Endocrine and Nutrition: pancreas, adipose cells

lies within abdominopelvic cavity

• 6 inches long
• 2 types:
• 1. exocrine pancreas
• 2. endocrine 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

• 1% of pancreatic cells (smaller percentage)
• clusters of endocrine cells are found in pancreatic islets of Langerhans and the cells secrete hormones into bloodstream

• 1. alpha cells
• 2. beta cells
• 3. delta cells
• 4. F cells

produce glucagon (inc. blood glucose by increasing rates of glycogen breakdown and glucose release by liver)

produce insulin (dec. blood glucose levels by increasing glucose uptake by cells increasing glycogen synthesis in skeletal muscle and liver)

secrete growth-hormone inhibiting hormone (GH-IH or somatostatin; dec. insulin and glucagon secretion, slows food absorption and enzyme secretion along digestive tract)

produce and secrete pancreatic polypeptide (inhibits gallbladder contractions and helps control rate of nutrient absorption by GI tract)

peptide hormone released by beta cells when glucose concentrations exceed normal levels (7-110 mg/dl)

(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

• 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

(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)

GLUT₄ found in striated muscle and adipose

• 1. brain
• 2. kidneys
• 3. digestive tract
• 4. RBCs

• (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
• 

• 1. factors that increase insulin secretion
• 2. factors that decrease 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)

• 1. dec. blood glucose
• 2. fasting
• 3. GH-IH/Somatostatin
• 4. sympathetic stimulation
• 5. leptin

peptide hormone released by alpha cells when blood glucose concentrations fall below normal range

• 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)

• (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

• 1. factors that increase glucagon secretion
• 2. factors that decrease 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

• 1. inc. blood glucose - causes inc. insulin
• 2. GH-IH/somatostatin

• Start: homeostasis - normal glucose levels
• pathways to disturb homeostasis:
• 1. rising blood glucose levels
• 2. declining 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

• 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

type of loose connective tissue

• 1. leptin
• 2. resistin

• 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)

• also produced by immune cells
• reduces insulin sensitivity throughout the body
• - thought to be a link between obesity and type 2 diabetes mellitus

• 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

• 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)
• 

• 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)

• 1. hyperglycemia
• 2. glycosuria
• 3. polyuria
• 4. polydipsia
• *same as type 2

• 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)

• 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

• 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)

• recombinant human insulin - first commercial use of recombinant technology
• works within 30 minutes, peaks in 3 hours

• recombinant human insulin
• works within 5-15 minutes, peaks in 1 hour
• pro: clumps less than Humulin™, so more bioavailable

• recombinant human insulin
• works within 1-2 hours, remains steadily active for 24 hours
• pro: slow release from injected tissue site

• recombinant human insulin
• works within 1-2 hours, remains steadily active for 24 hours
• pro: binds to albumin in circulation, slow release

• 1. hyperglycemia
• 2. glycosuria
• 3. polyuria
• 4. polydipsia
• *same as type 1

• 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)

• 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)

• 1. lifestyle modifications
• 2. oral Rx
• 3. non-oral Rx
• 4. analogue to GLP-1/incretin hormone (glucagon-like peptide-1)

• exercise and diet to reduce abdominal obesity
• weight loss of 10-15 lbs can restore insulin sensitivity

• 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

insulin

• 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

DPP-4 is an enzyme that breaks down incretin hormones

• 1. Byetta™ (Exenatide) - 2005 (top 200)
• 2. Januvia™ (sitagliptin) - 2006 (top 200)
• 3. Kombiglyze XR (metformin and saxagliptin) - 2010

• 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

• 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

• 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

• Normal hemoglobin (Hb) inside RBCs
• 4-6% is glycoslyated hemoglobin (Hb-A_1c)
• 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-A_1c levels of less than 6.5% or less than 7% (unless diabetic)

• 1. More glycosylated hemoglobin (Hb-A_1c)
• 6-10% is glycosylated hemoglobin (Hb-A_1c) --> decreased oxygen capacity of RBCs - feel fatigue
• 2. 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

• 1. diabetics have increased mortality
• -due to glucose damaging RBCs and blood vessels
• 2. damaged sperm
• -20% more mutations (May 2007, Human Repro)

(1) lower blood glucose --> (2) Hb-A_1c levels decreases --> (3) IF 1.0% reduction of Hb-A_1c --> (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)

• 1. syndrome X - metabolic disease
• 2. polycystic ovarian syndrome (PCOS)

• 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

• aka metabolic disease
• increases risk in:
• 1. diabetes
• 2. heart disease
• 3. stroke
• 4. peripheral artery disease (in women)

• aka metabolic disease
• 1. exercise and healthy eating
• 2. drugs (treatment of symptoms present)

• hormonal/endocrine disorder for females
• prevalence: 8% of all U.S. women - approximately 65% of women with PCOS are obese

• 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

• 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

• 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)