Endocrine and Nutrition: pancreas, adipose cells

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Endocrine and Nutrition: pancreas, adipose cells
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Endocrine role in nutrition: pancreas and adipose. IBHS 525 final. Bryant
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  1. Location of the pancreas
    lies within abdominopelvic cavity
  2. Characteristics of pancreas
    • 6 inches long
    • 2 types:
    • 1. exocrine pancreas
    • 2. endocrine pancreas
  3. context: characteristics of pancreas - 2 types of pancreas
    exocrine pancreas
    • 99% of pancreatic volume
    • clusters of gland cells (pancreatic acini) secrete an alkaline fluid with large amounts of digestive enzymes into ducts that lead into digestive tract
  4. context: characteristics of pancreas - 2 types of pancreas
    endocrine pancreas
    • 1% of pancreatic cells (smaller percentage)
    • clusters of endocrine cells are found in pancreatic islets of Langerhans and the cells secrete hormones into bloodstream
  5. context: endocrine pancreas
    4 types of cells in the islets of Langerhans
    • 1. alpha cells
    • 2. beta cells
    • 3. delta cells
    • 4. F cells
  6. context: endocrine pancreas - 4 types of cells in the islets of Langerhans
    alpha cells
    produce glucagon (inc. blood glucose by increasing rates of glycogen breakdown and glucose release by liver)
  7. context: endocrine pancreas - 4 types of cells in the islets of Langerhans
    beta cells
    produce insulin (dec. blood glucose levels by increasing glucose uptake by cells increasing glycogen synthesis in skeletal muscle and liver)
  8. context: endocrine pancreas - 4 types of cells in the islets of Langerhans
    delta cells
    secrete growth-hormone inhibiting hormone (GH-IH or somatostatin; dec. insulin and glucagon secretion, slows food absorption and enzyme secretion along digestive tract)
  9. context: endocrine pancreas - 4 types of cells in the islets of Langerhans
    F cells
    produce and secrete pancreatic polypeptide (inhibits gallbladder contractions and helps control rate of nutrient absorption by GI tract)
  10. what is insulin?
    peptide hormone released by beta cells when glucose concentrations exceed normal levels (7-110 mg/dl)
  11. general process of insulin physiology
    (1) ingestion of a meal --> (2) glucose absorbed from intestines into blood --> (3) glucose stimulates insulin release from pancreas --> (4) pancreas releases insulin --> (5) insulin allows glucose to enter cells for energy and/or storage
  12. context: endocrine pancreas - islets of Langerhans
    4 effects of insulin on target cells
    • 1. accelerates glucose uptake and utilization (insulin-dependent cells), increased ATP production
    • 2. stimulates glycogen formation in skeletal muscles and liver (glycogenesis ^ genesis = formation)
    • 3. inc. amino acid uptake and protein synthesis
    • 4. stimulates fatty acid and glucose uptake in adiptocytes
    • -fatty acids are stored as triglycerides, excess glucose is used to synthesize more triglycerides
  13. mechanism of insulin
    (1) high blood glucose stimulates insulin to bind to insulin receptors (enzyme-linked receptor/tyrosine kinase receptor) --> (2) autophosphorylation --> (3) intracellular actions - translocation of glucose transporters type 4 (GLUT4) to cell membrane --> GLUTs transport glucose into cells via facilitated diffusion (no energy required)
  14. Location of GLUT4 before mechanism of insulin
    GLUT4 found in striated muscle and adipose
  15. 4 cells that don't need insulin to take up glucose
    • 1. brain
    • 2. kidneys
    • 3. digestive tract
    • 4. RBCs
  16. process of regulation of insulin secretion
    • (1) glucose enters beta cells via GLUT2 --> (2) glycolysis - glucose is broken down --> (3) ATP is made --> (4) ATP-sensitive K+ channels close due to ATP around --> (5) depolarization occurs --> (6) voltage-gated calcium channels open --> (7) calcium stimulates exocytosis of insulin into bloodstream
  17. 2 categories of factors that affect insulin secretion
    • 1. factors that increase insulin secretion
    • 2. factors that decrease insulin secretion
  18. context: 2 categories of factors that affect insulin secretion
    6 factors that increase insulin secretion
    • 1. inc. blood glucose (mechanism discussed prior)
    • 2. inc. blood free fatty acids
    • 3. inc. blood amino acids
    • 4. GI hormones
    • 5. growth hormone, cortisol
    • 6. parasympathetic stimulation (ACh)
  19. context: 2 categories of factors that affect insulin secretion
    5 factors that decrease insulin secretion
    • 1. dec. blood glucose
    • 2. fasting
    • 3. GH-IH/Somatostatin
    • 4. sympathetic stimulation
    • 5. leptin
  20. context: endocrine pancreas - islets of Langerhans
    what is glucagon?
