pathogenesis of niddm

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R E V I E W A R T I C L E

Pathogenesis of NIDDMA Balanced Overview

RALPH A. DEFRONZO, MDRLCCARDOC . BONADONNA, MDELEUTERIO FERRANNINI, MD

Non-insulin-dependent diabetes mellitus (NIDDM) results froman imbalance be-tween insulin sensitivity and insulin secretion. Both longitudinal and cross-sectional

studies have demonstrated that the earliest detectable abnormality in NIDDMis animpairment in the body's ability to respond to insulin. Because the pancreas is ableto appropriately augmentits secretion of insulin to offset the insulin resistance,glucose tolerance remains normal. With time, however, the P-cell fails to maintain itshigh rate of insulin secretion and the relative insulinopenia (i.e., relative to the degreeof insulin resistance) leadsto the developmentof impaired glucose tolerance andeventually overt diabetes mellitus.Th e cause of pancreatic "exhaustion" remainsunknown but may be related to the effect of glucose toxiciry in a geneticallypredisposed P-cell. Information concerning the lossof first-phase insulin secretion,altered pulsatility of insulin release, and enhanced proinsulin-insulin secretory ratiois discussed asit pertains to altered p-cell function in NIDDM. Insulin resistanceinNIDDM involves both hepatic and peripheral, muscle, tissues.In the postabsorptivestate hepatic glucose outputis normal or increased, despite the presenceof fastinghyperinsulinemia, whereasthe efficiency of tissue glucose uptakeis reduced. Inresponse to both endogenously secreted or exogenously administered insulin, h epaticglucose production failsto suppress normally and muscle glucose uptakeis dimin-ished. The accelerated rateof hepatic glucose outputis due entirely to augmentedgluconeogenesis. In muscle many cellular defectsin insulin action have beende -scribed including impaired insulin-receptor tyrosine kinase activity, diminished glu-cose transport, and reduced glycogen synthase and pyruvate dehydrogenase.Th eabnormalities accountfor disturbances in the two major intracellular pathwaysofglucose disposal, glycogen synthesis, and glucose oxidation.In the earliest stages ofNIDDM, the major defect involves the inability of insulin to promote glucose uptakeand storage as glycogen. Other potential m echanisms that have been p ut forwardtoexplain the insulin resistance, include increased lipid oxidation, altered skeletalmuscle capillary density/fiber type/blood flow, impaired insulin transport across thevascular endothelium, increased amylin, calcitonin gene-related peptide levels, andglucose toxicity.

FROM THE DIVISION OF DIABETES, THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO;

THE AUDIEL. MURPHYVA HOSPITAL, SAN ANTONIO, TEXAS; AND THE INSTITUTE OF PHYSIOLOGY,C.N.R.,

PISA, ITALY.

ADDRESS CORRESPONDENCE TO RALPHA. DEFRONZO, MD, PROFESSOR OF MEDICINE, CHIEF, DIABETES

DIVISION, THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO,7 7 0 3 FLOYD CURL

DRIVE, SAN ANTONIO,I X 7 8 2 8 4 - 7 8 8 6 .

After an overnight fast, insulin-independent tissues, th e brain(50%), an d splanchnic organs

(25%) account for most of the total-body glucose disposal. Insulin-indepen-dent tissues, primarily muscle (14), areresponsible for the remaining 25%ofglucose utilization. Basal glucose uptakeis 2 mg k g "1 min"1, and this is pre-cisely matched by the releaseof glucosefrom the liver (1-4; Fig. 1). After glucoseingestion or infusion, this delicate bal-ance between tissue glucose uptake andhepatic glucose outputis disrupted and

the maintenanceof normal glucose ho-meostasis is dependent on threep ro -cesses that occurin a coordinatedan dtightly integrated fashion (Table1). Inresponse to glucose, pancreatic insulinsecretion is stimulated and the combina-tion of hyperinsulinemia plus hypergly-cemia promotes glucose uptakebysplanchnic Giver and gut) and peripheral(primarily muscle) tissuesan d su p -presses hepatic glucose production.Itfollows, therefore, that defectsat thelevel of the P-cell, muscle, and/or livercan lead to the developmentof glucoseintolerance or overt diabetes mellitus.Inthis review we emphasize the conceptthat the full-blown syndromeof non-insul in-dependent diabetes mell i tus(NIDDM) requires th e simultaneouspresence of two major defects, insulinresistance and impaired P-cell function.In most NIDDM individuals impairedtissue (muscle and/or liver) sensitivity toinsulin represents the primaryor inher-ited defect. If the P-cell fails to maintaina sufficiently high rateof insulin secre-tion to offset the insulin resistance, fast-ing hyperglycemia an d overt diabetesmellitus ensue. This sequenceof eventsis characteristicof both obese and leandiabetic individuals.In some NIDDMpatients the primary defect may startatthe levelof the P-cell and manifest itselfas an impairment in insulin secretion;insulin resistance develops concomi-tantly with or subsequent to the distur-bance in insulin secretion. Such individ-

uals are unusual and are represented by

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Table 1 Factors responsible for themaintenance of normal glucose tolerance in

healthy subjectsINSULIN SECRETION

TISSUE GLUCOSE UPTAKE

PERIPHERAL (PRIMARILY MUSCLE)

SPLANCHNIC (LIVER PLUSGUT)

SUPPRESSION OF HEPATIC GLUCOSE

PRODUCTION

Although ad ipose t i ssueis insulin sensit ive,iti s responsib lefor the disposal of only 1- 2%of an infused or ingested glucose load.

the lean diabetic.It should be empha-sized that, whichever defect,i.e., dimin-ished insulin secretionor insulin resis-tance, initiates the development ofNIDDM it subsequently leads to theemergence of the second abnormality.Importantly, both defects mustbepresent simultaneously before significantglucose intolerance will ensue. Althoughexcessive hepatic glucose metabolism,and specificallyan increase in gluconeo-genesis, playsan important rolein main-taining the diabetic state onceit has be-come firmly established,it is uncertainwhat role the liver plays in the develop-ment of early fasting hyperglycemiainNIDDM patients.

INSU LIN SECRETIONIN N I D D M |3-Cell functionin NIDDM has been thesubject of much controversy (1,5-7).

1.5

mg/kgmin

Glycogenolysis

Glycerol (2%)ruvote(l%)

Loctate(l6%)AminoAcids(6%)

Other

Glycolysis

GlucoseOxidation

SplanchnicGlucose Uptake

TOTAL BODYGLUCOSEUPTAKE

Figure 1 Sche matic representation of glucoseproduction and glucose utilization in nondiabetic

humans in the postabsorptive state. Drawn from

the data presented in refs. 2-4 and 149.

However, recent studies have demon-strated a consistent pattern that revealsa

complex interplay between insulin secre-tion, insulin sensitivity,and the severityof hyperglycemia.In Table 2 we summa-rized published studiesin which insulinsecretion has been quantitated in nor-mal-weight NIDDM subjects with fastinghyperglycemia (5). Because obesitycauses insulin resistance, whichin turnelicitsa compensatory increasein insulinsecretion (1,6,8),we focus initiallyonthe lean NIDDM patientto examine thepure impactof diabetes on insulin secre-tion. In subsequent sectionswe explorethe interaction between obesityand dia-betes on insulin sensitivityand insulinsecretion.

Fasting insulin concentrationsThe fasting plasma insulin concentrationhas invariably been foundto be normalor increased in NIDDM (Table2). Evenin those studies where normal fastingplasma insulin levels have been reported,they uniformly have beenin the highnormal range. Moreover, basal insulinsecretion, estimatedin NIDDM patientswith C-peptide,is increased (9,10).Re-cently, we measured the plasma insulinconcentrationin the basal stateand dur-in g an oral glucose tolerance test(OGTT) in 77 normal-weight NIDDMsubjects (11; Fig. 2). The relationshipbetween fasting glucoseand insulin lev-els is complex, resemblingan inverted"U." Asthe fasting glucose increases from80 to 140 mg/dl, there is a progressive

rise in fasting plasma insulin, whichrep-resents a compensatory responseby thepancreas to offset the deterioration inglucose metabolism. Whenthe fastingglucose exceeds 140 mg/dl, insulinse-cretion drops off precipitously.The in-ability of the pancreas to maintain itshigh rate of insulin secretionhas impor-tant pathophysiological im plications,be-cause it is at this point (fasting glucose140 mg/dl) that hepatic glucose produc-tion increasesin absolute termsand be-

gins to make a major contributionto the

Fasting 2 0

PlasmaInsulin IR

l5

60 IOO 140 180 220 260 300

Fasting Plasma Glucose (mg/dl)

F ig u re 2 Relationship between the fasting

plasma glucose concentration and the fastingplasma insulin concentration in normal-weight

control subjects, in individuals with impaired

glucose tolerance, and in non-insulin-dependent

diabetic subjects with varying degrees of fasting

hyperglycemia. As the fasting plasma glucose

concentration rises from baseline to 140 mg/dl,

there is a progressive increase in the fasting

insulin concentration. Thereafter, further risesin

the fasting glucose level are associated with a

progressive decline in fasting insulin. In diabetic

subjects with fasting glucose concentrations

>200-220 mg/dl, the fasting insulin levelde-

clines to values observed in control subjects.

From DeFronzo et al. (11). by Metabolism.

Table 2 S u m m a r y of plasma insulinresponse during glucose tolerance tests innonobese non-insulin-dependen t diabetic

subjects with fasting hyperglycem ia

PLASMA INSULIN

RESPONSE TO GLUCOSEFASTING

INSULIN EA RLY* LATE TO TA L

DECREASED

N O R M A L

INCREASED

027

5

2165

1312

7

16115

T h e 32 publ icat ions f rom whichth e ab o v esu mmary was p rep a redcan be found in ref. 5.*The ear ly phaseof insulin secretion referstoth e 0- to 1 0 -mi n p e r i o d d u r i n gth e in t rave-nous g lucose to lerance tes tand the 0- to6 0 -mi n p e r i o d d u r i n gth e oral glucose toler-

ance test .

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elevation in fasting plasma glucose con-centration (11). The simultaneous pres-

ence of fasting hyperglycemia an d fastinghyperinsulinemia indicates the presenceof severe insulin resistance. In the post-absorptive state both hep atic and perip h-eral tissues share in this insulin resis-tance (see subsequent discussion).

