"Effects of Insulin deficiency"

Transcription

1 "Effects of Insulin deficiency" Diabetes mellitus-- most important disease involving endocrine pancreas: Major manifestations: inappropriate hyperglycemia metabolic disorders

2 Two types: Type I diabetes -- insulin-dependent diabetes mellitus (IDDM) Type II diabetes -- non-insulin dependent diabetes mellitus (NIDDM) Properties of Type I diabetes: severe form; associated with ketosis (when untreated) usually juvenile in onset (occasionally adult onset) Catabolic disorder: insulin nearly absent plasma glucagon elevated pancreatic B cell: not responsive to insulinogenic stimuli exogenous insulin required to:» prevent ketosis» reduce hyperglucagonemia reverse catabolic state

3 Possible causes: infectious etiology-- genetic predisposition toxic environmental factor-- genetic predisposition» autoimmune response against pancreatic B cell antigens Pancreatic B cell functional damage: Autoimmune Mechanism Pancreatic beta cell destruction -- development of insulindependent diabetes mellitus

4 Overview of clinical presentation: Type I diabetes: Onset:IDDM -- before the age of 40 Peak incidence: age 14 Most symptoms secondary to hyperglycemia: polyuria (excessive urination) polydipsia (excessive thirst) polyphagia (excessive or voracious eating) First event may be metabolic: acute metabolic decompensation: diabetic coma First event may be degenerative, e.g. neuropathy

5 Diabetic metabolic abnormalities due to: (Diabetic Ketoacidosis): relative or complete insulin deficiency relative or significant glucagon access metabolic decompensation may follow an increase in glucagon/insulin ratio

6 Properties of IDDM and NIDDM Characteristic IDDM NIDDMGenetic locuschromosome 6unknownTypical age of onsetusually < 40 years of age> 40 years of ageplasma insulinlow to absentnormal to highplasma glucagonhigh, suppressiblehigh, resistantacute complicationketoacidosishyperosmolar comainsulin therapyresponsiveresponsive to resistantresponse to sulfonylurea drugsunresponsiveresponsive

7 Properties of IDDM and NIDDM Characteristic IDDM NIDDM Genetic locus Chromosome 6 unknown Typical age of onset Usually < 40 years of age > 40 years of age Plasma insulin Low to absent Normal to high Plasma glucagon High, suppressible High, resistant Acute complication Ketoacidosis Hyperosmolar coma Insulin therapy Responsive Responsive to resistant Response to sulfonylurea drugs Unresponsive Responsive

8 Type II diabetes a group of milder forms of diabetes occurring mainly in adults endogenous insulin: sufficient to prevent ketoacidosis -- abnormal insulin secretion resistance to insulin action at the tissue. Obesity: common risk factor NIDDM patients: deficiency in pancreatic B cell response to glucose impaired response worsened by hyperglycemia

9 Clinical Presentations: NIDDM: appears in middle age or later; mainly in overweight patients gradual onset of symptoms Presenting symptoms: extreme hyperglycemia hyperosmolality volume depletion CNS symptoms (ranging from clouded sensorium to coma)» seizure activity (Jacksonian)» transient hemiplegia Infections -- pneumonia and gram-negative sepsis (common, associated with very negative prognosis) patients with NIDDM: do not develop ketoacidosis patients with NIDDM: may develop hyperosmolar, nonketotic coma

10 Type II diabetes treatment : Overview diet weight reduction sulfonylurea drugs (if diet in weight reduction are inadequate) insulin may be required (in many patients)

11 Insulin Receptor: Insulin binds to target receptors (high affinity, high specificity) and liver, muscle, and fat tissue Insulin receptor: -- composition two heterodimers; each containing an alpha subunit (extracellular: recognition site) and a beta subunit which spans the membrane and contains a tyrosine kinase

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13 Glucose * Insulin

14 Action of Insulin: Target Sites Glucose Transporters GLUT 4: most important lowering blood glucose found in muscle and adipose cell membranesto inserted from storage vesicles GLUT-2: abnormalities in GLUT-2 transport into pancreatic B cells: may contribute to reduced insulin secretion (NIDDM)