    peptide hormone released by alpha cells when blood glucose concentrations fall below normal range
  21. context: endocrine pancreas - islets of Langerhans
    3 effects of glucagon on target cells
    • 1. stimulates breakdown of glycogen stores in skeletal muscle and liver (glycogenolysis ^ lysis = breakdown)
    • -glucose utilized by muscle cells, liver cells release glucose into bloodstream
    • 2. release fatty acids from adipocytes into bloodstream
    • -getting another energy source through the breakdown of triglycerides
    • 3. stimulates glucose production in liver
    • -liver cells take up amino acids from bloodstream, convert them to glucose, and release the glucose into circulation (gluconeogenesis ^ neo = new, genesis = formation)
  22. mechanism of glucagon
    • (1) low blood glucose stimulates glucagon to bind to glucagon receptors (GPCRs - Gs, cAMP) --> (2) antagonistic/opposing effects of insulin
    • *work together with insulin to maintain normal blood glucose levels
  23. 2 categories of factors that affect glucagon release
    • 1. factors that increase glucagon secretion
    • 2. factors that decrease glucagon secretion
  24. context: 2 categories of factors that affect glucagon secretion
    3 factors that increase glucagon secretion
    • 1. dec. blood glucose
    • 2. inc. amino acids stimulates glucagon
    • -only effect that's same as insulin: amino acids are quickly converted to glucose
    • 3. exercise
    • -in order to prevent a decrease in blood glucose
    • -sympathetic nervous system
  25. context: 2 categories of factors that affect glucagon secretion
    2 factors that decrease glucagon secretion
    • 1. inc. blood glucose - causes inc. insulin
    • 2. GH-IH/somatostatin
  26. blood glucose homeostasis (regulation)
    • Start: homeostasis - normal glucose levels
    • pathways to disturb homeostasis:
    • 1. rising blood glucose levels
    • 2. declining blood glucose levels
  27. context: blood glucose homeostasis (regulation) - 2 pathway
    pathway of rising blood glucose levels
    • general: insulin stimulated by inc. blood glucose causing dec. blood glucose
    • (1) homeostasis disturbed --> (2) beta cells secrete insulin --> (3) a) increased rate of glucose transport into target cell b) increased rate of glucose utilization and ATP generation c) increased conversion of glucose to glycogen (liver, skeletal muscles) d) increased amino acid absorption and protein synthesis e) increased triglyceride synthesis (adipose tissue) --> (4) blood glucose concentration declines --> (5) homeostasis restored
  28. context: blood glucose homeostasis (regulation) - 2 pathways
    pathway of declining blood glucose levels
    • general: glucagon stimulated by dec. blood glucose causing inc. blood glucose
    • (1) homeostasis disturbed --> (2) alpha cells secrete glucagon --> (3) a) increased breakdown of glycogen to glucose (liver, skeletal muscle) b) increased breakdown of fats to fatty acids (adipose tissue) c) increased synthesis and release of glucose (liver) --> (4) blood glucose concentration rises --> (5) homeostasis restored
  29. what is adipose tissue?
    type of loose connective tissue
  30. adipose tissue produces 2 hormones
    • 1. leptin
    • 2. resistin
  31. context: 2 hormones produced by adipose tissue
    leptin
    • released when adipocytes are absorbing lipids and glucose (like following a meal)
    • acts on CNS to suppress appetite
    • must be present for normal GnRH and gonadotropin synthesis (females must have a minimum level of fat for normal reproductive function - FSH, LH)
  32. context: 2 hormones produced by adipose tissue
    resistin
    • also produced by immune cells
    • reduces insulin sensitivity throughout the body
    • - thought to be a link between obesity and type 2 diabetes mellitus
  33. leptin vs obesity: effect of leptin knockout (KO)
    cure for obesity?
