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Diabetes mellitus
Hyperlipidemia
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Diabetes mellitus
Pancreas: Islets of Langerhans: site of hormone production
A (alpha) cells produce Glucagon B (beta) cells produce Insulin D (delta) cells produce Somatostatin
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Diabetes mellitus
Blood glucose levels are tightly regulated:
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Diabetes mellitus
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Diabetes mellitus
Insulin:
First protein whose sequence was identified (1955) 51 amino acids; synthesized as proinsulin (84 aa) 6-10 mg stored in the pancreas ~ 2 mg released per day
Liver, brain and red blood cells do not require Insulin for glucose uptake (only muscle and fat cells depend on insulin) Main release stimulus: elevated blood sugar Main effect: promote storage of glucose (increase in glucose uptake (GLUT4) and glycogen synthesis) Also inhibits lipolysis, and promotes lipogenesis and amino acid uptake 29 amino acids Main release stimulus: hunger (= low blood sugar)
Glucagon:
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Diabetes mellitus
Diabetis mellitus:
Group of metabolic diseases characterized by high blood sugar Elevated levels of blood glucose (hyperglycemia) lead to spillage of glucose into the urine (diabetes mellitus means sweet urine)
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Diabetes mellitus
Complications:
Short-term
Hyperglycemia, (hypoglycemia) Ketoacidosis
Long-term
Disruptions in blood flow => Cardiovascular complications => Amputations Microvascular disease: blood flow to microvasculature lowered (kidney, eye) Retinopathy blindness Nephropathy primary cause of morbidity and mortality Neuropathy nerve damage Erectile dysfunction
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Natural insulin and four modified insulins are used clinically: Regular (Natural) Insulin
Unmodified human insulin rapid acting with short duration (half-life 9 min) Only one that can be given IV (infusions, since injections are too brief acting) Useful for emergencies (hyperglycemic coma)
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Insulin Lente
mixed with zinc => forms micro-precipitates => takes longer to absorb => longer acting Only for s.c. administration Ultra-lente: longest acting
NPH Insulin
regular insulin mixed with protamine (large positively charged protein) => delayed absorption NPH = neutral protamine Hagedorn Long acting
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Sulfonylureas
Stimulate insulin release (increase sensitivity of B cell towards glucose: block ATPgated K+ channel => membrane depolarization => Ca++ increase => insulin secretion), reduce serum glucagon levels, increase insulin binding on target cells
Glipizide Glyburide
Troglitazone
First of its class Hepatotoxic! No longer in use
Rosiglitazone Pioglitazone
Half-life ~ 7hrs Half-life of active metabolites up to 150 hrs !
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Diabetes mellitus
Novel concepts:
Alpha-Glucosidases:
Intestinal enzymes in the small intestine Break down complex carbohydrates (Starch, Glygogen)
Alpha-Glucosidase Inhibitors:
Inhibit carbohydrate breakdown => less monosaccharides available for absorption Saccharides that act as competitive enzyme inhibitors DO NOT increase insulin levels !! Maybe useful in Type I diabetes as well?
Acarbose
Also inhibits alpha-amylases No significant absorption => no systemic side effects Used to prevent postprandial hyperglycemia Side effects: Diarrhea, flatulence (intestinal bacteria digest the carbohydrates!)
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Miglitol
Systemically absorbed No effect on alpha-amylases
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Diabetes mellitus
Novel concepts (contd): Incretins:
Gastrointestinal hormones: Glucagon-Like Peptide 1 (GLP1) Gastric Inhibitory Peptide (GIP) Both are inactivated by Dipeptidyl Peptidase 4 (DPP4) Insulin released before glucose levels become elevated Reduce gastric emptying => slower carbohydrate absorption Inhibit Glucagon release Reduce food intake
Incretin mimetic:
Exenatide
Originally identified in the saliver of the Gila Monster (Lizard spit) No effect if glucose levels are normal => no risk of hypoglycemic shock Long-term weight loss Only for s.c.injection
DPP4-Inhibitors:
No effect if glucose levels are normal => no risk of hypoglycemic shock Oral administration!
