Endocrinology: Insulin and Glucose Metabolism

• Disorders of Carbohydrate Metabolism concern abnormalities in how the body processes carbohydrates.
• S. M. Rizk is the author.

Disorders of Carbohydrates Metabolism

• Glucose serves as the primary fuel for all human cells.
• Glucose is the source of carbon for the synthesis of most other compounds in the body.

Glucose Homeostasis

• Maintaining stable glucose levels in the blood is a finely regulated homeostatic mechanism, involving
  • The liver
  • Extrahepatic tissues
  • Several hormones

Maintaining Glucose Homeostasis

• Blood glucose levels must be maintained within the narrow range of 65-99 mg/dl under homeostatic control.
• Hyperglycemia can cause cerebral dysfunctions due to its effect on extracellular osmolality.
• Hypoglycemia can cause impairment of cerebral functions, as the brain is highly dependent on blood glucose for energy.
• Liver cells are freely permeable to glucose via the GLUT 2 transporter.
• Extrahepatic tissues, like muscles and adipose tissue, are relatively impermeable to glucose, excluding pancreatic B cells.
• Glucose transporters in these tissues are regulated by insulin.
• Glucose uptake from the bloodstream is the rate-limiting step in glucose use in extrahepatic tissues.

The Liver's Role in Glucose Homeostasis After a Carbohydrate-Containing Meal:

• The liver removes about 70% of the glucose load through the portal circulation.
• Some glucose is oxidized, and some is converted to glycogen for use during fasting.
• Excess glucose is converted into fatty acids and triglycerides.
  • These are incorporated into VLDL particles
  • These are transported to adipose tissue stores

The Liver's Role in Glucose Homeostasis During the Fasting State:

• Blood glucose is maintained by glycogen breakdown in the liver in the short term.
  • This is limited by glycogen stores
  • Gluconeogenesis occurs mostly in the liver, but also in the kidneys
• Under fasting conditions, glucose is spared via the ability of muscle and other tissues adapting to fatty acid oxidation.

Hormones Involved in Blood Glucose Regulation:

• Insulin decreases blood glucose.
• The following increase blood glucose:
  • Glucagon
  • Epinephrine
  • Cortisol
  • ACTH
  • Growth Hormone
  • Thyroxine

Insulin

• Insulin is a peptide hormone produced by the β cells of the Islets of Langerhans in the endocrine portion of the pancreas.
• The Islets of Langerhans comprise only 1-2% of the total pancreatic cells.
• Insulin is the most important hormone coordinating fuel use by tissues and promotes anabolic processes like glycogen, triacylglycerol (TAG), and protein synthesis.
• Insulin's structure comprises 51 amino acids in two polypeptide chains, A (21 amino acids) and B, connected by two disulfide bonds, with an intramolecular disulfide bond in the A chain.
• Biosynthesis involves preproinsulin and proinsulin, sequentially cleaved to form active insulin and C-peptide in a 1:1 ratio.
• The C-peptide is essential for proper insulin folding, and due to its longer half-life in plasma, indicates insulin production/secretion.
• Insulin is stored in cytosolic granules, released by exocytosis when stimulated.
• Insulin is degraded by insulin-degrading enzyme present in the liver and kidneys.
• Insulin has a plasma half-life of ~6 minutes, allowing rapid changes in hormone levels.
• Insulin secretion by pancreatic β cells is closely coordinated with glucagon secretion from pancreatic α cells.
• The amount of glucagon and insulin release are typically regulated to equalize hepatic glucose production with peripheral tissue use, maintaining blood glucose between 70 and 140 mg/dl.
• Insulin secretion is increased by glucose, amino acids, and gastrointestinal peptide hormones due to its coordinating role.

