Background Insulin resistance appears to be the best predictorof the development of diabetes in the children of patients withtype 2 diabetes, but the mechanism responsible is unknown.
Methods We performed hyperinsulinemic–euglycemic clampstudies in combination with infusions of [6,6-2H2]glucose inhealthy, young, lean, insulin-resistant offspring of patientswith type 2 diabetes and insulin-sensitive control subjectsmatched for age, height, weight, and physical activity to assessthe sensitivity of liver and muscle to insulin. Proton (1H)magnetic resonance spectroscopy studies were performed to measureintramyocellular lipid and intrahepatic triglyceride content.Rates of whole-body and subcutaneous fat lipolysis were assessedby measuring the rates of [2H5]glycerol turnover in combinationwith microdialysis measurements of glycerol release from subcutaneousfat. We performed 31P magnetic resonance spectroscopy studiesto assess the rates of mitochondrial oxidative-phosphorylationactivity in muscle.
Results The insulin-stimulated rate of glucose uptake by musclewas approximately 60 percent lower in the insulin-resistantsubjects than in the insulin-sensitive control subjects (P<0.001)and was associated with an increase of approximately 80 percentin the intramyocellular lipid content (P=0.005). This increasein intramyocellular lipid content was most likely attributableto mitochondrial dysfunction, as reflected by a reduction ofapproximately 30 percent in mitochondrial phosphorylation (P=0.01for the comparison with controls), since there were no significantdifferences in systemic or localized rates of lipolysis or plasmaconcentrations of tumor necrosis factor , interleukin-6, resistin,or adiponectin.
Conclusions These data support the hypothesis that insulin resistancein the skeletal muscle of insulin-resistant offspring of patientswith type 2 diabetes is associated with dysregulation of intramyocellularfatty acid metabolism, possibly because of an inherited defectin mitochondrial oxidative phosphorylation.
Type 2 diabetes is rapidly becoming a worldwide epidemic.1 Althoughthe primary cause of this disease is unknown, insulin resistanceappears to have a major role, as evidenced by cross-sectionalstudies demonstrating insulin resistance in virtually all patientswith type 2 diabetes, as well as prospective studies demonstratingthe presence of insulin resistance one to two decades beforethe onset of the disease.2,3,4 In addition, insulin resistancein the offspring of patients with type 2 diabetes has been shownto be the best predictor of the development of the disease.5
Despite much work, little is known about the factors responsiblefor insulin resistance in persons at risk. In this regard, studiesmeasuring triglyceride content of muscle-biopsy specimens6 orintramyocellular lipid content by means of proton (1H) magneticresonance spectroscopy7,8,9 indicate a strong relation betweenintramuscular lipid content and insulin resistance in skeletalmuscle. Studies have also identified increases in plasma fattyacid concentrations10 and intramyocellular lipid content8 inthe insulin-resistant offspring of patients with type 2 diabetes,suggesting that dysregulation of fatty acid metabolism may mediatethe insulin resistance in these persons. Increases in the intramyocellularconcentration of fatty acid metabolites in turn have been postulatedto activate a serine kinase cascade, which decreases the insulin-stimulatedactivity of insulin receptor substrate 1–associated phosphatidylinositol3-kinase11,12,13,14 and results in reduced glucose transport12and glycogen synthesis.15,16
In the present study we examined a potential mechanism for theintramyocellular accumulation of lipids in young, lean, insulin-resistantoffspring of patients with type 2 diabetes. These subjects areideal candidates for studies examining the earliest defectsleading to insulin resistance, since in contrast to patientswith diabetes, they are young, lean, healthy, and unlikely tohave other confounding factors. Since increases in intramyocellulartriglyceride content could occur as a result of the increaseddelivery of fatty acids from lipolysis, decreased rates of mitochondrialoxidative phosphorylation, or both, we examined these processesin the insulin-resistant offspring of patients with type 2 diabetesand in insulin-sensitive control subjects. We assessed ratesof whole-body and subcutaneous fat lipolysis by measuring therates of [2H5]glycerol turnover in combination with microdialysismeasurements of the release of glycerol from subcutaneous fat.We determined the rates of in vivo mitochondrial phosphorylationand the ratio of inorganic phosphate to phosphocreatine in skeletalmuscle using phosphorus-31 (31P) magnetic resonance spectroscopy.In addition, since studies have also implicated several adipocyte-derivedhormones (tumor necrosis factor ,17 interleukin-6,18 resistin,19and adiponectin20) in causing insulin resistance, we also measuredplasma concentration of these factors in this group of insulin-resistantpersons.