Glucose-stimulated insulinsecretionIn lean NIDDM subjects glucose-stimu-lated insulin secretion has variably beenreported to be normal, increased, or de-

creased (1,5; Table 2). It must be empha-sized, however, that even a normal orincreased plasma insulin response is de-ficient when viewed relative to the levelof hyperglycemia and degree of insulinresistance. Numerous studies, includingour own (1, 12 -22 ), have shown that therelationship between insulin secretionduring an OGTT and the severity of di-abetes is complex and resembles thatseen in the fasting state. During a 2-horal glucose load (100 g), a nondiabeticindividual (fasting glucose 80 mg/dl) hasa mean plasma insulin concentration of45 fiU/ml. With the onset of fastinghyperglycemia the (3-cell recognizes thatthe glucose homeostatic mechanism hasbecome disrupted and augments its in-sulin secretory capacity in an attempt tooffset the disturbance in glucose metab-olism (Fig. 3). Thus, an individual with afasting glucose of 120 mg/dl (i.e., im-paired glucose tolerance [IGT] or earlydiabetes mellitus) secretes approximatelytwice as much insulin as a person withnormal glucose tolerance. When the fast-ing glucose exceeds 120 mg/dl, there is aprogressive decline in insulin secretion,and a diabetic person with a fasting glu-cose of 150-160 mg/dl secretes anamount of insulin that is similar to thatin a healthy nondiabetic individual.Note, however, that a normal insulin re-sponse in the presence of hyperglycemiais markedly abnormal. With further in-crements in fasting glucose (> 150-160mg/dl) the plasma insulin response,

when viewed in absolute terms, becomes

MeanPlasmaInsulin

ResponseDuringO G T T

(yaU/ml)

120 160Fasting Plasma Glucose

Cone, (mg/dl)

Figure 3 Starling's curve of the pancreas forinsulin secretion. In normal-weight patients withimpaired glucose tolerance and mild diabetesmellitus, theplasma insulin response to ingestedglucose (OGTT) increases progressively until the

fasting glucose reaches 120 mg/dl. Thereafter,further increases in the fasting glucose concen-tration are associated with a progressive declinein insulin secretion. Drawn from the data pre-sented in refs. 1, 4, 5, 134-136, and 167.

deficient. This inverted U-shaped curveis similar to that observed in the p ostab -sorptive state (Fig. 2). Finally, when thefasting glucose level exceeds 200220

mg/dl, the plasma insulin response be-comes markedly blunted, although thebasal rate of insulin secretion remainselevated and fasting hyperinsulinemiapersists (9,10,23). Even with severe fast-ing hyperglycemia, 24-h insulin profilesin NIDDM subjects reveal normal inte-grated insulin and C-p ep tide areas (2426). These normal values result from thecombination of high fasting and de-creased postprandial insulin/C-peptidesecretory rates.

The pancreatic function curvesdescribed above (Figs. 2 and 3) are con-sistent with the natural history of im-paired glucose tolerance and NIDDM inhumans (1,22,27-32) and the rhesusmonkey (33,34). The progression fromnormal to IGT is associated with amarked increase in both fasting and glu-cose-stimulated plasma insulin levels(1 ,22 ,27 ,31 ,32) . In these s tud ies(1,22,27,31,32) conversion to IGT is as-sociated with the development of severeinsulin resistance (Fig. 4). As the personwith IGT progresses to NIDDM with

mild fasting hyperglycemia ( 140 mg/dl) results from an inability ofthe P-cell to maintain its high rate ofinsulin secretion, both in the postabsorp-tive and stimulated states (Fig. 4). A sim-ilar picture of insulin secretion has beenreported with the development of diabe-tes in the rhesus monkey (33,34). Thesestudies (1,22,28,30,31,32) conclusively

document that hyperinsulinemia pre-cedes the development of NIDDM in h u-mans and exclude the possibility thatinsulinopenia initiates the process of di-abetes mellitus. Consistent with this se-quence of events, studies in ethnicgroups who are at high risk to developNIDDM (20,22,27,35-40) and in first-degree relatives of NIDDM individuals(37,41,42) have shown that hyperinsu-linemia predicts the eventual develop-

Mean 120Plasma InsulinDuring OOTT 100

(jiUVml)

O..- . .-080

250 Insulin-MsdlatsdGtucose

Plasma GlucoseDuring OGTT

CON OB OB- OB-GLU DIABINTOL Hi INS

Figure 4 Summ ary of plasma insulin (A,open circles) and plasma glucose (B ) responsesduring a 100-g oral glucose tolerance test(OGTT) and tissue sensitivity to insulin (A,closed circles) in control, obese nondiabetic, obeseglucose-intolerant, obese hyperinsulinemic dia-betic, and obese hypoinsulinemic diabetic sub-jects. See text for a detailed discussion. FromDeFronzo (1). by the American Diabetes As -sociation.

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ment of IGT and NIDDM. Most recently,hyperinsulinemia has been shown to

predict the development of NIDDM inwhites (43,44).

First-phase insulin secretionIn humans (45) and animals (46) insulinsecretion is biphasic, with an early burstof insulin release within the first 10 min,followed by a progressively increasingphase of insulin secretion that persists aslong as the hyperglycemic stimulus ispresent. This biphasic response is noteasily identifiable after oral glucose butcan be readily demonstrated after intra-venous glucose. It has been suggestedthat loss of the first phase of insulin se-cretion is the earliest detectable abnor-mality in patients who are destined todevelop NIDDM (47,48). From the datareviewed in Table 2 it is obvious that theearly phase of insulin secretion duringboth the OGTT and the intravenous glu-cose tolerance test is reduced in mostNIDDM subjects with fasting plasma glu-cose levels > 110120 mg/dl. The loss ofthe first phase of insulin secretion hasimportant pathogenetic consequences,because this early burst of insulin releaseplays an important role in priming thoseinsulin target tissues, especially the liver,that are responsible for the maintenanceof normal glucose homeostasis (49-52).However, loss of first-phase insulin se-cretion does not appear to be the primarydefect responsible for NIDDM. Recentstudies (27,28) have shown that progres-sion from normal to IGT or to NIDDM isassociated with a reduction in insulin

sensitivity and an increase in insulin se-cretion with an intact first-phase re-sponse. Although the first-phase insulin-secretory response is characteristicallylost in patients with well-establishedNIDDM (Table 2), this defect does notoccur until the fasting plasma glucoseconcentration rises to 115-120 mg/dl(53). Moreover, tight metabolic controlpartially restores the defect in first-phaseinsulin response (54-56), indicatingthat the defect is acquired and not inher-ited. In the same vein, first-phase insulin

response has been shown to be normal inthe relatives of patients with NIDDM

(57) and in the normal glucose-tolerantinsulin-resistant offspring of two diabeticparents (58).

Pulsatile insulin secretionIn humans (59) and animals (60) insulinis secreted in a pulsatile fashion andsome evidence suggests that pulsatile in-sulin delivery is more effective in pro-moting glucose disposal than continu ousadministration (61). However, this hasbeen refuted by others (62). A recentstudy reported that loss of oscillatory in-sulin secretion is a characteristic featureof relatives of patients with NIDDM (58)and suggested that this may be the ear-liest lesion in the natural history ofNIDDM. Somewhat differing resu lts havebeen reported by Polonsky et al. (63). Inpatients with established NIDDM, thenumber of pulses secreted during a 24-hperiod did not differ from control sub-jects, although the pulse amplitude wassignificantly reduced and their relation-ship to meals was distorted (63). Themeaning of these somewhat discrepantobservations remains uncertain becausethere is no conclusive evidence that lossof pulsatile insulin release has any ad-verse consequences on glucose homeo-stasis.

ProinsulinIt has been suggested that NIDDM indi-viduals may be more insulinopenic thanpreviously appreciated because of thepresence of high circulating levels ofproinsulin and 32-33 split proinsulin,which are biologically much less activethan insulin but cross-react substantiallyin the routine insulin radioimmunoassay(64). In nondiabetic subjects the abso-lute amount of proinsulin secreted issmall compared with insulin (65). How-ever, because the metabolic clearancerate of proinsulin is significantly lessthan that of insulin (66), it accounts for 10% of the total amount of circulatinginsulin that is measured in the basal and

glucose-stimulated states (65). With the

use of a specific proinsulin assay, severallaboratories have demonstrated that in

NIDDM individuals with m oderate to se-vere hyperglycemia, proinsulin makes u pa larger fraction of the immunoassayableinsulin (64,67-69). One study suggestedthat proinsulin accounts for >50% ofcirculating radioimmunoassayable insu-lin (64). However, in this study the dia-betic subjects had severe fasting hyper-glycemia (>225 mg/dl), only a singleearly time point (30 min) during theOGTT was analyzed, and proinsulin/insulin was assayed on samples that hadbeen stored for a prolonged period. Un-der such conditions, one would expect apreferential loss of insulin comparedwith proinsulin and its split products.This would artifactually increase the in-sulin-proinsulin ratio.

Nonetheless, the observations d e-scribed above have raised several impor-tant questions. When does the increasein proinsulin occur and are patients withIGT and/or NIDDM with mild fastinghyperglycemia characterized by true in-sulin deficiency? To address this issue,Yoshioka et al. (69) measured the insulinand proinsulin responses in nondiabetichealthy subjects, in subjects with IGT,and in NIDDM patients with a widerange of fasting plasma glucose levels.Subjects with IGT and mild fasting hy-perglycemia (


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insulin-insulin ratio was observed in theportal vein. However, as in diabetic hu-

mans (69), the percentage of increase inportal vein proinsulin in the rat wassmall (3-10%). The authors suggestedthat chronic hyperglycemia was respon-sible for the augmented rates of proin su-lin synthesis and secretion in this par-tially pancreatectomized diabetic ratmodel (70). In summary, it appears thatin diabetic humans circulating levels ofboth "true" biologically active insulinand proinsulin are increased. Only inmoderately severe to severe NIDDM in-

dividuals (fasting glucose > 16 0- 18 0mg/dl) is there a decrease in the biolog-ically active insulin component.

Etiology of insulin deficiency inNIDDMThe progression from normal glucosetolerance to IGT to NIDDM with mildfasting hyperglycemia (< 12 0-1 40 mg/dl) is characterized by progressive hyper-insulinemia (Figs. 2-4). However, oncethe fasting glucose concentration exceeds

140 mg/dl there is a decline in both fast-ing and glucose-stimulated plasma insu-lin levels. These observations suggestthat the decline in |3-cell function is ac-quired. In this section we review thosepathogenetic factors that have been im-plicated in this progressive impairmentin insulin secretion.

