Patho: Endocrine

• Diabetes

  Normal glucose levels 60-70 to 100ish 

  Issue w the metabolism of carbs 

  • When carbs are metabolized (broken down) they form glucose. This raises the BG levels and the pancreas should release insulin to allow for the glucose to go inside of the cells to be converted into ATP but in someone with diabetes, this process is disrupted.

  4 types of diabetes

  Type 1

  Type 2

  Gestational DM

  Specific types of DM d/t other causes
• Epidemiology of Diabetes

  30 million Americans; 1 in 10 people affected

  Major risk factors:

  • Obesity
  • Sedentary lifestyle 
  • Non-white people
  • Hispanic, african american, native american
• Glucose production

  1.Glucose is a major energy source for cell function.

  2. Glucose is a large molecule and requires insulin to facilitate its diffusion into a cell

  3. Insulin is a hormone produced by the Beta cells of the Islets of Langerhans.

  4. Once absorbed by a cell, glucose can be either used for energy production or stored in the form of glycogen converted into fat.

  5. Glycogen can be stored in any cell, but most abundant in liver and muscle cells.

  6. Glycogenesis formation of glycogen

  7. Glycogenolysis is breakdown of glycogen to glucose
• Insulin

  • Know where it is produced 
  • In the pancreas, beta langerhan cells 
  • There is a rapid release following a meal. 
  • It binds to insulin receptors (in the cells), allowing for glucose uptake
  • Enhances cellular permeability to amino acids (anabolic hormone)
  • Insulin promotes protein synthesis by signaling cells to take up amino acids from the bloodstream and use them for building proteins
  • AAs are the building blocks of proteins, so what happens when you increase the abundance of AAs? Hypertrophy - meaning, in some way this acts like a GH type of hormone
• • Hyperinsulinemia (too much insulin in the blood) occurs with insulin resistance 
  • In insulin resistance, cells become less responsive to insulin's signal, leading to high blood sugar levels. The pancreas tries to compensate by releasing more insulin, but eventually, it may not be able to keep up, potentially leading to hyperinsulinemia.
• Glucagon

  • In the Alpha cells of Islets of langerhan 
  • Islets of Langerhans: These are clusters of specialized cells located within the pancreas. They contain different types of cells that produce various hormones, including insulin and glucagon.
  • Glucagon counteracts insulin (meaning it elevates BG)
• Somatostatin

  • Delta cells of Islets
  • Slows GI tract to prolong absorption  (it is an inhibitor)
  • Allows for food to sit there longer 
• Incretins

  • group of gut hormones that play a significant role in regulating blood sugar levels, particularly after eating. 
  • stimulate insulin secretion
• GH, Cortisol, Epinephrine,Progesterone, and Estrogen

  • Can help increase insulin secretion or glucose stimulus for insulin
  • All in all, help increase insulin levels
• Glucose regulation during prolonged starvation or fasting

  Liver → fatty acids and glycerol

  • Fatty acids to ketones
  • Glycerol undergoes gluconeogenesis to make glucose to raise BG levels 

  Muscle → AA → gluconeogenesis → raise BG 

  Ketones are acidic - presence usually indicates a problem (metabolism is altered) 

  Relevant for individuals who are hypoglycemic (d/t not eating) - in particular type I diabetics
• Glucose regulation during prolonged starvation or fasting

  A) Glycogenolysis

  B) fat

  C) muscle

  D) ketones

  E) Amino acids

  F) gluconeogenesis

  G) raised blood glucose

  
• Diabetes

  Type I DM– Immune mediated destruction of beta-cells leading to absolute insulin deficiency

  Type II DM– Insulin resistance with relative insulin deficiency; OR– Secretory defect along with insulin resistance

  • May make some insulin (even too much insulin) but the insulin cannot do its job effectively 
  • Risk increase with age, obesity, and lack of physical activity
• Diabetes diagnostic criteria

  Fasting blood sugar

  • Pre-diabetes: 100 to 125mg/dL
  • Diabetes: 126 mg/dL or greater

  Hemoglobin A1C–

  • Pre-diabetes: 5.7 to 6.4%
  •  Diabetes: 6.5% or greater
• The HbA1c test measures the average blood sugar control over the past 2-3 months by checking how much glucose has attached to red blood cells = measure the % of the proteins are glycosylated → tells you how much glucose the body has been exposed over a period of 90-120 days. 