15 Liver: Endogenous insulin reaches the liver first (portal circulation) Hepatic Insulin Actions: increases glucose storage as glycogen resets liver to "fed" state -- influencing:» glycogenolysis» ketogenesis» gluconeogenesis Insulin also decreases hepatic:» urea production» protein catabolism» cyclic AMP

16 Insulin promotes:» triglyceride synthesis» increases hepatic phosphate and potassium uptake Muscle: Insulin enhances: protein synthesis (increasing amino acid transport; stimulation of ribosyl action) glycogen synthesis» by increasing glucose transport to the muscle» inducing glycogen synthase» inhibiting phosphorylase Adipose Tissue: Insulin: reduces free fatty acids in the circulation, promoting adipocytes triglyceride storage

17 Insulin preparations Overview Four principal types: ultra-short-acting-- (very rapid onset; short duration) clear solutions; neutral ph; zinc added to enhance stability short-acting --(rapid onset of action) clear solutions; neutral ph; zinc added to enhance stability intermediate-acting long acting -- (slow onset of action)

18 Insulin modifications: intermediate-acting and long acting insulins: turbid suspensions;neutral ph protamine and phosphate buffer added (NPH insulin) zinc in acetate buffer added (ultralente; lente insulins) Note: excess zinc in ultralente and lente insulin can precipitate some soluble regular insulin--affecting absorption

19 Ultra-short-acting insulin: Insulin lispro: new, monomeric insulin analog; recombinant technology duration of action: no more than 3-4 hours for insulin lispro. Short-acting insulin: Regular insulin -- short-acting, soluble crystalline, zinc insulin onset of action: 30 minutes duration of action: 5-7 hours duration and intensity of action: increases with dosage

20 Clinical Use: 1-IV treatment for diabetic ketoacidosis 2-management for rapidly changing insulin requirements (e.g. post surgery, acute infection)

21 Intermediate-acting and long acting insulins: Lente insulin (30% semilente {rapid onset}and 70% ultralente forms {delayed onset, prolonged duration of action}) NPH (neutral protamine Hagedorn or isophane) insulin: intermediate-acting; onset of action delayed by combining correct amounts of protamine insulin such that neither is uncomplexed.-onset and duration of action: NPH insulin -- similar to lente insulin: NPH insulin usually mixed with regular insulin: for twice daily administration

22 Insulin Mixtures: insulin lispro (popular, convenient pre-perennial insulin) may be mixed with a more sustained preparation for post-absorption control; acute insulin lispro mixing is acceptable: Insulin Species: Beef and pork insulins: common ratio: 70% beef/30% pork insulin Recombinant DNA techniques have allowed mass production of human insulin

23 Human insulins: Readily available: in regular, NPH, lente, or ultralente form.been Premixed formulation of 70% NPH and 30% regular human insulin is available

24 Human insulin: Advantages as effective as animal insulins much less immunogenic than beef-pork insulin; slightly less immunogenic import insulin Human insulin: more rapidly absorbed; slightly shorter duration of action

25 Insulin Treatment:overview insulin-dependent diabetes: Type I diabetes;iddm -- about 9% of the diabetic population non-insulin dependent diabetes: Type II diabetes; NIDDM -- about 20% of Type II diabetics use insulin Glycemic control in diabetes mellitus Tight glycemic control is advantageous except for: patients with advanced renal disease-- detrimental risks associated with hypoglycemia the elderly-- detrimental risks associated with hypoglycemia children under the age of 7 years (hypoglycemia poses a significant risk in the developing brain)

26 Complications of insulin treatment: Hypoglycemia: most common complication causes: delay in eating unusual physical exertion inappropriately high insulin dosage for the immediate need Autonomic hyperactivity -- manifestation of hypoglycemia sympathetic -- tachycardia, palpitations, sweating, tremor parasympathetic-- nausea, hunger

27 Treatment of hypoglycemia: Glucose administration For mild reactions: orange juice, glucose, sugar containing beverage, food (assumes patient is conscious) For more severe hypoglycemia (unconsciousness patient):» intravenous infusion ml. All of 50% glucose solution over a 2-3 minute interval.» Alternatively, in the absence of intravenous infusion, 1 mg of glucagon (subcutaneous or intramuscular administration) should restore consciousness within about 15 minutes (then allowing food consumption)

