Guyton and Hall Physiology Chapter 79 - Insulin, Glucagon, and Diabetes Mellitus

Pancreas Hormones

• The pancreas produces insulin and glucagon, as well as amylin, somatostatin, and pancreatic polypeptide
• These hormones are essential for regulating glucose, lipid, and protein metabolism
• This section focuses on insulin and glucagon's roles and how their dysfunction leads to diabetes mellitus

Pancreas Anatomy

• The pancreas has acini, which secrete digestive juices into the duodenum
• Islets of Langerhans secrete insulin and glucagon directly into the blood
• A human pancreas contains between 1 and 2 million islets of Langerhans
• Islets of Langerhans are 0.3 mm in diameter
• Alpha, beta, and delta cells make up an islet, each secreting a different hormone
• Beta cells (60%) secrete insulin and amylin in the center of each islet
• Alpha cells (25%) secrete glucagon
• Delta cells (10%) secrete somatostatin
• PP cells secrete pancreatic polypeptide
• Refer to Figure 79-1 for an illustration of the pancreas

Islet Communication

• Cell types present in the islets of Langerhans allow cell-to-cell communication to regulate hormone secretion
• Insulin inhibits glucagon secretion
• Amylin inhibits insulin secretion
• Somatostatin inhibits both insulin and glucagon secretion

Insulin's Isolation and Effects

• Insulin was isolated in 1922 by Banting and Best
• The discovery of insulin was a medical breakthrough for diabetes
• Although the hormone is associated with blood sugar, insulin affects carbohydrate, glucose and protein metabolism

Insulin and Energy

• Insulin secretion relates to energy abundance, especially excess carbohydrates
• Insulin stores excess energy as glycogen (mainly in the liver and muscles) & converts excess carbohydrates into fats, storing them in adipose tissue
• Insulin encourages amino acid uptake and conversion into proteins, inhibiting the breakdown of existing proteins

Insulin Synthesis

• Human insulin has a molecular weight of 5808
• The hormone consists of two amino acid chains connected by disulfide linkages; separating these chains results in loss of proper function

Insulin Production Process

• Insulin synthesis in beta cells starts with preproinsulin (molecular weight of about 11,500) formed by translation of insulin RNA
• Preproinsulin is cleaved into proinsulin (molecular weight of about 9000), which has three peptide chains: A, B, and C
• Proinsulin is cleaved in the Golgi apparatus to form insulin (chains A and B connected by disulfide linkages) and C peptide (connecting peptide)
• The insulin and C peptide are packaged into secretory granules and secreted in equal amounts
• Proinsulin accounts for 5-10% of the final secreted product
• Refer to Figure 79-2 for a schematic of the human proinsulin molecule

C Peptide

• C peptide binds to a membrane structure, likely a G protein-coupled receptor
• C peptide binds to membrane causing activation of sodium-potassium adenosine triphosphatase and endothelial nitric oxide synthase
• C peptide's role in regulating these enzymes is uncertain
• Measuring C peptide levels using radioimmunoassay determines how much natural insulin insulin-treated diabetic patients produce

Insulin Transportation

• Insulin circulates unbound. in the blood
• With a half-life of about 6 minutes, insulin clears from circulation within 10 to 15 minutes
• Insulinase degrades insulin in the liver, kidneys, muscles, and other tissues
• Rapid insulin removal is important for quickly turning its control functions off

Insulin Receptors

• Insulin binds to membrane receptor protein (molecular weight of about 300,000) to initiate effects on target cells
• Insulin receptors consist of 4 subunits: two alpha subunits outside the cell membrane and two beta subunits penetrating the membrane
• Insulin binds to alpha subunits, causing autophosphorylation of beta subunits inside the cell
• Autophosphorylation activates tyrosine kinase, phosphorylating intracellular enzymes like insulin-receptor substrates (IRS)
• IRS types (IRS-1, IRS-2, IRS-3) vary in different tissues.
• Insulin directs intracellular metabolic machinery by activating/inactivating enzymes
• Refer to Figure 79-3 for a schematic of the insulin receptor

