utilization for energy, glycogen creation (glycogen synthesis), conversion into fat (lipogenesis), and the hypoglycemic hormone (insulin).

Post-Prandial Regulation

• After meals, glucose absorbed from the intestine raises blood glucose, stimulating insulin secretion by pancreatic beta cells.
• Insulin then facilitates glucose uptake by most tissues, with the exception of the brain.

Regulation in Fasting State

• Normally, blood glucose falls to near-fasting levels 2 to 2.5 hours post-meal, prevented from dropping further by processes contributing glucose to the blood.
• For 3 hours, hepatic glycogenolysis sustains blood sugar levels, gluconeogenesis taking over.
• The liver is the main organ maintaining blood glucose.
• Hormones, such as glucagon, epinephrine, glucocorticoids, growth hormone, ACTH, and thyroxine, termed anti-insulin or hyperglycemic hormones, prevent blood glucose from falling too low.

Determination of Glucose in Body Fluids

• Glucose estimation commonly occurs in clinical labs.
• Blood is collected using potassium oxalate (anticoagulant) and sodium fluoride (glycolysis inhibitor).
• Fluoride inhibits enolase, halting glycolysis.
• Without fluoride, cells utilize glucose, giving falsely low readings.
• Capillary blood from fingertips can also be used.

Effects of Hormones on Glucose Level in Blood

• Insulin (hypoglycemic hormone) lowers blood glucose, favors glycogen synthesis, promotes glycolysis, and inhibits gluconeogenesis. Glucagon (hyperglycemic hormone) increases blood glucose, promotes glycogenolysis, enhances gluconeogenesis, depresses glycogen synthesis, and inhibits glycolysis.
• Cortisol (hyperglycemic hormone) raises blood sugar, increases gluconeogenesis, and releases amino acids from muscle.
• Epinephrine or Adrenaline (hyperglycemic) raises blood sugar, promotes glycogenolysis, increases gluconeogenesis, and favors amino acid uptake.
• Growth hormone (hyperglycemic) increases blood sugar, decreases glycolysis, and mobilizes fatty acids from adipose tissue.

Random Blood Sugar

• Blood sugar level is tested anytime without preparation.

Fasting Blood Sugar

• Sugar is estimated in the early morning, before breakfast, after 12 hours of fasting, also known as the post-absorptive state.

Post-Prandial Blood Sugar

• Post-prandial blood sugar is tested about 2 hours after a meal.

Normoglycemia

• A normal blood glucose level is referred to as normoglycemia.

Hyperglycemia

• Blood glucose levels above the normal range are referred to as hyperglycemia.

Hypoglycemia

• Blood glucose levels below the normal range are referred to as hypoglycemia.

Diagnostic Criteria for Diabetes Mellitus:

• Fasting plasma sugar greater than 126 mg/dL on more than one occasion.
• A 2-hour post-glucose load value during OGTT is greater than 200 mg/dL, even if it only occurs once.
• Both fasting and 2-hour values exceeding the specified limits on the same occasion.
• Random plasma sugar level above 200 mg/dL on more than one occasion, but a single random test result should be confirmed with a repeat test.
• Glycated hemoglobin (Glyco-Hb) or HbA1c level above 6.5% at any time, following the recommendations of the American Association of Clinical Chemistry and the American Diabetes Association.

Oral Glucose Tolerance Test (OGTT)

• OGTT is a diagnostic test where a large dose of glucose is administered, which is not physiological.
• In the test, blood sugar peaks at 1 hour and returns to fasting levels by about 2 hours.

Post-Glucose Load

• Post-glucose Load refers to the values obtained during an oral glucose tolerance test (OGTT) after administering a glucose load.

Physiological Tolerance Test

• This test involves taking a fasting blood sample followed by a heavy breakfast instead of a glucose load.
• A blood sample is taken 2 hours later to measure the post-prandial value, which should be less than 140 mg/dL in normal individuals.

Indications for OGTT

• To determine if a patient with symptoms of diabetes mellitus has an inconclusive fasting blood sugar result, between 100 and 126 mg/dL.
• In pregnant women, to investigate excessive weight gain.
• To rule out benign renal glucosuria.

Contraindications for OGTT

• In individuals with confirmed diabetes mellitus.
• Not indicated for the follow-up of diabetes, it is only indicated for the initial diagnosis.
• Do not perform on acutely ill patients.

Difference Between Modern and Classical GTT

• Both use the same glucose load.
• The classical procedure involves collecting blood and urine samples hourly for 2.5 hours (six samples total) and testing all blood samples for glucose while urine tested qualitatively. Modern times only involves collecting two blood samples.