Methods
Subjects
All subjects were recruited by means of local advertising overa two-year period (2001 to 2003) and were prescreened to confirmthat they were in excellent health, lean, nonsmoking, and takingno medications. A birth weight above 2.3 kg (5 lb) and a sedentarylifestyle, as defined by an activity index questionnaire,21were also required. Qualifying subjects (more than 150 persons)underwent a three-hour oral glucose-tolerance test (with a 75-goral glucose load), after which two subgroups of subjects wereconsecutively selected to identify extreme phenotypes for insulinresistance and increased insulin sensitivity.
Insulin-resistant subjects (3 men and 11 women) were definedas having an insulin sensitivity index22 of less than 4.0 (indicatinginsulin resistance; lower values indicate greater insulin resistance),at least one parent or grandparent with type 2 diabetes, andat least one other family member with type 2 diabetes. Insulin-sensitivecontrol subjects (five men and seven women) were defined byan insulin sensitivity index of greater than 6.3 (with or withouta family history of type 2 diabetes).
All qualifying subjects subsequently underwent a complete medicalhistory taking and a physical examination along with blood teststo verify that the following were normal: blood and plateletcounts; concentrations of electrolytes, aspartate aminotransferase,alanine aminotransferase, blood urea nitrogen, creatinine, cholesterol,and triglycerides; prothrombin time; and partial-thromboplastintime. In addition, subjects underwent 1H magnetic resonancespectroscopy studies to determine the triglyceride content ofliver and muscle. The subjects then underwent a hyperinsulinemic–euglycemicclamp study to assess the responsiveness of liver, muscle, andfat to insulin or 31P magnetic resonance spectroscopy studiesto assess the rates of muscle mitochondrial phosphorylationand the ratio of inorganic phosphate to phosphocreatine. Owingto the complexity of the protocol, not all the subjects wereable to complete both the magnetic resonance spectroscopy andclamp studies. Two of the 12 control subjects, who initiallyqualified on the basis of their insulin sensitivity index, weresubsequently excluded after the hyperinsulinemic–euglycemicclamp study identified them as insulin resistant, whereas allsubjects who were found to be insulin resistant on the basisof the insulin sensitivity index were also found to be insulinresistant on the basis of the clamp study.
Written consent was obtained from each subject after the purpose,nature, and potential complications of the studies had beenexplained. The protocol was approved by the human-investigationcommittee of Yale University.
Diet and Study Preparation
The subjects were instructed to eat a regular, weight-maintenancediet containing at least 150 g of carbohydrate per day for threedays before admission for either the clamp or magnetic resonancespectroscopy study. All subjects were instructed not to performany exercise other than normal walking for the three days beforethe study. To minimize changes in glucose metabolism resultingfrom ovarian hormonal effects, the female subjects were studiedduring the follicular phase (days 0 through 12) of the menstrualcycle.23 Subjects were admitted to the Yale–New HavenHospital General Clinical Research Center the evening beforethe clamp or 31P magnetic resonance spectroscopy study, andthe subjects continued to fast while having free access to regulardrinking water until the completion of the study the followingday.