P-Cell number is a critical deter-minant of the amount of insulin that issecreted by the pancreas. Most (71-76)but not all (77) studies have demon-strated a modest reduction (20-40%) inf$-cell mass in patients with well-estab-lished NIDDM. Morphologically, the is-lets of Langerhans appear normal andthere is no evidence of insulitis. The eti-ology of the decreased (3-cell mass re-mains undefined. Advancing age cannotexplain the loss of functioning (3-cellnumber (71-76). Obesity, another insu-lin-resistant state, is characterized by anincrease in (3-cell mass (75). Thus, thefinding of even a modest reduction in(3-cell mass is most im pressive. Non ethe-less, it is important to emphasize that a

>80-90% decrease in (3-cell mass is re-quired before sufficient insulinopenia de-

velops to cause overt diabetes mellitus(78). Moreover, it is unknown whether,in the earliest stages of the natural his-tory of NIDDM, |3-cell mass is dimin-ished whatsoever. It seems likely, there-fore, that factors in addition to (3-cell lossmust be responsible for the impairmentin insulin secretion.

A basic genetic defect in the in-sulin gene has been proposed to explainthe disturbance in insulin secretion inNIDDM, but there is little evidence to

support this hypothesis. As reviewed byPermutt and Elbein (79), mapping of theinsulin gene for restriction-fragment-length polymorphisms failed to revealany significant abnormalities. Most re-cently, the insulin gene has been clonedand its DNA sequence determined (80).Six families have been identified inwhom a point mutation in the insulingene has lead to the development of mildhyperinsulinemic diabetes that is similar,in some respects, to NIDDM in humans(81). However, such m utations appear tobe rare and are unlikely to account formost patients with NIDDM. In Pima In-dians and Nauruans, two populationswith a high prevalence of NIDDM, thecoding sequence of the insulin gene hasbeen shown to be normal (82). A topic ofconsiderable interest involves the genesthat activate insulin-gene transcription.Because 5'-flanking region cis-regulatoryelements have been described, it is pos-sible that deficiency of gene productsthat activate (or conversely, excess ofgene products which inhibit) the pro-moter region of the insulin gene may beresponsible for the development of hy-poinsulinemia in NIDDM.

Recently, it has been suggestedthat amylin may contribute to the defectin insulin secretion in NIDDM. This hor-mone is a 37 amino acid peptide that isstructurally similar to calcitonin gene-related peptide. It is produced by theP-cell, packaged with insulin in secre-tory granules, and cosecreted into thesinusoidal space (83-86). This peptide

has been shown to be the precursor forthe amyloid deposits that frequently are

observed in patients with NIDDM (85-89). At very high dosages amylin hasbeen shown to inhibit insulin secretionby the perfused rat pancreas in vitro (90)and to precede the appearance of glucoseintolerance in spontaneously diabeticmonkeys (91). In this latter model theseverity of the diabetes is correlatedclosely with the amount of amylin that isdeposited within the pancreas (91). Afterits secretion, amylin accumulates extra-cellularly in close contact w ith the (3-cell,

and it has been postulated that theseamylin deposits might cause f$-cell dys-function and eventually death by impair-ing the transport of nutrients from theplasma to the (3-cell or by interferingwith the glucose-sensing and/or insulin-secreting apparatus of the 3-cell (85-87). Although an attractive hypothesis,Bloom et al. (92,93) failed to find anyinhibitory effect of amylin on insulin se-cretion when the peptide was infused inpharmacological dosages in rats, rabbits,and humans. In summary, the evidencethat amylin is responsible for the defectin f}-cell dysfunction in NIDDM in hu-mans is not very strong. Similarly, calci-tonin gene-related pep tide, which sharesa 46% homology with amylin, has beenshown to have no effect on insulin secre-tion when infused intravenously in rats(94). The newest hormone that has beenimplicated in the impairment of insulinsecretion in NIDDM is galanin (95). This29 amino acid peptide is released bypancreatic sympathetic nerve terminals

in response to neural stimulation, inhib-its both basal and stimulated insulin se-cretion, and is a glucagon secretagogue(95).What role, if any, this novel peptideplays in the pathogenesis of NIDDM re-mains to be determined.

The most likely explanation forthe acquired defect in insulin secretionrelates to the concept of glucose toxicity(1,7,96,97). Much evidence in supportof this hypothesis has been producedboth in humans and animals. In NIDDMpatients, tight metabolic control, how-

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ever, achieved (i.e., diet, insulin therapy,sulfonylureas), leads to an improvement

in insulin secretion (7 ,96 ,98 -10 4 and inthe article byj. Leahy, this issue, p. 442).Although it is well established that sul-fonylurea agents enhance insulin secre-tion, weight loss has no direct effect onP-cell function (105), and insulin ad-ministration actually inhibits insulin se-cretion (106). The observation that im-proved glycemic control, independent ofthe method via which it is achieved,leads to improved (3-cell function (96),provides strong clinical support that hy-perglycemia exerts a deleterious effect oninsulin secretion.

A more rigorous test of the glu-cose toxicity hypothesis requires that theplasma glucose concentration be loweredwithout altering circulating substrate lev-els (other than glucose) with an agentthat does not have any direct effect oncellular metabolism. This goal can beachieved by the chronic administrationof phlorizin, a potent inhibitor of renaltubular glucose transport (96). In dia-betic animals phlorizin restores normo-glycemia without altering plasma insulin,amino acid, free fatty acid, or other sub-strate/hormone concentrations (107). Inrats made diabetic by removal of 90% ofthe pancreas, mild fasting hyperglycemiaand moderately severe glucose intoler-ance develop (107). In control rats asquare wave of intravenous glucose (hy-perglycemic clamp) elicits the typical bi-phasic pattern of insulin secretion, withan early burst of insulin release withinthe first 10 min followed by a progres-sively increasing pattern of insulin re-lease over the subsequent 50 min. Inpartially pancreatectomized rats the firstphase of insulin secretion was totally lostand the second phase was markedly im-paired (Fig. 5). This rat model closelyresembles insulinopenic NIDDM in hu-mans. Restoration of normoglycemia byphlorizin treatment returned both thefirst and second phases of insulin secre-tion to normal (107; Fig. 5). These re-sults indicate that impaired (3-cell func-

tion in partially pancreatectomized rats is

6

5

4

3

2

1PLASMAINSULIN

RESPONSE(ng/ml 6

per g ofpancreas) 5

4

3

2

1

0

First Phase (0 -10 min)

BSecond Phase (10 - 60 min)

CONTROL PANX

Figure 5 First-phase (A) and second-phase(B) insulin secretion in control rats, in 90% par-tially pancreatectomized rats, and in pancretec-tomized rats treated with phlorizin. Phlorizincompletely corrected the defects in first- an dsecond-phase insulin secretion. From Rossettietal. (96). by the American Diabetes Associa-tion.

functional in nature and cannot be at-tributed to "P-cell death." Otherwise,one would not observe a recovery ofP-cell function with improved glycemiccontrol. Additional support for this hy-pothesis is derived from the P-cell re-sponse to nonglucose stimuli. Thus, argi-nine infusion causes a threefold greaterrise in insulin secretion in partially pan-createctomized diabetic versus controlrats, and this potentiated insulin re-sponse is returned to normal after cor-rection of the hyperglycemia with phlo-rizin (96,107). This potentiated insulinresponse to amino acids and othernonglucose stimuli most likely explainsthe normal daylong plasma insulin levelsin NIDDM patients, despite the presenceof mod erate to severe fasting h yperglyce-mia (24-26).

Weir and Leahy et al. (108-110)provided additional support for the glu-

cose toxicity hypothesis. In both the par-

tially pancreatectomized and neonatalstreptozocin-induced diabetic rat models

the insulin response to hyperglycemia inperfused pancreatic tissue was markedlyimpaired in diabetic versus control ani-mals. In contrast, the insulin secretoryresponse to arginine, isobutyl methyl-xanthine, and isoproterenol was eithernormal or increased. In an elegant seriesof studies these authors demonstratedthat the defect in insulin secretion wasnot the consequence of diminishedP-cell mass alone, but resulted from su-perimposed mild hyperglycemia (111). Asustained rise in the plasma glucose con -centration of as little as 15 mg/dl causeda 75% inhibition of insulin secretion bythe in vitro perfused pancreas. These re-sults provide support for the conceptthat a minimal elevation in the meanplasma glucose concentration, in thepresence of a reduced p-cell mass, canlead to a major impairment in insulinsecretion by the remaining pancreatic tis-sue (96). A deleterious effect of hypergly-cemia on P-cell function also has beendemonstrated in normal rats af terchronic (72-h) glucose infusion (112,113). The studies of Giroix et al. (114),Kergoat et al. (115), Grill et al. (116),and Imanura et al. (117) are in agree-ment with those of Weir and Leahy et al.The potential mechanism(s) responsiblefor the downregulation of insulin secre-tion have been reviewed by Rossetti andDeFronzo (96).

From the in vivo and in vitrostudies reviewed above, it seems reason-able to postulate that chronic hypergly-cemia is responsible, at least in part, forthe P-cells' inability to respond to anacute hyperglycemic challenge. This con-cept, which we have referred to as glu-cose toxicity, has far reaching implica-t ions (1,96) . Firs t , i t means thathyperglycemia no longer simply can beviewed as a manifestation, i.e., a labora-tory marker, of diabetes mellitus. Rather,the hyperglycemia must be considered asa pathogenetic factor that impairs insulinsecretion and, therefore, perpetuates the

diabetic state. Second, the glucose toxic-

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50 -

PlasmaInsulin(nU/ml)

25

Diet (17) Sulfonylureas (26) Insulin (7)

AfterTherapy

B400 r

PlasmaGlucose 2 5 (mg/dl)

20 0

2 3 0 ITime (hours)

Figure 6 Plasma insulin (A) and glucose (B ) concentrations in non-insulin-dependent diabeticpatients before and after treatment with diet, sulfonylureas, and insulin. Improved glycemic control,

regardless of the means by which it was achieved, uniformly led to an improvem ent in insulinsecretion. From Kosaka et al. (99). by Diabetologia.

ity hypothesis has important therapeuticimplications and may help to explain theuniform improvement in insulin secre-tion observed after many diverse maneu-vers, all of which have in common theability to lower the plasma glucose con-centration. Thus, acute and chronic ca-loric restriction, intensified insulin ther-apy, and sulfonylurea drugs all reduce

the plasma glucose concentration and areassociated with a concomitant increase ininsulin secretion. The results of Kosakaet al. (99) are particularly relevant to thisargument (Fig. 6). NIDDM subjects withmoderately severe fasting hyperglycemia(>200 mg/dl) were treated with each ofthree regimens: I) weight loss, which hasno effect on insulin secretion; 2) exoge-

nous insulin, which inhibits endogenousinsulin secretion; and 3) sulfonylureas,

which augment insulin secretion. Withall three treatment schedules, the abilityof the fi-cell to secrete insulin uniformlyimproved (Fig. 6). The only commonfeature that links these three therapeuticinterventions is a reduction in the plasmaglucose concentration. These resultsstrongly suggest that it is the normaliza-tion of the plasma glucose concentrationand removal of glucose toxicity that leadsto the improvement in insulin secretion.