    • made Leptin KO mice which means they lack the gene for leptin
    • leptin KO ice were obese and had an insatiable appetite
    • injecting exogenous leptin returned mice to normal, leaner state
    • Humans: most obese humans have high levels of leptin (leptin resistance)
    • -maybe by alterations in leptin receptor or intracellular signaling pathway
  34. Diabetes mellitus (DM)
    • group of diseases characterized by high blood glucose levels
    • prevelance: 7.8% of U.S. population has diabetes (all ages, 2007)
    • -23.1% of all people 60 years or older have diabetes
    • Diabetes: excess urination (polyuria)
    • -results in excess thirst (polydipsia)
    • Mellitus: excess glucose in urine (glycosuria)
    • -results from excess glucose in blood (hyperglycemia)
  35. 3 types of diabetes mellitus (DM)
    • 1. Type 1 (accounts for 5-10% of cases)
    • -previously called juvenile-onset or insulin-dependent
    • 2. Type 2 (accounts for 90-95% of cases)
    • -previously called adult-onset or non-insulin-dependent
    • 3. Gestational (transient)
    • -aka. pregnancy-onset (about 1/2 later develop type 2 DM)
  36. context: 3 types of diabetes mellitus (DM)
    4 symptoms of type 1 DM
    • 1. hyperglycemia
    • 2. glycosuria
    • 3. polyuria
    • 4. polydipsia
    • *same as type 2
  37. context: 3 types of diabetes mellitus (DM)
    2 causes of type 1 DM
    • 1. decreased level of or lack of insulin
    • 2. due to destruction of beta cells by 3 ways:
    • a) autoimmune disease- antibodies against beta cells
    • b) viral infection
    • c) genetics (small component)
  38. context: 3 types of diabetes mellitus (DM)
    2 results of having type 1 DM
    • 1. dehydration, unexplained weight loss
    • 2. untreated DM:
    • -DKA (diabetic ketoacidosis) - hyperglycemia with lack of insulin causes cells in body to switch to metabolism of fat, which causes production of ketoacids (ketones), which lowers blood pH
  39. context: 3 types of diabetes mellitus (DM)
    4 drug treatments for type 1 DM
    • need exogenous insulin to survive
    • typically need a combination of short and longer acting insulin; pre-prepared combo's available
    • insulins (top 200):
    • 1. Humulin™ (isophane or regular)
    • 2. Humalog™ (lispro)
    • 3. Lantus™ (glargine)
    • 4. Levemir™ (detemir)
    • *can use an insulin pump:
    • dosage instructions are entered into the pump's small computer and the appropriate amount of insulin is then injected into the body in a calculated, controlled manner (subcutaneously)
  40. context: 3 types of diabetes mellitus (DM) - 4 drug treatments for type 1 DM
    Humulin™ (isophane or regular)
    • recombinant human insulin - first commercial use of recombinant technology
    • works within 30 minutes, peaks in 3 hours
  41. context: 3 types of diabetes mellitus (DM) - 4 drug treatments for type 1 DM
    Humalog™ (lispro)
    • recombinant human insulin
    • works within 5-15 minutes, peaks in 1 hour
    • pro: clumps less than Humulin™, so more bioavailable
  42. context: 3 types of diabetes mellitus (DM) - 4 drug treatments for type 1 DM
    Lantus (glargine)
    • recombinant human insulin
    • works within 1-2 hours, remains steadily active for 24 hours
    • pro: slow release from injected tissue site
  43. context: 3 types of diabetes mellitus (DM) - 4 drug treatments for type 1 DM
    Levemir (detemir)
    • recombinant human insulin
    • works within 1-2 hours, remains steadily active for 24 hours
    • pro: binds to albumin in circulation, slow release
  44. context: 3 types of diabetes mellitus (DM)
    4 symptoms of type 2 DM
    • 1. hyperglycemia
    • 2. glycosuria
    • 3. polyuria
    • 4. polydipsia
    • *same as type 1
  45. context: 3 types of diabetes mellitus (DM)
    2 causes of type 2 DM and 4 sets of possible causes/risk factors
    • 1. resistance to insulin
    • -excess abdominal fat, obesity - due to excess hormones and cytokines released from adipocytes
    • 2. genetic (more so than type 1)
    • risk factors (possible causes):
    • 1. gestational diabetes - risk factor for type 2 DM
    • 2. inc. cholesterol, inc. triglycerides, inc. LDLs, dec. HDL, inc. blood pressure (metabolic syndrome)
    • 3. obesity (especially abdominal fat)
