Insulin + Glucagon

• Insulin


  Hormone that promotes storage of ingested nutrients and inhibits their release
• Glucagon


  Hormone that breaks down fuel stores
• Fuel homeostasis problem

  • Metabolic processes constantly require energy, but food intake is intermittent
  • Solution is to ingest more calories than immediately needed and store them in reservoirs, then break down the fuel reservoirs for vital organs when not in a fed state
• Anabolic phase


  1. Synthesis of compounds constituting the body's structure and generally require energy (e.g. protein synthesis and glycogen synthesis)

  2. Begins with food ingestion and lasts for several hrs

  3. Caloric intake > demand energy storage

  4. Anabolic hormones: Build fuel stores (e.g. insulin & GH)
• Catabolic phase


  1. Oxidative processes that release energy (e.g. Ox phos and ETC chain)

  2. Begins 4-6 hrs after food ingestion; lasts until person eats again

  3. Demand > caloric intake energy mobilization

  4. Catabolic hormones: Break down fuel stores (e.g. glucagon, epinephrine & cortisol)
• Pancreas

  • Contains both endocrine and exocrine gland cells
  • Endocrine glands: sources of insulin, glucagon, and somatostatin

  
• Pancreas cell types

  • α cells (25%) secrete glucagon
  • β cells (60%) secretes insulin
  • δ cells secrete somatostatin

  
• Insulin

  • Protein hormone: 2 chains (A & B) + 2 disulfide bridges
  • B chain contains the core of biological activity
  • A chain contains most of the species-specific sites (insulin highly conserved among vertebrates)

  
• Insulin synthesis

  1. Gene directs synthesis of a preprohormone

  2. Signal peptide cleaved prohormone (I + C-peptide)

  3. C-peptide released in 1:1 ratio (+ small amt of proinsulin)

  4. Proinsulin has only 2% of the biological activity of insulin

  
• 1. C peptide


  • Indicates β cell function
  • Not removed by liver
  • Half-life is 3-4x insulin: 30 min
  • Function was to help fold insulin, now may be a hormone

  
• Insulin half-life

  • 4-6 min; cleared by receptor-mediated endocytosis, then lysosomal insulinases
  • ~50% of insulin is removed in a single pass thru the liver

  
• Insulin receptor


  • Tyrosine kinase-containing receptor
  • 2 α and 2 β subunits
  • Binding causes conformational change which activates TK
  • Autophosphorylation of the β subunit amplifies and prolongs the signal
  • Tyrosine kinase also phosphorylates cytoplasmic proteins (IRS-1 and IRS-2)
  • Insulin receptor complex can be internalized and degraded
• Insulin secretion regulation

  1. Adult pancreas secretes ~40-50 units I/day

  2. Basal level: 10 µU/ml (50% of total daily I)

  3. Mealtime: increases 8-10 min after a meal, peaks in 30-45 min, rapid decline and return to baseline 90-120 min

  4. Secretion is biphasic: early phase burst, late phase slower rise

  
• Incretins


  Amplify glucose-induced insulin release

  
• Insulin actions

  • Promotes storage of ingested nutrients and inhibits their release
  • Synthesizes proteins, CHO, lipids, nucleic acids
  • Major sites of action: liver, muscle, adipose tissue

  
• Glucose transporters

  • 14 glucose transporters encoded by human genome
  • SGLT1 & SGLT2: Na+ dependent
  • GLUT 1 & 3: ubiquitous, high affinity
  • GLUT 2: low affinity, bidirectional
  • GLUT 4: regulated by insulin, sequestered intracellularly
  • GLUT 5: transports fructose

  
• Insulin effects on glucose metabolism

  • 25-50 µU/ml necessary to affect liver and muscle
  • 10 µU/ml required to stimulate glucose uptake into fat
  • 1-2 µU/ml necessary to inhibit lipolysis

  
• Insulin is powerfully antiketogenic
• Ketoacidosis


  Triggered by lack of insulin and increase in counterregulatory hormones due to stress

  
• Diabetes mellitus is characterized by an absolute or relative deficiency of insulin and an absolute or relative excess of glucagon

