Background Troglitazone decreases insulin resistance and hyperglycemiain patients with non-insulin-dependent diabetes mellitus (NIDDM),but its effects on subjects without diabetes are not known.
Methods We performed oral and intravenous glucose-tolerancetests, studies with the euglycemic-hyperinsulinemic clamp, meal-tolerancetests, and 24-hour blood-pressure measurements at base lineand after the administration of troglitazone, 200 mg orallytwice daily, or placebo for 12 weeks in 18 nondiabetic obesesubjects, 9 of whom had impaired glucose tolerance.
Results The mean (±SD) rates of glucose disposal increasedfrom 4.7 ±1.7 to 6.0 ±1.7 mg per kilogram of bodyweight per minute (P = 0.004) and from 9.0 ±1.8 to 9.9±1.3 mg per kilogram per minute (P = 0.02) during insulininfusions of 40 and 300 mU per square meter of body-surfacearea per minute, respectively, in the troglitazone group. Theinsulin-sensitivity index, calculated from the results of intravenousglucose-tolerance tests, increased from 0.7 ±0.6 x 10-4to 1.6 ±0.9 x 10-4 in subjects given troglitazone, andtheir glycemic response to oral glucose and to mixed meals decreased.The mean fasting plasma insulin concentration decreased by 48percent (P = 0.002), and the plasma insulin response to oralglucose and mixed meals decreased by 40 and 41 percent, respectively.The changes were similar in the subjects with normal glucosetolerance and those with impaired glucose tolerance. Systolicand diastolic blood pressure decreased by 5 ±2 mm Hg(P = 0.05) and 4 ±2 mm Hg (P = 0.04), respectively, aftertreatment with troglitazone. There were virtually no changesin the placebo group.
Conclusions Troglitazone decreases insulin resistance and improvesglucose tolerance in obese subjects with either impaired ornormal glucose tolerance. The ability of troglitazone to reduceinsulin resistance could be useful in preventing NIDDM.
Non-insulin-dependent diabetes mellitus (NIDDM) is likely todevelop in persons with impaired glucose tolerance. The proportionof study subjects in whom the condition progresses to diabetesdepends on their characteristics, the length of follow-up, andthe means of assessment1,2,3,4,5. Insulin resistance is characteristicof impaired glucose tolerance and is a metabolic abnormalitythat precedes the development of glucose intolerance and NIDDM6,7,8,9.In subjects with impaired glucose tolerance, insulin resistanceand hyperinsulinemia are often associated with dyslipidemiaand hypertension,10 and these people also have an increasedrisk of premature atherosclerosis. Since insulin resistanceappears to be central to the etiologic process of this entiresyndrome, treatments that improve the action of insulin couldbe beneficial. Although weight reduction and exercise have sucha beneficial effect, compliance and widespread application areproblematic. Until recently, no drugs for the treatment of insulinresistance were available.
This situation changed with the introduction of a class of drugstermed thiazolidinediones. Troglitazone is a member of thisclass of antidiabetic drugs that improve insulin resistance.Although its exact mechanism of action is unknown, troglitazoneappears to improve the action of insulin in liver, skeletalmuscle, and adipose tissue directly,11,12,13 and it reduceselevated plasma glucose and insulin concentrations in diabeticanimals with hyperinsulinemia12.
The administration of troglitazone to patients with NIDDM improvesboth fasting and postprandial hyperglycemia and insulinemia14.This reduction in hyperglycemia is associated with a near normalizationof the rates of hepatic glucose production and a 40-to-60-percentincrease in insulin-mediated glucose disposal as measured bythe glucose-clamp technique14. In the aggregate, these resultsare consistent with an effect of troglitazone on the insulinresistance of the liver and skeletal muscle. In this study wemeasured a spectrum of metabolic variables in a group of obesesubjects with insulin resistance who did not have diabetes,half of whom had impaired glucose tolerance, before and after12 weeks of treatment with troglitazone or placebo, in a randomizeddouble-blind fashion.