Measurement of Metabolites and Hormones
Plasma glucose concentrations were measured with the use ofa YSI 2700 STAT Analyzer (Yellow Springs Instruments). Plasmaconcentrations of insulin, glucagon, adiponectin, and resistinwere measured with the use of double-antibody radioimmunoassaykits (Linco). Plasma tumor necrosis factor and interleukin-6were measured with the use of Quantine High Sensitivity kits(R&D Systems). Plasma fatty acid concentrations were determinedwith the use of a microfluorometric method.24 Urine nitrogencontent was measured at the Mayo Medical Laboratories (Rochester,Minn.). Microdialysate glycerol concentrations (in 0.5-µlsamples) were measured with the use of enzyme-linked colorimetryby a CMA 600 microdialysis analyzer (Microdialysis).25 Ethanolconcentrations were determined enzymatically with the use ofa YSI 2700 STAT Analyzer.25 Gas chromatography–mass spectrometryanalyses of the enrichment of [6,6-2H2]glucose and [2H5]glycerolin plasma were performed with the use of a Hewlett–PackardMass Selective Detector (model 5971A) as previously described.25
Magnetic Resonance Spectroscopy of Intramyocellular and Intrahepatic Triglyceride Content
On a separate day, after a 12-hour fast, all subjects were transportedby wheelchair to the Yale Magnetic Resonance Center, and localized1H magnetic resonance spectroscopy spectra of the soleus muscleand liver were acquired on a 2.1-T Biospec Spectrometer (BrukerInstruments) as previously described.25
Hyperinsulinemic–Euglycemic Clamp Studies
Basal rates of glucose and glycerol turnover were assessed duringa three-hour basal period and insulin-stimulated rates wereassessed with a three-hour hyperinsulinemic–euglycemicclamp with the use of 20 mU of insulin per square meter of body-surfacearea per minute, [6,6-2H2]glucose, and [2H5]glycerol as previouslydescribed.26 Rates of whole-body energy expenditure and glucoseand fat oxidation were assessed by indirect calorimetry (DeltratrackMetabolic Monitor, Sensormedics) during the last 30 minutesof the 3-hour base-line period and during the last 30 minutesof the clamp period.27 Localized rates of in vivo lipolysiswere assessed before and during the clamp procedure with theuse of microdialysis probes (CMA/60, CMA, Microdialysis) insertedinto the fat deposits in two locations on the abdomen, 4 to6 cm below the umbilicus, as previously described.25
Magnetic Resonance Spectroscopy of Mitochondrial Phosphorylation
Rates of mitochondrial phosphorylation were assessed by 31Pmagnetic resonance spectroscopy saturation transfer performedat 36.31 MHz with the use of a flat, concentric probe made ofan inner coil 9 cm in diameter (for 31P) and a 13-cm outer coiltuned to proton frequency for scout imaging and shimming aspreviously described.28 Unidirectional rates of ATP synthesiswere measured with the use of the saturation-transfer methodapplied to the exchange between inorganic phosphate and ATP.The steady-state magnetization of inorganic phosphate was measuredin the presence of a selective irradiation of the resonanceof ATP and compared with the magnetization of inorganic phosphateat equilibrium in a control spectrum (without irradiation ofthe resonance of ATP).28 The total acquisition time for 31Pmagnetic resonance spectra was about 120 minutes. The ratioof inorganic phosphate to phosphocreatine in the soleus musclewas measured by 31P magnetic resonance spectroscopy as previouslydescribed.29,30
Statistical Analysis
Statistical analyses were performed with StatView software (AbacusConcepts). To detect statistically significant differences betweencontrol subjects and insulin-resistant subjects, we used unpairedStudent's t-tests for independent samples, with a two-sidedP value of less than 0.05 considered to indicate statisticalsignificance. Non-normally distributed data (i.e., data regardingthe area under the curve) were logarithmically transformed.All data are expressed as means ±SE in the text.
Results
Characteristics of the Subjects
Insulin-sensitive control subjects and insulin-resistant subjectswere frequency matched for age, weight, height, body-mass index,and activity index and had similar fasting plasma concentrationsof glycosylated hemoglobin, adiponectin, tumor necrosis factor, interleukin-6, and resistin (Table 1). In contrast, the insulinsensitivity index was markedly lower in the insulin-resistantsubjects than in the insulin-sensitive control subjects (mean[±SE], 2.8±0.2 vs. 10.2±1.4; P<0.001).
Table 1. Characteristics of the Two Groups of Subjects.