  
• Diabetes is diagnosed if one of the following criteria is met: symptoms of diabetes and blood glucose of 200 mg/dL, fasting blood glucose > 126 mg/dL, 2 hr OGTT > 200 mg/dL, or hemoglobin A1c > 6.5%

  
• 96 million Americans have pre-diabetes (fasting blood glucose 100-125 mg/dL)
• Diabetes is more common among Pacific Islanders, Native Americans, esp African Americans + Asian Americans, than whites
• Obesity/diabetes

  Great genes in the wrong century
• T2D symptoms: Suddenly person is hungrier and thirstier than usual. Despite this, they lose weight. Urination is copious.

  
  

  Classic symptoms of DKA: Abdominal pain, nausea, and vomiting
• AMPk

  Activation of AMPK switches off ATP-consuming processes (ie, GNEO) while switching on catabolic processes that generate ATP (ie, lipid oxidation)
• Study: Obesity did not increase the risk of type 2 if those people had very low levels of POPs in their bodies
• The Lancet (2006): "This finding would imply that virtually all the risk of diabetes conferred by obesity is attributable to POPs, and that obesity is only a vehicle for such chemicals. This possibility is shocking."

  
• POPs tied to both type 1 (enhance autoimmunity) and type 2
• Thrifty genotype


  When cells get overfat, scientists call them "angry fat" that release inflammatory proteins = interfere with IRS-associated insulin signaling

  
• Causes of Insulin Resistance

  • Abnormal ß-cell secretory product
  • Abnormal insulin molecule
  • Incomplete conversion of proinsulin to insulin
  • Circulating insulin antagonists
  • Elevated levels of counter regulatory hormones, e.g., GH, cortisol, glucagon, or catecholamines
  • Anti-insulin antibodies
  • Anti-insulin receptor antibodies
  • Target tissue defects
  • Insulin receptor defects
  • Post receptor defects

  
• OGTT: blood taken 2 hrs after consuming a glucose-laden drink

  
• Possible symptoms of T2D: Fatigue, sores that don't heal, numbness
• Rx vs Lifestyle

  The Diabetes Prevention Program: n = 3,000 overweight, w/ bl glc < pre-diabetes range, Assigned to placebo, metformin, or lifestyle changes, Lifestyle: 2.5 hrs/wk brisk walking + lower fat diet, Result: After 3 years, lifestyle intervention cut risk of diabetes in half (with just a 9 lb loss!), Key to prevention: weight loss, Exercise helped in those who did not lose weight, but weight loss outperformed exercise, Metformin worked, but only half as well as weight loss
• Many chronic complications occur when tissues that are freely permeable to glucose are exposed to hyperglycemia
• DCCT: 76% retinopathy, 50% nephropathy, 60% neuropathy
• Hypoglycemia


  Not a complication of diabetes, Complication of treatment of diabetes, An imbalance between: Diabetes meds and food intake/activity, Hypoglycemia begets hypoglycemia - ANS becomes less responsive to bl glc; particularly dangerous w/ sleep
• Glucagon

  Glucagon's effects are what you would expect if the GLUCose is GONe, Actions of glucagon are opposite I - Mobilization of glucose (glycogenolysis and GNEO), Lipolysis in liver (small stores) and AT, Ketogenesis (directs FFA to β-oxidation not Tg synthesis), The I/G ratio determines the net physiological response - Fasting: I/G = 2 (Fed state I/G = 30)

  
• Glucagon Synthesis

  Pancreatic islets α-cells synthesize preproglucagon proglucagon glucagon, Intestinal cells: alternative processing of proglucagon GLP-1, Glucagon secretion - Major: hypoglycemia, Minor: aa, Epi, SNS, cortisol, GH

  
• Glucagonoma


  Signs/symptoms - "5 Ds:" Depression, Diabetes, Declining Weight, Deep Vein Thrombosis, and Dermatitis (erythematous scaly rash), Diagnosis - blood glucagon level, Treatment - Somatostatin analogues (octreotide) & surgery