Methods
Study Subjects and Protocol
We studied 18 obese subjects (15 men and 3 women), 9 of whomhad impaired glucose tolerance according to criteria outlinedby the World Health Organization15 -- that is, a fasting plasmaglucose concentration below 140 mg per deciliter (7.8 mmol perliter) and a plasma glucose concentration between 140 and 199mg per deciliter (7.8 and 11.0 mmol per liter) two hours afteran oral-glucose challenge. The characteristics of the subjectsat base line are shown in Table 1. Obesity was defined as abody-mass index (the weight in kilograms divided by the squareof the height in meters) of more than 27; subjects with valuesabove 39 were excluded. Persons with a history or laboratoryevidence of chronic illness were also excluded, as were womenwho were capable of childbearing and persons taking medicationsthat could influence glucose metabolism. The protocol was approvedby the human subjects committee, and all subjects gave writteninformed consent.
Table 1. Base-Line Clinical Characteristics of the Study Subjects.
Starting at least five weeks before the study and then for theduration of the study, the subjects followed a weight-maintainingdiet (28 to 32 kcal per kilogram of body weight) consistingof 50 percent carbohydrate, 35 percent fat, and 15 percent protein.Inpatient meals were prepared under the supervision of the metabolicnutritionist; the outpatient diet was prepared according tospecific instructions given to each subject, and the subjectswere asked to record their food intake at home. Fat-free bodymass was measured by weighing the subjects under water16. Thesubjects received either troglitazone, 200 mg twice daily orally(12 subjects; 7 with impaired glucose tolerance), or placebo(6 subjects; 2 with impaired glucose tolerance) for 12 weeksin accordance with preassigned randomization codes. The pharmacists,investigators, and study subjects were not aware of the treatmentcode, which was broken only after the completion of all analyses.The subjects were seen and examined weekly to monitor theirgeneral well-being and potential adverse reactions. Compliancewas monitored by weekly pill counts. Each subject's dietaryrecords were reviewed weekly by the metabolic nutritionist toensure compliance. Physical activity was maintained at a constantlevel throughout the study, and caloric intake was adjustedas necessary to ensure weight maintenance. Body weight, bloodpressure, fasting plasma glucose concentrations, and serum chemicaland hematologic profiles were determined at each visit.
Base-Line and Final Metabolic Assessments
The subjects were hospitalized for 7 to 10 days for the base-lineand final studies. Blood pressure was recorded continuouslyfor 24 hours with a Spacelabs (Redmond, Wash.) portable recordingsystem. On separate days, in random order, the subjects underwenta standard three-hour oral glucose-tolerance test (75 g), aseven-hour meal-tolerance test (with two identical liquid-formulameals of the same composition as the study diet, each containing33 percent of the daily calories, prepared in the metabolickitchen, which were consumed at 8:30 a.m. and 12:30 p.m.), andan intravenous glucose-tolerance test (300 mg of glucose perkilogram)17. On two other days, in random order, studies withthe euglycemic-hyperinsulinemic clamp in which insulin was infusedat rates of 40 and 300 mU per square meter per minute for atleast 240 minutes were performed as previously described14.Glucose turnover was measured by a concomitant infusion of [3-3H]glucose,with the variable tracer method,18 and calculated with the Steeleequations19. Plasma glucose, insulin, and glucagon concentrationswere measured as described previously14.
