New Concepts in Diabetes and Its Treatment - part 2 docx

Studies of genes involved in insulin secretion or insulin action havebeen successful to a certain extent by showing the implication of the insulin-receptor substrate-1 IRS-1 gene, the ra

from the elevated glucose values In type 2 diabetes there is also an increasedrelease of proinsulin, which may account for 30% of total insulin compared

to 15% in normal subjects

Concerning the insulin response to intravenous glucose, as occurs duringIVGTT, in type 2 diabetes there is a marked reduction in the first phase ofinsulin release The second phase may also be reduced in diabetic patients withfasting glycemia?250 mg/dl, but may be normal or increased in ‘compensated’patients with fasting glycemia=200 mg/dl (even if also in these instances theinsulin response should be regarded as diminished, considering the existinghyperglycemia) Reduced insulin response is also recorded during prolongedglucose infusion

The insulin response to nonglucose stimuli, such as intravenous arginine,secretin, isoproterenol, isoprenaline, tolbutamide, or even a mixed meal, may

be normal in type 2 diabetic patients with fasting glycemia=200 mg/dl This

is due to the potentiation of the insulin response to nonglucose stimuli exerted

by the hyperglycemia present in the diabetic patients

Finally, in type 2 diabetic patients the oscillations in insulin secretion,which are significant for glycemic control, cannot be detected, even in thepatients with mild form of the disease

Causes of the Insulin Secretory Defect

A major role is certainly played by genetic predisposition, but severalbiochemical mechanisms and neurohormonal factors may contribute Little

is known about susceptibility genes to the common polygenic forms of type

2 diabetes Studies of genes involved in insulin secretion or insulin action havebeen successful to a certain extent by showing the implication of the insulin-receptor substrate-1 (IRS-1) gene, the ras associated with diabetes (rad) gene,the glucagon receptor gene, or the sulfonylurea receptor (SUR) gene (amongothers) in a low percentage of cases of type 2 diabetes in particular populations.However, the majority of susceptibility genes are still to be described.Recently, an inherited or acquired defect of FAD-linked mitochondrialglycerophosphate dehydrogenase in b-cells has been proposed to contribute

to the impairment of insulin release in type 2 diabetes

Intravenous administration ofb-endorphins or naloxone to type 2 diabeticpatients enhances both basal and OGTT stimulated insulinemia, which sug-gests a possible pathogenetic role of these compounds in the dysfunction ofb-cells

Prostaglandins may also be implicated, as suggested by the improvement

of insulin response to intravenous glucose and the increase of the slope of

glucose potentiation after infusion of sodium salicylate (inhibitor of glandin synthesis) A similar effect has been observed with the a-adrenergicblocking agent phentolamine, which suggests a role of thea-adrenergic system.

prosta-It has also been suggested that galanin and pancreostatin, peptides whichinhibit insulin secretion, may be increased in the pancreatic islets of type 2diabetic patients Finally, hyperglycemia, once established, may contribute toaggravate theb-cell dysfunction, through several mechanisms most of whichare included in the concept of ‘glucotoxicity’ The glucotoxicity concept mayhelp to explain the beneficial effect on insulin secretion obtained in type 2diabetic patients after adequate treatment achieving glycemic control as well

as the transient improvement in theb-cell function which may occur in type 1diabetic patients after therapeutical control of hyperglycemia (‘honeymoon’phenomenon)

It has been proposed that at least one factor contributing to the esis of type 2 diabetes is desensitization of the GLP-1 receptor onb-cells Atpharmacological doses, infusion of GLP-1, but not of GLP, can improve andenhance postprandial insulin response in type 2 patients Agonists of GLP-1receptor have been proposed as new potential therapeutic agents in type 2diabetic patients

pathogen-It should also be emphasized that complex alterations of glucidic andlipidic metabolism in theb-cells may play a role In particular, in obese/diabetichyperinsulinemic subjects, LC-CoA derived from the enhanced availability ofFFA may affect the b-cells’ secretory response according to the followingmechanism: as the glycemic level increases, the b-cells utilize more glucose;this leads to enhanced production of malonyl-CoA, which blocks the intrami-tochondrial transport of LC-CoA, which therefore accumulates in the cytosoland (through its complex biological effects) stimulates insulin secretion (seealso chapter III and figure 3 for details)

Altered expression of genes encoding enzymes in the pathway of CoA formation and FFA oxidation contributes to the b-cell insensitivity toglucose in some patients with type 2 diabetes Clearly, the detrimental impact

malonyl-of diabetic hyperlipidemia onb-cell function has been a relatively neglectedarea, but future pharmacological approaches directed at preventing ‘lipotox-icity’ may prove beneficial in the treatment of diabetes