Insulin Secretion

• Ingestion of a carbohydrate-rich meal leads to a rise in blood glucose, the primary stimulus for insulin secretion.
• The β cells are the most important glucose-sensing cells containing GLUT-2 transporters and expressing glucokinase like the liver.
• Glucokinase phosphorylates glucose proportional to glucose concentration because it is not inhibited by glucose 6-phosphate at high glucose.
• Increased metabolism increases the ATP to ADP ratio, inhibiting the KATP-channels and leading to membrane depolarization.
• Membrane depolarization and then opening of voltage-dependent calcium channels (VDCC) result in increased cytosolic calcium.
• Ca2+ cases insulin-containing vesicles to be exocytosed from the β cell.
• Sulfonylureas treat type 2 diabetes via increased insulin secretion by closing ATP-sensitive K+ channels.
• In pancreatic β-cells, glucose release requires Ca2+ influx.
• Low blood glucose results in decreased ATP, increased K+ efflux, hyperpolarization, decreased Ca2+ influx, and decreases insulin secretion.
• Elevated blood glucose results in increased ATP and decreased K+ efflux.
• Transiently elevated plasma amino acid levels (arginine) enhance glucose-stimulated insulin secretion after protein ingestion.
• Glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are glucose-dependent intestinal peptides.
• GLP-1 and GIP increase the sensitivity of the β cells to glucose.
• Released after food ingestion from the small intestine, the peptides causing an anticipatory rise in insulin levels and therefore are known as incretins.
• The same glucose amount given orally, results in a much greater insulin secretion than if given intravenously (IV)
• GLP-1 and GIP are inactivated in the circulation by dipeptidyl peptidase-4 (DPP-4), a target for new diabetes drugs.
• GLP-1 agonists and DPP-4 inhibitors are available.
• Insulin synthesis/release decreases with low dietary fuels and during physiologic stress, preventing hypoglycemia.
• Norepinephrine/epinephrine primarily mediate these effects.

Metabolic Effects of Insulin:

• Liver:
  • Promotes increased glycogen synthesis.
  • Reduces gluconeogenesis and glycogenolysis
• Muscles:
  • Promotes increased glycogen synthesis and glucose intake.
• Adipose:
  • Promotes increased glucose uptake.

Glucagon

• Several hours after carbohydrate ingestion results in lowered blood glucose levels, which occurs because of the ongoing oxidation of glucose.
• Lowered blood glucose triggers glucagon secretion and decreases insulin release.
• Glucagon increases blood glucose and decreases liver glycogen stores.

Metabolic Effects of Glucagon:

• Carbohydrates Metabolism:
  • Increases Blood Glucose via the Liver which increases Glycogenolysis and Gluconeogenesis
• Lipids Metabolism:
  • Increases fatty acids in the Liver which increase TAG Degradation in adipose tissue
• Protein Metabolism: -Increases uptake of AA by Liver for Carbon skeleton to gluco neogenesis.

Hormones effects, a comparison

• Insulin acts on Glycogenolysis, Gluconeogenesis, Ketogenesis and Lipolysis
• Glucagon and Epinephrine act on Glycogenolysis, Gluconeogenesis, Ketogenesis and Lipolysis

Blood Glucose Variations:

• Includes Hypoglycemia.
• Includes Hyperglycemia.

Hypoglycemia

• Hypoglycemia is characterized by:
  • Central nervous system (CNS) symptoms, including confusion, aberrant behavior, or coma.
  • A simultaneous blood glucose level ≤50 mg/dl.
  • Symptoms resolved within minutes with glucose administration.
• It is a medical emergency.
• The CNS requires a continuous bloodborne glucose supply to serve as a metabolic fuel.
• Transient hypoglycemia can cause cerebral dysfunction.
• Severe, prolonged hypoglycemia causes brain damage.
• Signs and Symptoms of Hypoglycemia include:
  • Mild:
    • Trembling
    • Anxiety
    • Heart Thumping
    • Hunger
    • Sweating
    • Nausea
  • Moderate:
    • Difficulty concentrating
    • Vision changes
    • Confusion
    • Difficulty speaking
    • Weakness
    • Headache
    • Drowsiness
    • Dizziness
  • Severe:
    • Seizures
    • Coma

Causes of Hypoglycemia:

• Treatment complications due to Diabetes Mellitus with either high dose of insulin or insulin secretagogues (e.g. sulfonylurea).
• Skipping a meal or performing excessive exercise after the usual insulin or oral hypoglycemic dose.
• Blood glucose level returns to normal when not fed.
• Unconscious patients: glucagon given subcutaneously/intramuscularly.
• Postprandial hypoglycemia.
• This is the second most common form of hypoglycemia.
• Results from exaggerated insulin release.
• Follows a meal, causes transient hypoglycemia and mild adrenergic symptoms.
• In fully conscious patients: treat with oral carbohydrate.
• Eat frequent small meals.
• Fasting hypoglycemia
• Low blood glucose during fasting is rare but can be serious.
• Results from reduced hepatic glucose production by glycogenolysis or gluconeogenesis.
• Patients with hepatocellular damage or adrenal insufficiency or fasting individuals who have consumed large quantities of ethanol shows low blood glucose level
• Alcohol-related hypoglycemia:
  • The abundance of NADH favors the reduction of pyruvate to lactate and of oxaloacetate (OAA) to malate.
  • Ethanol-mediated increase in NADH causes gluconeogenic precursors to be diverted into alternate pathways, resulting in decreased glucose synthesis
  • It Precipitates hypoglycemia.
  • Those particularly in individuals depleted of liver gycogen.
• Insulinoma:
  • Tumor that secretes insulin from the pancreatic islets B cells.
  • Results in elevated insulin levels (hyperinsulinemia) with decreased blood glucose levels.
• Non-Pancreatic tumors
  • Hypoglycemia as a paraneoplastic phenomenon is associated with advanced malignancy.
• Alterations of metabolism:
  • Associated with sepsis as severe infections.
  • They can cause hypoglycemia though the mechanism is as yet, unclear.
• End-stage renal failure as the kidney, like the liver, is a gluconeogenic organ.
• Miscellaneous causes include severe malnutrition, prolonged starvation and inherited metabolic disorders (e.g., glycogen storage diseases).
• Neonatal hypoglycemia:
  • Appears in the first few days after birth.
  • Hypoglycemia in the neonate is.
    • Particularly important, at high risk of hypoglycemic brain damage.
• Babies from diabetic mothers:
  • Fetuses are exposed to maternal hyperglycemia.
  • Leads to pancreatic islet cell hyperplasia and elevated insulin levels.
  • The neonate is unable to suppress its high insulin levels from delivery and develops hypoglycemia.
• Inborn error of metabolism:
  • Such as glycogen storage diseases and galactosemia