Insulin sensitivity was estimated by two methods. The insulin-sensitivityindex represents the ability of endogenous insulin to increasethe disappearance of glucose from the extracellular fluid, bothby inhibiting hepatic glucose production and by stimulatingperipheral glucose use. It is calculated from the plasma insulinand glucose values measured after the intravenous administrationof glucose17. The clamp-derived insulin-sensitivity index isan index of the effect of a change in the plasma insulin concentrationon glucose clearance (the rate of glucose uptake divided bythe plasma glucose concentration) per unit of body-surface area.The index for each subject was calculated with the use of thebasal hepatic glucose output, basal plasma insulin concentrations,the glucose-disposal rate, and mean plasma insulin concentrationsfrom the studies with the euglycemic-hyperinsulinemic clampin which the insulin-infusion rate was 40 mU per square meterper minute. Thus, the clamp-derived insulin-sensitivity index= (GDR/I x G), where GDR (glucose-disposal rate) is expressedin milligrams per square meter per minute, I (insulin) is expressedin microunits per milliliter, and G (glucose) is expressed inmilligrams per deciliter, as previously described20.
Statistical Analysis
Single-variable statistical comparisons were made with pairedt-tests for pretreatment and post-treatment results. The resultsof glucose-tolerance and meal-tolerance tests were subjectedto analysis of variance for repeated measures. The incrementalarea under the curve (for the glucose- and meal-tolerance tests)was calculated by summing the areas of successive trianglesand rectangles under the graph for mean increases above thebasal values. All statistical tests were two-tailed.
Results
The subjects' weights and levels of physical activity did notchange during the study. Troglitazone was well tolerated byall subjects, and none had any subjective side effects or persistentabnormalities in laboratory variables.
The mean fasting plasma glucose concentration decreased slightlyin the troglitazone group and did not change in the placebogroup (Table 2). There was a 48 percent decrease in the meanfasting plasma insulin concentration in the former group (P= 0.002), and no substantial change in the latter. The fastingplasma glucagon concentrations and rates of basal hepatic glucoseoutput did not change substantially in either group.
Table 2. Summary of Metabolic Measurements before and after the Administration of Troglitazone or Placebo for 12 Weeks in Nondiabetic Obese Subjects.
Oral Glucose-Tolerance Tests
For the troglitazone group as a whole, the average base-lineplasma glucose concentrations met the criteria for impairedglucose tolerance, whereas the values were normal after treatment(Figure 1). For example, mean (±SD) values at two hourswere 146 ±25 and 126 ±17 mg per deciliter (8.1±1.4 and 7.0 ±0.9 mmol per liter) before and aftertroglitazone treatment, respectively, and the incremental areaunder the glucose curve decreased by 25 percent. All but oneof the seven subjects in the troglitazone group who had impairedglucose tolerance before treatment had normal glucose toleranceafter treatment. The mean two-hour values in these seven subjectswere 164 ±14 and 131 ±19 mg per deciliter (9.1±0.8 and 7.3 ±1.1 mmol per liter) before and aftertroglitazone treatment, respectively, and the incremental areaunder the curve decreased by 36 percent (P = 0.03). Troglitazonealso reduced plasma insulin concentrations, with a 40 percentdecrease in the incremental area under the curve (P = 0.002)(there was a 48 percent decrease in this variable in the sevensubjects with impaired glucose tolerance; P = 0.008). Therewas no change in either plasma glucose or insulin concentrationsin the placebo group.
Figure 1. Results of Oral Glucose-Tolerance Tests before and after the Administration of Troglitazone or Placebo for 12 Weeks in Obese Subjects without Diabetes.
Values are means ±SE. To convert values for glucose to millimoles per liter, multiply by 0.056. To convert values for insulin to picomoles per liter, multiply by 6.
Meal-Tolerance Tests
The plasma glucose and insulin responses to the two mixed mealsare shown in Figure 2. Treatment with troglitazone resultedin a 24 percent reduction in postprandial plasma glucose concentrations(incremental area under the glucose curve) and an even greaterfall (41 percent, P = 0.006) in plasma insulin concentrations.The plasma glucose and insulin concentrations were virtuallyunchanged in the placebo group. The effect of troglitazone wasgreater among the subjects with impaired glucose tolerance,in whom the area under the glucose curve decreased by 40 percentafter troglitazone therapy. Plasma free fatty acid and glucagonconcentrations did not change in either group.