    • 4. Polycystic ovarian syndrome (PCOS)
  46. context: 3 types of diabetes mellitus (DM)
    1 result of having type 2 DM
    • 1. high insulin levels (change endothelium and lead to clotting problems and high blood glucose levels
    • -over time insulin secretion can decrease (need for exogenous insulin)
  47. context: 3 types of diabetes mellitus (DM)
    3 approaches for treatment for type 2 DM + 1 possible approach to treatment
    • 1. lifestyle modifications
    • 2. oral Rx
    • 3. non-oral Rx
    • 4. analogue to GLP-1/incretin hormone (glucagon-like peptide-1)
  48. context: 3 types of diabetes mellitus (DM) - 3+1 treatment approaches for type 2 DM
    lifestyle modifications
    • exercise and diet to reduce abdominal obesity
    • weight loss of 10-15 lbs can restore insulin sensitivity
  49. context: 3 types of diabetes mellitus (DM) - 3+1 treatment approaches for type 2 DM
    3 types of oral Rx
    • 1. antihyperglycemic drugs (dec. gluconeogenesis in liver)
    • -Biguanides: Metformin (top 200)
    • 2. hypoglycemic drugs (inc. insulin secretion)
    • -Sulfonylureas: Glipizide (top 200), Glyburide (top 200), Glimepiride (top 200)
    • 3. antihyperglycemic drugs (in. insulin sensitivity)
    • -Thiozolidinediones: Glitazones: Rosiglitazone (Avandia™), Pioglitazone (Actos™) (top 200) - significant increase risk for heart failure
  50. context: 3 types of diabetes mellitus (DM) - 3+1 treatment approaches for type 2 DM
    non-oral Rx
    insulin
  51. context: 3 types of diabetes mellitus (DM) - 3+1 treatment approaches for type 2 DM
    analogue to GLP-1/ incretin hormone (glucagon-like peptide-1)
    • Exendin-4 (from Gila monster saliva)
    • 2nd process of insulin stimulation by meal (endogenously):
    • (1) GI tract secretes glucagon-like peptide-1 (GLP; incretin hormone) --> (2) GLP-1 bind to GLP-1 receptors in pancreas --> (3) pancreas a) increase insulin production and secretion b) decrease glucagon secretion
  52. context: diabetes mellitus (DM) - 3 drugs that target 2nd process of insulin stimulation for diabetes
    Dipeptidyl Peptidase-4 (DPP-4)
    DPP-4 is an enzyme that breaks down incretin hormones
  53. context: diabetes mellitus (DM)
    3 drugs that target 2nd process of insulin stimulation for diabetes
    • 1. Byetta™ (Exenatide) - 2005 (top 200)
    • 2. Januvia™ (sitagliptin) - 2006 (top 200)
    • 3. Kombiglyze XR (metformin and saxagliptin) - 2010
  54. context: diabetes mellitus (DM) - 3 drugs that target 2nd process of insulin stimulation for diabetes
    Byetta™ (Exenatide)
    • 2005 (top 200)
    • synthetic version of exendin-4
    • binds and activates glucagon-like peptide-1 receptor (resistant to breakdown by dipeptidyl peptidase-4 (DPP-4))
    • s.c. injection 60 minutes before a meal
    • *Oct. 16th 2007: FDA warns of possible link between diabetes drug and acute pancreatitis
  55. context: diabetes mellitus (DM) - 3 drugs that target 2nd process of insulin stimulation for diabetes
    Januvia™ (sitagliptin)
    • 2006 (top 200)
    • oral drug, once a day
    • Dipeptidyl Peptidase-4 (DPP-4) inhibitor:
    • (1) inhibiting enzyme causes decreased breakdown of incretins --> (2) increased incretin levels --> (3) a) increased insulin production b) decreased glucose from the liver
  56. context: diabetes mellitus (DM) - 3 drugs that target 2nd process of insulin stimulation for diabetes
    Komiglyze XR (metformin and saxagliptin)
    • 2010 (November 5th)
    • first and only once-a-day metformin extended-release (XR) plus dipeptidyl peptidase-4 (DPP-4) inhibitor combination tablet
    • intended to treat 3 main problems of DM type 2:
    • 1. increases insulin secretion in a glucose-dependent manner
    • 2. suppresses hepatic gluconeogenesis
    • 3. improves insulin sensitivity
  57. context: Future complications of diabetes (1 and 2)
    Non-diabetic
    • Normal hemoglobin (Hb) inside RBCs
    • 4-6% is glycoslyated hemoglobin (Hb-A1c)
    • process:
    • (1) normal glucose levels in blood --> (2) glucose sticks to hemoglobin (sugar + protein = glycosylated protein) --> (3) decreases ability for RBCs to carry oxygen
    • goal: recommendation of Hb-A1c levels of less than 6.5% or less than 7% (unless diabetic)
