INSULIN RESISTANCEBOYLE - METABOLIC BRAIN DISORDERS

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Skeletal Muscle Insulin Resistance Is thePrimary Defect in Type 2 DiabetesRALPH A. DEFRONZO, MDDEVJIT TRIPATHY, MD

Insulin resistance is a characteristic fea-ture of type 2 diabetes and plays a ma-jor role in the pathogenesis of thedisease (1,2). Although �-cell failure isthe sine qua non for development of type2 diabetes, skeletal muscle insulin resis-tance is considered to be the initiating orprimary defect that is evident decades be-fore �-cell failure and overt hyperglyce-mia develops (3,4). Insulin resistance isdefined as a reduced response of targettissues (compared with subjects with nor-mal glucose tolerance [NGT] without afamily history of diabetes), such as theskeletal muscle, liver, and adipocytes, toinsulin. Because skeletal muscle is the pre-dominant site of insulin-mediated glucoseuptake in the postprandial state, here wewill focus on recent advances about the timeof onset, as well as the mechanism, of theskeletal muscle insulin resistance.

RESEARCH DESIGN ANDMETHODS — The euglycemic insulinclamp technique (5) is considered to bethe gold standard for measuring insulinaction in vivo. With this technique,whole-body insulin action is quantified asthe rate of exogenous glucose infusion(plus any residual hepatic glucose pro-duction) required to maintain the plasmaglucose concentration at euglycemic lev-els in response to a fixed increment in theplasma insulin concentration. Because80–90% of the infused glucose is takenup by skeletal muscle under conditions ofeuglycemic hyperinsulinemia, insulinsensitivity measured with the insulinclamp technique primarily reflects skele-tal muscle (6). Another advantage of thistechnique is that it can be combined withindirect calorimetry to measure differentsubstrate oxidation rates and with muscle

biopsy to examine the biochemical/molecular etiology of the insulin resistance.Measurement of insulin sensitivity by thefrequently sampled intravenous glucose tol-erance test reflects both hepatic and periph-eral insulin resistance and correlates wellwith the insulin clamp technique (7).

Because insulin clamp studies are notfeasible in large epidemiological studies,other surrogate markers of insulin sensi-tivity from glucose and insulin values inthe fasting state or after an oral glucosetolerance test (OGTT) have been devel-oped (8–10). The homeostatic model as-sessment correlates reasonably well withthe insulin clamp (10), but it primarilyreflects hepatic insulin sensitivity, sincethe fasting plasma glucose is determinedmainly by the rate of hepatic glucose pro-duction (HGP) and insulin is the primaryregulator of HGP. The correlation be-tween homeostatic model assessment andthe insulin clamp also is less robust whenanalyzed in subgroups of glucose toler-ance (11). During an OGTT, significant(�30 – 40%) amounts of glucose aretaken up by the splanchnic bed, and HGPis less completely suppressed than duringthe insulin clamp technique (12). As a re-sult, the plasma glucose concentrationduring OGTT is affected by both hepaticand peripheral (primarily muscle) insulinresistance. Therefore, indexes of insulinresistance from the OGTT, e.g., the Mat-suda index, reflect both hepatic and pe-ripheral insulin resistance and correlatewell (R value �0.70) with insulin sensi-tivity measured with the euglycemic insu-lin clamp (9).

Normal glucose homeostasisSkeletal muscle is the major site of glucoseuptake in the postprandial state in hu-