Insulin Secretion in Other Types of Diabetes

Various, less common types of diabetes are known to occur, in which thesecretory defect is based upon different mechanisms, as outlined in chapter I

on Etiological Classification

Pharmacological Stimulation of Insulin Secretion

Insulin Secretion as Modified by Sulfonylureas

The main drugs able to stimulate insulin secretion are the sulfonylureas.These compounds have been used in the management of type 2 diabetes since

1955 and, when properly utilized, are easy to use and appear to be effectiveand safe It is estimated that 30–40% of diabetic patients are taking oralsulfonylureas Indications and contraindications for sulfonylureas are shown

in tables 1 and 2, respectively

Table 1 Patients candidate for sulfonylurea treatment

Most patients with type 2 diabetes, not well controlled with dietary restriction and exercise Children and adults with the MODY (maturity-onset diabetes of youth) type of diabetes Obese-diabetic patients with marked insulin resistance

Lean type 2 diabetic patients with preserved insulin secretory capacity

Table 2 Contraindications to sulfonylurea treatment

Patients with type 1 diabetes

Patients with pancreatic diabetes

Patients with an acute illness or stress or undergoing surgery

Patients with hepatic or liver diseases

Patients predisposed to hypoglycemia:

Severe neonatal hypoglycemia

Diabetic female patients during lactation

Patients with a history of severe adverse reactions to sulfonylureas

Di fferent Sulfonylureas

The first oral hypoglycemic drug was synthesized in 1926 by altering theguanidine molecule The sulfonylureas used today are derived from this nativemolecule The ‘first-generation’ sulfonylureas, which were developed initially,are effective in large doses, while the ‘second-generation’ drugs, developed morerecently, are effective in smaller doses Some sulfonylureas, such as tolbutamide,

Table 3 Main characteristics of sulfonylureas

Glibenclamide (or glyburide) 1.25–20 1–2 16–24 Liver/kidney

1 Repaglinide is a nonsulfonylurea hypoglycemic agent of the meglitinide family.

have a short duration of action (6 h), others, such as chlorpropamide, have along duration of action (up to 60 h), several others show an action of inter-mediate duration Some characteristics of the sulfonylureas which are or havebeen in clinical use are summarized in table 3

‘First-Generation’ Sulfonylureas Tolbutamide has a ‘short’ duration of

action (see table 3) and is carboxylated by the liver to a totally inactivederivative Being metabolized only in the liver, this compound may be useful

in nephropathic diabetic patients

Tolazamide has a more potent hypoglycemic activity than tolbutamideand an ‘intermediate’ duration of action (see table 3) It is metabolized only

by the liver with the production of some very little active metabolites excreted

in the urine (85%) It is safer in the elderly and in nephropathic diabeticpatients Tolazamide also has a diuretic action

Chlorpropamide has a more potent hypoglycemic activity than mide and a ‘very long’ duration of action (see table 3), and therefore it caninduce more hypoglycemic episodes than tolbutamide It is hydroxylated bythe liver with production of some active metabolites excreted in the urine (by80–90%) and, thus, is contraindicated in the elderly and in nephropathicdiabetic patients Several side or toxic effects may occur with chlorpropamide,

tolbuta-such as alcohol-induced flushing, occasional hypersensitivity reactions as well

as water retention and hyponatremia (due to sensitization of renal tubules toantidiuretic hormone)

Acetohexamide has a more potent hypoglycemic activity than tolbutamideand an intermediate duration of action It is reduced by the liver to 1-hydroxy-hexamide which is a potent hypoglycemic drug, excreted by 60% in the urine.Thus, it is contraindicated in the elderly and in nephropathic diabetic patients.Acetohexamide also has diuretic and uricosuric actions

‘Second-Generation’ Sulfonylureas Glyburide or glibenclamide has been

used since 1969 It has a 50–100 times more potent hypoglycemic activity thanthe ‘first-generation’ drugs and has a relatively long duration of action It ismetabolized by the liver to several both inactive and mildly active metabolites,excreted partially in the urine (50%) and partially in the bile (50%) It mayinduce severe hypoglycemic episodes and is contraindicated in the elderly and

in nephropathic diabetic patients Glyburide absorption is not affected by foodbut it takes 30–60 min to achieve adequate plasma levels, so that this drugshould be taken before the morning meal