Oral Glucose-Tolerance Test
All subjects had normal glucose-tolerance tests, but the plasmaconcentrations of glucose (Figure 1A) and insulin (Figure 1B)before and during the test were significantly higher in theinsulin-resistant subjects. Fasting plasma fatty acid concentrationswere similar in the insulin-sensitive control subjects (0.37±0.05mM) and the insulin-resistant subjects (0.47±0.05 mM,P=0.17) and decreased by approximately 80 percent in both groupsduring the glucose-tolerance test. There were no significantdifferences in the fasting plasma glucagon concentrations betweenthe insulin-sensitive control subjects (56±4 pg per milliliter)and the insulin-resistant subjects (59±3 pg per milliliter,P=0.64).
Figure 1. Mean (±SE) Plasma Concentrations of Glucose (Panel A) and Insulin (Panel B) before and during an Oral Glucose-Tolerance Test in 9 Insulin-Sensitive Controls and 14 Insulin-Resistant Subjects.
P=0.016 for the comparison of the areas under the curve for glucose concentration of control subjects and insulin-resistant subjects, and P=0.002 for the comparison of the areas under the curve for insulin concentration of control subjects and insulin-resistant subjects. To convert values for glucose to millimoles per liter, multiply by 0.05551. To convert values for insulin to picomoles per liter, multiply by 6.0.
Hyperinsulinemic–Euglycemic Clamp Studies
Fasting rates of glucose production were similar in the nineinsulin-sensitive control subjects (2.3±0.1 mg per kilogramof body weight per minute) and the eight insulin-resistant subjects(2.0±0.3 mg per kilogram per minute, P=0.41) for whomresults were available and were completely suppressed in bothgroups during the period of hyperinsulinemic–euglycemicclamping. In contrast, the rates of glucose infusion requiredto maintain euglycemia were approximately 60 percent lower inthe insulin-resistant subjects than in the insulin-sensitivecontrol subjects during clamping (3.3±0.3 mg per kilogramper minute vs. 7.7±0.5 mg per kilogram per minute, P<0.001)and the insulin-stimulated rates of peripheral glucose uptakewere also approximately 60 percent lower in the insulin-resistantgroup (P<0.001) (Figure 2A). This reduction in peripheralglucose metabolism could be attributed mostly to a reductionof approximately 70 percent (P<0.001) in nonoxidative glucosedisposal in the insulin-resistant subjects (data not shown).There were no significant differences in fasting or insulin-stimulatedrates of whole-body glucose or fat oxidation between the twogroups (data not shown). Fasting rates of whole-body energyexpenditure tended to be lower in the insulin-resistant groupthan in the control group (21.8±0.7 kcal per kilogramper 24 hours vs. 24.6±1.1 kcal per kilogram per 24 hours,P=0.06), and the same was true for insulin-stimulated rates(21.6±0.9 kcal per kilogram per 24 hours and 24.9±0.7kcal per kilogram per 24 hours, respectively; P=0.01).
Figure 2. Insulin-Stimulated Rates of Muscle Glucose Metabolism (Panel A), Intramyocellular Lipid Content (Panel B), and Rates of Muscle Mitochondrial Phosphorylation Activity (Panel C) in Insulin-Sensitive Controls and Insulin-Resistant Subjects.
Whole-Body and Localized Rates of Glycerol Metabolism
Fasting rates of glycerol turnover were similar in the controlgroup and the insulin-resistant group (0.21±0.03 µmolper minute and 0.18±0.02 µmol per minute, respectively;P=0.32), as was the insulin-induced suppression of glycerolturnover during the clamp study (0.11±0.01 µmolper minute and 0.09±0.01 µmol per minute, respectively;P=0.64). Consistent with this finding, the interstitial glycerolconcentration, as assessed by microdialysis, decreased by asimilar degree in the insulin-sensitive control subjects (36±7percent) and the insulin-resistant subjects (41±6 percent,P=0.67) during the hyperinsulinemic–euglycemic clamp study.