mans. Under euglycemic hyperinsuline-mic conditions, �80% of glucose uptakeoccurs in skeletal muscle (13). Studies us-ing the euglycemic hyperinsulinemicclamp and femoral artery/vein catheter-ization to quantitate glucose uptake haveallowed investigators to quantify leg mus-cle glucose uptake. Because adipose tissueuses �5% of an infused glucose load andbone is metabolically inert, the great ma-jority of leg glucose uptake can be ac-counted for by skeletal muscle. Duringphysiological hyperinsulinemia (80–100�U/ml), leg muscle glucose uptake in-creases linearly with time, reaching a pla-teau value of �10 mg/kg leg weight perminute after 60 min (13,14). In contrast,in lean type 2 diabetic subjects, the onsetof insulin action is delayed and the abilityof insulin to maximally stimulate glucoseuptake is markedly blunted. During thelast hour of the insulin clamp, insulin-stimulated leg muscle glucose uptake isreduced by �50% in type 2 diabetes (14).These studies support the notion that theprimary defect in insulin action in pa-tients with type 2 diabetes resides in theskeletal muscle. Similarly, using the fore-arm catheterization technique, a numberof investigators have demonstrated re-duced insulin-mediated glucose uptakeby the peripheral tissues, primarily mus-cle (15). Quantitation of leg muscle glu-cose uptake in type 2 diabetes withpositron emission tomography has pro-vided additional evidence for the pres-ence of severe muscle insulin resistance intype 2 diabetes (16). In the postabsorptivestate, the majority (�70–75%) of glucoseuptake (�2 mg/kg per min) occurs in in-sulin-insensitive tissues (brain, erythro-cytes, and splanchnic tissues) (17,18),with only �25% of glucose uptake occur-ring in insulin-sensitive tissues. In thepostabsorptive state, total body glucoseuptake is precisely matched by the rate ofendogenous glucose production, primar-ily by the liver and to a smaller extent bythe kidney (19). Thus, hepatic glucoseproduction is the main determinant of thefasting plasma glucose concentration andis regulated primarily by the plasma insu-lin and, to a lesser extent, glucagon con-centrations (20).

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From the University of Texas Health Science Center, San Antonio, Texas.Corresponding author: Ralph A. DeFronzo, albarado@uthscsa.edu.The publication of this supplement was made possible in part by unrestricted educational grants from Eli

Lilly, Ethicon Endo-Surgery, Generex Biotechnology, Hoffmann-La Roche, Johnson & Johnson, LifeScan,Medtronic, MSD, Novo Nordisk, Pfizer, sanofi-aventis, and WorldWIDE.

DOI: 10.2337/dc09-S302© 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly

cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

D I A B E T E S P R O G R E S S I O N , P R E V E N T I O N , A N D T R E A T M E N T

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Glucose disposal during OGTTAfter a mixed-meal or oral glucose load,the ensuing hyperglycemia and hyperin-sulinemia work in concert to suppressHGP and stimulate glucose uptake by thesplanchnic (liver) and peripheral (mus-cle) tissues (12,21). After glucose is trans-ported into the cell, it is phosphorylatedand subsequently oxidized to carbon di-oxide and water or converted to glycogen,which can be stored in the liver or skeletalmuscle (22). Glycogen synthesis is regu-lated by the enzyme glycogen synthase,and glycolysis primarily is controlled bythe enzyme complex of pyruvate dehy-drogenase. In humans, the rate of glucoseoxidation and the nonoxidative glucosemetabolism (primarily reflects glycogensynthesis) in the insulin-stimulated statecan be estimated by indirect calorimetryor magnetic response spectroscopy(23,24). Approximately 75% of glucose ismetabolized nonoxidatively, and im-paired glycogen synthesis is one of theearliest metabolic defects seen in thepathogenesis of type 2 diabetes (1,2).

Intracellular pathways of glucosedisposalUnder physiologic conditions, approxi-mately two-thirds of all glucose-6-phosphate is converted to glycogen, andone-third enters glycolysis. Of the glucosethat enters the glycolytic pathway, themajority (80–90%) is converted to car-bon dioxide and water, whereas the re-maining 10–20% is converted to lactate.Studies using indirect calorimetry and eu-glycemic clamp technique have shownthat the glucose oxidation is more sensi-tive (lower half-maximum) but saturatesearlier (lower maximum) than glycogensynthesis, which has low sensitivity buthigh capacity. Skeletal muscle is the pre-dominant site of glycogen synthesis.

