chapter 41 week 7

Introduction to Diabetes

• Diabetes mellitus is a prevalent disease, affecting approximately 10% of the U.S. population, with rising incidence worldwide.

Diabetes Insipidus

• Characterized by a deficiency in Antidiuretic Hormone (ADH).
• ADH, also known as vasopressin, is produced in the hypothalamus, transported to the posterior pituitary gland, and then secreted.
• It acts on the collecting ducts in the kidneys, promoting the insertion of aquaporins, which are water protein transporters.
• ADH facilitates water reabsorption from urine, leading to more concentrated urine and reduced urine volume.
• In diabetes insipidus, the absence of ADH prevents water reabsorption, resulting in:
  • Polyuria: Excessive urination.
  • Polydipsia: Excessive thirst due to water loss and subsequent volume depletion stimulating the thirst center in the hypothalamus.
  • Polyphagia: Increased eating.
• Normal urine output is 1-2 liters per day, while individuals with diabetes insipidus may excrete 3-5 gallons per day.
• The urine osmolarity in diabetes insipidus is low due to the high water volume.

Diabetes Mellitus

• Characterized into Type 1 and Type 2, as well as gestational diabetes and pre-diabetes.

Type 1 Diabetes

• Characterized by a lack of insulin due to the autoimmune destruction of beta cells in the Islets of Langerhans.
• The body's own immune system attacks and destroys beta cells, leading to insufficient insulin production.

Type 2 Diabetes

• Characterized by insulin resistance or insufficient insulin production.
• Beta cells may produce insulin, but either the amount is inadequate, or the insulin receptors are not functioning properly.
• Even if there are enough insulin produced, the receptors aren't working, leading to insulin ineffectiveness.

Gestational Diabetes

• Develops during pregnancy and typically resolves after labor, although some women may develop diabetes later in life.

Prediabetes

• A state where blood sugar levels are higher than normal but not high enough to be diagnosed as diabetes.

Serological Definitions

• Normal blood sugar (non-fasting): 70-140 mg/dL.
• Normal fasting blood sugar: 70-100 mg/dL.
• Prediabetes (non-fasting): 140-200 mg/dL.
• Prediabetes (fasting): 100-125 mg/dL.
• Diabetes (fasting): Over 126 mg/dL.
• Diabetes (postprandial): Over 200 mg/dL.

Pancreas Physiology

• Retroperitoneal organ behind the stomach.

Exocrine Function

• 99% of the pancreas is exocrine, producing digestive enzymes via acinar cells.
• Enzymes are released in inactive forms called zymogens, which are activated in the duodenum.
• Zymogens are produced by the rough endoplasmic reticulum in acinar cells and stored in vesicles for release into ducts.

Endocrine Function

• 1% of the pancreas is endocrine, consisting of the Islets of Langerhans, which produce hormones.
• Delta cells: 10% of islet cells, produce somatostatin. (Somatostatin roles are not very important in relation to diabetes.)
• Alpha cells: 20% of islet cells, produce glucagon.
• Beta cells: Majority of islet cells, produce proinsulin, which is cleaved into C-peptide and insulin.
• C-peptide has clinical importance. It is checked when blood samples are being taking, and it is used to see if the pancreas is producing the right ammount of insulin.

Insulin Production

• Proinsulin is synthesized in beta cells and cleaved into C-peptide and insulin.
• Beta cells possess glucose receptors: GLUT1 and GLUT3.
• When glucose enters the beta cell, it undergoes glycolysis, the Krebs cycle, and the electron transport chain. Also Adenosine Triphosphate (ATP) is produced
• ATP production closes potassium channels, causing the cell to depolarize.
• Depolarization opens calcium channels, increasing intracellular calcium levels.
• Increased calcium triggers the exocytosis of vesicles containing proinsulin, releasing C-peptide and insulin.

Here we have FOX receptor for glucose. Here we see that in beta cell has a special receptor for glucose. These are, we call it, GLUT1 and GLUT3. You don't have to know this for your exam, but it's important physiology knowledge. GLUT one and GLUT three.
*So when glucose come in, it gets, with the aerobic metabolism, it gets, glycolysis, Krebs cycle, and then, and then, we have electron chain, and then we have ATP production ATP production. That ATP production will close. Let me change the color. Here we have the gate of the potassium. Potassium usually gets out of the cell due to concentration gradient but this ATP will close actually this gate, potassium gate. Potassium cannot get out, it stays inside the cell. Potassium has positive charge, so beta cell becomes depolarized. When it becomes depolarized, let me change again the color. Here we have a calcium gate. So it with that depolarization, open the calcium gate and calcium comes in. We have increased intracellular calcium and the calcium will increase the exocytosis. Of those vesicles with the proinsulin. Here inside the vesicle we have proinsulin and they come out and they get a C peptide and then we have insulin as I shown here. So this is the way your insulin is getting produced. The reason I explain it because I'm gonna use it later when we are talking about pathophysiology and treatment.