  58. context: Future complications of diabetes (1 and 2)
    2 effects of chronic hyperglycemia
    • 1. More glycosylated hemoglobin (Hb-A1c)
    • 6-10% is glycosylated hemoglobin (Hb-A1c) --> decreased oxygen capacity of RBCs - feel fatigue
    • 2. chronic glucose damages endothelium (blood vessels)
  59. context: Future complications of diabetes (1 and 2) - 2 effects of chronic hyperglycemia
    6 "events"/damages from chronic glucose damages endothelium (blood vessels)
    • 1. vascular "events"
    • -increases atherosclerosis (fat deposition)
    • -increases clotting (embolism risk)
    • -aneurysm
    • 2. nephropathy (kidney damage)
    • -22% increased risk
    • 3. retinopathy (eye damage)
    • -20% increased risk
    • 4. footopathy (foot damage)
    • -13% increased risk
    • 5. cardiovascular "events" (major cause of morbidity and mortality risk in diabetics)
    • -7% increased risk of:
    • a) congestive heart failure (CHF)
    • b) myocardial infarction (MI; heart attack)
    • c) stroke (brain attack)
    • 6. neuropathy (neuron damage)
    • -pain
  60. context: Future complications of diabetes (1 and 2)
    big picture: 2 points
    • 1. diabetics have increased mortality
    • -due to glucose damaging RBCs and blood vessels
    • 2. damaged sperm
    • -20% more mutations (May 2007, Human Repro)
  61. context: Future complications of diabetes (1 and 2)
    general process to lower Hb-A1c levels
    (1) lower blood glucose --> (2) Hb-A1c levels decreases --> (3) IF 1.0% reduction of Hb-A1c --> (4) a) 50% drop in microvascular damage (damage to blod vessels) b) 35% drop in complications (of kidneys, eyes, limbs) c) 20% drop in cardiovascular events (MI, stroke)
  62. 2 syndromes to know
    • 1. syndrome X - metabolic disease
    • 2. polycystic ovarian syndrome (PCOS)
  63. context: 2 syndromes to know
    syndrome X
    • aka metabolic disease
    • presence of 3 or more of 5 factors:
    • 1. central (abdominal) obesity - elevated waist circumference
    • 2. elevated triglycerides
    • 3. dec. HDL levels
    • 4. elevated blood pressure (hypertension)
    • 5. elevated blood glucose (may be due to insulin resistance
  64. context: 2 syndromes to know
    4 risks increased by syndrome X
    • aka metabolic disease
    • increases risk in:
    • 1. diabetes
    • 2. heart disease
    • 3. stroke
    • 4. peripheral artery disease (in women)
  65. context: 2 syndromes to know
    2 types of treatments for syndrome X
    • aka metabolic disease
    • 1. exercise and healthy eating
    • 2. drugs (treatment of symptoms present)
  66. context: 2 syndromes to know
    polycystic ovarian syndrome (PCOS)
    • hormonal/endocrine disorder for females
    • prevalence: 8% of all U.S. women - approximately 65% of women with PCOS are obese
  67. context: 2 syndromes to know
    9 symptoms of polycystic ovarian syndrome (PCOS)
    • 1. menstrual irregularities
    • 2. polycystic ovaries
    • 3. infertility/anovulation
    • 4. obesity
    • 5. acne
    • 6. hirsutism (excess growth of facial hair)
    • 7. alopecia - hair loss
    • 8. insulin insensitivity/diabete mellitus type 2
    • 9. metabolic syndrom/hypertension
  68. context: 2 syndromes to know
    2 causes of polycystic ovarian syndrome (PCOS)
    • 1. obesity/insulin insensitivity
    • -process: (1) inc. adipose desensitizes insulin receptors --> (2) insulin levels inc.
    • 2. infertility/male characteristics
    • -process: (1) inc. insulin levels --> (2) inc./excess androgen production --> (3) hormone imbalance of androgen --> (4) a) formation of cysts in ovaries b) infertility c) menstrual irregularities d) acne e) hair growth problems
  69. context: 2 syndromes to know
    5 types of treatments for polycystic ovarian syndrome
    • depending on symptoms:
    • 1. weight loss
    • -5% weigh loss can improve symptoms
    • 2. birth control pill
    • -for those who need contraception; acne
    • 3. Spiranolactone (Top 200)
    • -antagonist to aldosterone
    • -for acne, hirsutism, hypertension
    • 4. Clomiphene (CLOMID)
    • -for infertility
    • 5. Metformin (Top 200)
    • -for insulin insensitivity, diabetes mellitus type 2, infertility (combined with clomiphene)

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