Figure 2. Results of Meal-Tolerance Tests before and after the Administration of Troglitazone or Placebo for 12 Weeks in Obese Subjects without Diabetes.
Values are means ±SE. To convert values for glucose to millimoles per liter, multiply by 0.056. To convert values for insulin to picomoles per liter, multiply by 6.
Measurements of Insulin Resistance
The results of the glucose-clamp studies are shown in Figure 3.At infusion rates of both 40 and 300 mU of insulin per squaremeter per minute, there was a significant increase in the rateof glucose disposal in the group given troglitazone. At thelower (and more physiologic) rate of insulin infusion, the meanrate of glucose disposal increased from 4.7 ±1.7 to 6.0±1.7 mg per kilogram per minute (P = 0.004); 10 of 12subjects had increased values. At the higher rate of insulininfusion, the rate of glucose disposal increased from 9.0 ±1.8to 9.9 ±1.3 mg per kilogram per minute (P = 0.02). Therewere virtually no changes in the placebo group. The values forthe clamp-derived insulin-sensitivity index, which approximatethe slope of the effect of this range of insulinemia (from basalconcentrations to concentrations of approximately 90 micro Uper milliliter [approximately 540 pmol per liter]) in stimulatingglucose disposal, increased from 1.6 to 2.8 (P = 0.007) aftertroglitazone treatment (the increase was more than twofold inthe subgroup with impaired glucose tolerance but did not changein the placebo group). The values for the insulin-sensitivityindex as calculated from the results of the intravenous glucose-tolerancetest17 more than doubled, from 0.7 ±0.6 x 10-4 to 1.6±0.9 x 10-4 (P = 0.002), in the troglitazone group (Figure 3);10 of the 12 subjects had improved values. There was a smallbut not statistically significant decrease in the placebo group.
Figure 3. Measurements of Insulin Resistance before and after the Administration of Troglitazone or Placebo for 12 Weeks in Obese Subjects without Diabetes.
Values are means ±SE. Panel A shows the results of studies with the euglycemic-hyperinsulinemic clamp in which insulin was infused at a rate of 40 mU per square meter per minute. Panel B shows the results of studies with the euglycemic-hyperinsulinemic clamp in which insulin was infused at a rate of 300 mU per square meter per minute. Panel C shows the values for the insulin-sensitivity index as calculated from basal values and values measured during the studies with the euglycemic-hyperinsulinemic clamp in which insulin was infused at a rate of 40 mU per square meter per minute. Panel D shows the values for the insulin-sensitivity index as calculated from the results of intravenous glucose-tolerance tests.
Blood Pressure and Plasma Lipid Concentrations
Troglitazone treatment was associated with a statistically significantreduction in systolic blood pressure of 5 ±2 mm Hg (P= 0.05) and in diastolic blood pressure of 4 ±2 mm Hg(P = 0.04) (Table 2). There was an increase in systolic bloodpressure in the placebo group. The mean plasma low-density lipoproteincholesterol, high-density lipoprotein cholesterol, and triglycerideconcentrations at base line were similar in both groups, andthe values did not change substantially in either group.
Discussion
A 12-week course of treatment with troglitazone in a group ofnondiabetic subjects with insulin resistance decreased insulininsensitivity, glucose intolerance, hyperinsulinemia, and hypertension.These abnormalities have been reported as potential risk factorsfor the development of cardiovascular disease10. Our resultssuggest that primary treatment of insulin resistance may improvethe overall risk profile for cardiovascular disease.
These results are consistent with the reported effects of troglitazonein vitro and in animals. Thus, although its exact mechanismof action is unknown, this drug works directly on skeletal muscle,liver, and adipose tissue to potentiate the action of insulin13.It also has potent glucose- and insulin-reducing effects andreduces insulin resistance in diabetic animals with hyperinsulinemia12.Treating patients with NIDDM with troglitazone reduces hyperglycemia,hyperinsulinemia, and hypertriglyceridemia and improves insulinsensitivity11,14.