Effects of Insulin Stimulation

• Cell membranes increase glucose uptake, especially in muscle and adipose cells
• Increased glucose is phosphorylated, becoming a substrate for carbohydrate metabolism
• Intracellular vesicles with glucose transport proteins translocate to the cell membranes, facilitating glucose uptake
• Vesicles separate from the cell membrane in 3-5 minutes when insulin is unavailable and return to be used again
• Increased permeability to amino acids, potassium ions, and phosphate ions occurs
• Intracellular metabolic enzyme activity levels change in a matter of 10–15 minutes
• Hours/days later, rates of translation of messenger RNAs and DNA transcription change, allowing insulin to change the cell's enzymatic machinery

Insulin and Carbohydrate Metabolism

• After a carbohydrate-rich meal, blood glucose increases and causes rapid insulin secretion
• Insulin leads to rapid glucose uptake, storage, and usage in tissues, especially the muscles, adipose tissue, and liver

Insulin and Muscle Metabolism

• Muscles typically use fatty acids for energy, not glucose
• Resting muscle membranes are only slightly permeable to glucose unless stimulated by insulin
• Muscles use large amounts of glucose during exercise because muscle contraction increases glucose transporter 4 (GLUT 4) which allows glucose to enter the cell
• With extra insulin, muscles can also uptake glucose during times of high blood glucose

Glycogen Storage

• If muscles are unused after a meal, glucose is stored as muscle glycogen (up to 2–3% concentration)
• Glycogen can be used for later energy needs, including short periods of extreme energy usage and anaerobic bursts

Insulin and Liver Metabolism

• Insulin causes rapid glucose storage in the liver as glycogen following a meal
• Between meals, insulin secretion decreases and glycogen turns back into glucose for release into the blood

Insulin and Liver Metabolism Steps

• Insulin stops the enzyme liver phosphorylase, which breaks down liver glycogen
• Insulin increases the activity of glucokinase to increase glucose uptake
• Inactivation happens when phosphorylating glucose after it goes into liver cells
• Insulin increases activities of glycogen synthesis enzymes (especially glycogen synthase)
• Glucose increases to 5-6% of liver mass overall

Inter-meal Glucose Release

• Low blood glucose transpires when decrease in insulin secretion occurs
• Aforementioned effects reverse for glycogen storage when there's a lack of insulin
• Process causes the halting of glycogen creation & prevents glucose uptake by the liver
• Lack of insulin (and increase in glucagon) activates phosphorylase, which splits glycogen into glucose phosphate to increase blood glucose
• Since phosphorylase was inhibited by insulin, lack of insulin activates glucose phosphatase
• The activation causes the split of the phosphate radical away from glucose
• Reaction sets molecular glucose free to diffuse back into the blood
• Liver removes excess glucose & returns it to counteract a drop between meals (60% of meal ends up stored then returned)

Insulin and Fatty Acids

• Insulin promotes the conversion of excess glucose into fatty acids and inhibits gluconeogenesis in the liver Excess glucose becomes fatty acids & packaged as triglycerides in very low density lipoproteins and transported to adipose tissue
• Insulin decreases the amount and activity of liver enzymes that perform gluconeogenesis

Insulin's Affect on the Brain

• Insulin has little effect on glucose uptake or usage in the brain where most of the cells are permeable to glucose for usage without insulin
• Brain depends on glucose for energy, blood glucose level must be maintained to avoid hypoglycemic shock
• Hypoglycemic shock can develop at 20-50mg/100ml levels