Molecular basis of insulin actionIn the early stages of development of type2 diabetes, impaired glycogen synthesis inmuscle is the primary defect responsiblefor the insulin resistance. The initial stepin muscle glucose metabolism involvesactivation of the glucose transport system,leading to influx of glucose into insulintarget tissues. The free glucose that hasentered the cell is then metabolized by aseries of enzymatic steps that are underthe control of insulin. In skeletal muscleand adipose tissue, insulin promotes glu-cose uptake into the cells by activating acomplex cascade of phosphorylation-dephosphorylation reactions. In skeletal

muscle, insulin binds to the insulin recep-tor leading to phosphorylation of threekey tyrosine molecules on the insulin re-ceptor. Once the insulin receptor hasbeen phosphorylated, insulin receptorsubstrate (IRS)-1 moves to the cell mem-brane and becomes phosphorylated oncontiguous tyrosine molecules. Tyrosinephosphorylation of IRS-1 results in acti-vation of the p85 regulatory subunit ofphosphatidylinositol (PI)-3 kinase andactivates the p110 catalytic subunit, lead-ing to an increase in phosphatidylinosi-tol-3,4,5 triphosphate. This results inactivation of downstream protein kinaseB (also called Akt) and phosphorylation ofAkt substrate 160 (AS160), which facili-tates the translocation of GLUT4 to thesarcolemma and subsequent entry of glu-cose into the cell (25). Intracellular glu-cose is rapidly phosphorylated byhexokinase II and directed to oxidative ornonoxidative pathways. Maintaining theintegrity of the IRS-1/PI-3 kinase/Aktpathway is essential for normal insulin-mediated glucose uptake in skeletal mus-cle (26).

What is the initial metabolic defectin the pathogenesis of type 2diabetes?By the time that hyperglycemia is mani-fest, multiple metabolic abnormalities arepresent in individuals with type 2 diabe-tes. Because the majority of type 2 dia-betic subjects are obese, they also havedaylong elevation of the plasma free fattyacid (FFA) concentration and increasedcirculating levels of inflammatory cyto-kines (1,2). Because elevated plasma glu-cose, FFA, and cytokine concentrationsall can induce insulin resistance, it is ex-tremely difficult to separate the contribu-tion of each of these metabolic defects inthe pathogenesis of type 2 diabetes. Toexamine what is the earliest defect(s) inthe development of type 2 diabetes, inves-tigators have used two approaches. First,one can study the lean, normal glucosetolerant, first-degree relatives of two par-ents with type 2 diabetes. These individ-uals have a very high lifetime risk (�40%)of developing type 2 diabetes (4). In cer-tain high-risk populations, such as Mexi-can Americans, the prevalence of diabetesin the offspring of two type 2 diabetic par-ents can reach 70–80%. The advantage ofstudying this genetically predisposedgroup is that they do not have other con-founding factors that contribute to insulinresistance, such as obesity and hypergly-cemia. Thus, they represent an ideal

model to study the early metabolic defectsin the pathogenesis of type 2 diabetes. Asecond approach uses the long-term fol-low-up of normal glucose tolerant sub-jects as they progress to impaired glucosetolerance and subsequently to type 2 dia-betes. This prospective approach hasbeen used in Pima Indians (27).

What is the evidence that muscleinsulin resistance is the initialmetabolic defect in type 2 diabetes?Multiple investigators unequivocally havedemonstrated that lean NGT offspring oftwo parents with type 2 diabetes exhibitmoderate to severe skeletal muscle insulinresistance (28–33). The natural history oftype 2 diabetes is depicted in Fig. A1 (allfigures can be found in an online appendixavailable at http://care.diabetesjournals.org/cgi/content/full/dc09-S302/DC1) (1,34).As Europoid individuals progress fromNGT to IGT, insulin sensitivity declinesmarkedly but glucose tolerance deterio-rates minimally because of a markedincrease in insulin secretion. Similar ob-servations have been made in Pima Indi-ans (Fig. A2) (35) and Mexican Americansand Caucasians residing in San Antonio(Fig. A3) (30,32,36). These results, span-ning a wide range of ethnic groups, clearlydemonstrate that insulin resistance, andnot insulin deficiency, initiates the se-quence of events leading to the devel-opment of type 2 diabetes. However,progressive �-cell failure is requiredand ultimately responsible for type 2diabetes to become fully manifest(1,34,35,37,38).

