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Prof.MUDr Jiřina Martínková, CSc 2006/2007
Classification and the nomenclature of diabetes mellitus (DM):
DM is a chronic metabolic disorder characterised by a high blood
glucose concentration-hyperglycemia (fasting plasma glucose > 7.0 mmol//L, or plasma glucose > 11.1 mmol/L 2hr after a meal) caused by insulin deficiency, often combined with insulin resistance. Hyperglycemia occurs because of uncontrolled hepatic glucose output and reduced uptake of glucose by skeletal muscle with reduced glycogen synthesis. When the renal threshold for glucose reabsorption is exceeded, glucose spills over into the urine -glycosuria and causes an osmotic diuresis - polyuria, which in turn, results in dehydration, thirst and increased drinking – polydipsia. Diabetic ketoacidosis is an acute emergency- it develops because of accelerated fat breakdown to acetyl-CoA, which, in the absence of aerobic carbohydrate metabolism, is converted to acetoacetate and beta-hydroxybutyrate (which cause acidosis) and acetone (a ketone)
Various complications develop as a consequence of the metabolic derangements in DM, often over many years Many of these are the results of disease of blood vessels, either large (macrovascular disease) of small (microangiopathy). Macrovascular disease consists of acclerated atheroma, which is much more common and severe in diabetic patients. Microangiopathy particularly affects the retina (blindness), kidney (chronic renal failure) and peripheral nerves (diabetic neuropathy,which is associated with accumulation of osmotically active metabolites of glucose. Coexisting hypertension promotes progressive renal damage.
Type 2 diabetes consists of combined defects of insulin secretion and action ranging from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance.ANTIDIABETIC DRUGS Classification and the nomenclature of diabetes mellitus (DM): Type 1 diabetes encompasses cases resulting from pancreatic B cell destruction (immune-mediated in most cases). .
and most patients with DM2 are obese. Type 2 diabetes (DM2) represents a heterogenous group comprising milder forms of DM that occur predominantly in adults.2). Circulating endogenous insulin is often subnormal or relatively inadequate because of tissue insensitivity.ANTIDIABETIC DRUGS Type 1 diabetes (DM1) is a severe form associated with ketosis in the untreated state. It occurs most commonly in juveniles but occasionaly in adults. there is an accompanying deficiency of the pancreatic B cells ´s response to glucose (Fig. In addition to tissue insensitivity to insulin. It is a catabolic disorder form in which circulating insulin is virtually absent. plasma glucagon elevated. is a common risk factor. which generally results in impaired insulin action. . and the pancreatic B cells fail to respond to insulinogenic stimuli (Fig. Obesity. the nonobese.1).
Fig. 1. units prediabetes/diabetes Type 2 Basal level early phase normal Type 1 late phase permitted . Schematic diagram of two-phase release of insulin in response to a constant glucose infusion glucose Arb.
In contrast. Degradation The liver and kidney are the two main organs that remove I from the circulation. in insulin-treated diabetics receiving s. I . I is released from pancreatic B cells at a low basal rate and at much higher stimulated rate in response to a variety of stimuli. presumably by hydrolysis of the disulfide connection between the A and B chains through insulinase. with the kidney removing 35-40% of the endogenous hormone.ANTIDIABETIC DRUGS INSULIN (I) is a small protein which contains two chains (A and B) linked by disulfide bridges. The liver normally clears the blood of approximately 60% of the insulin released from the pancreas as the terminal of portal vein blood flow.c. this ratio is reversed. Further degradation by proteolysis occurs. . especially glucose.
muscle and adipose tissue (Fig. the insulin-receptor complex is internalised. . liver. which is entirely extracellular and constitues the recongition site. which spans the membrane. 1) The full insulin receptor consists of two heterodimers.ANTIDIABETIC DRUGS The insulin receptor Once I has entered the circulation. and a beta subunit. When insulin binds to alpha subunit at the outside surface of the cells. each containing an alpha subunit. it is bound by specialised receptors identified in only a few target tissues (e. tyrosine kinase activity is stimulated in the beta portion (nine substances have been identified for the activated insulin receptors to be phosphorylated). Finally. Selfphosphorylation of the beta portion results in translocation of certain proteins such as glucose transporter from sequestered sites within adipocytes and muscle cells to exposed locations on the cell surface.The beta subunit contains a tyrosine kinase.g.
INSULIN RECEPTOR Binding sites Cell membrane Intracellular space Tyrosin kinase . Schematic diagram of the two-phase release of insulin in response to a constant glucose infusion.Fig. 2.
which are released by eating.ANTIDIABETIC DRUGS Downregulation of insulin receptors: appears in clinical situation associated with elevated blood levels. 2). glucagon. it is produced by aminoacids. such as obesity of insulinoma. secretin). gastrointestinal tract hormones (gastrin. stimuli include fatty acids. In contrast. The first phase is missing in DM2 and both are missing in DM1. and drugs that act on sulfonylurea receptors. Other Insulin release is inhibited by the sympathetic nervous system (the role of alpha2adrenoceptors) and several peptides (somatostatin) . Schematic diagram of the two-phase release of insulin in response to a constant glucose infusion (Fig. the parasympathetic nervous system stimulation.