  • Lifespan of a RBC is about 120 days. Glucose is sticky so it can stick to the RBC and that is how they measure it. 
• Type I DM

  Peak onset between at age 11-13 years

  Whites 1.5-2x greater incidence than others

  Seems to have genetic factor

  Normal weight or underweight

  • Bc they are not producing insulin, so the excess glucose (that is normally stored as fat) does not get stored 

  It is a/w

  Diabetic ketoacidosis (DKA) can be life-threatening (pH as low as 6.8, presence of ketones)
• Type I Dm

  Symptoms of Type I Diabetes Mellitus

  Polydipsia• Polyuria• Polyphagia

  • Too thirsty, peeing a lot, too hungry
  • d/t the cells not having enough glucose = cell is being starved 

  Weight loss

  Fatigue

  Recurrent infections

  Genital pruritus(fungal/candidal growth)

  Blurred vision
• Type II DM

  Occurs in 90-95% of those with DM

  Incidence in all age groups has doubled since 1980 – d/t food policy, diet, …

  Risk increases after age 40

  High in many traditionally hunter/gatherer groups (Native American/American Indian/ FirstNations)

  “Diabesity” – obesity, diabetes, chronic inflammatory processes

  • Increase risk of CVD 
• Metabolic syndrome

  Seen with abnormal glucose/insulin levels. It is the dysregulation of some metabolic processes. 

  Diagnose if 3+ of the following are abnormal 

  Glucose (elevated fasting glucose) 

  Lipid levels (triglyceride levels greater than 150, HDL less than 40) BP (elevated)

  Waist circumference greater than 40 in men, 35 in women

  r/o risk for CVD 

  • Esp atherosclerosis 
• Gestational diabetes

  Affects 4% of pregnant women

  Increases in hormones (especially estrogen) → increase insulin resistance 

  The insulin produced by the mother can pass through the placenta → babies born with excess insulin = hypoglycemia. Other issue is it may lead to large-for-gestational-age.

  Neonates with risk for obesity
• Maternal risk factors for gestational DM 

  • HTN, obesity, h/o GDM, strong FHx of DM, Urine + for glucose at prenatal visit, previous big baby (9 lbs), unexplained still birth in the past, prev delivery of infant with birth defect. 

  Bottom line is we don't know though bc many women who develop GDM don’t have any risk factors
• Urgent! Complications of Diabetes Mellitus

  Hypoglycemia– Excess exogenous insulin, inadequate food intake, excessive physical activity

  • Risk - neuro symptoms like confusion, disorientation, seizures, stupor, LOC, coma, death

  Diabetic ketoacidosis (DKA)– a/w Type I DM

  Hyperosmolar hyperglycemic nonketotic syndrome (HHNKS)–  a/w Type II DM
• Hypoglycemia sx

  Signs and symptoms

  – Sweating

  – Hunger

  – Dizziness

  – Nervousness

  – Tremulousness

  – Irritability

  – Headache

  – Heart palpitations

  – Confusion

  – Disorientation

  – Inability to concentrate

  – Seizures

  – Stupor or loss of consciousness

  Can lead to coma and death
• DKA

  Serum glucose > 250 mg/dL

  Serum bicarbonate < 18 mmol/dL (LOW) - metabolic acidosis 

  Serum pH < 7.30 (LOW)

  Presence of an anion gap

  • Measures the difference—or gap—between the negatively charged and positively charged electrolytes in your blood.
  • If gap is high your blood is acidic, if low your blood is not acidic enough 

  Presence of urine and serum ketones

  • More ketones leads to more glucose formation adding to the initial problem of elevated BG (but because the pancreas is malfunctioning, the glucose can't get into the cells so the body doesn't recognize there is enough sugar)
• Hyperosmolar Hyperglycemic Nonketotic Syndrome (HHNKS)

  Insulin is not working effectively = leads cells to believe the cells are starved 

  Serum glucose > 600 mg/dL

  Serum pH > 7.30 (close to normal, not as acidotic bc no ketones are present) 

  Serum bicarbonate >15 mmol/L 

  Serum osmolality >320 mOsm/L  (high) 

  Absence (or very small amount) of ketones
• Main tx for both DKA and HHNKS - give insulin to correct BG levels, and IV fluids to hydrate. DKA might need mechanical ventilation. 
• Long-Term Complications of Diabetes (part 1)

  Vascular– Accelerates atherosclerosis, CAD, CVA, PAD, retinopathy, nephropathy; – Endothelium is over activated (d/t excess glucose) and injured (small vessels) = makes it easy for LDL to get deposited underneath, enhanced leukocyte attachment and migration. Chronically, it can lead to a loss of a response of the endothelial cells and underlying cells = don't respond to NO bc they don't produce as much
• Long-Term Complications of Diabetes (part 2)

  Microalbuminuria progressing to end-stage renal disease (ESRD)