In humans, �75– 80% of insulin-stimulated muscle glucose disposal dur-ing a euglycemic insulin clamp isconverted to glycogen, whereas the re-maining 20–25% is oxidized to CO2 andH2O (39). In type 2 diabetes, impairedglycogen synthesis secondary to reducedglycogen synthase activity is the earliestdetectable metabolic defect (39 – 41).Gulli et al. (32) studied the lean NGT off-spring of two diabetic Mexican Americanparents using a two-step euglycemic insu-lin clamp (20 and 40 mU/m2 per min)that produced steady-state elevations inthe plasma insulin concentration of �40and �80 �U/ml, respectively, which areclose to the half-maximal suppression ofHGP and stimulation of muscle glucoseuptake and glycogen synthesis. At bothplasma insulin concentrations, glucoseuptake was decreased by 33 and 43%, re-spectively (32) (Fig. A4). The impairmentin glucose uptake was accounted for en-

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tirely by reduced nonoxidative glucosemetabolism (Fig. A4), which representsglycogen synthesis. No defect was notedin the suppression of hepatic glucose pro-duction by insulin (Fig. A5). These resultsindicate that the defect in insulin actionprimarily is localized to skeletal muscleand involves the glycogen synthetic path-way. During both the OGTT and hyper-glycemic clamp (Fig. A6), insulinsecretion (total, early, and late responses)was significantly increased, excluding aprimary defect in �-cell function in thepathogenesis of type 2 diabetes in thisethnic population.

A similar defect in insulin-stimulatedglycogen synthesis has been reported byGroop et al. in the Botnia study (42,43).Using nuclear magnetic resonance (NMR)spectroscopy, Perseghin et al. (44) di-rectly quantified the defect in muscle gly-cogen synthesis in NGT offspring of twodiabetic parents. This technique allowsone to monitor glycogen synthesis nonin-vasively over real time. These investiga-tors demonstrated that reduced glycogensynthesis could account for almost all ofthe decrease in insulin-stimulated glucosedisposal in skeletal muscle. Of note, theseverity of skeletal muscle insulin resis-tance in the offspring of two diabetic par-ents is of similar magnitude to that seen intype 2 diabetic individuals.

Before the incorporation of glucoseinto glycogen, it first must be transportedinto the cell and phosphorylated by hex-okinase II to glucose-6-phosphate. Usinga novel triple isotope (12C-mannitol, 13C-0-methyglucose, 3-3H-glucose) tech-nique in combination with brachialarterial/deep vein forearm catheterizationand the euglycemic clamp, Pendergrass etal. (45) quantitated muscle glucose up-take and phosphorylation in the insulin-resistant NGT offspring of two type 2diabetic parents (Fig. A7). The NGT off-spring demonstrated a severity of whole-body and forearm muscle insulinresistance similar to that observed in leanand obese type 2 diabetic subjects and inNGT obese insulin-resistant individuals.Similarly, the NGT offspring manifesteddefects in muscle glucose transport andphosphorylation that were similar tothose in lean and obese type 2 diabeticsubjects (Fig. A7). Using 14C-NMR tomeasure muscle glucose-6-phosphatelevels, Rothman et al. (46) demonstrated asimilar defect in combined glucose trans-port/phosphorylation in the NGT off-spring of two type 2 diabetic parents.