Intramyocellular and Intrahepatic Triglyceride Content
The intramyocellular lipid content in the soleus muscle wasapproximately 80 percent higher (P=0.005) in the 12 insulin-resistantoffspring in whom it was measured than in the 10 insulin-sensitivecontrol subjects in whom it was measured (Figure 2B). Therewas no significant difference with respect to intrahepatic triglyceridecontent between insulin-resistant subjects (2.35±1.49percent) and insulin-sensitive control subjects (0.47±0.16percent, P=0.29).
Rates of Mitochondrial Phosphorylation and Ratio of Inorganic Phosphate to Phosphocreatine
Rates of mitochondrial phosphorylation in skeletal muscle wereapproximately 30 percent lower (P=0.01) in the 13 insulin-resistantsubjects in whom it was evaluated than in the 10 control subjectsin whom it was evaluated (Figure 2C). The ratio of inorganicphosphate to phosphocreatine in the soleus muscle was reducedby approximately 20 percent (P=0.002) in the insulin-resistantsubjects (0.113±0.004), as compared with the controlsubjects (0.137±0.005).
Discussion
The lean, insulin-resistant offspring of patients with type2 diabetes had severe insulin resistance, as compared with insulin-sensitivecontrol subjects matched for age, height, weight, and activity.The difference could be attributed largely to a reduction ofapproximately 70 percent in insulin-stimulated nonoxidativemuscle glucose metabolism. Using 1H magnetic resonance spectroscopyto measure intramyocellular lipid content, we found that insulinresistance in muscle was accompanied by an increase of approximately80 percent in intramyocellular lipid content in the insulin-resistantsubjects, as compared with the insulin-sensitive control subjects.These data are consistent with those of previous studies inhumans7,8,9 and rodents,31,32 which have suggested that dysregulatedintramuscular fatty acid metabolism has an important causativerole in insulin resistance and may have a similar role in fat-inducedinsulin resistance in the skeletal muscle of the insulin-resistantoffspring of patients with type 2 diabetes.
To assess whether the increase in intramyocellular lipid contentin the insulin-resistant subjects was due to increased deliveryof fatty acids to the muscle, we measured whole-body and localizedrates of lipolysis. Rates of whole-body lipolysis were similarin the control subjects and the insulin-resistant subjects duringthe basal state and were both suppressed to a similar degreeduring the hyperinsulinemic–euglycemic clamp study. Ina manner consistent with this finding, we found that the extentof insulin-induced suppression of the localized rates of lipolysisin subcutaneous fat, as assessed by microdialysis, was alsosimilar in both groups. Taken together, these data suggest thatinsulin resistance was confined largely to skeletal muscle andthat increased basal rates of peripheral lipolysis and defectsin insulin-induced suppression of lipolysis do not have a majorrole in causing the increased intramyocellular lipid contentin the insulin-resistant subjects.
To assess whether decreased mitochondrial activity may contributeto the increased intramyocellular lipid content, we also assessedthe rates of muscle mitochondrial phosphorylation using 31Pmagnetic resonance spectroscopy. We found that the mitochondrialrates of ATP production were reduced by approximately 30 percentin the muscle of the insulin-resistant subjects, as comparedwith the insulin-sensitive control subjects. Consistent withthis finding of altered mitochondrial function, we also founda reduced ratio of inorganic phosphate to phosphocreatine, whichmay reflect a lower ratio of type I fibers (mostly oxidative)to type II fibers (mostly glycolytic) in the insulin-resistantsubjects.29,30 This finding is consistent with those of a biopsystudy by Nyholm et al., who found an increased number of typeIIb muscle fibers in overweight, insulin-resistant, first-degreerelatives of patients with type 2 diabetes.33 Taken together,these data suggest that the insulin-resistant offspring of patientswith type 2 diabetes have an inherited reduction in mitochondrialcontent in muscle, which in turn may be responsible for thereduced rates of mitochondrial oxidative phosphorylation.