Action of insulin on glucose transporters I has an important effect on several transport molecules that facilitate glucose movement across cell membranes (GLUT 1-GLUT 4) GLUT-4 (inserted into the membranes of muscle and adipose cells) is responsible for insulin-mediated uptake of glucose GLUT-2 (B-cells of pancreas) mediates transport of glucose into pancreatic Bcells. Its defects may contribute to the reduced insulin secretion that characterizes DM2 . 1.ANTIDIABETIC DRUGS Effects of insulin (I) on its targets I promotes the storage of fat as well as glucose (both sources of energy) within specialised target cells and influences cell growth and metabolic functions of a wide variety of tissues.
where it acts to: increase storage of glucose and to reset the liver to the fed state by reversing a number of catabolic mechanisms associated with the postabsorptive state:glycogenolysis. and gluconeogenesis These effects are brought about directly through activation or repression of selective enzymes or indirectly by reducing fatty acids flux to the liver via antilipolytic action on adipocytes. promotes triglycerides synthesis.ANTIDIABETIC DRUGS 2. and increases potassium and phosphate uptake by the organ. In addition I decreases urea production. . protein catabolism. ketogenesis. Action of insulin on liver The first major organ reached by endogenous insulin via portal circulation in the liver.
Effect of insulin on muscle promotes protein synthesis by increasing amino acid transport and by stimulating ribosomal activity. It also promotes glycogen synthesis to replace glycogen stores expended by muscle activity. 4. Effect of insulin on adipose tissue I acts to reduce circulating free fatty acids and to promote triglyceride storage in adipocytes (the most efficient means of storing energy). .ANTIDIABETIC DRUGS 3.
combined with increased exercise Insulin is essential for the treatment of DM1 .Treatment of DM Diet is the cornestone.
coli is available for clinical use as Humulin and dispensed as either regular.Pharmacokinetics Insulin is destroyed in the GIT.m. and must be given parenterally (s. H u m a n i n s u l i n s are produced by recombinant DNA techniques – by inserting the human proinsulin gene into E. lente or ultralente Humulin. Once absorbed. Pulmonary absorption occurs and inhalation of an aerosol is a new route of administration. it is inactivated enzymatically in the liver and kidney Species of insulin Beef (slightly more antigenic) and purified monospecies pork insulin.. NPH. coli or yeast and treating the extracted proinsulin to form the human insulin molecule.). Declining costs for biosynthesis of human insulin generally supplanted purified pork insulins. Human insulin from E. .v. i. insulin has an elimination half-life of approximately 10 min.c. i..
alteration of the insulin peptide provides an opportunity to change the absorption rate of the molecule. . in which two aminoacids (proline and lysine) have been reversed in their position without any influence on receptor binding. The advantage is quick dissociation into monomers and rapid absorption. Its use is associated with significantly improved glycemic control (without increasee incidence of hypoglycemia). ultra-short acting insulin. varying in the timing of their peak affect and duration of action (Fig.Insulin lispro monomeric insulin produced by recombinant technology. Used for emergency (ketoacidosis). for rapid response (surgery). Various formulations of insulin are available. 3). Insulin lispro (ultra-short acting insulin) and glargine ultra-long acting insulin are the first to use.Insulin Insulin analogues . Peak serum value is reached in 1 hr.
These preparations include isophane insulin and amorphous or crystalline insulin zinc suspension.v. the only type of insulin that should be administered i.acting insulin regular insulin (HM-R). thus forming finely divided amorphous solid or relatively insoluble crystals. intermediate . which are injected as a suspension from which insulin is slowly absorbed.acting insulin are made by precipitating insulin with protamine or zink. . neutral protamine or isophane insulin) is an intermediate insulin with the delayed onset of action achieved by combining appropriate amount of insulin and protamine. NEPHAN INSULIN (NPH.Insulin short .acting and long. soluble crystalline zinc insulin.
injection the crystalline depot to provide a peakless basal insulin replacement that can last more than 24 hours. which precipitates after s. . peakless. GLARGINE – soluble. The attachment of two arginine molecules to the chain B and substitution of a glycine for asparagine created an analogue.c. ultra-long acting insulin.Insulin LENTE INSULIN is a mixture of 30% semilente . ULTRALENTE INSULIN –HUMULIN ULTRALENTE – a poorly soluble crystal zinc insulin that has a delayed onset and prolonged duration of action.an amorphous precipitate of insulin with zinc ions in acetate buffer that has a relatively rapid onset of action + 70% of ultralente insulin. This is needed in type1 patients to achieve basal insulin concentratin throughout the 24 hrs that are comparable to those achieved in normal subjects by basal endogenous secretion.
Insulin Tab. 1 HUMAN INSULINS and ANALOGUES Onset (hr) 0.5-1 1-2 3-4 Onset (min/hr) 0.5-1 missing Duration (hr) 6-8 12-18 18-26 Duration (hr) 3-5 30 INSULINS NPH Lente Ultralente ANALOGUES Lispro glargine .15-15 (min) 3-4 (hr) Maximum (hr) 2-3 4-10 10-15 Maximum (hr) 0.