Action of Insulin

• The main goal of insulin is to lower blood glucose levels.
• It enhances protein synthesis, preventing muscle breakdown.
• Inhibits gluconeogenesis, preventing the production of glucose from amino acids.
• Enhances fat deposition and prevents lipolysis (fat breakdown).
• Stimulates growth through the liver secretion of Insulin-like Growth Factor 1 (IGF-1), also known as somatomedin.

Insulin Effects on the Body:

• Enhances glycolysis.
• Stimulates fat production and inhibits fat breakdown.
• Promotes the synthesis of tissue protein.

Homeostasis of Blood Glucose Level

• When blood glucose levels rise, such as after a meal:
  • Gastrointestinal hormones, such as Glucose-dependent Insulinotropic Polypeptide (GIP) and Glucagon-like Peptide-1 (GLP-1) are released.
  • GIP and GLP-1 stimulate beta cells to produce insulin.
  • High blood glucose directly stimulates insulin production.
• Insulin acts on adipose and muscle cells, increasing the number of GLUT4 transporters on the cell membrane.
  • This increases glucose uptake from the blood, leading to decreased blood glucose levels.
• When blood glucose levels fall, such as during fasting:
  • Alpha cells produce glucagon.
  • Other hormones, such as cortisol, growth hormone, and catecholamines, also contribute.
  • Glucagon promotes glycogenolysis in the liver, breaking down glycogen into glucose.
  • Glucagon, through glycogenolysis, increases the concentration of sugar in the blood.

Fed State (After Meal)

• Two phases of insulin release:
  • First phase: Pancreas produces insulin upon tasting and smelling carbs.
  • Second phase: Glucose stimulates the beta cells receptor, and ATP closes potassium channels, calcium channels open, and insulin is produced.
• Incretin effect: GIP and GLP-1 stimulate insulin production and inhibit glucagon release.
  • These hormones tell the beta cells that glucose is coming, so it stimulate them to produce insulin.
• Insulin promotes glycolysis and glycogenesis in muscle tissue.
  *Insulin promotes glycogenesis. It tells the liver to store excess sugar and form glycogenesis.

Fasting State

• The ultimate goal of glucagon is to raise blood glucose levels.
• Glycogenolysis: The breakdown of glycogen increases glucose levels.
• Gluconeogenesis: Glucose is made from amino acids or fatty acids.
• Lipolysis: Fat is broken down.
• Glucagon is the primary hormone responsible, with support from steroids, growth hormone, and catecholamines.
  *In the fasting state, we produce glucagon. The glucagon is mainly in charge, but there are hormones that support glucagon like steroids, and catecholamines.

Characteristics of Diabetes Mellitus

• Chronic hyperglycemia due to an imbalance in blood glucose regulation.

Diagnosis

• Random blood glucose over 200 mg/dL with classic diabetes symptoms.
• Fasting blood glucose over 126 mg/dL.
• Glucose Tolerance Test: 75g glucose is given, measuring blood glucose at one and two hours.
  • If blood goes over 200\frac{mg}{dL}, then the diagnoss is confirmed
• A1C: Measures glycosylation of hemoglobin over approximately three months.
  • A1C above 6.5% indicates diabetes.

Clinical Symptoms

• Polyuria: Increased urination due to glucose in the urine pulling water along.
• Polydipsia: Excessive thirst due to water loss through urine.
• Polyphagia: Increased appetite.
• Weight loss.

Glucose Regulation Through Exercise

• Insulin levels drop, while glucagon and catecholamine levels rise.
• Muscle glucose uptake increases, lowering blood glucose levels.
• Lipolysis is stimulated, breaking down fat.
• Glycogenolysis in the liver increases glucose levels.
• Muscle contractions increase insulin sensitivity.

Stress and Glucose Production

• Corticosteroids (glucocorticoids) promote glucose production.
• Glucagonolysis and lipolysis are stimulated.
• Chronic stress leads to gluconeogenesis, increasing glucose levels.