Impaired Glucose Tolerance (IGT)

• Here, blood sugar values are above normal but below diabetic levels.

Impaired Fasting Glycemia (IFG)

• Here, the fasting plasma sugar is above normal, between 110 and 126 mg/dL, but the 2-hour post-glucose value is within normal limits, less than 140 mg/dL.

Gestational Diabetes Mellitus (GDM)

• GDM is carbohydrate intolerance noticed for the first time during pregnancy, excluding known diabetics who become pregnant.

Modern diabetes mellitus detection in pregnancy

• A glucose challenge test is conducted in all antenatal women between 22 and 24 weeks of gestation, administering a 50g oral glucose load indifferent of what time it is. A 2-hour reading of above 140mg/dL necessitates a 75g OGTT.
• Some obstetricians prefer forgoing the screening, and going straight for a 75g OGTT: where both a fasting sample, and readings 1 and 2 hours after glucose consumption are taken.
• Women diagnosed with GDM face increased risks, both for themselves in later life, and their child.

Alimentary Glucosuria

• Normal fasting and 2-hour glucose values but exaggerated blood glucose rise after ingesting glucose.

Renal Glucosuria

• Normal renal threshold for glucose 175-180 mg/dL.
• A renal threshold is lowered resulting in cases of glycosuria while blood sugar levels stay inside normal limits. This is called renal glycosuria.
• Harmless in pregnancy, affecting approximately 10% of pregnant women within their last trimester.
• Renal glucosuria is associated with renal diseases that cause tubular transport defects, like Fanconi's syndrome. Glycosuria cases have been seen in conjunction with aminoaciduria and phosphaturia.
• GFR decreases where there is little to no tubular reabsorption impairment. Seen in arteriosclerosis old age, and diabetic nephrosclerosis (Kimmelsteil-Wilson Syndrome).

Corticosteroid Stressed GTT

• Two doses of oral cortisone (100mg), taken at 8- and 2-hours before, then an oral glucose consumption, will read at normal blood sugar values with figures at 1 hour less than 180mg/dL, and 2 hours less than 160mg/dL.
• Seldom done nowadays, cortisone is limited in usage for predicting pre-diabetic states during the test.

Intravenous GTT

• Used on patients with suspected malabsorption from oral GTT results, 25g of glucose is administered intravenously over 5 mins.

Renal Threshold

• 175-180mg/dL is typically the point that glucose is excreted into the urine.

Reducing Substances in Urine

• Benedict's tests detect sugar presence. The urine is boiled with Benedict's reagent (cupric sulfate, sodium carbonate, and sodium citrate), resulting in reduction of the cupric ions in Benedict's reagent to cuprous oxide, forming a precipitate.
• The precipitate color corresponds to sugar concentration; a blue color signifies sugar absence, green indicates 0.5%, yellow signifies 1%, orange signifies 1.5%, and red signifies 2% or higher.
• Urine dipsticks are also viable testing tool.

What is Glycosuria:

• The excretion of reducing sugars in urine.

Glycosuria vs Glucosuria:

• Glucosuria is specifically glucose in urine, but glycosuria is any sugar; often the terms are incorrectly interchanged.

Lactosuria

• Is the second most common reducing sugar in urine, often spotted in pregnant women within their third trimester during lactation.
• A methyl amine test is used to spot it, creating a red coloring, when methylamine is mixed in the urine alongside heat.

Fructosuria

• When fructose's metabolism is not properly functioning due to a genetic deficiency, it leaves through the urine instead.

Galactosuria

• The absence of galactose-1-phosphate uridyl transferase causes urine to contain galactose.

Pentosuria

• Xylulose is excreted due to enzyme deficiencies in xylitol dehydrogenase/xylulose reductase, is marked by L-xylulose in the urine.

Bial's Test

• A green marker signals the presence of pentoses, composed of orcinol within a hydrochloric acid reagent.

Diabetes Mellitus

• Is marked by a combination of hyperglycemia, ketonuria, ketonemia and glucosuria, is often the primary cause of ketosis.
• The deficiency of insulin accelerates lipolysis, resulting in larger quantities of fatty acids for launch circulating. The cycle's oxidation is restricted and gluconeogenesis is heightened due to reduced oxaloacetate availability.

Starvation

• A lack of glycogen leads to oxaloacetate converting to gluconeogenesis. Alternate fuel sources are then required, and lipolysis occurs as a result. Furthermore, the lack of glucose in the system means high glucagon counts favoring ketogenesis, causing hyperemesis.