Hyperglycemia

• Blood glucose level rises above the normal average level.
• The cause maybe either:
  • Diabetes mellitus is the most common cause
  • Disturbance in hyperglycemic hormones
  • Temporarily in severe stress
  • in patients receiving intravenous fluid containing glucose

Diagnostic Criteria for Diabetes:

Fasting plasma glucose (FPG):

• Used to check the blood glucose levels.
• Fasting means after not having anything to eat or drink (except water) for at least 8 hours before.
• It is usually done first thing in the morning, before breakfast.

Oral glucose tolerance test (OGTT):

• Measures how well the body can break down and use sugar (glucose) and clear it from the bloodstream.
• Drinks beverage with 75 g glucose; Blood samples are drawn at 30 min intervals for 2 hours.
• Glucose levels for: Diabetes, Renal threshold, impaired GT and Normal

Glycated hemoglobin (A1C)

• Occurs When blood glucose enters the erythrocytes. Glucose reacts spontaneously and non-enzymatically.
• Creates free amino groups on globin forming covalently glycated protein.
• The extent of glycation depends on the average blood glucose levels.
• Factors exist that aren't easily controlled like lifespan of red blood cells. The A1C value reflects average since red cell lifespan is 2-3 months
• Glycation of Hb depends on average glycemia but also on the rate of production or destruction of RBCs
• Condition Linked to Short RBC Lifespan such as: Hemolytic anemia, splenomegaly or low A1C levels independent serum of glucose
• Other things that elevates A1C high also include: Production of RBC
• Chron disease who received erythropoietin
• Who have a received Blood transfusion
• Presence of hemoglobin opathies like sickle cell etc

Serum Fructosamine

• It measures glycated protein mainly albumin. When glucose level was is elevate over a period period time glucose molecules combine with proteins in blood.
• The more glucose, the greater the amount of glycated protein farmed. Due to a shorter-half for plasma fructosamine, only controls glucose from proceeding 1-2 Weeks

Normoglycemia

• This is state of having a normal level of glucose in the blood.
• Defined under specific rules, with a level from 65 to 99 mg/DI for FPG
• It is a A1C less than 5.7% and a 2-h PG level.
• All must be present

Prediabetes

• "Prediabetes" is used for individuals with glucose levels not meeting criteria for diabetes but with carbohydrate abnormalities. It must meet criteria for:
• Fasting glucose, is impaired, with a FPG. Levels is from 100 to 125 MG/DL Impaired glucose with a 2-h PG tolerance of 140-199 MG/DL A1C : is from 5.7 to 6.4%

Diabetes

• Is met if a diagnosis has multiple criteria of

Diagnosis: of A1C 6.5%, A2 hr/PG, level of 200 MG/DL, in which criteria for a diagnosis of Diabetes In a patient with classic symptoms of hyper glycemia or hyperglycemic crisis a random plasma level more then 200 MG/DL

• It may be one condition with multiple heterogeneous but it's a multi factorial, primarily polygenic for elevated Fasting Blood Glucose.
• Maybe it is in ability to produce or to respond to insulin.

Type 1 Diabetes:

• Autoimmune caused by an autoimmune destruction Leads to absolute insulin deficiency

Classification for: Diabetes

• Type 1 diabetes,
• Type 2 diabetes, -Specific types of diabetes to other causes
• Gestational diabetes mellitus .

Type 2 Diabtetes:

• Non insulin dependent
• Its adult onset.
• Peripheral resistance and relative deficincy. May not need this in its entirity.
• It grows gradually in a less accute and obvious way.
• Those old or in an obese and old.
• It is determined with genetic factures.