28 Insulin Therapy: immunopathology Injection site lipodystrophy: atrophy of subcutaneous fat rare complication due to availability of more highly concentrated insulin preparations of neutral ph Hypertrophy of subcutaneous fatty tissue is a problem if insulin is injected repeatedly at the same site -- liposuction can correct

29 Categories Oral hypoglycemics sulfonylureas, e.g. glipizide (Glucotrol) biguanides, e.g. metformin (Glucophage) competitive inhibitors of intestinal brushborder alpha-glucosidases, e.g. acarbose (Precose) thiazolidinediones-- e.g. troglitazone (Rezulin)--, rosiglitazone (Avandia)---

30 Sulfonylureas: Mechanism of action A: promotion of insulin release for pancreatic B cells sulfonylureas bind to a pancreaticb cell potassium channel receptor potassium efflux is inhibited, causing depolarization depolarization activates a voltage-gated calcium channel, causing calcium influx insulin is released

31 Mechanism of action B: Serum glucagon concentration reduction sulfonylureas reduce serum glucagon levels -- a possible contributor to hypoglycemic effects unknown mechanism; probably indirect (secondary) inhibition due to enhanced release of both somatostatin and insulin Mechanism of action C: Possible potentiation of insulin action at target tissues:

32 Table: SulfonylureasTolbutamide (Orinase)tolazamide (Tolinase)acetohexamidechlorpropamide (Diabinese)glyburide (Micronase, DiaBeta)glipizide (Glucotrol) glimepiride (Amaryl)

33 Tolbutamide: (Orinase) well absorbed; shorter duration of action safest sulfonylurea for use in the elderly rare acute toxic reactions some drug drug interactions (dicumarol, phenylbutazone, or some sulfonamides)

34 Chlorpropamide: (Diabinese) slowly metabolized; active metabolites some drug drug interactions (dicumarol, phenylbutazone, or some sulfonamides) chloropropamide may induce prolonged hypoglycemia in elderly patients dilutional hyponatremia -- results from enhanced vasopressin secretion and potentiation of its effect at the renal tubule by chlorpropamide (Diabinese). rare hematologic toxicity

35 Tolazamide (Tolinase) comparable to chlorpropamide in potency; shorter duration of action slow absorption; delayed effect on blood glucose metabolized to biologically active compounds Acetohexamide: intermediate duration of action (between Tolbutamide (Orinase) and chlorpropamide (Diabinese) hours hepatically metabolized to inactive metabolite

36 Second Generation sulfonylureas: glyburide (Micronase, DiaBeta), glipizide (Glucotrol), glimepiride (Amaryl)-- fewer adverse effects Glyburide: (Micronase, DiaBeta) metabolized in the liver; short plasma half-life but prolonged biological effect few adverse effects (not counting hypoglycemia) does not cause water retention (as does chlorpropamide (Diabinese))

37 contraindicated: hepatic impairment renal insufficiency Glipizide: (Glucotrol) shortest half-life (2-4 hours); extended released formulation available hour action less likely than glyburide (Micronase, DiaBeta) to produce serious hypoglycemia {due to shorter half-life} extensively metabolized by the liver (90%); 10% excreted unchanged by the kidney contraindicated: hepatic dysfunction renal insufficiency Glimepiride: (Amaryl)

38 Glimepiride: (Amaryl) monotherapy -- once a day administration or in combination with insulin most potent -- lowest dose of the sulfonylureas long duration of action: half-life = 5 hours hepatic metabolism: complete to inactive products Secondary Failure and Tachyphylaxis to Sulfonylureas: Treatment failures occur Possibly due to pancreatic B cell refractoriness or to loss of dietary compliance Combination of sulfonylureas and insulin would appear justified only in the presence of severe insulin resistance

39 Biguanides Metformin: (Glucophage) Proposed Mechanism of Action: glycolysis stimulation-- increased glucose removal from blood decreased hepatic gluconeogenesis decreased glucose absorption rate from the GI tract reduced plasma glucagon Clinical Use: in patients with refractory obesity and insulin resistance Advantages: does not cause hypoglycemia does not increased weight