Metabolic Acidosis

• A consequence of excess keto acids in the body, it is marked when acetate and beta-hydroxybutyrate accumulate.

Reduced Buffers

• A consequence of metabolic acidosis, it causes a reduction in buffers where plasma bicarbonate gets used for acid buffering.

Kuassmaul's Respiration

• The need to compensate by hyperventilation causes Kussmaul's respiration.

Smell of Acetone

• The smell is a telltale sign in the breath during ketosis.

Osmotic Diuresis

• An effect caused by ketonuria that can lead to substantial dehydration.

Hyperglycemic Coma

• It is important to compare its telltale symptoms to ketosis, as their treatment is exact opposites. Detection can be done mostly through careful blood glucose estimations.

Post-Prandial Hypoglycemia

• This can be caused by too much insulin being secreted, marked by its transient states around 2 to 3 hours after a meal.

Insulinoma

• Refers to an insulin-secreting tumor.

The word "insulin"

• The word comes from the Latin "insula," meaning "island" or "islet."

Largerhans

• Identified alpha and beta cells in pancreatic islets in 1869.

Von Mering & Minkowski

• Induced experimental diabetes via pancreatectomy in 1889.

Banting & Best

• Extracted insulin from a pancreas in 1922 and injected it into a diabetic dog. Marjorie.

Abel

• Managed to crystallize insulin for the first time in 1927, and was awarded the Nobel Prize for his work in 1923.

Sanger

• Determined insulin’s amino acid arrangement in 1954.

Biosynthesis of Insulin

• The beta cells within the islets of Langerhans initiate a protein manufacturing process, a process that yields both pre-pro and pro-insulin precursors.
• Endoplasmic reticulum transforms pre-proinsulin, rapidly converted by leader sequence removal, which has 109 amino acids.
• The pro-insulin is shipped to the Golgi complex, a site where protease enzymes cleave it to C-peptide by removing residues numbering 86 on the original compound, forming insulin comprised now of just 51 acids coupled together.

Insulin Secretion:

• Insulin secretion unfolds across two distinct stages. First, an increase in glucose triggers high Km GLUT2 channels to receive, and beta cells convert into ATP that depolarizes membranes through closure at potassium channels, followed quickly by calcium flowing through these newly open channels.
• Packed into special granules which release into a surrounding environment through membrane fusion, their concentration ultimately reduces and metabolizes too far away from intended targets to maintain normal physiology.

Hormones:

• Secretin, gastrin, and pancreozymin (enhanced after taking food).

Liver

• Insulin degrades rapidly, is halved in less than 5 minutes.

Protein Synthesis

• Insulin stimulates synthesis and retards degradation.

Protein Utilization

• Glycolysis is stimulated by insulin and involves the activity/increase of key glycolytic enzymes. Glycogen synthase enzyme is activated, triggering greater storage.

The Blood Sugar Level

• It is lowered by promoting utilization and storage.

Factors Increasing Insulin Secretion

• Glucose, gastrointestinal hormones, proteins and amino acids, parasympathetic and beta-adrenergic stimulation, glucagon and growth hormone, tolbutamide, and incretin hormones.

Insulin Receptors

• It acts by tethering a plasma membrane containing receptor, forming an elaborate compound with smaller segments inside-2 alpha (to welcome insulin), and 2 beta (cytoplasmic section.)

Decreased insulin

• Is caused by epinephrine and alpha-adrenergic stimulation.

Action of Corticosteroids

• They act primarily through the gluconeogenesis and glycogen deposition.

Effects Of Diabetes on Protein Metabolism

• The increased breakdown of proteins and amino acids to provide gluconeogenesis substrates causes muscle wasting.

Cardinal Symptoms Of Metabolic Ramifications:

• Excessive blood glucose causes a urinary excretion.
• Causing glucosuria and related osmotic effect, there is more associated water causing polyuria.
• With greater polyuria-electrolyte disruption there is a stimulation of thirst.
• Patients tend to eat greater portions to replace glucose/protein losses.
• Breakdown of said protein/fat leads to weight loss, can be confused with cancer, AIDS, hyperthyroidism tuberculosis.
• Recurring infections like boils can form.

Diabetes Complications:

• One being ketoacidosis, more prevalent with type-1.
• Caused by excessive ketone excretion that results from high synthesis within extrahepatic tissues.

Diabetes Test:

• Rothera's test spots ketone bodies well in the urine, and for supportive evidence, electrolyle samples and acid-based gases are also viable tests.