Glipizide has been used since 1973, has a 50–100 times more potenthypoglycemic activity than the ‘first-generation’ drugs (comparable to that ofglyburide) and has an ‘intermediate’ duration of action (see table 3) It ismetabolized by the liver to several inactive metabolites, excreted in the urine(by 68%) and in the feces (by 10%) It may induce severe hypoglycemic episodes(similarly to glyburide) and is contraindicated in the elderly and in nephro-pathic diabetic patients The absorption of glipizide is delayed by about 30 minwhen it is ingested with a meal, so that it is recommended to take the drug

30 min before meals Glipizide has a greater effect than glyburide in raisingpostprandial plasma insulin level and lowering postprandial plasma glucoselevel while glyburide has a better effect than glipizide in raising fasting insuline-mia and reducing fasting glycemia (probably, reducing fasting hepatic glucoseproduction) For this metabolic difference, a ‘combined’ administration of thetwo sulfonylureas was suggested

Gliclazide has a potent hypoglycemic activity (comparable to that ofglyburide and glipizide) and has an ‘intermediate’ duration of action It ismetabolized by the liver to several probably inactive metabolites, excreted inthe urine (by 60–70%) It has been suggested that gliclazide exerts antiplateletaggregating activity, with a potential preventing effect on diabetic microangi-opathy, although this effect has not been confirmed

Gliquidone has a short duration of action (the mean half-life was mately 1.2 h and the mean terminal half-life was 8 h), is metabolized in theliver to totally inactive or minimally active derivatives, and is excreted in theintestine (by about 100%) For these reasons, gliquidone is safer in the elderly

approxi-and in nephropathic diabetic patients A newly developed sulfonylurea, ride, has been reported to have a more potent hypoglycemic action thanglibenclamide while its ability to stimulate insulin secretion is much weaker,possibly due to less stimulation of insulin secretion and more pronouncedextrapancreatic effects It is effective at lower dosage, has a more rapid onset

glimepi-of action than glibenclamide and a long duration glimepi-of action There is increasedplasma elimination of glimepiride with decreasing kidney function, which isexplainable on the basis of altered protein binding with an increase in unbounddrug

E fficacy and Interactions Good response with sulfonylureas will occur

in 70–75% of patients during the first years of treatment, provided that thepatient selection is appropriate Primary failure occurs in 15–25% of casesand may depend on a poor selection of the patients (unrecognized type 1diabetic patients treated with sulfonylureas) Chronic therapy may be associ-ated with progressively less beneficial effects (secondary failure), sometimes

as result of intercurrent factors which impair insulin action and secretion(such as stress, infections, dietary disregard, etc.) (see also chapter III onInsulin Resistance and Its Relevance to Treatment) The response to thehypoglycemic drugs may be restored with the disappearance of the intercur-rent event All sulfonylureas are bound to serum albumin and, since a largenumber of drugs may compete for ionic binding sites on albumin, sulfonylu-reas can influence the effect of many drugs (and these drugs, conversely,can influence the effect of sulfonylureas) The physician must understandpotential interactions with a number of commonly used drugs, that maysignificantly alter the activity of the sulfonylureas both diminishing (diuretics,b-blockers, corticosteroids, estrogens, indomethacin, alcohol, rifampicin, etc.)

or increasing (sulfonamides, salicylates, clofibrate, chloramphenicol, MAOinhibitors, probenecid, allopurinol, b-blockers, alcohol, etc.) their hypogly-cemic effect It is noteworthy that some drugs (such as b-blockers andalcohol) can alter sulfonylureas activity in opposite directions Sulfonylureas

of ‘second generation’ may have less interactions than those of the ‘firstgeneration’

Some data of literature demonstrate that serum levels of sulfonylureas(tolbutamide, chlorpropamide, glyburide and gliquidone) in treated diabeticpatients show extremely interindividual variations, with no correlation betweenthe dose and the plasma level

Mechanism of Sulfonylurea Action

Acute E ffects on Insulin Secretion Sulfonylureas act primarily by acutely

stimulating release of insulin from pancreatic b-cells (obviously, in presence

of functioning pancreatic islets), and this stimulation of insulin secretion is a

direct effect, as unquestionably proven by studies with perfused pancreases,isolated perifused islets and cultures ofb-cells.