Another strategy to examine what is

the earliest defect responsible for the de-velopment of type 2 diabetes is to pro-spectively follow individuals who are athigh risk for the development of type 2diabetes. This has been done by Weyer etal. (47) in Pima Indians. At-risk individ-uals received a euglycemic insulin clampto measure insulin sensitivity (primarilyreflects muscle) and an intravenous glu-cose tolerance test to quantitate insulinsecretion and were followed sequentiallyuntil they developed diabetes. At-risk in-dividuals were markedly resistant to insu-lin but, at the stage of NGT, their �-cellswere able to secrete sufficient amounts ofinsulin to offset the insulin resistance(Fig. A8). With time, both progressors (totype 2 diabetes) and nonprogressors (re-mained as NGT) experienced a furthermodest reduction (11–14%) in insulinsensitivity. However, nonprogressorswere able to offset the worsening insulinresistance in muscle by augmenting insu-lin secretion (30%), whereas progressionto type 2 diabetes was associated with a78% decline in the acute insulin responseto an intravenous glucose challenge (Fig.A8). Using a similar approach, Warram etal. (4) also demonstrated that insulin re-sistance was a strong predictor for the fu-ture diabetes. Because the great majorityof glucose disposal after intravenous glu-cose administration occurs in muscle,these results provide strong evidence thatinsulin resistance in muscle is the earliestdemonstrable defect in the natural historyof type 2 diabetes, but that the develop-ment of overt type 2 diabetes occurs onlyin those individuals whose �-cells are un-able to compensate for the defect in insu-lin action (37,38,48,49).

Insulin resistance begets insulinresistanceThe normal �-cell response to insulin re-sistance, irrespective of the etiology of theinsulin resistance, is to increase its secre-tion of insulin (1,2,39). However, achronic physiologic increase in theplasma insulin concentration has a detri-mental effect on skeletal muscle insulinsensitivity. Del Prato et al. (50) demon-strated that a 72 pmol/l (11 �U/ml) in-crease in the plasma insulin concentrationin healthy NGT insulin-sensitive individ-uals for as little as 72–96 h reduced insu-lin-stimulated glucose disposal (insulinclamp technique) by 30–40%. The defectin insulin action was accounted for en-tirely by impaired nonoxidative glucosedisposal (Fig. A9). On the other hand,chronic euglycemic hyperinsulinemia did

not alter insulin-mediated suppression ofhepatic glucose production (50). Koop-mans et al. (51,52) showed that chronichyperinsulinemia (threefold increaseabove baseline) in conscious rats for 7days resulted in a reduction in insulin-mediated total-body glucose uptake, glu-cose storage, and glycolysis by 39, 62, and26%, respectively. Hepatic glucose pro-duction was normally suppressed after 7days of hyperinsulinemia. Because themajority (�80–90%) of glucose disposalduring the euglycemic insulin clamp oc-curs in muscle, these results demonstratethat a physiologic elevation in the plasmainsulin concentration will exacerbate theunderlying muscle insulin resistance.Iozzo et al. (53) performed a 240-min eu-glycemic insulin clamp study with musclebiopsies in healthy volunteers. Subjectsthen received a low-dose insulin infusionfor 72 h (plasma insulin concentration143 � 25 pmol/l [21 � 2 �U/ml]), fol-lowed by a repeat insulin clamp withmuscle biopsies. After 72 h of sustainedphysiologic hyperinsulinemia, insulin-stimulated muscle glycogen synthase ac-tivity, total body glucose uptake, andnonoxidative glucose disposal (primarilyreflects glycogen synthesis in muscle)were significantly reduced. Taken to-gether, these findings indicate that hyper-insulinemia is not only a compensatoryresponse to insulin resistance, but also aself-perpetuating cause of the defect inmuscle insulin action.

Molecular etiology of the skeletalmuscle insulin resistance ingenetically predisposed individualsUsing the euglycemic insulin clamp withskeletal muscle biopsy, a number of in-vestigators have examined the insulin sig-nal transduction system in humanskeletal muscle of type 2 diabetic subjectsand consistently demonstrated defects inIRS-1 tyrosine phosphorylation and PI-3kinase and Akt activation (26,54,55). Toexamine whether similar defects arepresent in genetically predisposed indi-viduals, Pratipanawatr et al. (36) exam-ined insulin signaling in NGT subjectswith a strong family history of type 2 di-abetes and demonstrated that both thebasal and insulin-stimulated IRS-1 ty-rosine phosphorylation and PI 3-kinaseactivity associated with IRS-1 were signif-icantly decreased (Fig. A10). Insulin stim-ulation of PI 3-kinase activity is a requisitefor activation of glucose transport andglycogen synthesis. Increased serinephosphorylation of IRS-1 has been shown