Insulin and Fat and Protein Metabolism

• Insulin increases glucose transport into and usage in the cells
• Promotes deposition of fat in adipose cells
• Insulin affects fat metabolism- long-term effect of insulin deficiency is extreme atherosclerosis, leading to heart attacks, strokes, and other vascular accidents
• Insulin increases glucose utilization, decreasing fat utilization, and promotes fatty acid synthesis for fat storage in adipose tissue
• Liver synthesizes fatty acids after glycogen concentration reaches 5-6%
• Insulin activates lipoprotein lipase in adipose tissue capillary walls, splitting triglycerides into fatty acids for absorption & conversion to triglycerides

Protein and Fat Storage

• Insulin inhibits hormone-sensitive lipase, preventing fatty acid release from fat cells
• Insulin promotes glucose transport into fat cells, forming α-glycerol phosphate, combining with fatty acids to form triglycerides
• Triglyceride creates storage fat in fat cells, but only when insulin is available due to otherwise blocked fatty acids in lipoproteins

Other Harmful Effects of Insulin Deficency

• Lack of insulin enhances fat usage for energy
• Enzyme hormone-sensitive lipase in fat cells becomes strongly activated; causes triglycerides stored to produce increased quantities of fatty acids and glycerol in circulating fluids
• Refer to Figure 79-5, which shows the effect of removing the pancreas on the approximate concentrations of blood glucose, plasma free fatty acids, and acetoacetic acid

Effect of No Insulin

• Absence of insulin results in free fatty acids rising more intensely than glucose concentrations
• Excess fatty acids promote liver conversion into phospholipids and cholesterol
• Triglycerides discharged into the blood via lipoproteins create a lipid concentration of several percent rather than the normal 0.6%
• High lipid concentration promotes atherosclerosis in severe diabetics

Ketosis and Acidosis Due To Lack of Insulin

• Carnitine activates in the mitochondria of liver cells; Beta oxidation rapidly releases abundant amounts of cholesterol-A
• A portion of excess acetyl-CoA condenses and releases aceto-acetic acid into circulation
• During insulin production halting: Some aceto-acetic gets transformed into B-hydroxybutyric acid and acetone in what's called ketosis
• Aceto-acetic plus b-hydroxybutric can cause severe acidosis and coma that leads to death

Insulin and Protein Storage

• Carbohydrates, protein and fats get stored in tissues during a meal with significant nutrients available in circulating blood; insulin ensures storage.
• Here are various factors: Insulin stimulates the transport of animo acids into the cells (strong animo acid transfers entail: Valine, leucine, isoleucine)
• Shares common genetic material with growth hormone capacity for increased uptake of amino acids; animo acids do no need to be completely like each other
• Insulin increases the translation of messenger RNA forming new proteins that "turn on the on/off switch" for proteins
• Over long periods of time; increases the rates of transcription of selected DNA that gives rise to high levels of RNA- more importantly the promotion of fat and carbohydrate enzymes.

Insulin Effects

• Four major effects from insulin
• Amino acid transport is stimulated into the cells
• More new proteins are produced by increases in translation of messenger RNA
• Over longer periods of time; DNA transcription rates cause more RNA
• Insulin hinders protein catabolism by slowing amino acid-release out of cells

Insulin Deficiency

• In summary, insulin aids in the creation of proteins and prevent their degradation
• Nearly all storage comes to a halt if insulin stops being provided; protein stops being produced and animo acids leave a dump into plasma

Insulin and Growth

• Insulin is essential to producing new proteins
• A figure was presented displaying: a depancrated rat without insulin scarcely grows; Insulin on its own brings nearly no groth

Mechanisms of Insulin Secretion

• Increased blood concentration results in pancreatic beta cells
• Have a large amount of glucose transported that permit influx that aligns by the blood's concentration
• Glucose is phosphorylated to form glucose 6 phosphate by glucokinase, which regulates secretion
• Refer to Figure 79-7 for the basic mechanisms of glucose stimulation of insulin secretion by beta cells of the pancreas