Available data suggest that sulfonylureas bind to a specific receptor (closelyassociated with the ATP-sensitive K+-channels) on the outside of plasmamembrane of theb-cells Recent studies with human pancreatic islets showedthat3H-glibenclamide binds to saturable sites in islet membrane preparations

in a linear fashion This binding was both temperature- and time-dependent.Scatchard analysis of the equilibrium binding data indicated the presence

of a single class of saturable, high-affinity binding sites The displacementexperiments showed the following rank order of potency of the oral hypogly-cemic agents tested: glibenclamide> glimepiride ? tolbutamide ? chlorprop-amide A metformin This binding potency order was parallel with theinsulinotropic potency of the evaluated compounds Glimepiride has beenreported to bind to a 65-kDa subunit of the sulfonylurea receptor This charac-teristic may entail a minor effect of the K-channel in other tissues, such asmyocardium (where the closure of K-channels may interfere with the repolar-ization process)

Upon binding to their receptors, sulfonylureas inhibit the K+-channels,diminish K+efflux and cause depolarization of the plasma membrane Thisdepolarization induces voltage-dependent Ca2 +-channels to open and extracel-lular Ca2 +to enter the cell Increased cytoplasmic Ca2 +stimulates the fusion

of the secretory granule membrane with cell membrane, followed by extrusion

of insulin outside the cell (exocytosis) (see also fig 1)

Metabolic studies demonstrate that sulfonylureas stimulate the first phase

of insulin release and have little effect on the second phase They can act inthe absence of glucose but also may potentiate glucose-mediated insulin release

As consequence of the stimulation of secretion, sulfonylureas can induce phological alterations of theb-cells such as degranulation, loss of zinc andaspects of emiocytosis

mor-Chronic E ffects on Insulin Secretion Whether chronic sulfonylurea

treat-ment results in increased insulin secretion is a controversial problem Thefinding that after chronic treatment of type 2 diabetic patients insulinemiareturns to pretreatment level, without deterioration of glucose control, suggestslong-term extrapancreatic effects of sulfonylureas The lower plasma glucoseachieved with sulfonylurea drugs in type 2 diabetic patients might be expected

to stimulate less insulin secretion (blood glucose is the major stimulus to insulinrelease), and this can explain the inability of some studies to demonstratethe chronic effect of sulfonylurea in stimulating insulin secretion Availableliterature data, however, do not support the concept that the improvement ofglycemia during chronic sulfonylurea treatment can be attributed solely to anincreased insulin secretion

Table 4 Extrapancreatic effects of sulfonylureas

Hormonal e ffects

Potentiation of insulin action on skeletal muscle and adipose tissue glucose transport Potentiation of insulin action on hepatic glucose production (activation of glycogen synthase and glycogen synthesis)

Decrease of hepatic insulin extraction

Decrease of insulin degradation (inhibition of insulinase activity)

Stimulating e ffect on gastrointestinal hormone release

Direct metabolic e ffects

Insulin receptors (partial restoration of their number in plasma membrane in type 2 diabetic patients)

obese-Liver (increase in fructose 2,6-bisphosphate; increase in glycolysis; decrease in esis; decrease in long-chain fatty acid oxidation)

gluconeogen-Skeletal muscle (increase of glucose and amino acid transport; increase of fructose bisphosphate)

2,6-Myocardial tissue (increase of contractility; increase of oxygen consumption; increase of glycogenolysis; decrease of Ca2+-ATPase; increase of glucose transport and glycolysis; increase of phosphofructokinase activity and pyruvate oxidation)

Adipose tissue (increase in glycogen synthase; inhibition of lipolysis, increase in glucose transport)

Platelet arachidonic acid metabolism (inhibition of cycloxygenase and 12-lipoxygenase ways)

path-Other E ffects Sulfonylurea treatment does not appear to stimulate

proin-sulin biosynthesis On the other hand, studies performed with in vivo and invitro animal perfused pancreases, or with isolated perifused islets and islet-cell cultures, reported an acute and chronic sulfonylurea-induced inhibition ofthe biosynthesis of proinsulin (through unknown mechanisms) Sulfonylureas,acutely or chronically, do not alter glucagon secretion both in normal subjectsand diabetic patients Sulfonylureas appear to stimulate pancreaticd-cell soma-tostatin release (with unclear physiological effect)

Extrapancreatic E ffects of Sulfonylureas Diverse in vitro and in vivo

extrapancreatic effects of sulfonylureas have been reported over the last 30years (most of which, however, were obtained with drug concentrations largerthan those achieved in therapeutic use) (table 4) These effects of sulfonylureasare due to direct actions on liver and/or muscle and, occurring in the absence

of changes in insulin binding, are probably mediated by postreceptor events

As a whole, the extrapancreatic effects of sulfonylureas are of minor clinicalsignificance A possible exception is glimepiride, which may exert more signifi-cant extrapancreatic actions, including activation (through dephosphorylation)

of GLUT-4

Table 5 Sulfonylurea side or toxic effects

Hematologic reactions (agranulocytosis, bone marrow or red cell aplasia, hemolytic anemia) Skin reactions (rash, pruritus, erythema, purpura, photosensitivity)

Hypersensitivity reaction (rush, fever, arthralgia, angiitis, jaundice, etc.)