Summary: insulin secretionNIDDM involves defects in both insulinsecretion and insulin action (1). Duringthe very earliest stages in the natural his-tory of NIDDM, insulin secretion is aug-mented compared with age- and weight-matched control subjects. Although onecould postulate that enhanced insulin se-cretion by the pancreatic (3-cells repre-sents the primary abno rmality in NIDDMand that the insulin resistance developssecondary to chronic hyperinsulinemia(32), there is little proof to support thispathogenetic sequence. Most of the avail-able evidence suggests that insulin resis-tance is the primary metabolic distur-bance in NIDDM and tha t theaugmented f$-cell response represents acompensatory adaptation by the fi-cellsto offset the defect in insu lin action . U ntilthis jun ctur e, we have focused o ur atten-tion on the (3-cell. We now review whatis known about defect(s) in the insulin-sensitive tissues, muscle, and liver. Sub-sequently, we return to the fJ-cell to ex-amine the dynamic interaction betweeninsulin action and insulin secretion(1 ,8 ,11 ,12 ,22 ,27 ,30-34 ,41 ,118 ,119) ,because it is the disruption of this finelyregulated balance that leads to the emer-gence of overt diabetes mellitus with fast-ing hyperglycemia.

INSULIN RESISTANCE INN I D D M As discussed in the preced-ing sections, longitudinal and cross-sectional studies have provided conclu-sive evidence that hyperinsulinemia

32 4 DIABETES CAR E, VOLUME 15, NUMBER 3, M ARCH 1992


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DeFronzo

antedates the development of NIDDM(1,13-22,27,28,30,32). Moreover, nu-

merous studies that used the euglycemicinsulin-clamp technique (45) have dem-onstrated that the progression from nor-mal to 1GT is associated with the devel-opment of severe insulin resistance(1,22,27,31,41), whereas both fastingand glucose-stimulated insulin responsesare markedly increased (Figs. 2-4).These observations provide convincingevidence that insulin resistance, not im-paired insulin secretion, initiates theprocess of NIDDM in humans.

Himsworth et al. (120), with thecombined OGTT/intravenous insulin tol-erance test, were the first to demonstratethat insulin sensitivity was diminished indiabetic patients. Subsequent investiga-tors who used various techniques (insu-lin-tolerance test [121,122], quadrupleinfusion technique [123-126], insulin-suppression test [127,128], forearm per-fusion technique [129,130], modified in-sulin-tolerance test [131], the minimalmodel [119], radioisotope turnovermethodology [131a]) provided addi-tional support for the presence of insulinresistance in NIDDM. With the use of themore physiological insulin-clamp tech-nique, D eFronzo et al. (45) provided themost conclusive documentation of insu-lin resistance in NIDDM. In the largestpublished series involving >50 normal-weight diabetic patients with mild fastinghyperglycemia (150 8 mg/dl), a 3 5 -40 % decrease in insulin-mediated glu-cose disposal was demonstrated inNIDDM subjects (1,4,7,132-136; Fig.7), and there was a nearly complete sep-aration between the diabetic and controlgroups. Three additional points are wor-thy of comm ent: 1) in lean NIDDM su b-jects with more severe fasting hypergly-cemia (198 10 mg/dl) the severity ofinsulin resistance was only slightly (10-20%) greater than in diabetic subjectswith mild fasting hyperglycemia (1,136-139);2) the impairment in insulin actionis observed at all plasma insulin concen-trations, spanning the physiological and

pharmacological range (1,137-141; Fig.

GlucoseUptake

(mg/kgmin)

Controls NIDDM

Figure 7 Insulin-mediated who le-bo dy glu-cose uptake in 38 normal-weight non-insulin-dependent diabetic (NIDDM)patients (right bar)and in 33 age- and weight-matched control sub-jects (left bar). Tissue sensitivity to insulin wa sreduced by 40% in theNIDDM group. Eachindividual diabetic subject is represented by asolid circle. Drawn from the data presented inrefs. 1,4, 5, 134-136, and 167.

8); and 3) in diabetic patients with overtfasting hyperglycemia, even maximallystimulating plasma insulin concentra-

tions do no t elicit a normal glucose met-abolic response und er euglycemic con di-tions (137-141).

Site of insulin resistanceAfter the stimulation of insulin secretion,whole-body glucose homeostasis is de-

Total BodyGlucose

Uptake(mg/m 2-min)

500-,

400-

300-

200-

100

o

6-.

SO 1 0 0 1 5 0 2 0 0 2 5 0Insulin Cone

Figure 8 Dose-response curv e relating theplasma insulin concentration to the rate of insu-lin-mediated whole-body glucose uptake in con-trol (closed circles) an d non-insulin-dependentdiabetes mellitus (open circles) subjec ts.*P < 0.01 vs. control subjects. From Groop etal. (138). by the Journal of Clinical Investi-gation.

pendent on three tightly coupled mech-anisms: 1) suppression of hepatic glucose

production, 2) augmentation of glucoseuptake by splanchnic (hepatic plus gas-trointestinal) tissues, and 3) stimulationof glucose uptake by peripheral tissues.Glucose utilization, in turn, is dep enden ton enhanced flux through two majormetabolic pathways: glycolysis (glucoseoxidation and anaerobic glycolysis) andglycogen synthesis. In the following dis-cussion, the contribution of each of theseprocesses to insulin resistance in NIDDMis reviewed.

Hepatic glucose production (HGP).With tritiated glucose, DeFronzo et al.showed that the liver of healthy subjectsp r o d u c e s g l u c o s e a t 1 . 8 - 2 . 2mg k g "1 min"1 in the postabsorptivestate (1,2,5,132-136,138). This fluxprovides glucose to meet the obligatoryneeds of the brain and other neural tis-sues that utilize glucose at a constant rateof -1 .0-1 .2 mg k g "1 min"1 (3,142).Brain-glucose uptake accounts for50% of glucose disposal during thepostabsorptive state, is insulin indepen-dent and therefore occurs at the samerate during absorptive and interabsorp-tive periods, and is not altered inNIDDM (142). After glucose ingestion,insulin is released into the portal veinand carried to the liver where it binds tospecific receptors on the hepatocyte andsuppresses hepatic glucose output. Fail-ure of the liver to perceive this signal,i.e., secondary to insulin resistance, re-sults in impaired suppression of HGPand resultant hyperglycemia. In NIDDMsubjects with moderate fasting hypergly-cemia a consistent increase in basal HGP

of 0.5 mg kg min has beendemonstrated. When extrapolated over24 h, the liver ofa 70 -kg diabetic subjectwith mild to moderate fasting hypergly-cemia produces an additional 50 g ofglucose each day. In NIDDM the increasein basal HGP is closely correlated(r = 0.847, P < 0.001) with the degreeof fasting hyperglycemia (1,2,4,7,132-136,138; Fig. 9). These results indicatethat in NIDDM subjects with overt fast-

D I A BETES CA RE, V O LU ME1 5 , NUMBER 3 , M A R C H 1 9 9 2 325


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Paihogenesis of NIDDM

HepaticGlucose

(mgf tg -min )

3.00

3.00

2.90

2.00

1.90

r = 0.847

p< 0.001

0

' & a

oo

0 o o

9


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DeFronzo

1.0

0.6Net

Splanchnic QlucosoBalance

(mg/kg-mln) .1.0

-0.5

-1.6

20 40 60 80 100 120 140 160 180Time (Minutes)

Figure 12 Time course of change in the netsplanchnic glucose balance in non-insulin-dependent diabetic (open circles) an d control(closed circles) subjects. The difference betweendiabetic and control subjects is small, statisticallyinsignificant, and cannot account for the markedimpairment in total body glucose metabolismobserved during the euglycemic insulin-clampstudy. Also, note that the total amount of glucosedisposed of by the splanchnic area represents 40 -5 0% ) in tissue sensitivity to

LegGlucoseUptake

(mg/kg leg wlper min)

0 20 40 60 80 100 120 140 160 180

Time (Minutes)

Figure 13 Time course of change in leg glu-cose uptake in non-insulin-dependent diabetic(open circles) an d control (closed circles) sub-

jects. In the postabsorptive state glucose uptakein the diabetic group was significantly greaterthan in control subjects. However, the ability ofinsulin (euglycemic insulin clamp) to stimulateleg glucose uptake was markedly delayed andreduced by 50% in the diabetic subjects. FromDeFronzo et al. (4). by the Journal of ClinicalInvestigation.

insulin, which is observed during theeuglycemic insulin clamp study.Peripheral (muscle) glucose uptake.During a euglycemic insulin clampstudy, suppression of HGP is either nor-mal or slightly impaired in NIDDM sub-jects with modest fasting hyperglycemia(150 mg/dl), whereas splanchnic glu-cose uptake is normal (Figs. 10 and 12).Therefore, by exclusion, peripheral (ex-trahepatic) tissues must be the primarysite of insulin resistance. This has beenconfirmed by simultaneous femoral ar-tery/vein catheterization to quantitate legglucose exchange (4; Fig. 13). In thebasal state leg glucose uptake wasslightly but significantly (P < 0.01) in-creased in the diabetic group, a findingconsistent with observations by other in-vestigators (146,164-166). This increasein basal tissue glucose uptake also is con-sistent with results obtained from radio-isotope turnover studies (1,2,4,5,12,105 ,132-136 ,143-148 ,157 ,164-166) .This accelerated rate of tissue glucoseuptake in NIDDM subjects is due to themass action effect of hyperglycemia thatpassively drives glucose into cells(2,151). However, the metabolic fate ofthe glucose that is taken up is not nor-

mal. In the postabsorptive state glucose

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DeFronzo

Table 3 Balance sheet for the disposition of an oral glucose load in nondiabetic subjects

