rxstudyguidesuic.files.wordpress.com · Web viewOral glucose tolerance test = plasma glucose rises higher and returns to baseline slower than normal people for people with diabetes

(Last Updated: 08/18/2018) Created by: Socco, Samantha

Diabetes MellitusWaller, D. (2016). Diabetes. Lecture presented at PHAR 410 Lecture in UIC College of Pharmacy,

Chicago.

Overview of Insulin

Islets of Langerhans secrete glucagon and insulin o Function in regulation of intermediate metabolism of carbs and proteins and fats o Also secrete:

Somatostatins = regulation of islet cell secretion Pancreatic polypeptide = regulation of ion transport in intestine

Insulin = anabolic increases storage Glucagon = catabolic breaks down Insulin excess = hypoglycemia Insulin deficiency = diabetes mellitus Islets of Langerhans Anatomy

o β islets make up 2%, exocrine portion makes up 80%, ducts/blood vessels make up the rest

o Blood from islets drain into hepatic portal vein o A cells secrete glucagon, B cells secrete insulin, D cells secrete somatostatin, F

cells secrete pancreatic polypeptide o B cells are the major cells located in the center of the islets. Tend to be

surrounded by A cells (next most common), then D and F cells o B cell granules with insulin polymers (w/ zinc) found in cytoplasm

Have different shaped granules, while A ell granules are fairly uniform


Insulin structure o Polypeptides containing two chains of amino acids linked by disulfide bridges o Synthesized in rough E.R of B cells

Transported into Golgi, packaged into granules, Granules plasma membrane contents released through exocytosis Insulin goes through the basal lamina of the B cell basal lamina of the

capillary fenestrated capillary endothelium bloodstream o Pre-hormone from E.R

Folded with disulfide bonds proinsulin C peptide is removed before secretion of functional insulin

Fate of Secreted Insulin o IGF-1 and IGF-II have insulin-like effectso t1/2 = 5 minutes. Binds to insulin receptor internalized destroyed by

proteases in endosomes Principle Actions of Insulin:

o Rapid = increases transport of glucose, amino acids, and K+ into insulin-sensitive cells

o Intermediate = Stimulation of protein synthesis Inhibition of protein degradation


Activation of glycolytic enzymes and glycogen synthase Inhibition of phosphorylase and gluconeogenic enzymes

o Delayed (hrs) = increase in mRNAs for lipogenic and other enzymes


Tissue-Specific Action of Insulin o Adipose tissue

Increases glucose entry Increases fatty acid synthesis Increases glycerol phosphate synthesis Increases triglyceride deposition Activation of lipoprotein lipase Inhibition of hormone sensitive lipase Increase in K+ reuptake

o Muscle Increased glucose entry Increased glycogen synthesis Increased amino acid uptake Increased protein synthesis in ribosomes Decreased protein catabolism Decreased release of gluconeogenic amino acids Increased ketone uptake Increase in K+ reuptake

o Liver Decrease in ketogenesis Increased protein synthesis Increased lipid synthesis Increased glycolysis

o General Increased cell growth

Glucose Transporters


o Enters cells by facilitated diffusion o Enters intestines and kidneys by active transport with Na+

o Insulin can increase # of glucose transporters (GLUTs) in adipose, muscle, other tissue

o GLUTs 1-7: amino and carboxy ends are inside the cell All have a specific function GLUT 4 = transporter in adipose and muscle that’s sensitive to insulin

stored in vesicles and transported with use of kinase o Phosphorylation of glucose once in the cell leads to storage (decreases the

concentration) o Insulin and glucose decrease K+ levels which helps hyperkalemia in people with

renal failure can result in hypokalemia Mechanism of Action

o Insulin receptor is tetramer made up of two α and two β glycoprotein subunits α -subunit is extracellular and binds insulin β -subunit spans the membrane intracellular portions have kinase

activity insulin binds to insulin receptor and IGF-1 receptor

* IGF-1 and IGF-2 can bind to all 3 receptor types

Insulin receptor substrates (IRS-1) mediate some of insulin’s effects Growth promoting protein anabolic effects are mediated via phosphatidylinositol 3-kinase

(PI3K)

Consequences of Insulin Deficiency

Oral glucose tolerance test = plasma glucose rises higher and returns to baseline slower than normal people for people with diabetes

Impaired glucose tolerance due in part to reduced entry of glucose into cells Insulin facilitates glycogen synthesis and inhibits glucose output in liver

Insulin binds Tyrosine kinase β subunit is activated

Autophosphorylation of β subunits on

tyrosine residues

Phosphorylation of cytoplasmic proteins

(dephosphorylation of others)


o Fails in diabetes

Diabetes Mellitus

Type 1 = insulin dependent o Autoimmune disorder causing overproduction of B cells in the islets of

Langerhans Type II = dysregulation of insulin release from B cells

o Insulin resistance in peripheral tissues o Characterizations:

Polyuria (having to urinate frequently) Polydipsia (frequent thirst) Weight loss in spite of increased appetite Hyperglycemia Glycosuria (glucose in the urine) Ketosis (ketones in the bloodstream) Acidosis Coma

o Abnormalities due to reduced entry of glucose into peripheral tissues and liberation of glucose into circulation from the liver

o Entry of amino acids in the muscle decreased and lipolysis increased

Effects of Hyperglycemia

Glycosuria = renal capacity for glucose reabsorption o Causes dehydration. Leads to body compensation (thirst)

