Pancreas Function and Hormones

Pancreas Function

• Study of the pancreas includes understanding its endocrine function and the physiological effects of insulin
• It also involves knowing the causes of diabetes mellitus symptoms

Endocrine and Exocrine Gland

• The endocrine part of the pancreas contains pancreatic islets or islets of Langerhans
• Alpha and beta cells are the most noticeable cells in these islets at a microscopic level

Alpha Cells and Glucagon

• Alpha cells produce glucagon in response to decreased blood glucose
• Glucagon stimulates the liver to break down glycogen into glucose via glycogenolysis, increasing blood glucose
• Glucagon also triggers lipolysis, the hydrolysis of stored fat, releasing free fatty acids into the blood
• This process provides energy substrates during fasting and increases gluconeogenesis
• Continued glucagon infusion can still cause hyperglycemia even after liver glycogen stores are depleted

Delta Cells and Somatostatin

• Delta (δ) cells secrete somatostatin (SS), a polypeptide hormone with inhibitory functions
• SS is produced in the GI tract and hypothalamus
• SS can inhibit pancreatic and gastrointestinal hormones
• It binds to five different SS receptors and is involved in motility, mucous, hormone secretion, and inflammation
• In the GI system, somatostatin inhibits gastrin release, parietal cell acid secretion, gastric acid secretion, and decreases bile flow
• In the pancreas, SS inhibits glucagon and insulin secretion from α- and β-cells

Beta Cells and Insulin

• Beta cells secrete insulin, a protein composed of an A chain (21 amino acids) and a B chain (30 amino acids) linked by sulfur atoms
• Insulin is stored in granules within beta cells and released into capillaries in response to stimuli
• These capillaries then empty into the portal vein, carrying blood from the stomach, intestines, and pancreas to the liver
• The primary factor stimulating insulin secretion is the concentration of glucose in arterial blood perfusing the islets
• Increased blood glucose stimulates insulin secretion, while decreased blood glucose reduces it
• Amino acids, fatty acids, keto acids, and gastrointestinal hormones can also stimulate insulin secretion
• Somatostatin and sympathetic nervous system activation inhibit insulin secretion
• Insulin causes glucose absorbed after a meal to be stored as glycogen in the liver
• When blood glucose falls between meals, insulin secretion decreases, and liver glycogen is broken down into glucose

Insulin's Effect on Glucose Metabolism

• When glucose entering the liver exceeds glycogen storage capacity, insulin converts excess glucose into fatty acids
• These fatty acids are packaged as triglycerides in very-low-density lipoproteins and transported to adipose tissue for fat deposition
• Insulin increases glucose transport and use by most body cells, except brain cells
• Brain cells are permeable to glucose and can use it without insulin
• Brain cells primarily use glucose for energy, making it crucial to maintain blood glucose levels
• Low blood glucose levels (20 to 50 mg/100 ml) can cause hypoglycemic shock, leading to fainting, seizures, and coma

Effects of Insulin Deficiency

• Insulin deficiency causes lipolysis, releasing free fatty acids and glycerol into the blood, increasing plasma free fatty acid concentration
• Free fatty acids become the primary energy substrate for most tissues
• Excess fatty acids in liver cells lead to excessive acetoacetic acid formation in the mitochondria
• A large part of the excess acetyl-CoA is condensed to form acetoacetic acid, which is released into the circulating blood
• The absence of insulin also depresses the utilization of acetoacetic acid in the peripheral tissues
• Acetoacetic acid is converted into b-hydroxybutyric acid and acetone, known as ketone bodies; high levels in body fluids lead to ketosis

Insulin and Protein Metabolism

• Insulin promotes protein synthesis and storage after a meal when nutrients are abundant
• It stimulates amino acid transport into cells, inhibits protein catabolism, and reduces amino acid release, especially from muscle cells
• In the liver, insulin reduces the rate of gluconeogenesis

Protein Depletion and Insulin Lack

• Insulin deficiency halts protein storage, increases protein catabolism, stops protein synthesis, and releases amino acids into the plasma
• The plasma amino acid concentration increases, and excess amino acids are used for energy or gluconeogenesis
• Amino acid degradation leads to enhanced urea excretion, resulting in protein wasting

Diabetes Mellitus

• Diabetes mellitus is a syndrome characterized by impaired carbohydrate, fat, and protein metabolism
• Type I diabetes (insulin-dependent) is caused by lack of insulin secretion
• Type II diabetes (non-insulin-dependent) is caused by decreased target tissue sensitivity to insulin, known as insulin resistance
• Both types alter the metabolism of all main foodstuffs, preventing efficient glucose uptake and use by most cells (except brain cells)
• Blood glucose concentration increases, cell glucose use decreases, and fat and protein use increases