G LU C O S E

M E A N SE

( G )

R A N G E

( G )

1. INGESTED

2 . APPEARING IN PERIPHERAL PLASMA (ORAL)

3 . RELEASED BY TH E LIVER

4 . TA K EN UP BY SPLANCHNIC TISSUES

5 . TA K EN UP BY PERIPHERAL TISSUES

6 . REMAINING IN THE GLUCOSE SPACE

7. UNRECOVERED

8 . " S AV ED " BY THE LIVER

T R U E NE T SPLANCHNIC BALANCE( 4 3 )

SPLANCHNIC "CONSERVATION" ( 4 + 8 )

SPLANCHNIC OVERALL CONTRIBUTIONT O GLUCOSE

HOMEOSTASIS ( 4 + 8 - 3 )

68 350 415 219 448 6

2 218 318 2

4 337 4

55-9332-56

5-200.7-3428-83

- 2 to 158-31

12-26-17 to 17

20-62

22 4 1-42

Based on ref. 187 .

a dual isotope techniqueto examine thecontribution of splanchnic and periph-eral tissuesto overall glucose disposalinhealthy subjects (Table3) . During the3.5 h after glucose (68 g) ingestion, 19g

or 28% of the oral load was takenup bythe splanchnic tissues, whereas48 g or71% was disposed of by peripheraltis-sues; during the same period basal HGPdeclined by 53%. With the use of thesame double tracer (146,172,188,189)and hepatic vein catheter(190) tech-niques, remarkably similar percentageshave been reportedfor splanchnicglu-

cose uptake (24-29%)and suppressionof HGP (50-60%)in nondiabeticsub-jects by other investigators.Of the pe -ripheral tissues that participatein thedisposal of ingested glucose,the contri-

bution of the brain (an insulin indepen-dent tissue) is fixed at 1.0-1.2 mgk g "1 min "1 and accounts for 15-18g or 20-30% of total glucose utiliza-tion after glucose ingestion (142,172,188-190). Four studies (172,188-190)examined the role of skeletal muscleinthe disposalof oral glucoseand the re-sults have varied froma low of 26 % of

the ingested glucose load (188)to a highof 56% (189), with a mean valueof 45%.

Some of this variability results from esti-mates of the fraction of body mass thatismuscle. This fractionis age and sex de-pendent and can vary from as high as38%, determined by dissecting cadavers(191), to 26%, determinedby neutronactivation (192).The data of Katz et al.(190) have been revised according to thislatter estimate.The results summarizedabove indicate several important differ-ences between the tissues responsibleforthe maintenanceof normal glucoseh o-

meostasis during intravenous versus oralglucose in nondiabetic subjects.In re-sponse to glucose ingestion 1) HGP isless completely suppressed, 2) peripheraltissue (primarily muscle) glucose uptakeis quantitatively less important,and 3)splanchnic glucose uptakeis quantita-tively much more significant.The lesscomplete suppressionof HGP afterglu-cose ingestion maybe related to activa-tion of local sympathetic nerves thatin-nervate the liver (19 3).

Five studies used the double-tracer techniqueto examine the disposi-tion of an oral glucose loadin NIDDM(144,146,163,172,194) (Table4). Infour of the studies forearm catheteriza-tion was also used to look at muscleg lucose up take (144 ,146 ,172 ,194) .Note, however, that significant differ-ences in body weight, severityof diabe-

Table 4 S u m m a r y of glucose metabolism following glucose ingestionin non-insulin-dependen t diabetic patients

INSULIN

SUPPRESSION INC RE- INCREMENTAL

SPLANCHNIC O F HEPATIC MENTAL FOREARM FOREARM

GLUCOSE GLUCOSE ABSO LUTE TISSUE GLU COS E GLUCOSE GLUCOSE

R E F.

FERRANNINI

F I RTH

MlTRAKOU

FlRTH

M C M A H O N

No.

16 314 417 214 619 4

T E S T

O G T T

O G T T

O G T T

MMMM

BODY WEIGHT

NORMAL WEIGHT

O B ES E

O B ES E.

O B ES E

O B ES E

RESPONSE*

si 44

N , DELAYED

N

4

UPTAKE

Nsi 4si 4si 4

t t

PRODUCTION

44 44 44 44 4

TISSUE R d

4 4tN

s i tt

44444

44

44

CLEARANCE

4 44 44 44 44 4

UPTAKE

NNN

t

UPTAKE

sl4444

T h e n u m b e r of arrows ind icatesth e m a g n i t u d e of change; OGTT, o ral g lucose to lerance tes t ;MM , mixed meal ;N , n o rmal ; si , slight.

*I n all s tud ies th e plasma insu l in response was def ic ien t when v iewed relat iveto th e plasma g lucose concen t rat ion ;R d , rate of glucose d isposal .

DIABETES CARE, VOLUME15 , NUMBER 3 , MARCH 1992 329


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tes, plasma insulin response, and com-position of the meal existed among the

five studies (Table 4). Nonetheless, avery uniform picture emerges concerningthe tissues and mechanisms responsiblefor the impairment in oral glucose toler-ance (Table 4). The data of Ferrannini etal. (163) are illustrative of the metabolicabnormalities in NIDDM. During the 3.5h after glucose ingestion, glucose toler-ance was markedly impaired in NIDDMversus control subjects (mean plasmaglucose 298 23 vs. 147 7 mg/dl).The disturbance in glucose metabolism

in NIDDM patients was accounted for bytwo factors: 1) after glucose ingestion,tissue glucose uptake was significantlyreduced (44 vs. 60 g over 3.5 h; Fig. 15)and 2) HGP continued at a higher rate(17 vs. 10 g over 3.5 h; Fig. 15).Splanchnic glucose uptake w as similar indiabetic and control groups. These re-sults indicate that the combined effect ofhyperglycemia plus hyperinsulinemia tosuppress HGP after glucose ingestion isimpaired in NIDDM, and this difference

in HGP (7 g over 3.5 h) accounts for

GLUCOSEfim/3 5 hr) '

I1JL

TOTAL ORAL ENDOGENOUS TISSUEGLUCOSE GLUCOSE GLUCOSE GLUCOSE

A P P EA R A N C E- ' D I SP O S AL

Figure 15Schematic representation of he-patic glucose production an d tissue glucose up-take in non-insulin-dependent diabetic (cross-hatched bars) and control (open bars) subjectsafter glucose ingestion. Data have been e xtrap-olated to a 3.5-h period. See text for a moredetailed discussion. From Ferrannini et al. (163). by Metabolism.

approximately one-third of the defect intotal-body glucose hom eostasis, whereas

the defect in peripheral, presumablymuscle, glucose uptake (14 g over 3.5 h)accounts for the remaining portion of thedisturbance in overall glucose metabo-lism. From the quantitative standpoint,nearly identical results have been re-ported by others (144,146,172,194).Note that the double-tracer technique isassociated with significant variability be-cause it involves the subtraction of twolarge numbers (Ra of [3H] glucose minusRa of [14C] glucose) to calculate sup pres -

sion ofHGP. Therefore, small differencesin suppression of HGP between labora-tories are likely to have little physiolog-ical meaning. The inherent variability ofthe method, variation in patient charac-teristics, and differences in insulin secre-tory response easily can explain the 1020 % differences in suppression of HGPrepor te d by var ious inves t iga tors(144,146,163,172,194). The importantmessage is that everyone has foundthat suppression of HGP is impairedin NIDDM and that this defect canaccount for about one-third to one-half of the disturbance in whole-bodyglucose homeostasis following glucoseingestion. Splanchnic glucose uptakehas been repor ted to be normal(163) , slightly decreased (144,146,172), or increased (194) and does notappear to contribute significantly tothe impairment in oral glucose toler-ance.

Some special comment is war-ranted concerning whole-body tissueglucose disposal after glucose ingestion.When viewed in absolute terms, moststudies have shown it to be normal (172)or increased (144,146,194; Table 4).However, when viewed in terms of theprevailing plasma glucose concentration,the efficiency of glucose disposal, i.e.,glucose clearance, is severely reduced.Most importantly, it is not the absoluterate of glucose disposal, but rather theincrement in glucose disposal abovebaseline that determines the rise inplasma glucose concentration above its

fasting value. In NIDDM subjects thebasal rate of whole-body tissue glucose

uptake is significantly enhanced (1,11).Consequently, in every published studythe incremental response in tissue glu-cose uptake was moderately to severelyreduced in NIDDM (144,146,163,172,194; Table 4). Similar results have beenreported for forearm muscle glucose up-take (144,146,172,194). Although theabsolute rate of forearm glucose uptakeafter glucose ingestion is normal, the in-crement above baseline is impaired (144,146,172,194; Table 4). Similar conclu-sions concerning tissue glucose uptakecan be drawn from the data of Chen et al.(195), although these later investigatorsdid not label the oral glucose load with[14C]glucose. Thus, all published results(144,146,163,172,194), including thoseby Gerich et al. (172), are totally consis-tent and indicate the important contribu-tion of impaired muscle glucose disposalin NIDDM. The conclusion by Gerich(196) that muscle does not play an im-portant role in impaired oral glucose tol-erance in NIDDM stems from the failureto recognize that it is the incrementalincrease in muscle glucose disposal thatdetermines the rise in plasma glucoseconcentration above baseline.

In summary, the results of theOGTT indicate that both impaired sup-pression of HGP and decreased tissue(muscle) glucose uptake contribute ap-proximately equally to the glucose in-tolerance of NIDDM. Diminished

splanchnic glucose uptake is not an im-portant contributory factor to the im-paired disposal of an oral glucose load inNIDDM.