  • Proteins typically get reabsorbed back into the body, you don’t pee it. However, longstanding damage to the nephron = you might see the proteins (like albumin) leaking out of the nephron into the urine = microalbuminuria 
• Long-Term Complications of Diabetes (part 3)

  Neuropathies (can lead to not always feeling chest pain from a heart attack)

  • Abnormalities with the nerves - things feel differently or don't sense/respond to stimuli as appropriately

  Impaired immunity and wound– immunosuppression 

  • Impairs ability for wound to heal = amputations 

  Reproductive– Vaginitis, balanitis; – GDM

  • balanitis : inflammation of the glans penis (head of the penis)

  Psychological– Anxiety, depression, eating disorder
• Overview of endocrine signaling

  When the endocrine system dysfunctions, there is an imbalance of hormones that can cause hyperfunction hypofunction of the target organ. Dysfunction can occur at the hypothalamus, the pituitary, or with the individual endocrine gland itself (organ). 

  Hypothalamus—Pituitary—Endocrine gland
• When the endocrine system dysfunctions, there is an imbalance of hormones that can cause hyperfunction hypofunction of the target organ. Dysfunction can occur at the hypothalamus, the pituitary, or with the individual endocrine gland itself (organ). 

  Stimulation -Hypothalamus—Pituitary—Tropic Hormones -Endocrine gland
• Regulation of Hormone Release

  Chemical factors– changes in blood glucose (GH, insulin), calcium level (affects hormone production: PTH)

  Endocrine factors–endocrine gland controlling another (pancreas produces insulin, insulin controls other organs)
• Regulation of Hormone Release

  Neural control

  • Direct Innervation: Certain endocrine glands, like the adrenal glands, receive nerve signals directly from the nervous system. These signals can stimulate or inhibit hormone release.
  • Hypothalamus Connection: The hypothalamus, a key player in hormonal control, is also directly linked to the nervous system. It can receive signals from various parts of the brain, allowing emotions, stress, and sensory input to influence hormone release
• Hormones tend to bind to receptors. They are either water or fat soluble → bind to receptor which leads to series of effects that causes a response. 

  Water soluble hormones need a membrane receptor, second messenger (amplifies a signal, such as cAMP) and protein kinase A or C for the cellular response. 

  Fat soluble can pass through to the intracellular receptor.

  How the signal gets turned off

  • Negative signal mechanism
• Negative feedback - shuts down signaling

  A) -

  B) -

  C) +

  D) +

  
• Pituitary as the “Master Gland"Pea sized gland deep in brain that serves as the coordinating center for the endocrine system

  Anterior pituitary –adenohypophysis (tropic hormones)

  • FLAT PEG 💥
  • FSH, LH, ACTH, TSH, Prolactin, (E=nothing), GH

  Posterior pituitary -neurohypophysis

  • ADH, Oxytocin
• Hypothalamic-Pituitary Adrenal(HPA) Axis

  Stress happens: You encounter a stressful situation (emotional, physical)

  The hypothalamus detects the stress and releases CRH.

  The CRH travels to the pituitary gland, prompting it to release another hormone called ACTH.

  ACTH reaches the adrenal glands, stimulating them to release cortisol.

  Cortisol increases blood sugar levels, boosts energy, decrease digestion = cope w stressor

  Once the stressor is gone, cortisol levels start to drop. This signals the hypothalamus and pituitary gland to turn off CRH and ACTH production.
• Endocrine dysfunction

  Three major types of endocrine conditions:

  – Hormone deficiency

  – Hormone excess

  – Hormone resistance

  Endocrine dysfunction:

  – Primary disorder, dysfunction caused by the endocrine gland itself

  – Secondary disorder,dysfunction caused by abnormal pituitary activity

  – Tertiary disorder,dysfunction caused by hypothalamic origin
• Autoimmunity in Endocrine Dysfunction

  Autoimmunity triggers inflammation in the target organ

  Result is either hypofunction hyperfunction of the gland 

  Abs can cause destruction of gland *
• Neoplasia in Endocrine Dysfunction

  Tumors can be a source of excess hormones that don’t respond to the feedback loop

  A pituitary tumor can affect multiple endocrine glands under its control

  Lung tumors have been known to secrete many different hormones (NEC tumors like SCLC)
• Disorders of the Pituitary

  Hypopituitarism, hyposecretion of 1 or more of the pituitary (trophic) hormones:

  – Adrenocorticotropic hormone (ACTH)

  – Growth hormone (GH)

  – Prolactin

  – Thyroid-stimulating hormone (TSH)

  – Luteinizing hormone (LH)

  – Follicle stimulating hormone (FSH)

  Incidence is unclear, estimates between 2 to 37 per 100,000

  Congenital hypopituitarism is a rare disease of 1 in 3,000 or 4,000 births