DeFronzo and Tripathy

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to impair insulin signaling (tyrosine phos-phorylation of both insulin resistanceand IRS-1) in type 2 diabetes (56). Inlean insulin-resistant NGT offspring oftype 2 diabetic parents, increased serinephosphorylation of IRS-1 in skeletal mus-cle has been documented in associationwith impaired activation of Akt (57) (Fig.A11). Thus, at the earliest stage in the nat-ural history of type 2 diabetes, i.e., theNGT insulin-resistant offspring of twotype 2 diabetic parents, the molecular eti-ology of the muscle insulin resistance al-ready is well established and is virtuallyidentical to that in their diabetic parents.

Relationship between muscle insulinresistance and altered FFA/musclelipid metabolismGulli et al. (32) were the first to demon-strate that the NGT offspring of two type 2diabetic parents demonstrated markedmuscle insulin resistance but normal sen-sitivity to the suppressive effect of insulinon hepatic glucose production. However,a normal basal rate of HGP in the face offasting hyperinsulinemia could be con-strued to indicate the presence of hepaticinsulin resistance. More impressive wasthe elevated fasting plasma FFA concen-tration in the presence of fasting hyperin-sulinemia and the impaired suppressionof plasma FFA during the euglycemic in-sulin clamp (Fig. A12). These findings in-dicate the presence of marked adipocyteresistance to the antilipolytic effect of in-sulin. Impaired insulin-mediated sup-pression of whole-body lipid oxidationalso was present in the NGT offspring(Fig. A12). Petersen et al. (58) docu-mented an increase in intramyocellularlipid content in the offspring of two type 2diabetic parents. This observation is ofimportant clinical significance, since di-acylglycerol, long-chain fatty acyl CoAs,and ceramides all have been shown tocause serine phosphorylation of insulinresistance and IRS-1 and lead to the de-velopment of insulin resistance in skeletalmuscle (59,60). Collectively, these resultssuggest that intramyocellular accumula-tion of toxic lipid metabolites plays an im-portant role in the pathogenesis of muscleinsulin resistance.

To further address this question,Kashyap et al. (30) infused a lipid emul-sion for 4 days to cause a physiologic ele-vation in the plasma FFA concentration inNGT insulin-resistant offspring of twotype 2 diabetes parents and in NGT insu-lin-sensitive subjects without any familyhistory of diabetes. Four days of physio-

logical elevation in the plasma FFA con-centration in the offspring did not causeany further worsening of insulin-stimulated whole-body glucose disposal,nonoxidative glucose disposal, glucoseoxidation, or preexisting defects in insu-lin-stimulated insulin receptor tyrosinephosphorylation (30). In contrast, inhealthy control subjects, chronic lipid in-fusion was associated with a marked de-cline in insulin-stimulated glucose uptakeand insulin receptor tyrosine phosphory-lation (30). When the insulin-resistantoffspring were treated with acipimox for 7days to reduce the plasma FFA concentra-tion and intramyocellular FACoA con-centration, a marked improvement ininsulin sensitivity was observed (61).These data lend further support to the ob-servation that insulin resistance in skele-tal muscle is an early metabolic defect inthe pathogenesis of type 2 diabetes andthat muscle lipid accumulation plays acentral role in the etiology of the muscleinsulin resistance.