The measures of insulin resistance we used did not all showthe same degree of improvement. For example, after troglitazonetreatment the increase in glucose disposal during the glucose-clampstudy in which a high dose of insulin was infused was not asgreat as the increase during the study in which a lower doseof insulin was infused. This finding is fully consistent withour previous observations that impaired glucose tolerance ischaracterized by decreased insulin sensitivity with little changein insulin responsiveness21. In other words, insulin resistanceis manifested at physiologic plasma insulin concentrations,with a normal response to pharmacologic concentrations. Treatmentthat improves the insulin resistance in subjects with impairedglucose tolerance would therefore have its greatest effect atphysiologic insulin concentrations. The results of the calculationsof insulin sensitivity support this conclusion. In both tests,which measure insulin sensitivity over the physiologic rangeof insulin concentrations, troglitazone treatment was associatedwith an even greater improvement in this index than in glucosedisposal. Although the exact cellular mechanisms causing insulinresistance in the type of subjects we studied are not known,our results suggest that troglitazone exerts its effects ata cellular site relevant to the basic defect in these subjects.
Oral glucose tolerance was improved after troglitazone treatment;the mean postprandial plasma glucose concentrations decreased,as did the concentrations measured during glucose-tolerancetests. Predictably, this improvement was greatest in the subjectswhose glucose values were highest initially; six of seven subjectswith impaired glucose tolerance had normal glucose toleranceafter troglitazone treatment.
It has been proposed that insulin resistance, hyperinsulinemia,or both can cause hypertension in some subjects, but the mechanismsare poorly understood10. Our results, showing that troglitazone,a drug that improves the action of insulin, can also lower bloodpressure, strengthen the association between the syndrome ofinsulin resistance and hypertension.
The fact that troglitazone can improve insulin resistance, lowerplasma insulin concentrations, and normalize glucose tolerancein subjects with impaired glucose tolerance could have implicationsfor the prevention of NIDDM. Insulin resistance is a primarymetabolic defect in most patients with NIDDM6,7,8,9. Thus, insulinresistance and hyperinsulinemia are present many years beforeglucose tolerance deteriorates6,7. Acquired factors, such asobesity, a sedentary lifestyle, and aging, may be contributory,but insulin resistance is probably a primary inherited featurein most patients with NIDDM. In the presence of normal beta-cellfunction, this will lead to hyperinsulinemia but relativelynormal glucose tolerance9. Thus, in the compensated insulin-resistant,hyperinsulinemic state one has either normal glucose toleranceor impaired glucose tolerance, but not diabetes. In patientsin whom diabetes develops, the process of compensatory hyperinsulinemiaeventually fails and beta-cell function declines, leading tohyperglycemia. Therefore, interventions that might ameliorateinsulin resistance in the prediabetic state could be of potentialbenefit in preventing the development of NIDDM, assuming thatthe agents' effects on insulin resistance would be sustainedduring prolonged periods of treatment.
In summary, treatment of nondiabetic obese subjects who haveinsulin resistance with the new antidiabetic agent troglitazonedecreases insulin resistance, reduces hyperinsulinemia, improvesglucose tolerance, and reduces both systolic and diastolic bloodpressure.
Supported in part by a grant from the National Institutes ofHealth (DK 33651), a grant from the General Clinical ResearchCenters of the National Institutes of Health (MO1 RR00827),and a grant from the Sankyo Pharmaceutical Company. Dr. Ludvikis a recipient of a Max-Kade Foundation Postdoctoral FellowshipAward.
Dr. Olefsky is a consultant to Parke Davis Company, which holdsthe license for troglitazone in the United States.
We are indebted to the staff of the Special Diagnostic and TreatmentUnit at the San Diego Veterans Affairs Medical Center, to Ms.Elizabeth Hansen for assistance in the preparation of the manuscript,to Ms. Reena Deutsch for statistical advice, and to the studyparticipants, who gave generously of their time and energy.