Intracellular glucose deficiency. Even though you have hyperglycemia (too much glucose) the cells can’t take it in and the body is tricked into thinking you need more glucose

o Mechanisms activated that in crease catabolism of protein and fat Get ketosis

Changes in protein metabolism o Amino acids taken in by liver and used to make glucose o Glucagon stimulated gluconeogenesis as well as adrenal glucocorticoids o Activity if enzymes that convert pyruvate to glucose increases o Protein depletion poor resistance to infections

Fat metabolism in diabetes o Increased lipid catabolism and formation of ketone bodies o Decreased synthesis of fatty acids and triglycerides o Insulin inhibits hormone sensitive lipase in adipose


Plasma levels of free fatty acids (FFAs) increase o In liver, FFAs are converted to Acetyl-CoA which is converted to ketone bodies

Decreased activity of lipoprotein lipase increased triglycerides and chylomicron in plasma

o Acetyl-CoA Acetoacetate Acetone or β-hydroxybutyrate Leads to increase in H+ acidosis To compensate, the body increases respiration and you can end up

dehydrated and in a coma Na+ levels decrease but K+ levels stay steady

o Hyperosmolar coma can also happen just from hyperosmolarity of the plasma o Lactic acidosis (accumulation of lactic acid) also can cause coma

Insulin Excess: Usually effects the nervous system (brain utilizes glucose)

Plasma glucose decreases o Palpitations, sweating, nervousness

Neuroglycopenic symptoms at lower glucose levels o Hunger, confusion, cognitive abnormalities o Lethargy, convulsions, coma, death

Body tries to compensate by inhibiting secretion of insulin o Increases secretion of growth hormone, cortisol, glucagon, epinephrine

Regulation of Insulin Secretion

Normal range is 0-70 µU/mL Stimulators:

o Glucoseo Mannoseo Amino acids o Intestinal hormones o β -keto acids o Acetylcholine o Glucagon o cAMPo β-adrenergic stimulators o theophylline o sulfonylureas

Inhibitors:o Somatostatin


o 2-deoxyglucoseo Manneheptuloseo α-adrenergic stimulators o β-adrenergic blockers o galanin o diazoxideo thiazide diuretics o K+ depletion o Phenytoin o Alloxan o Microtubule inhibitors o Insulin

Carbohydrate Overview

Carbs are good for energy and structural components o 1 carbon: 2 hydrogens: 1 oxygen

Monosaccharides = the building blocks o Glucose o Galactoseo Fructoseo Condensation = linking monosaccharides o Hydrolysis = breaking monosaccharides

Disaccharides o Maltose = α-glucose + α-glucose o Lactose = β-galactose + β-glucose o Sucrose = α-glucose + β-fructose

Oligosaccharides = short chain (<20 monosaccharides) Polysaccharides = long chain (>20 monosaccharides)

o Glycans o Homopolysaccharides = single type of monosaccharide o Heteropolysaccharide = 2 or more types of monosaccharide o Can be branched or unbranched

Starch = storage form in plants. Main part of human diet o Only glucose o Can be branched (α1-6 amylopectin) or unbranched (α1-4 amylose)

Glycogen = glucose only. Storage in animals o Branched or unbranched o Branched occurs more frequently here than in starch

Dextrans = structural components in bacteria and yeasts


o α1-3 and α1-6 but can have α1-2 or α1-4 Cellulose = structural component in plants

o Unbranched glucose (β1-4) o Humans cant hydrolyze this bond



Glucagon

Keeps homeostatic conditions of metabolism o Promotes breakdown to provide energy

When blood glucose decreases, α-cells secrete glucagon No effect in skeletal muscles (no receptors there for it) but does have an effect on

adipose tissue: o Breakdown of triglycerides to glycerol and fatty acids o Creates ketone bodies for fuel for the brain/muscle

Promotes gluconeogenesis Breakdown of glycogen liver secreted glucose to the bloodstream Proteolysis amino acids gluconeogenesis glucose Glucagon synthesis:

o α -cells of pancreas ribosome translates mRNA for glucagon o Pre-pro-glucagon ER pro-glucagon secreted into the blood Adipose

tissue or liver Intestinal cells can transcribe glucagon

o But pro-glucagon cleaved into different peptides: Glucagon-like proteins and GRPP

Liver o G-protein coupled receptor with effector protein adenylyl cyclase o Glucagon binds to G-protein coupled receptor - conformational change G-

protein activates adenylyl cyclase converts ATP to cAMP Activates protein kinase A (PKA) (to bind to regulatory subunit of AKAP)

Causes increase in glycogen degradation, decrease in glycogen synthesis, decrease in glycolysis, and increase in gluconeogenesis

Glucagon Actions: o Promotes breakdown of glycogen to glucose o Inhibits conversion of glucose to glycogen o Inhibits glycolysis (glucose pyruvate) o Stimulates gluconeogenesis (acetyl Co-A or pyruvate to glucose) o Stimulates degradation of triglycerides to glycerol and fatty acids (by activating

hormone sensitive lipase) Fatty acids Acetyl Co-A glucose or ketone bodies


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