Hormones in Secretion

• Adenosine triphosphate (ATP): Formed by glucose 6 phosphate
• Blocks ATP-sensitive potassium channels of the cell to increase secretion
• Closure of potassium channels depolarizes the cell to create influx that stimulates fusion
• Some nutrients increase ATP and stimulate insulin
• Insulinotropic peptide and Acetylcholine amplify/enhance the effect of glucagon that don't have major effects separately

Factors that Decrease Insulin Secretion

• Somatostatin
• Norepinephrine
• Fasting

Factors that Increase/Decrease Insulin Secretion

• Table 79-1 provides factors that increase or decrease secretion

Regulating Insulin Secretion

• Believed previously that only blood glucose concentration regulated secretion amount
• Found that amino acids were the most important factors

Stimuli Impacting Insulin Secretion

• The stimuli include both blood glucose in excess and amino acids
• The impacts result in increases
• The increases result in a rise in blood concentration
• The rise in blood causes a high level of secretion within the span for 25-times the range
• The blood also reduces within 3-5 minutes when reduced back to a fasting state
• Refer to Figure 79-8 for an increase in plasma insulin after a sudden increase in blood glucose to two to three times the normal range

Insulin and Glucagon Concentration

• Figure 79-9 displays secretion from blood after achieving stimuli glucose levels

Other Factors Stimulating Insulin Secretion

• Arginine and lysine work in stimilating, where it is important because insulin creates transport for intracellular protein

Gastrointestinal Hormones

• Incretins enhance the rate for release from pancreatic beta cells and block glucagon

Insulin

• A direct effect of blood glucose on the hypothalamus also stimulates the nerve system
• In summary, insulin increases blood glucose causing better fat utilization

Glucagon

• The most important effect of glucagon occurs to increase blood concentration
• Is a polypeptide

Effects of Glucagon

• Causes breakdown of liver with an amplified amount by increased availability

Gluconeogenesis

• Still causes sugar blood to be increased but created from animo acids during Gluconeogenesis
• Other Effects entail activation of adipose (with help of Glucagon that helps convert animio acids for more availability)

Regulating Glucagon

• This involves the concentration being controlled by blood
• Is in the opposite direction from Insulin action
• Displayed in figure 79-10
• Causes the function to correct itself from hypoglycemic states

Factors Stimulating Secretion of Glucose

• Includes high concentration of animo acids and occurs during exercise

Hormones Inhibiting Output

• Includes somatostatin, a hormone that occurs form ingestaion

Blood Sugar Effects

• Liver is is an important buffer system that balances concentration
• Includes function/feedback for glucagon and insulin (as both always stabilize)

Brains Protection against Low Blood Sugar

• To protect against, if conditions drop: Direct effect on the hypothalamus (which stimulate nerves for a liver release)
• Another way of protecting yourself has some hormones that affect glucose utilization

Glucose Regulation

• Occurance that brains and retinae require that energy is in a steady state so that it may properly use itself
• Too great concentration causes dehydration due to exerting osmotic pressure
• Levels that are too high causes excretion

Overview

• Diabetes Mellitus happens by either insufficient insulin secretion (or weaker effectiveness)

2 Diabetes Types

• Type 1 (diabetes mellitus): occurs due to failing insulin production
• Type 2 (diabetes Mellitus): happens since tissues fail to listen to insulin; the tissue then reduces the sensitivity (insulin resistance)
• In type 1: the main effect reduces sugar effectiveness and helps cause more fatty acids
• Type 1 - Occurs from pancreas cells being injured (diseases impair production to cause the issue)

Diabetes Type 1 & 2

• Autoimmune and Viral diseases result in damaged production by various impacts and effects for genetics
• Type 1: Occurs circa-14 US level (often diabetes mellitus for the youthful) but still has many other effects
• Glucose ends up rising too high (with a range of 300/1200 mg per 100 ml) that generates adverse effects
• Figure presented high concentration as well