40 May be used in combination with sulfonylureas when sulfonylurea monotherapy is not effective Toxic/adverse effects: most common -- gastrointestinal (20% frequency) anorexia, nausea, vomiting, diarrhea dose-related usually occurs upon initiation of therapy -- often transient in effect Decreased vitamin B12 absorption; may require vitamin B12 supplementation Contraindicated in: renal disease

41 alcoholism hepatic disease chronic cardiopulmonary disease (its associated with tissue hypoxia --biguanides may increase the risk of lactic acidosis)

42 Alpha-glucosidase Inhibitor Acarbose (Precose) oligosaccharide analog -- strongly binds to intestinal disaccharidases (e.g. alpha-glucosidase) Competitive in addition of alpha-glucosidase reduces postprandial glucose rise (reduction: 30-50%) results in delayed carbohydrate absorption: starches, dextrins, maltose, sucrose (not lactose) Adverse Effects: most common: flatulence hypoglycemia may occur or give used in combination with insulin or sulfonylureas Drug-drug interaction: acarbose interferes with metformin absorption Miglitol (Glyset) similar to acarbose (Precose) but possibly with less hepatotoxicity Acarbose (Precose) and miglitol (Glyset) have similar similar gastrointestinal effects

43 Thiazolidinedione Derivatives Troglitazone (Rezulin) Mechanism of Action: Increases tissue insulin sensitivity Clinical Effectiveness: decreased insulin resistance decreased insulinemia reduced fasting and postprandial hyperglycemia in Type II diabetics (noninsulin dependent diabetics, NIDDM) Rosiglitazone (Avandia)-- FDA approved for management of Type II diabetes Approval as monotherapy or in combination with metformin (Glucophage) might be used with insulin or a sulfonylurea Apparently as effective does troglitazone (Rezulin) in controlling blood glucose without liver toxicity

44 Long-term safety/benefits of rosiglitazone (Avandia) in patients with Type II diabetes: yet to be determined. Pharmacokinetics: Well absorbed following oral administration (half-life: 3-4 hours) Hepatic metabolism Adverse Effects: absence of liver failure; no drug-related jaundice! no ALT (alanine aminotransferase) abnormalities reported in clinical trials fluid retention-- similar to that seen with troglitazone (Rezulin) increases in LDL & HDL cholesterol-- about 15%

45 Precautions: Thiozolidinediones may cause hepatotoxicity-- Package insert recommends: ALT determination prior to treatment and every two months for one-year, then periodically ALT levels > 2.5 times above upper normal limit: do not start treatment After treatment initiation, ALT levels > 3 times above normal: stop treatment

46 Pioglitazone (Actos) Overview Pioglitazone (Actos): thiozolidinedione, reduce insulin resistance Clinical use: May be used as monotherapy May be used in combination with a sulfonylurea,metformin (Glucophage), or insulin Adverse Effects: Moderate weight gain edema, mild anemia No reports of hepatic toxicity (Liver function monitoring every two months -- recommended) Conclusion: pioglitazone (Actos) similar to rosiglitazone (Avandia) effectiveness; long-term safety unknown

47 Glucagon Overview Glucagon, a peptide, produced by A cells of the pancreatic islets of Langerhans Rapidly inactivated in plasma (degraded also at hepatic, renal, and tissue receptor sites) Pharmacological consequences: increased blood glucose, decreased hepatic glycogen insulin released from normal pancreatic B cells catecholamines from pheochromocytoma calcitonin from medullary carcinoma

48 Cardiovascular Effects: positive inotropic action (increased myocardial contractility) positive chronotropic (increased heart rate) these effects mediated by camp Smooth Muscle Effects: (large doses): intestinal smooth muscle relaxation Clinical Use: Management of Severe Hypoglycemic States emergency treatment in insulin-dependent unconscious patients in which intravenous glucose cannot be administered (a conscious patient would be treated by drinking orange juice or other high sugar content foods) Glucagon is available for parenteral use.

49 Endocrine Diagnoses/Analysis: evaluation of pancreatic B cell secretory insulin reserve provocative hormonal discharge from suspected: insulinoma thyroid medullary carcinoma Beta-blocker Overdosage: (useful for enhancing myocardial performance independent of the beta-receptor) Adverse Effects transient nausea/vomiting -- generally mild

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