Type I Diabetes

• Type 1 diabetes is due to lack of insulin production by beta cells
• Injury or diseases affecting beta cells can lead to type I diabetes
• Viral infections or autoimmune disorders may be involved in beta cell destruction
• A hereditary tendency for beta cell degeneration may also exist
• Type I diabetes usually begins around age 14 and is called juvenile diabetes mellitus
• It develops abruptly, with increased blood glucose, increased fat utilization, and protein depletion

Blood Glucose and Urine

• Lack of insulin reduces glucose utilization and increases glucose production, raising plasma glucose to 300 to 1200 mg/100 ml
• High blood glucose causes more glucose to filter into renal tubules than can be reabsorbed, leading to glucose spillage into the urine
• This occurs when blood glucose exceeds 180 mg/100 ml, the blood "threshold" for glucose appearance in urine

High Blood Glucose and Tissue Injury

• Very high blood glucose levels (8 to 10 times normal) cause severe cell dehydration
• Excessive glucose in extracellular fluids causes osmotic water transfer out of cells
• Glucose loss in urine causes osmotic diuresis, resulting in massive fluid loss and dehydration
• Polyuria (excessive urination), intracellular and extracellular dehydration, and increased thirst are classic diabetes symptoms

Chronic High Glucose Concentration

• Poorly controlled blood glucose over long periods causes blood vessels in multiple tissues to malfunction and undergo structural changes
• There is an increased risk of heart attack, stroke, end-stage kidney disease, retinopathy, blindness, ischemia, and gangrene
• Chronic high glucose also damages other tissues, such as causing peripheral neuropathy and autonomic nervous system dysfunction
• Abnormalities can impair cardiovascular reflexes and bladder control, decrease sensation in extremities, and cause other peripheral nerve damage

Diabetes and Metabolic Acidosis

• Carbohydrate to fat metabolism shift in diabetes increases keto acid release (acetoacetic acid and b-hydroxybutyric acid) into plasma
• The patient develops severe metabolic acidosis from excess keto acids, exacerbated by dehydration from excessive urine formation
• The condition can cause diabetic coma and death unless treated with insulin and fluids

Insulin and Growth Hormone

• Insulin and GH are counter-regulatory hormones in terms of glucose and lipid metabolism
• They also mutually regulate each other's secretion, forming a regulatory network
• The balance between insulin and GH is associated with fuel and energy metabolism
• Insulin is required for protein synthesis and is essential for animal growth

Protein Loss

• Failure to use glucose leads to increased use and decreased storage of fat and protein
• Severe untreated diabetes causes rapid weight loss and lack of energy, despite eating large amounts of food (polyphagia)

Type II Diabetes

• Type II diabetes is more common than type I, accounting for ~90% of cases
• Onset typically occurs after age 30, often between 50 and 60 years, and develops gradually
• This syndrome is referred to as adult-onset diabetes
• There has been a rise in younger individuals (less than 20 years old) with type II diabetes, associated with increasing obesity

Metabolic Syndrome

• Insulin resistance is part of "metabolic syndrome", which includes: obesity (especially abdominal fat), insulin resistance, fasting hyperglycemia, lipid abnormalities, and hypertension

Metabolism

• Type II diabetes pancreatic beta cells become "exhausted" and unable to produce enough insulin to prevent hyperglycemia, especially after carbohydrate-rich meals
• Early stages can be treated with exercise, caloric restriction, and weight reduction, without insulin
• Drugs may increase insulin sensitivity or release from the pancreas
• Later stages may require insulin to control plasma glucose

Diagnosing Diabetes

• Urinary glucose tests are used to determine glucose quantity in urine
• A normal person loses undetectable amounts, whereas diabetics lose varying amounts based on disease severity and carbohydrate intake
• Fasting blood glucose normally ranges between 80 to 90 mg/100 ml with the upper limit of normal being 110 mg/100 ml
• A level above 110 often indicates diabetes or insulin resistance
• Glucose tolerance test involves ingesting 1 gram of glucose per kilogram of body weight. Levels rise from about 90 mg/100 ml to 120-140 mg/100 ml and fall back to normal in 2 hours
• Diabetics have fasting blood glucose above 110 mg/100 ml, often above 140 mg/100 ml, and glucose tolerance is abnormal above 200 mg/100 ml