Glucose Loss

• As glucose levels (plasma); they fail to properly filter to get reabsorbed. As such a common value causes greater than thousands to get lost
• All effects come to trigger polyuria and thirst is generated

High Glucose & Kidney Diseases

• Vessels and tissue damage can often result
• With greater susceptibility in vascular injury; one may have high chances to cause Heart failure-Strok- Blindness + renal disease and a few others

Using Fats with Imbalances

• Increase for utilization creates the need too rapidly add b-hydroxybutyric that becomes acidification in plasma (happens when rapid breathing can't properly buffer)
• Low 7.0 ph- caused rapid death within hours ( displayed in figure 79/11)

Body Protein Issues

• Untriggered diabetes leads to an increased use of proteins and decreased storage (leading to an eating disorder that occurs, however untreated may cause death)
• For Type 1- doctors use a regular and increased duration type insulin, with a regiment being presented. Animal pancreas made a change from previous insulin

Type 2 Diabetes

• Occurs from cases after the age of 30-60
• This leads to many impacts one of being a growing influx of obesity (one of the largest reasons for children)
• Has genetic influences, but has abnormalities
  • Insulin Resistance results in higher insulin The higher insulin then does not yield correct results

Causes of Insulin Resistance

• Obesity for visceral adiposity occurs with a syndrome and fasting hyperglycemia(increased triglycerides as major effects)
• If insulin resistance gets too prolonged results in severe high glucose amounts during carbohydrate ingestion
• Glucose is not sufficient results in significant cases for clinical effects

Other Reasons for Insulin Resistance

• PCOS- causes increase in ovarian androgens and is found in many effects for women
• Cuhshing Syndrome produces excess formation of glucocorticoids affecting sensitivity (genetic factors can result or cardiovascular risks)
• For type 2 Diabetes: One needs too (control is lost or a combination of drugs and incretin help)
• SGLT2 (sodium glucose): greatly can reduce reabsorption by an additional help source of medicine (as shown in Table 79- the major functions show improvement to risks for a cardio problem

Diagnosing Diabetes

• Urine and blood checks (displays as well by 79.3 on a types comparison) display problems
• When measuring Urinary Glucose: (undetectable is normally the right range) but the more ingested gives better clarity due to the correlation with the disorder
• Fasting the Blood: normally around 80- and 90mg/ml, the effects will make it significantly different that tests may differentiate problems

Hemloglobin

• Shows elevation for long periods
• Has good effects that assess and gives clear detail

Test

• Glucose tolerance will test the levels in blood and often shows a curve change from normal ingestion

Key Tests

• Check and measure acetones if needed along with keto acids (figure 79-12 presented the data)
• If badly handled (arteroscloerosis) one will experience blood pressure along with lesions
• With treatment; the body can properly make use of glucose

Tumors

• Insulinoma- the main factor caused comes from a tumor or result in hyper/hypoglycemia

Insulin Shock

• Causes various forms of hallucination (an emphasized nervous system), and will be extremely low without the need of insulin
• The range of problems lead too seizures with a coma being almost impossible to differentiate

Some Causes of Insulin Resistance

• Obesity/overweight (especially excess visceral adiposity)
• Excess glucocorticoids (Cushing's syndrome or steroid therapy)
• Excess growth hormone (acromegaly)
• Pregnancy, gestational diabetes
• Polycystic ovary disease
• Lipodystrophy (acquired or genetic; associated with lipid accumulation in liver)
• Autoantibodies to the insulin receptor
• Mutations of insulin receptor
• Mutations of the peroxisome proliferators' activator receptor γ (PPARγ)
• Mutations that cause genetic obesity (e.g., melanocortin receptor mutations)
• Hemochromatosis (a hereditary disease that causes tissue iron accumulation)

Table 79-3 Clinical Characteristics of Patients With Type 1 and Type 2 Diabetes Mellitus

• Lists clinical characteristics of Type 1 and Type 2 Diabetes Mellitus