Ketone Bodies Formation and Utilization

• Ketone bodies include beta-hydroxybutyric acid, acetoacetate, and acetone.
• In the presence of insulin, free fatty acids combine with glycerol to form triglycerides (lipogenesis).
• In the absence of insulin (e.g., type 1 diabetes), free fatty acids are converted to acetyl CoA, which is then converted to ketone bodies in the liver.
• Ketone bodies can be detected in the breath (acetone smell), urine (ketonuria), and blood. These ketone bodies are normally not present unless you are fasting for a very long time.
• Ketone bodies can be used by extrahepatic tissues for energy production via the Krebs cycle.
  *The bottom line Get from free fatty acids. We get ketone bodies in the blood, in the breath, in the urine folks. I'm gonna use this later, especially in form of complication in the type one diabetes if they get ketoacidosis situation.

Type 1 Diabetes Mellitus

• Destruction of beta cells of the pancreas, leading to absolute insulin deficiency.
• Usually immune-mediated (autoimmune) or idiopathic.
• Typically presents in young individuals.
• Lack of insulin leads to unopposed glucagon activity, resulting in:
  • Glycogenolysis and gluconeogenesis in the liver.
  • Hyperglycemia.
  • Free fatty acids are converted to ketones, leading to ketoacidosis.
• Ketoacidosis: A serious consequence of type 1 diabetes. If the person goes to the cafe or restaurant, and they beginn to eat, and they forgot to take their insulin, they are brought to hospital ER with the ketoacidosis because their ammount of glucose was very high. The levels can go high, and they go into ketoacidosis.
  • Symptoms include fruity acetone smell breath and Kussmaul respiration.
  • Ketone bodies in the urine (ketonuria) and metabolic acidosis occur.
  • Metabolic acidosis is often accompanied by hyperkalemia.

Type 2 Diabetes Mellitus

• Typically presents in older adults (over 45-50 years old).
• Characterized by insulin resistance or insufficient insulin production.
• Hyperinsulinemia may occur, where insulin is produced but ineffective due to receptor dysfunction.
• Risk factors include obesity, aging, female sex, and sedentary lifestyle.
• Ketoacidosis is rare.
• Nonketotic Hyperglycemic Hyperosmolar Coma (NHHOC) may occur, more common in older adults. The brain cell shrinks, and becomes smaller. Your brain may not be able to handle this shrinkage ,leading to a coma.

Comparing DKA and Hyperosmolar Hyperglycemic State (HHS)

Gestational Diabetes Mellitus

• Appears during pregnancy and is usually glucose intolerance.
• Caused by placental hormones and weight gain.
• Risk factors include severe obesity and previous gestational diabetes.
• Acute hyperglycemia can result from changes in nutrition, lack of exercise, or missed medication.

*Down phenomenon, as the name says, it's coming the early morning, why? Because you have some of these glucose hormones like growth hormone cortisol, glucagon, epinephrine, they are getting released in early morning, actually around four to five in the morning, and that's why your blood glucose goes up. This is what we call a down filament. Please remember, it's starting in the early morning.

Acute and Chronic Hyperglycemia

• Acute symptoms:
  • Polyuria, polydipsia, polyphagia, blurred vision.
  • Increased susceptibility to infection.
• Chronic hyperglycemia:
  • Intermittent changes in blood sugar can lead to metabolic syndrome, hypertension, and cardiovascular disease.
  • Complications divided into vascular and neuropathic categories.

Vascular Complications

• Macrovascular (large blood vessels):
  • Damage to vessels supplying the heart and brain, leading to heart disease and stroke.
  • Prevention includes caloric restriction, exercise, fat absorption control, and hypertension management.
  • Dyslipidemia contributes to coronary heart disease.
• Microvascular (small blood vessels):
  • Damage to small vessels in the retina and nephron (glomerulus).
  • Thickening of basement membrane caused by glycosylation-induced inflammation, fibrosis, and scar tissue.
    • Retinopathy: Blindness
    • Nephropathy: Renal failure and nephrosclerosis (protein loss in urine).
  • Prevention includes blood sugar control and hypertension management.

Oral Antidiabetic Agents (Overview)

• Biguanides (e.g., metformin): First-line choice for diabetes.
• Gliitazones (e.g., pioglitazone, rosiglitazone).
• Sulfonylureas (end in "-mide").
• Gliptins.
• Alpha-Glucosidase inhibitors: Block glucose absorption in intestine, but cause diarrhea and abdominal pain.

Treatment and Education

• Type 1 diabetes requires 100% insulin.
• Type 2 diabetes may require insulin later in the disease course.
• Different types of insulin:
  • Rapid-acting (aspart, lispro, glulisine): Administered before meals.
  • Long-acting (glargine, detemir): One or two doses per day.
  • Start with 2-3 units before each meal and adjust based on blood glucose measurements.

Assessment of Efficacy

• A1C monitoring for long-term blood glucose control.
• Blood glucose monitoring.
• Urine testing for ketones and glucose.