Several studies have also implicated a number of novel adipocyte-derivedfactors in mediating insulin resistance in patients with obesityand in those with type 2 diabetes.17,18,34,35,36,37 To addressthe potential role of resistin, tumor necrosis factor , interleukin-6,and adiponectin in mediating insulin resistance in our insulin-resistantsubjects, we measured the plasma concentrations of these factorsand found no significant differences between the two groups.These data suggest that alterations in plasma concentrationsof these adipocyte-derived factors do not have a major rolein mediating insulin resistance in these persons.
Taken together, our results support the hypothesis that insulinresistance in these young people is due to dysregulation ofintramyocellular fatty acid metabolism, which may be causedby an inherited defect in mitochondrial oxidative phosphorylation.Such a defect might be due to a reduction in mitochondrial content,which in turn might be attributable to a reduced ratio of typeI to type II muscle fibers. These results are similar to thosein lean, elderly, insulin-resistant subjects, whose insulinresistance, in contrast to that in insulin-resistant offspring,is most likely attributable to acquired defects in mitochondrialbiogenesis, which lead to reductions in skeletal-muscle mitochondrialcontent.38 Furthermore, since mitochondria have a critical rolein mediating glucose-induced insulin secretion,39 the presenceof similar inherited defects in beta-cell mitochondrial functionor content, in the setting of peripheral insulin resistance,might explain the increased incidence of diabetes in the insulin-resistantoffspring of patients with type 2 diabetes.5 These data alsoidentify mitochondrial oxidative phosphorylation as a potentialtarget for the prevention and treatment of type 2 diabetes.
In this regard it is of interest that a common Gly482Ser polymorphismof the peroxisome-proliferator–activated receptor coactivator1, a transcriptional regulator of genes responsible for mitochondrialbiogenesis and fat oxidation,40 has been linked to an increasedrelative risk of type 2 diabetes in Danish populations41 aswell as to altered lipid oxidation and insulin secretion inPima Indians.42 In addition, two recent studies involving DNA-microarrayanalysis suggest that there is a coordinated reduction in theexpression of genes encoding peroxisome-proliferator–activatedreceptor coactivator 1, which are involved in oxidative phosphorylation,in the skeletal muscle of overweight patients with type 2 diabetes,43obese Mexican-American patients with type 2 diabetes,44 andoverweight nondiabetic subjects with a family history of diabetes.44
Supported by grants (K23 DK-02347, R01 AG-23686, R01 DK-063192,R01 DK-49230, P30 DK-45735, and M01 RR-00125) from the PublicHealth Service and the Yamanouchi USA Foundation.
We are indebted to Drs. Michael Lehrke and Mitch Lazar for assistancein measuring plasma resistin concentrations; to Dr. James Dziurafor statistical assistance; to Yanna Kosover, Mikhail Smolgovsky,Anthony Romanelli, Aida Groszmann, Andrea Belous, Jonas Lai,Sandra Alfano, and the staff of the Yale–New Haven HospitalGeneral Clinical Research Center for expert technical assistancewith the studies; and to the volunteers for participating inthis study.
Source Information
From the Departments of Internal Medicine (K.F.P., D.B., R.G., G.I.S.) and Cellular and Molecular Physiology (G.I.S.) and the Howard Hughes Medical Institute (S.D., G.I.S.), Yale University School of Medicine, New Haven, Conn.
Address reprint requests to Dr. Shulman at the Howard Hughes Medical Institute, Box 208020, Yale University School of Medicine, 300 Cedar St., S269 CAB, New Haven, CT 06510, or at gerald.shulman{at}yale.edu.
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(2009). Rescuing 3T3-L1 Adipocytes from Insulin Resistance Induced by Stimulation of Akt-Mammalian Target of Rapamycin/p70 S6 Kinase (S6K1) Pathway and Serine Phosphorylation of Insulin Receptor Substrate-1: Effect of Reduced Expression of p85{alpha} Subunit of Phosphatidylinositol 3-Kinase and S6K1 Kinase. Endocrinology
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, interleukin-6, resistin, or adiponectin. 
resonance of ATP and compared with the magnetization of inorganic phosphate at equilibrium in a control spectrum (without irradiation of the 
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