Specific Types of Diabetes

-It includes: - Latent, - Autoimmune, - And many different genetic types

• Also drugs use or by radiation can also be used
• Includes -Latent autoimmune diabetes of adults (LADA) -Monogenic diabetes syndromes (such as neonatal diabetes and maturity-onset diabetes of the young),. - Diseases of the exocrine pancreas such as cystic fibrosis, - and drug or chemical reduced diabetes where transplantations occur

Latent Diabetes

• Its autoimmune and begins at the adulthood It shares immunologic features and metabolic features of 1 and 2 The immunology. Requires different criterias Like being the age, or being positive for auto antibodies.
  • It is usually like with other conditions.
• That people have for control was usually the diabetes that do not require insulin
• Those with hyper glycemia did not need great management.

Monogenic diabetes syndromes

• Are rare conditions of elevated glucose. Can occur before six months of age. Diabetes for the is for these patient. Or what can be called: neonatal and
• Transient or permeant
• These patients usually have low levels of insulin and that usually requires a exogenous need for insulin. The diabetes with it is always resolved for their first three. Then after they reach puberty. Reappears again

Cystic Fibrosis

• A genetic condition

Pancreatic Diabetes:

• A general pancreatic dysfunction
• Diverse Etiology:
  • Panceraitis and trauma
  • Cycstic Fibrosis
  • Hypoglycemia

Drug and Chemically induced type diabetes

• Medication that includes glucocorticosols
• Certain HIV infections anti psychotics are known to increase diabetes.

Gestational Diabetes:

• It has abnormal tolerance and severity of diabetes that's recognized during pregnancy. Reverts after delivery during pregnancy.

Complications from Diabetes, and Acute Conditions

• Complications from diabetes:
  • Acidosis because and imbalance from between the use and products that result due. 25 to 40% It may be brought on to an infection or physical stress it

• The treatment with that for DKA is rehydration. and electrolyte replacement.
  

• To correct high blood is to have

Hyperglycaemic

• Non Ketonic Comma for 25 high blood is levels like it has,

• That might be in a hyperglycaemic levels and diabetes That might be in a hyperglycaemia with the diabetic conditions

• A very low or high that would be a result from an illness

Mechanism of tissue injury

Tissue are can be resulted through a glycoside pathway

Hyperglycemia and Sorbitol Pathway

Are for the mechanisms of tissue injury. That results in the hyper glycemic conditions.

• For altered cell over turn
• You could have a reaction from cyte effects. and this is just so osmotic effects,

Glycogen storage disease:

• Where caused defects in glycogen breakdown.
• The stored glycogen may have are normal aberrant structure.

Glycogeon

Are a result of the effects for on enzymes due to the liver.

Storage disease type 1:

The most common of store diseases

• Usually from block gluconeogenic pathways fasting.
  • There are resultingly accompanied there that there will up
  • There this glucose shunt may or then transfer back glycogen in into. The liver are back to increase that concentration due to this it can cause to have a a lactic acidosis.
• But it has to be remembered that will be caused with Glucose deficiencies with glucose as that is shown in the image for glycogen..

- Galactosemia

Deficiency of galactose phosphate enzyme:

• Can cause hypo glycemia
• Galactirol produces access so as results in cataract.

Essential fructose

Deficiencies in fructose cause increase amount of glucose in the blood. Essential fructosuria due to this cause a deficiency that normally is found in with a liver, kidney, and small Intestinal mucosa that does not show any particular clinical symptoms.

Other diseases are and can include:

• Those who show abnormalities with enzymes, have lower ATP amount . Red blood cells and those also lack mitochondia that depend on glyolysis and ATP.

That's that has. Has also a hemoglobin that affects it has to do by with a an increased red cell. The shift right

• Which has two and three of 2 point3. Di phosphate group..

(G6PD),

Where that certain medications that usually take anti malaria medicine have those particular in abilities. . Have those erythrocytes problems that could That is what causes the G6PB deficiency.

• Or one who like to be very careful with oxidizing substances. Where there is favas or substances that are usually causes with that that causes increased damage, with that are also anti malaria agents.

Fructose: one

The patient that depends has exogenous has what is and are then it in: those that can't synthesize lactate, pyruvate, or glycerone from Those will high glycemia will can have a low glucose and or low glucose and that are there will accumulate all of it.

Explore the characteristics, function, and regulation of insulin in glucose metabolism. Understand how insulin secretion is coordinated, its degradation process, and factors affecting A1C testing. Learn about hyperglycemia, OGTT, and the impact of conditions like kidney disease on A1C results.