Based on the preceding discus-sion, it is obvious that there are impor-tant differences between OGTT and eu-glycemic insulin clamp with respect tothe quantitative importance of the liverversus peripheral tissues (muscle) in theglucose intolerance of NIDDM. Duringthe insulin clamp the defect in suppres-sion of HGP is quantitative small,

330 DIABETES CARE, VOLUME 15 , NUMBER 3, MARCH 1992


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DeFronzo

whereas the impairment in tissue (mus-cle) glucose uptake is largely responsible

for the defect in total-body glucose ho-meostasis. In contrast, after glucose in-gestion both impaired suppression ofHGP and d iminished tissue (muscle) glu-cose uptake contribute approximatelyequally to the disturbance in whole-body glucose homeostasis in NIDDM.None of the available studies allows oneto define whether the defects in hepaticand peripheral (muscle) glucose metab-olism during OGTT are the result of in-sulin resistance, diminished insulin se-cretion, or an impairment in the massaction effect of glucose (i.e., glucose re-sistance) to promote its own uptake be-cause plasma glucose and insulin con-centrat ions varied widely betweensubjects and insulin resistance was notmeasured (144,146,163,172,194,195).Lastly, it should be noted that the im-paired suppression of HGP is likely toassume added importance in everydaylife where mixed meals are normally con-sumed. Under such conditions plasmaamino acid, FFA, and glucagon concen-trations rise, rather than fall as occursduring an OGTT. Hyperglucagonemia,increased delivery of gluconeogenic pre-cursors, and enhanced FFA oxidationwould be expected to further augmentgluconeogenesis and lead to an evengreater impairment in the suppression ofHGP. In fact, such a sequence of eventshas been demonstrated by Shank et al.(197).

In summary, the results obtainedwith the OGTT are in agreement withthose from the euglycemic insulin clampand, in addition, emphasize the impor-tant contribution of the liver to the im-pairment in glucose homeostasis inNIDDM.

FASTING HYPERGLYCEMIA INNIDDM: PANCREAS VERSUSMUSCLE VERSU S LIVER Longi-tudinal and cross-sectional (1,22,27,28,30,31-36) s tudies have demon-strated conclusively that the triad of

insulin resistance, fasting hyperinsuline-

mia, and meal-stimulated hyperinsuline-mia antedate the onset of 1GT and

NIDDM in humans. Once overt fastinghyperglycemia (>140 mg/dl) has devel-oped, HGP is elevated and correlatesclosely with the severity of fasting hyper-glycemia (1,2,4,5,12,132-136,138,140,143-148). It is important to emphasize,however, that by the time the fastingglucose concentration has risen to 140mg/dl, the diabetic state has been p resentfor a very long period, > 5 - 1 0 yr. Thus,these studies cannot establish whether,in the earliest stages of NIDDM, fastinghyperglycemia results from an excessiverate of HGP, decreased efficiency of tis-sue glucose uptake, or some combina-tion of the two. This question was ad-dressed by DeFronzo et al. (11). BasalHGP and tissue glucose uptake werequantitated in 77 lean NIDDM patientsand compared with 72 age-, sex-, andweight-matched healthy individuals.Thirty-three NIDDM subjects had fastingplasma glucose levels below 140 mg/dland 44 above 140 mg/dl (Fig. 9). Thecutoff point of 140 mg/dl was chosen fortwo reasons: 1) it defines the level atwhich NIDDM is diagnosed according tothe National Diabetes Data Group (198)and 2) it represents the plasma glucoseconcentration at which diabetic subjectstip over the top of Starling's curve of thepancreas and fasting plasma insulin lev-els begin to decline (Fig. 2). In the 33diabetic individuals with fasting plasmaglucose concentrations


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Pathogenesis of NIDDM

interest, were not examined. Moreover,the obesity index of the diabetic (body

mass index [BMI] 27.8 0.6 kg/m2

) pa-tients in the earlier publication of Gerichet al. (164) was much greater than re-ported in the more recent review article(BMI 25.8 0.8 kg/m2; 196), and it isobvious that the patient populations inthese two papers (164,196) must bequite different. Therefore, it is not appro-priate to equate the metabolic distur-bances described in the earlier paper(164) with the patient population re-ported in the more recent publication

(196). In summary, neither the previous(164) nor present (196) publication ofGerich justifies the statement that in "in-dividuals with fasting plasma glucoseconcentrations between 6 and 7 mM,rates of glucose production are elevated"(196). Rather, the data of Gerich et al.(196) are consistent with the previouslypublished results of DeFronzo et al. (11),Eriksson et al. (41), and Gulli et al. (58)and indicate that HGP is not elevated inthe early stages of NIDDM in humans.Similar results have been reported in atype II diabetic primate model (33,34).

During the postabsorptive statethe rate ofHGP equals the rate of glucoseuptake by all of the tissues in the body. Itfollows, therefore, that tissue glucose uti-lization, when viewed in absolute terms,is increased in NIDDM. However, whenviewed in the context of the elevatedplasma glucose and insulin concentra-tions, it is clear that the efficiency oftissue glucose uptake, i.e., the metabolicclearance rate of glucose, must be re-

duced early in the course of NIDDM (11;Fig. 16). As the fasting plasma glucoseconcentration rises from 105 to 140 m g/dl, glucose clearance declines linearly(r = 0.700, P 140 mg/dl, the restraining effect of hyperinsu line-

mia on the liver is lost and HGP increases

2. 3

2.3

2.1

GlucosoClearance 1.9ml/kg-mln)

1.7

1.3

1 3

11

09

"*s

- * & :

%^*9>

V*p

&o c

oO o

0 J$) 0

0 0

0

0

0 0)

0

00

Fasting Plasma Glucose (mg/dl)

Figure 16 Summary of the metabolic clear-ance rate of glucose in 77 normal-weight non-

insulin-dependent diabetic subjects (open circles)

with fasting plasma glucose concentrations rang-ing from 105 to >300 mg/dl. Seventy-two age-

and weight-matched control subjects are shown

by the open circles. In the 33 diabetic subjects

with fasting plasma glucose concentrations 140 mg/dl, the rate of decline in

glucose clearance began to slow and reached a

plateau at glucose levels >180 mg/dl. From De-

Fronzo et al. (11). by Metabolism.

progressively (r = 0.847, P 180 mg/dlthe whole-body glucose disposal raterises in direct proportion to the elevatedfasting glucose concentration and theglucose clearance remains constant, al-though reduced by 40-50% com-pared with the postabsorptive state. Be-cause the renal tubular threshold forglucose reabsorption is 180 mg/dl(199), the constancy of glucose clearanceat plasma glucose concentration abovethis level most likely is explained by thedevelopment of glucouria.

Two important questions remainto be answered concerning glucose me-tabolism in the postabsorptive state.First, why is the development of fastinghyperinsulinemia (Fig. 2) sufficient to

prevent excessive HGP (Fig. 9), yet inad-equate to maintain a normal basal rate of

tissue glucose clearance (Fig. 16). Thisparadox is readily appreciated by exam-ining the dose-response relationship be-tween the plasma insulin concentrationversus HGP and tissue glucose disposal(8,138,140,141,152). When the plasmainsulin concentration is increased from 8to 15 to 27 |xU/ml in nondiabetic sub-jects, basal HGP is suppressed by 33 and68%, respectively, whereas whole-bodyglucose uptake fails to increase abovebaseline (138). Thus, in NIDDM sub-

jects, as the fasting plasma insulin con-centration increases (Fig. 2), the result-ant hyperinsulinemia is sufficient tooffset any hepatic insulin resistance andto maintain a normal absolute rate ofhepatic glucose output. However, thesmall increment in fasting plasma insulinis not capable of stimulating tissue glu-cose uptake (138,200-202), and theglucose clearance drops progressively(Fig. 16).

The decline in whole-body glu-

cose clearance in the postabsorptive statecan only partially be explained by a de-crease in glucose uptake by peripheraltissues (11). In NIDDM subjects De-Fronzo et al. (4) showed that basal legglucose uptake is significantly increased.Moreover, because the rise in leg glucoseuptake was proportional to the increasein fasting glucose concentration, leg (in-cluding muscle) glucose clearance wasvirtually identical in control and NIDDMsubjects (4). In contrast, Gerich et al.(164) and Firth et al. (146) reportedslightly, although significantly, reducedrates of glucose clearance by forearm tis-sues in NIDDM in the postabsorptivestate. With the hepatic vein cathetertechnique, DeFronzo et al. (4) showedthat at least part of the decline in wholebody glucose clearance resides within thesplanchnic tissues Giver plus gastrointes-tinal). However, from a purely quantita-tive standpoint tissues, in addition tothose within the splanchnic region (4)and muscle (146,164), also must con-

tribute to the decline in whole-bo dy glu-

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DeFronzo

Plasma Glucose Plasma Insulin

(mg/dl)

25

20

15

10

5

Hepatic GlucoseProduction

GlucoseClearance

1.91.8

(mg/kg*min) 1.7

1.6

1.5

2.0

1.9

1.8 (ml/kg*min)

1.7

1.6

Figure 17 The effect of overnight insulin infusion to normalize the basal rateof hepatic glucoseproduction in 19 normal-weight non-insulin-dependent diabetic (NIDDM) subjects (shaded bars) andin 72 age- and weight-matched control subjects (cross-hatched bars). Despite similar rates of hepatic

glucose production and a >2-fold increase in the plasma insulin concentration (P< 0.01), the fastingplasma glucose remained significantly elevated in NIDDM vs. control subjects. The decreased glucoseclearance in NIDDM subjects indicates a diminished efficiencyof tissue glucose uptake. FromDeFronzo et al. (11). by Metabolism.

cose clearance. The brain and other neu-ral tissues represent a prime candidate toexplain the decrease in glucose clear-ance. In the postabsorptive state, 5 0 -60% of total glucose disposal occurs inthe cerebral tissues. Brain-glucose up-take is insulin indep endent and saturatesat a plasma glucose concentration of- 4 0 mg/dl (142,185,186). It is not sur-prising, therefore, that brain-glucose up-take remains normal in NIDDM individ-uals, despite fasting hyperglycemia(142), and that the brain- (and conse-quently whole body) glucose clearancedeclines in NIDDM subjects with pro-gressive increases in the basal glucoseconcentration. It remains to be definedwhether tissues, in addition to muscle,

splanchnic, and brain, also contribute to

the decline in basal glucose clearance inNIDDM. It should be emphasized, how-ever, that the lower absolute rate of glu-cose disposal in NIDDM patients studiedat comparable levels of fasting glucoseand a twofold greater plasma insulinconcentration as control subjects (11) in-dicates that the decline in whole-bodyglucose clearance must be accounted forby tissues other than the brain.