Mitochondria are the main organelleswhere fatty acids are oxidized and inves-tigators have focused on their structureand function in patients with type 2 dia-betes. Studies using the leg balance tech-nique have documented that fat oxidationis reduced in both type 2 diabetic andobese insulin-resistant nondiabetic indi-viduals (62), suggesting that musclemitochondrial oxidative capacity is im-paired. Recently, two groups indepen-dently showed that NGT offspring of twotype 2 diabetic parents had a reduced ex-pression of key mitochondrial genes in-volved in the regulation of oxidativemetabolism in skeletal muscle (63,64).The most commonly underexpressedfunctional genes were those coding forenergy generation, including multipleglycolytic, tricarboxylic acid cycle, andoxidative phosphorylation genes. Evi-dence in support of a role for mitochon-drial dysfunction as a cause of muscleinsulin resistance in the NGT offspring oftwo type 2 diabetic parents has been pro-vided by Shulman and colleagues. Using31P-NMR, these investigators demon-strated impaired mitochondrial activity inNGT insulin-resistant offspring of type 2diabetic parents (57,58,65). Whereas mi-tochondria from NGT subjects withoutany family history of diabetes respondedto insulin by increasing ATP productionby 90%, mitochondria from insulin-resistant offspring increased ATP produc-tion by only 5% (Fig. A13). The authorspostulated that muscle mitochondrial

dysfunction was the primary defect, lead-ing to elevated intramyocellular fatty acidmetabolites (as a consequence of reducedfat oxidation) and subsequent insulin re-sistance (58,66). However, recent studiesby Abdul-Ghani et al. (67) have shownthat even small increases in palmitoyl car-nitine (5–10 �mol/l) can markedly im-pair ATP synthesis in mitochondriaisolated from human muscle. Thus, it isunclear which is the cart and which is thehorse: mitochondrial dysfunction leadingto increased intramyocellular lipid con-tent and insulin resistance or increasedmuscle lipid content (i.e., secondary toelevated plasma FFA levels and/or exces-sive lipid ingestion) leading to mitochon-drial dysfunction and insulin resistance.

SUMMARY — The maintenance ofnormal glucose homeostasis depends on afinely balanced dynamic interaction be-tween tissue (muscle, liver, and fat) sen-sitivity to insulin and insulin secretion.Even in the presence of severe insulin re-sistance, a perfectly normal �-cell is capa-ble of secreting sufficient amounts ofinsulin to offset the defect in insulin ac-tion. Thus, the evolution of type 2 diabe-tes requires the presence of defects inboth insulin secretion and insulin action,and both of these defects can have a ge-netic as well as an acquired component.When type 2 diabetic patients initiallypresent to the physician, they will havehad their diabetes for many years, and de-fects in insulin action (in muscle, liver,and adipocytes) and insulin secretion willbe well established (1,2,39). At this stage,it is not possible to define which defectcame first in the natural history of the dis-ease and which tissue is the primary de-fect responsible for the insulin resistance.Although insulin resistance represents theearliest detectable abnormality in thegreat majority of type 2 diabetic people, ina minority of individuals (i.e., glucoki-nase deficiency), it is clear that a �-celldefect initiates the disturbance in glucosehomeostasis. Nevertheless, it is now clearthat in any given diabetic patient, what-ever defect (insulin resistance or impairedinsulin secretion) initiates the distur-bance in glucose metabolism, it will even-tually be followed by the emergence of itscounterpart (Fig. A14).

Insulin resistance is a nearly universalfinding in patients with established type 2diabetes. In normal-weight and obese in-dividuals with IGT and in type 2 diabeticsubjects with mild fasting hyperglycemia(110–140 mg/dl, 6.1–7.8 mmol/l), both