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Sitagliptin Vildagliptin
Diabetes mellitus
Novel concepts (contd): Amylin:
Pancreatic hormone (also from b-Islet cells) Reduces gastric emptying Inhibit Glucagon release Promotes satiety (=> decreased food intake)
Amylin mimetics:
Pramlintide
Only drug other than insulin approved for Type I Diabetes !! Used in combination with insulin
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Hyperlipidemia
Artherosclerosis:
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Hyperlipidemia
Artherosclerosis:
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Hyperlipidemia
Artherosclerosis:
Initiating mechanism:
Endothelial cells (EC) bind LDL When activated (e.g. injury), EC and attached macrophages produce ROS ROS oxidize LDL, which results in lipid peroxidation This leads to the destruction of the LDL receptors which normally clear LDL Oxidized LDL is phagocytosed by macrophages via scavenger receptors Upon ingestion of oxidized LDL, macrophages become foam cells One species of LDL, lipoprotein(a) contains apoprotein(a) which is structually similar to plasminogen. Plasminogen activator on EC processes plasminogen into the fibrinolytic enzyme plasmin. LDL displaces plasminogen on EC => plasmin reduced => thrombosis promoted
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Hyperlipidemia
Lipoprotein metabolism:
Absorbed lipids released by enterocytes in form of chylomicrones Chylomicrones bypass the liver, enter the circulation via lymph and are hydrolyzed in target tissues by lipoprotein lipases
VLDL particles provide target tissues with fatty acids => become LDL particles
HDL particles transfer cholesterol from tissues to LDL particles
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Hyperlipidemia
Cholesterol:
60-70% (=1000 mg) synthesized (not from food!): Liver, intestines, reproductive organs Rate-limiting enzyme: HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA reductase)
< 200mg/dl: no risk 200-240 mg/dl: moderate risk > 240 mg/dl: high risk
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Hyperlipidemia
Lipid-lowering drugs:
HMG-CoA reductase inhibitors (Statins):
Bear structural resemblance to HMG-CoA Reversible competitive inhibitors of HMG-CoA reductase Isolated from Aspergillus sp. Side effects: Hepatotoxicity, GI disturbances, myopathy
Lovastatin
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Hyperlipidemia
Lipid-lowering drugs:
HMG-CoA reductase inhibitors (Statins):
Fluvastatin (Lescol) Pravastatin (Pravachol)
Both drugs are already in active form Fluvastatin
Atorvastatin (Lipitor)
Long-lasting inhibition of HMGR Pravastatin
Atorvastatin
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Hyperlipidemia
Lipid-lowering drugs:
HMG-CoA reductase inhibitors (Statins):
Statins accumulate in the liver (usually an undesired drug effect) Cholesterol synthesis is predominantly effected in the liver => hepatocytes must meet their cholesterol requirements through different mechanisms => Hepatic upregulation of the LDL-receptors => increase in LDL uptake => decrease in circulating LDL
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Hyperlipidemia
Lipid-lowering drugs:
Fibrates:
Fibric acid derivates PPARa agonists: stimulate b-oxidation of fatty acids Also stimulate lipoprotein lipase activity Reduce hepatic VLDL production Affect predominantly VLDL levels (little effect on LDL) Increase in HDL ! Side effects: Myositis (unusual, but severe)
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Hyperlipidemia
Lipid-lowering drugs:
Bile acid binding resins:
Anion exchange resins
Prevent reabsorption and enterohepatic recirculation of bile acids => increase in hepatic LDL receptors => increase in hepatic LDL uptake => Reduced LDL in the plasma Side effects: resins are not absorbed => no systemic side effects mostly bloating, constipation, diarrhea Interfer with absorption of drugs (e.g. digoxin) and fat-soluble vitamins Not particularly appetizing
Cholestyramine Colestipol
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Hyperlipidemia
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