The defects in basal HGP and tis-sue glucose disposal are better appreci-ated by studying NIDDM subjects afteran overnight infusion of insulin designedto normalize basal HGP (11). To accom-plish this goal a peripheral plasma insu-lin concentration of 24 |xU/ml (2-foldgreater than control subjects) was re-

quired (Fig. 17). In nondiabetic subjects

a similar infusion of insulin inhibitedbasal HGP by >60% (Fig. 10). Despite

similar rates of HGP in control and dia-betic subjects, the fasting glucose con-centration remained elevated in the latter(105 3 vs. 92 1 mg/dl, P < 0.01).The persistent elevation in the basalplasma glucose can only be explained bya decreased efficiency of tissue glucoseremoval, as reflected by the decreasedglucose clearance (1.71 vs. 2.00 ml-kg"1 min"1, P < 0.01). Furth er evi-dence in support of an impairment intissue glucose uptake comes from studiesin which NIDDM individuals received anovernight insulin infusion to normalizethe fasting plasma glucose concentration(11; Fig. 18). At identical plasma glucoseconcentrations, the absolute rate of tissueglucose uptake was significantly reducedin NIDDM versus control subjects (1.68vs. 1.84, P < 0.01), although the plasmainsulin concentration was more thantwofold elevated in the former group.These data convincingly demonstratethat under comparable conditions of eu-glycemia the tissues of NIDDM subjectsare unable to metabolize glucose at ratescomparable to control subjects. In con-trast to the suggestion of Gerich (164,196), these results cannot simply be ex-plained by a failure of the brain to pas-sively enhance its uptake of glucose inresponse to a progressive rise in the fast-ing plasma glucose concentration.

From available data it is not pos-sible to establish which defect, i.e., he-patic insulin resistance or decreased effi-ciency of t issue glucose removal ,develops first in the evolution of fastinghyperglycemia in NIDDM. Three equallyplausible sequences can be postulated.First, it is possible that both defects de-velop in parallel. As hyperglycemia en-sues (due both to excessive HGP anddecreased tissue glucose uptake), basalinsulin secretion is stimulated (Fig. 2).The resultant hyperinsulinemia restoresHGP to baseline, whereas the resultanthyperglycemia returns tissue glucose u p-take to normal. This sequence of events

would result in normal basal rates of

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Plasma Glucose Plasma Insulin

(ixU/ml)

Glucose Disposal1.9

Glucose Clearance2.1

2.0

1.9 (ml/kg*min)

1.8

1.7

Figure 18 The effect of overnight insulin infusion to normalize the fasting plasma glucoseconcentration in 11 normal-weight non-insulin-dependent diabetic (NIDDM) subjects (shaded bars)and in 72 age- and weight-matched control subjects (cross-hatched bars). Despite identical plasmainsulin concentrations, the absolute rate of whole-body tissue glucose uptake in the postabsorptivestate was significantly reduced in the NIDDMgroup (P < 0.01). From DeFronzo et al. (11). by

Metabolism.

HGP and tissue glucose uptake b ut at theexpense of fasting hyperglycemia andfasting hyperinsulinemia (1,11). This isanalogous to the development of second-ary hyperparathyroidism in patients withimpaired renal function. As the glomer-ular filtration rate declines, there is asmall imperceptible rise in the serum

phosphate concentration, which in turnleads to a small imperceptible decline inthe serum calcium concentration (203).The resultant hypocalcemia causes stim-ulation of the parathyroid hormone,which enhances renal phosphate excre-tion and returns the serum phosphateconcentration to normal. The restorationof normophosphatemia leads to a rise inserum calcium concentration to baselinevalues. As this scenario is repeated, theresult is a significant increase in serumparathyroid hormone concentration (i.e.,analogous to the elevated plasma glucose

and insulin levels in the development ofIGT and NIDDM) with normal serumcalcium and phosphate concentrations(i.e., analogous to the normal rate ofHGP and tissue glucose uptake inNIDDM). Importantly, because the smallincrement in plasma insulin concentra-tion has no or little stimulatory effect on

tissue glucose uptake (8,138,200-202),whole-body glucose clearance falls.Alternatively, decreased effi-

ciency of tissue glucose uptake couldrepresent the primary defect responsiblefor fasting hyperglycemia in NIDDM. Asthe plasma glucose concentration rises,insulin secretion is enhanced and the re-sultant hyperglycemia returns tissue glu-cose uptake to normal, whereas the re-su l tan t hyper insu l inemia has twoopposing actions:1) it induces hepaticinsulin resistance by downregulatingboth receptor and postreceptor events

(204-209), and 2) it has a direct sup-pressive effect on HGP. Because thesetwo metabolic actions of insulin offseteach other, the absolute basal rate ofHGP remains unaltered. In addition, he-patic insulin resistance could initiate thedevelopment of fasting hyperglycemia inNIDDM by causing a small imperceptiblerise in plasma glucose concentration.This, in turn, would stimulate insulinsecretion, returning the elevated rate ofbasal HGP to normal. Tissue glucose up -take, however, would remain unalteredbecause the small rise in plasma insulin

concentration is insufficient to stimulatetissue glucose uptake (8,138,200-202).This would lead to an "apparent" declinein the efficiency of tissue glucose re-moval, i.e., tissue glucose clearancewould fall. Gerich (196) stated that "forplasma glucose to increase, glucose pro-duction must exceed glucose uptake."Strictly speaking, this is not correct.What is true is that for the plasma glu-cose concentration to increase, glucoseproduction must transiently exceed glu-cose uptake or, conversely, tissue glucoseuptake must transiently decrease belowthe rate of glucose production (see pre-ceding discussion). Studies performedunder steady-state conditions after ametabolic perturbation has occurred andthe system has reequilibrated cannot re-construct the sequence of events that ledto the establishment of the new steadystate. Thus, it is not possible to definewhich defect, i.e., hepatic or peripheralinsulin resistance, comes first in the nat-ural history of NIDDM, or if both defectsdevelop simultaneously and in a parallelfashion.

It is interesting to speculate aboutwhich factors might be responsible forthe progressive rise in HGP at fastingplasma glucose concentrations >140160 mg/dl. One obvious explanation isthe progressive decline in basal plasmainsulin level that occurs in NIDDM pa-tients with fasting plasma glucose con-centrations > 14 0-1 60 mg/dl. Consis-tent with this thesis, basal HGP andfasting insulin levels in this group were

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DeFronzo

strongly and inversely correlated (11).Other factors that could account for the

rise in HGP include a worsening of he-patic insulin resistance with progressiveseverity of diabetes or an accelerated rateof hepatic gluconeogenesis.

In summary, the results reviewedabove demonstrate that in NIDDM sub-jects with mild fasting hyperglycemia( 140 mg/dl) glucoseclearance falls further, whereas HGP isincreased and correlates closely with theelevation in fasting glucose concentra-tion.

DYNAMIC INTERACTIONBETWEEN INSUL IN ACTION A NDINSULIN SECRETION IN NI DD M NIDDM subjects are characterized by ab-normalities in both tissue (muscle andliver) sensitivity to insulin and pancreaticinsulin secretion. To fully appreciate theevolution of the full-blown diabetic con-dition, it is necessary to examine the dy-namic interaction between insulin actionand insulin secretion in the same indi-vidual over a wide range of insulin sen-sitivity. Recently, three groups haveprovided such information (1,22,27-32,118,135,136,167). DeFronzo (1) andFelber et al. (31,136,167) studied fourgroups of subjects who were subdividedas follows: group 1, 47 obese subjectswith a mean ideal body weight of 148%(this group was further subdivided into24 subjects with normal glucose toler-ance and 23 with 1GT); group 2, 35 obese(ideal body weight 147%) subjects withdiabetes mellitus (fasting glucose >140mg/dl) (group 2 was further subdividedinto those with a hyperinsulinemic re-sponse and those with a hypoinsulinemicresponse during an OGTT); group 3, 13

normal-weight age-matched control sub-

jects. All subjects received a 100-g oralglucose load to provide a measure of

glucose tolerance and insulin secretion.Insulin sensitivity was quantitated withthe euglycemic insulin-clamp (4-100|xU/ml) technique (45), and indirect cal-orimetry (210) was used to measure ratesof glucose oxidation and nonoxidativeglucose disposal. The latter measure hasbeen shown to primarily reflect glycogensynthesis (168,211,212).

An integrated su mmary of the re-sults are presented in Fig. 4. In obesenondiabetic subjects, tissue sensitivity to

insulin was markedly reduced by 4050%, yet oral glucose tolerance remainednorm al because the (3-cell was capable ofappropriately augmenting its insulinsecretory capacity to offset the defect ininsulin action. The progression to IGTwas associated with a further reductionin insulin-mediated glucose disposal(Fig. 4). However, glucose tolerance wasonly mildly impaired because the (3-cellwas able to further augment its secretionof insulin to counteract the deteriorationin insulin sensitivity. Further progressionfrom IGT to overt diabetes mellitus washeralded by a modest decline in insulinsecretion without any worsening of theinsulin resistance. However, this modestdecline in insulin secretion, in the pres-ence of severe insulin resistance, resultedin marked glucose intolerance and frankdiabetes mellitus (Fig. 4). The obese di-abetic person has tipped over the top ofStarling's curve of the pancreas (1; Figs.2 and 3). Although the plasma insulinresponse remained increased compared

with control subjects, it was not appro-priately elevated for the degree of insulinresistance. Lastly, the obese diabeticgroup with a low insulin response man-ifested the greatest glucose intolerance,and this was due entirely to a progressivedecline in insulin secretion without anychange in insulin sensitivity (Fig. 4). Thepreceding sequence of events leadingfrom obesity with normal glucose toler-ance to obesity with IGT to obesity withdiabetes has been confirmed in a long-

term prospective study (31) involving

the same subjects w ho previously partic-ipa ted in the longi tud ina l s tudy

(1,136,167). These observations under-score the critical interaction between in-sulin resistance and insulin secretion.Both abnormalities must be looked at inconcert. Insulin resistance alone is notsufficient to cause frank diabetes melli-tus. The onset of overt diabetes requiresa concomitant defect in insulin secretion.This construct is entirely consistent withthe classic overfeeding studies of Sims etal. (213). Healthy lean subjects who re-ceived an increased caloric intake gained20-30 lb over 3-5 mo, and this wasassociated with the d evelopment of mo d-erate to severe insulin resistance in mus-cle tissue (forearm catheterization tech-nique). Nonetheless, glucose toleranceremained normal because the pancreaswas capable of augmenting its insulinsecretory capacity to precisely counter-balance the impairment in insulin action.