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the basal and glucose-stimulated plasmainsulin levels are increased. Although thefirst-phase insulin response may be de-creased in some, but not all, of these sub-jects, the first phase consistently isincreased in the NGT offspring of twotype 2 diabetic parents and the total insu-lin response is increased in NGT offspringand in IGT subjects. In each of thesegroups, tissue sensitivity to insulin, mea-sured with the insulin clamp technique,has been shown to be diminished. Pro-spective studies conclusively have dem-onstrated that hyperinsulinemia andinsulin resistance precede the develop-ment of IGT and that IGT represents theforerunner of type 2 diabetes. This sce-nario has been well documented in PimaIndians, Mexican Americans, and PacificIslanders. It is noteworthy that all of thesepopulations are characterized by obesityand a younger age at onset of diabetes.Such results provide conclusive evidencethat insulin resistance is the inherited de-fect that initiates the diabetic condition inthe majority of type 2 diabetic patients.Studies in NGT first-degree relatives of di-abetic individuals and in the offspring oftwo diabetic parents indicate that the in-herited defect in insulin action resultsfrom an abnormality in the glycogen syn-thetic pathway in muscle and more prox-imal defects in glucose transport/phosphorylation and insulin signaltransduction. As the insulin resistanceprogresses and muscle glucose uptake be-comes further impaired, the postprandialrise in plasma glucose concentration be-comes excessive, but the increase in basalhyperinsulinemia is sufficient to maintainthe fasting plasma glucose concentrationand HGP within the normal range. None-theless, there is an excessive postprandialrise in plasma glucose concentration, anda longer time is required to restore nor-moglycemia after each meal. Eventually,however, the insulin resistance becomesso severe that the compensatory hyperin-sulinemia is no longer sufficient to main-tain the fasting glucose concentration atthe basal level. The development of hy-perglycemia further stimulates �-cell se-cretion of insulin, and the resultanthyperinsulinemia causes a downregula-tion of insulin receptor number and of theintracellular events involved in insulin ac-tion, thus exacerbating the insulin resis-tance. Initially, the hyperglycemia-induced increase in insulin secretionserves a compensatory function to main-tain near-NGT. In some individuals, thepersistent stimulus to the �-cell to over-

secrete insulin leads to a progressive lossof �-cell function. Chronic hyperglyce-mia (glucose toxicity) and/or distur-bances in lipid metabolism (lipotoxicity)may contribute to the defect in insulinsecretion. The resultant insulinopenialeads to the emergence/exacerbation ofpostreceptor defects in insulin action.Many of the intracellular events involvedin glucose metabolism depend on thesurge of insulin that occurs three to fourtimes per day in response to nutrient in-gestion. When the insulin response be-comes deficient, the activity of the glucosetransport system becomes severely im-paired and a number of key intracellularenzymatic steps involved in glucose me-tabolism become depressed. Addition-ally, when severe insulinopenia ensues,plasma FFA levels rise, further contribut-ing to the defects in intracellular glucosedisposal. There is also compelling evi-dence that hyperglycemia per se candownregulate the glucose transport sys-tem, as well as a number of other intracel-lular events involved in insulin action(glucose toxicity), and a similar argumentcan be made concerning the intracellularderangement in lipid metabolism. Thispathogenetic sequence can explain all ofthe clinical and laboratory features ob-served in type 2 diabetic patients. Insofaras the cellular defect is generalized, bothhepatic and peripheral tissues (skeletalmuscle and adipocytes), and possibly the�-cells themselves, would manifest insu-lin resistance, and the numerous meta-bolic alterations characteristic of thediabetic state could be related to one andthe same primary defect.

The NGT offspring of two type 2 dia-betic parents also manifest marked adipo-cyte resistance to the suppressive effectsof insulin on lipolysis. One could argue,therefore, that the adipocyte representsthe primary tissue responsible for the in-sulin resistance. According to this sce-nario, the elevated plasma FFA levelsproduce insulin resistance in muscle andliver and impair �-cell function. Adipo-cytes in the NGT offspring of two type 2diabetic parents also secrete excessiveamounts of inflammatory and insulinresistance producing adipocytokinesthat could initiate/exacerbate the insu-lin resistance in skeletal muscle. As re-viewed by Iozzo in this symposium, theadipocyte insulin resistance could begenetic in origin or induced in uteroduring the third trimester by nutritionaldeprivation or overfeeding.

There is less evidence to support arole for the liver as the organ responsiblefor the insulin resistance. However, theNGT offspring of two type 2 diabetic par-ents have a normal rate of HGP in thepresence of fasting hyperinsulinemia,suggesting the presence of hepatic resis-tance to the suppressive effect of insulinon glucose production. Therefore, onecould argue that the resultant fasting hy-perinsulinemia leads to the developmentof insulin resistance in skeletal muscle.

Acknowledgments— No potential conflictsof interest relevant to this article werereported.

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