3 lispro arbitrary units permitted .Fig.
Pens eliminate the need to carry syringes and bottles of insulin to the workplace and while traveling. These contain replaceable cartridges of U100 human insulin and retractable needles.Normally. NPH insulin. insulin lispro. Disponsable insulin pens are also available for regular insulin. injections of insulin. and the insulin is infused through thin plastic tubing that is connected . though temporarily altered rates can be superimposed to adjust for a short-term change in requirement. the 24hours basal rates are relatively constant from day to day.Insulin INSULIN DELIVERY SYSTEMS Insulin pen injectors: to facilitate multiple s. Continuous subcutaneous insulin infusion device (insulin pumps): the devices have a manually programmable pump that delivers individualized basal and bolus insulin replacement based on blood glucose self-monitoring results.c. portable pen-sized injectors have been developed. It is usually placed on a belt or in a pocket .
Inhaled insulin has a rapid onset and a relatively short duration of action. and infusion set need to be changed using sterile techiques every 2 or 3 days.Insulin INSULIN DELIVERY SYSTEMS (to continue) to the subcutaneously inserted infusion set. . A regular insulin is the only insulin specifically approved for pump use. It should be used to cover mealtime insulin requirements or to correct high glucose levels. The use is encouraged for individuals who are unable to obtain target control while on multiple injection regimens and in circumstances where excellent glycemic control is desired (pregnancy). The insulin reservoir. tubing.
4.Fig. Portable pen injectors permitted .
if severe. In older diabetics. . in those taking longer-acting insulins. can cause brain damage. tremulousness (the sympathetic nerv syst. sweating. hyperactivity) + nauzea. if the patient is unconscious. bizarre behavior.m. are insulins mainly symptoms of impaired function of the CNS : mental confusion. hunger --convulsions + coma (parasympathetic hyperactivity). or. insulin palpitations. glucose or i. to give i.allergy is unusual but can occur as local or systemic reactions . ultimately coma The treatment is to take a sweet drink or snack.hypoglycemia common and. glucagon.v. Warning signals of more rapid development due to regular insulin:tachycardia.Insulin Adverse effects: .
v.) in emergency treatment of hyperglycemic diabetic emergencies (ketoacidosis) many patients with DM2 ultimately require insulin treatement short-term treatment of patients with DM2 or impaired glucose tolerance during intercurrent events (operations. myocardial infarction) emergency treatment of hyperkalemia: insulin is given with glucose to lower extracellular K+ via redistribution into cells - . infections. An intermediate-acting preparation is often combined with a short-acting preparations taken before meals soluble insulin is used (i.Insulin Clinical uses of insulin: .patients with DM1 require long-term maintenance treatment with insulin.
Oral hypoglycemic agents Biguanides Sulfonylureas Meglitidines Thiazolidinediones Alpha-glucosidase inhibitors .
GIT disturbancies (anorexia + weight loss. diarrhea) = transient .lactic acidosis rare but potencially fatal Metformin should be avoided in patients who predispose to lactic acidosis (renal and hepatic disease.increases glucose uptake and utilisation in muscle + reduces hepatic glucose production (gluconeogenesis) Adverse effects: . heart failure…) Use: DM2.Oral hypoglycemic agents Biguanides -Metformin Lowers blood glucose. patients obese and who fail treatment with diet alone. It does not cause hypoglycemia .
. . most are excreted in the urine their action is increased in the elderly and in patients with renal disease . well absorbed orally. all bind strongly to plasma albumin and compete for these binding sites with salicylates and sulfonamides. are generally contraindicated in pregnancy .Oral hypoglycemic agents Sulfonylureas stimulate insulin secretion by B-cells (the equivalent of phase 1secretagogues) and thus reducing plasma glucose. cross the placenta severe hypoglycemia at birth s. Pharmacokinetics: .
glipizide .Oral hypoglycemic agents First generation: Tolbutamide Second generation glibenclamide.
. with a peak concentration and peak effect within approximately 1 hour after digestion.Oral hypoglycemic agents Meglitidines A new class of insulin secretagogues modulates B cell insulin release by regulating potassium efflux through the potassium channels repaglinid has a very fast onset of action.
pioglitazone Their main action is to diminish insulin resistance by increasing glucose uptake and metabolism in muscle and adipose tissues. .Oral hypoglycemic agents Thiazolidinediones a recently introduced class of drugs that enhance target tissue insulin sensitivity. Alpha-glucosidase inhibitors Acarbose and miglitol are competitive inhibitors of the intestinal enzymes and modulate the postprandial digestion and absorption of starch and disacharides.rosiglitazone.
drugs that act on the sulfonylurea receptors are well tolerated but often promote weight gain.metformin is preferred for obese patients unless contraindicated by factors that predispose to lactic acidosis .Oral hypoglycemic agents Clinical uses of oral hypoglycemic drugs: -DM2 as a supplement to diet and excercise to reduce symptoms from hyperglycemia . .
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