The sequence of events describedabove has been confirmed in both hu-mans and monkeys (22,27,30-34,118).Reaven et al. (118) studied five groups oflean subjects with a wide range of glu-cose tolerance. As reported by DeFronzoet al. (1,136,167) in obese individuals(Fig. 4), in lean individuals' (118) pro-gression from normal glucose toleranceto IGT was associated with the develop-ment of severe insulin resistance, whichwas offset by an increase in insulin secre-tion (Fig. 19 ). The emergence of NIDDMwas associated with a stepwise decline ininsulin secretion, which paralleled thedecrease in glucose tolerance (Fig. 19);

tissue sensitivity to insulin did notchange or decreased only slightly as su b-jects progressed from IGT to overtNIDDM (Fig. 19). A similar sequence ofevents has been demonstrated in a pro-spe c t i ve s t udy i n P ima I nd i a ns(22,27,30,32). This study (22,27,30,32)is of particular importance because invivo insulin action is inherited as a famil-ial trait in this population (212). Thesame sequence of events leading to thedevelopment of NIDDM in whites(1,41,118,136,167) and Pima Indians

DIABETES CAR E, VOLUME 15, NUMBER 3, M ARCH 1992 33 5


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MeanPlasmaInsulinCone.

(nU/ml)

100

50

TT T

400 -I

Glucose 3 0 0 'Clearance 200(ml/m?min)

CON < 8 8-15

FastingPlasma Glucose

Figure 19 Insu lin-m edia ted glucose clearance (mea sured with the insulin suppression test) andthe plasma insulin response (measured with oral glucose tolerance test) in control (CON) subjects,

subjects with impaired glucose tolerance (1GT), and non-insulin-dependent diabetic individuals

(shaded bars) with varying severity of glucose intolerance. See text for a more detailed discussion. Th e

fasting plasma g lucose concentrations is given in mM. From Rea ven et al. (118). by Diab etologia.

(22,27,30,32) has been described in therhesus monkey (33,34). With advancingage, the monkey becomes obese and de-velops a diabetic condition that closelymimics NIDDM in humans. In this pri-mate model insulin resistance representsthe earliest detectable abnormality. How-ever, because of the compensatory in-crease in insulin secretion, fasting plasmaglucose concentration, basal HGP, andglucose tolerance remain normal.

Three recent studies have at-tempted to define the primary defect re-sponsible for NIDDM by examining in-sulin action and insulin secretion in thenormal glucose-tolerant first-degree rel-atives of NIDDM patients (41) and in theoffspring of one (28) and two diabeticparents (58), respectively. The rationaleunderlying this approach is based on theassumption that NIDDM is an inheriteddisease and that the study of normal glu-cose-tolerant individuals (who are athigh risk to develop diabetes later in life;

214-220) of affected diabetic familymembers will reveal the basic metabolicdefect in NIDDM. In the studies of Eriks-son et al. (41), Gulli et al. (58), andWarram et al. (28) insulin secretion(both the 1st and 2nd phases) in re-sponse to oral and intravenous glucosewas increased. In contrast, insulin sensi-tivity was reduced by 3040%. Theseresults demonstrate that insulinopeniadoes not precede the development ofNIDDM in hum ans. Rather, insulin resis-tance represents the earliest detectabledefect in NIDDM.

As discussed above, it has be-come fashionable to view the insulin re-sistance in NIDDM as the primary defectand hyperinsulinemia as a compensatoryresponse. Although somewhat specula-tive, it is entirely plausible that the in-crease in insulin secretion represents theprimary disturbance and that the insulinresistance results from a downregulationof both receptor and postreceptor events

by chronic sustained hyperinsulinemia(20 4-2 10 ). Consistent with this hypoth-

esis, Lillioja et al. (32) recently docu-mented that in Pima Indians with IGT ofa similar degree to that in whites, theplasma insulin response during anOGTT was 50% greater. This greaterhyperinsulinemic response could not beexplained by differences in plasma glu-cose levels during the OGTT, obesity,age, sex, or severity of insulin resistancebetween the two groups. Thus, it is pos-sible that, at least in Pima Indians, aug-mented (3-cell function represents the

initial or primary disturbance in NIDDMand that the insulin resistance developssecondarily to chronic hyperinsulinemia.

In summary, the results reviewedin this section indicate that in the earliestdetectable stage of NIDDM, i.e., normalglucose-tolerant offspring of two diabeticparents and normal glucose-tolerant rel-atives of NIDDM individuals, insulin re-sistance is well established and is offsetby the presence of compensatory hyper-insulinemia. Overt diabetes mellitus de-velops only in individuals whose(3-cellsare unable to meet the increased andsustained demand for insulin secretion.

CELLULAR MECH ANIS MS OFINSULIN RESISTANCE Stimulation of glucose metabolism by insulinrequires that the hormone must firstbind to specific receptors that are presenton the cell surface of all insulin-targettissues (221-224). During the process ofinsulin binding and internalization, a"second messenger" is generated (225-227). Unfortunately, the precise natureof this second messenger remains con-troversial at present. Many candidateshave been suggested, but, as ofyet, nonehas gained universal acceptance. Consid-erable evidence suggests that at least oneof the second messengers for insulin ac-tion, tyrosine kinase, is an enzyme com-plex, which is an integral part of thereceptor itself (221,223,224,228,229).Once the second messenger for insulinaction has been generated, it initiates a

series of events that promote intracellular

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DeFronzo

glucose metabolism. The initial step in-volves activation of the glucose-transport

system with the resultant influx of glu-cose into insulin-target tissues, primarilymuscle (230-235). The free glucose thathas entered the cell subsequently isphosphorylated by hexokinase and me-tabolized by a series of enzymatic stepsthat are under the control of insulin. Ofthese, the most important are glycogensynthase (which controls glycogen syn-thesis) and pyruvate dehydrogenase(which regulates glucose oxidation).

Insulin receptorIn NIDDM individuals both receptor andpostreceptor defects have been shown tocontribute to the insulin resistance. Nu-merous studies have demonstrated thatinsulin binding to monocytes and adipo-cytes from NIDDM patients is reducedon mean by -2 0 -3 0 % (236-246) . Thereduction in insulin binding is due to adecrease in the number of insulin recep-tors without alteration in insulin-recep-tor affinity. In addition to a decrease inthe number of cell surface receptors, var-ious defects in insulin-receptor internal-ization and processing have been de-scribed (235,245,247). However, somecaution should be used in interpretingthese insulin bind ing studies because thetwo major organs for insulin action invivo are the liver and muscle, and fewstudies have examined insulin bind ing tothese tissues in humans. In obese dia-betic individuals insulin binding to sol-ubilized receptors obtained from skeletalmuscle biopsies has been shown to be

normal wh en expressed per m illigram ofprotein (248,249). Several other lines ofevidence indicate that dim inished insulinbinding cannot satisfactorily explain thedefect in insulin action in NIDDM: 1)decreased insulin-receptor number can-not be demonstrated in approximatelyone-third of all NIDDM subjects, espe-cially those with high fasting plasma glu-cose levels (239 ,250 -26 2); 2) Lonnrothet al. (257), Olefsky et al. (258), andothers have failed to find a correlation

between the reduction in insulin binding

and the severity of insulin resistance inNIDDM patients; and 3) studies that

have examined the dose-response rela-tionship between insulin-mediated glu-cose uptake and the plasma insulin con-cent ra t ion have demons t ra ted thepresence of a severe postreceptor defectin insulin action (138,140,141,152,259).In patients with IGT and/or with verymild diabetes, the dose-response curvewas shifted to the right but very highplasma insulin concentrations were ableto overcome the insulin resistance andelicit a normal glucose metabolic re-

sponse. This picture is most consistentwith a receptor defect in insulin action(260), and this has been documented inisolated adipocytes (152). In contrast, indiabetic patients with moderate to severefasting hyperglycemia, the dose-responsecurve was both shifted to the right andexhibited a decrease in maximum rate ofinsulin-stimulated glucose disposal (Fig.8). These results are most consistent witha postreceptor defect in insulin action(260), and indeed no decrease in insulinbinding could be demonstrated in thisgroup of diabetic patients (152).

In summary, the above results in-dicate that in diabetic subjects with mod-erate to severe fasting hyperglycemia,postbinding defects in insulin action areresponsible for the observed insulin re-sistance. In individuals with IGT or mildfasting hyperglycemia, a modest defect ininsulin bindin g may exist. These individ-uals are usually hyperinsulinemic, an d it

is likely that the mild decrease in insulinbinding results from a downregulation ofinsulin-receptor number by sustainedhyperinsulinemia (204,205,207).

In the most general sense, post-binding defects in insulin action can beexplained by one of three metabolic dis-turbances: impaired generation of insu-lin's second messenger, diminished glu-cose t ranspor t in to ce l l s , and apostglucose transport abnormality insome critical enzymatic step involved in

glucose utilization.

Insulin second messengerDuring the last decade there has been an

explosion of knowledge about the struc-ture-function of the insulin receptor andthe mechanisms that couple the receptorto the intracellular sites of insulin action(221-224,229,235). Nonetheless, theprecise identification of the second mes-senger for insulin action has remainedelusive. Phosphorylation/dephosphory-lation of key intracellular proteins ap-pears to be an important signaling mech-anism that couples insulin bindin g to theintracellular action of insulin (221-224,235,238,261). The insulin receptoris a complex glycoprotein that is com-prised of two a-subunits and two P -sub-units that are linked by disulfide bonds.The a-subunit of the insulin receptorfaces outward and contains the insulinbinding domain, whereas the (3-subunitfaces inward and expresses insulin-stimulated kinase activity directedtoward its own tyrosine residues (221-224,235). The a-subunit is totally extra-cellular, whereas the P-subunit is a trans-me m br a ne p r o t e in . Cons id e r a b l eevidence indicates that insulin-receptorphosphorylation of the (3-subunit, withsubsequent activation of insulin-receptortyrosine kinase, represents an importantsecond messenger for many of the hor-mone's varied actions (221-224,235). Invitro mutagenesis experiments haveshown that insulin receptors, whichcompletely lack tyrosine kinase activity,are ineffective in mediating insulin stim-ulation of cellular metabolism (262-264). Similarly, mutations in any of the

three major phosph orylation sites (at res-idues 1146, 1150, and 1151) diminishinsulin-receptor kinase activity and leadto a decrease in insulin's acute metaboliceffects (265). Because of the potentiallyimportant role of tyrosine kinase in theinsulin-signaling mechanism, numerousinvestigators have examined tyrosine ki-nase activity in various cell types (skele-tal muscle, adipocytes, hepatocytes, anderythrocytes) from normal-weight andobese NIDDM subjects (240,244,246,248,25 2,266-27 0). In nondiabetic sub-

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Pathogenesis ofMDDM

jects insulin-receptor tyrosine kinase ac-tivity increased linearly with the glucose

disposal rate througho

pathogenesis of niddm

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