Alcohol-induced flushing (most frequently associated with chlorpropamide treatment) Gastrointestinal complaints (nausea, vomiting, jaundice or hepatitis or cholestasis) Antithyroid activity

Diuretic e ffect or antidiuresis with hyponatremia

Cataract formation (reported in some dogs treated with high doses of glimepiride) Teratogenicity

Side or Adverse E ffects of Sulfonylureas The most important adverse effect

of sulfonylureas is hypoglycemia which, although occurring less often thanwith insulin, when it occurs it tends to be more severe, prolonged and sometimesfatal The incidence of sulfonylurea-induced hypoglycemia is 0.19–4.2/1,000treatment years (compared to 100/1,000 patients/year for insulin-induced hy-poglycemia) and is most frequent in patients taking long-acting drugs (such

as glyburide and chlorpropramide) which, for this reason, should be avoided

in patients with predisposing conditions (the best treatment of hypoglycemia

is prevention) The case fatality rate of hypoglycemia induced by sulfonylureas

is 4.3% (see also chapter VIII on Clinical Emergencies in Diabetes 2: cemia) It is noteworthy that sulfonylureas predispose to hypoglycemia duringand after exercise In this regard, it has been claimed that glimepiride maintains

Hypogly-a more physiologicHypogly-al regulHypogly-ation of insulin secretion during physicHypogly-al exercise,with less risk of hypoglycemia

Other sulfonylurea side effects or toxic reactions occur at low rate (1.5%for glyburide) (table 5) and appear within the first 2 months of treatment Thechlorpropamide alcohol flushing (CPAF), occurring in 30–40% of type 2 and10% of type 1 diabetic patients, is linked to a genetic predisposition to diabetesdevelopment (autosomic trait) and can be considered a good genetic marker

of type 2 diabetes mellitus

Other Drugs Modifying Insulin Secretion

Repaglinide is a nonsulfonylurea hypoglycemic agent of the meglitinidefamily, a new class of drugs with insulin secretory capacity which exert arapid- and also short-acting effect, thus entailing reduced risk of long-lasting,and hence dangerous, hypoglycemia Repaglinide appears to bind to receptor

sites different from those of sulfonylureas (two binding sites have been fied) Repaglinide lowered fasting and postprandial blood glucose levels inanimals, healthy volunteers and patients with type 2 diabetes mellitus Repagli-nide is rapidly absorbed and eliminated, which may allow a relatively fastonset and offset of action Excretion occurs almost entirely by nonrenal mecha-nisms In comparative clinical trials in patients with type 2 diabetes mellitus,repaglinide 0.5–4 mg twice or 3 times daily before meals provided similarglycemic control to glibenclamide (glyburide) 2.5–15 mg/day Addition ofrepaglinide to existing metformin therapy resulted in improved glycemic con-trol In contrast with glibenclamide, use of repaglinide allowed patients tomiss a meal without apparently increasing the risk of hypoglycemia.

identi-GLP-1 has insulinotropic action, which may explain the increased insulinresponse after oral compared to intravenous glucose administration, and exertsseveral other functions such as reduction of glucagon concentration, reduction

of gastric emptying, stimulation of proinsulin biosynthesis and reduction offood intake (upon intracerebroventricular administration in animals) On thesegrounds, GLP-1 seems to offer an interesting perspective in treatment ofdiabetic patients The observations that GLP-1 induces both secretion andproduction of insulin, and that its activities are mainly glucose-dependent, led

to the suggestion that GLP-1 may present a unique advantage over sulfonylureadrugs in the treatment of type 2 diabetes This peptide is able to lower andperhaps normalize fasting hyperglycemia and to reduce postprandial glycemicincrements (especially in type 2 diabetic patients) but its usefulness is notcompletely established Due to rapid proteolytic cleavage, the half-life of GLP-1

is too short for therapeutical use with subcutaneous injections GLP-1 analogueswith different pharmacokinetic properties (or some preparations that could

be orally administered) are in development Given the large amount of GLP-1present in L-cells, it appears worthwhile to look for some agents that could

‘mobilize’ this endogenous pool of the ‘antidiabetogenic’ gut hormone GLP-1.Interference with sucrose digestion usinga-glucosidase inhibition moves nutri-ents into distal parts of the gastrointestinal tract and, thereby, prolongs andaugments GLP-1 release

Antiarrhythmic agents with Vaughan Williams class Ia action have beenfound to induce a sporadic hypoglycemia Recent investigation has revealedthat these drugs induce insulin secretion from pancreaticb-cells by inhibitingATP-sensitive K+(K-ATP) channels in a manner similar to sulfonylurea drugs

It is possible that in the future, pharmacological compounds will be foundthat may act on GK and improveb-cell insulin secretion

Suggested Reading

Belfiore F, Rabuazzo AM, Iannello S, Campione R, Castorina S, Urzı´ F: Extrapancreatic action of glibenclamide: Reduction in vitro of the inhibitory e ffect of glucagon and epinephrine on the hepatic key glycolytic enzymes phosphofructokinase and pyruvate kinase Eur J Clin Invest 1989;19:367–371 Draeger E: Clinical profile of glimepiride Diabetes Res Clin Pract 1995;28(suppl):139–146.

Drucker DJ: Glucagon-like peptides Diabetes 1998;47:159–169.

Goldberg RB, Einhorn D, Lucas CP, Rendell MS, Damsbo P, Huang WC, Strange P, Brodows RG:

A randomized placebo-controlled trial of repaglinide in the treatment of type 2 diabetes Diabetes Care 1998;21:1897–1903.

Lebovitz HE: Oral hypoglycemic agents; in Rifkin H, Porte D (eds): Diabetes mellitus Theory and Practice, ed 4 New York, Elsevier, 1990, pp 554–574.

Matschinsky FM: Banting Lecture 1995: A lesson in metabolic regulation inspired by glucokinase glucose sensor paradigm Diabetes 1996;45:223–241.

Philipson LH, Steiner DF: Pas de deux or more: The sulfonylurea receptor and K+channels Science 1995;268:372–373, 423–429.

F Belfiore, Institute of Internal Medicine, University of Catania, Ospedale Garibaldi,

I–95123 Catania (Italy)

Tel +39 095 330981, Fax +39 095 310899, E-Mail francesco.belfiore@iol.it

The Insulin Receptor

The insulin receptor is a heterodimer composed of two chains or subunits,thea- and the b-chain, linked by disulfide bridges The a-subunit is extracellular

in location and is the site of insulin binding Theb-subunit is transmembrane

in location and originates from the signal transduction

Normally there is a large surplus in the number of receptors (i.e there is

a large amount of spare receptors) Nevertheless, considering that insulinbinding to its receptors is a random phenomenon, it follows that the higherthe number of insulin molecules or receptor units, the higher the number ofinsulin molecules which will bind to the receptor units An increase in theinsulin level causes a decrease in the receptor number on the plasma membrane(downregulation of insulin receptors), a phenomenon that may occur in condi-tions of persistent hyperinsulinemia (insulin-resistant states, including obesity)

Fig 1 Schematic representation of dose-response curves of insulin action in the normal

state and in conditions of impaired insulin action For explanation, see the text.

When the receptor number is decreased, the number of insulin molecules thatbind to the receptors at a given insulin level will be reduced, and thereforethe insulin effects will be diminished, i.e there is insulin resistance However,

by increasing the insulin level, the number of insulin molecules that bind tothe receptors can be increased toward the normal and therefore the insulin

effects can be restored; moreover, by increasing further the insulin level, themaximum effect can be reached This condition is called decreased insulinsensitivity By plotting the insulin concentrations (on the abscissa) against theinsulin effect (on the ordinate), the insulin dose-response curve is obtained.This curve, in the case of insulin resistance due to reduced receptor number,will be shifted to the right, as the maximum effect is reached at very highinsulin levels On the other hand, when the insulin resistance is due to defects

in postreceptor steps of insulin action (see below), the dose-response curve isflattened and the maximum insulin effect is not reached even at very highinsulin concentrations When the two conditions coexist, the insulin dose-response curve will be shifted to the right and flattened (fig 1)

Concerning the fate of the insulin-receptor complexes, several data suggestthat they are internalized and delivered to endosomes, the acidic pH of whichinduces the dissociation of insulin molecules from insulin receptors and theirsorting in different directions: insulin molecules are targeted to late endosomes