Source Information
From the Department of Medicine, University of California, San Diego, Division of Endocrinology and Metabolism, La Jolla (J.J.N., B.L., P.B., J.O.), and the Veterans Affairs Medical Center, San Diego, Calif. (M.J.).
Address reprint requests to Dr. Olefsky at the Division of Endocrinology and Metabolism, 9111-G, University of California, San Diego, La Jolla, CA 92093.
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Hull, R. L., Westermark, G. T., Westermark, P., Kahn, S. E.
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(2004). Transcriptional Activity of Peroxisome Proliferator-activated Receptor {gamma} Is Modulated by SUMO-1 Modification. J. Biol. Chem.
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Snitker, S., Watanabe, R. M., Ani, I., Xiang, A. H., Marroquin, A., Ochoa, C., Goico, J., Shuldiner, A. R., Buchanan, T. A.
(2004). Changes in Insulin Sensitivity in Response to Troglitazone Do Not Differ Between Subjects With and Without the Common, Functional Pro12Ala Peroxisome Proliferator-Activated Receptor-{gamma}2 Gene Variant: Results from the Troglitazone in Prevention of Diabetes (TRIPOD) study . Diabetes Care
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Baek, S. J., Kim, J.-S., Nixon, J. B., DiAugustine, R. P., Eling, T. E.
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Kumagai, T., Ikezoe, T., Gui, D., O'Kelly, J., Tong, X.-J., Cohen, F. J., Said, J. W., Koeffler, H. P.
(2004). RWJ-241947 (MCC-555), A Unique Peroxisome Proliferator-Activated Receptor-{gamma} Ligand with Antitumor Activity against Human Prostate Cancer in Vitro and in Beige/Nude/ X-Linked Immunodeficient Mice and Enhancement of Apoptosis in Myeloma Cells Induced by Arsenic Trioxide. Clin. Cancer Res.
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Hsueh, W. A., Bruemmer, D.
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Cho, D.-H., Choi, Y. J., Jo, S. A., Jo, I.
(2004). Nitric Oxide Production and Regulation of Endothelial Nitric-oxide Synthase Phosphorylation by Prolonged Treatment with Troglitazone: EVIDENCE FOR INVOLVEMENT OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) {gamma}-DEPENDENT AND PPAR{gamma}-INDEPENDENT SIGNALING PATHWAYS. J. Biol. Chem.
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Levin, K., Hother-Nielsen, O., Henriksen, J. E., Beck-Nielsen, H.
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(2003). Adipose-specific peroxisome proliferator-activated receptor {gamma} knockout causes insulin resistance in fat and liver but not in muscle. Proc. Natl. Acad. Sci. USA
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Muller, Y. L., Bogardus, C., Beamer, B. A., Shuldiner, A. R., Baier, L. J.
(2003). A Functional Variant in the Peroxisome Proliferator-Activated Receptor {gamma}2 Promoter Is Associated With Predictors of Obesity and Type 2 Diabetes in Pima Indians. Diabetes
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Romualdi, D., Guido, M., Ciampelli, M., Giuliani, M., Leoni, F., Perri, C., Lanzone, A.
(2003). Selective effects of pioglitazone on insulin and androgen abnormalities in normo- and hyperinsulinaemic obese patients with polycystic ovary syndrome. Hum Reprod
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Chapelsky, M. C., Thompson-Culkin, K., Miller, A. K., Sack, M., Blum, R., Freed, M. I.
(2003). Pharmacokinetics of Rosiglitazone in Patients with Varying Degrees of Renal Insufficiency. J Clin Pharmacol
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(2003). Troglitazone, a Peroxisome Proliferator-activated Receptor gamma (PPARgamma ) Ligand, Selectively Induces the Early Growth Response-1 Gene Independently of PPARgamma . A NOVEL MECHANISM FOR ITS ANTI-TUMORIGENIC ACTIVITY. J. Biol. Chem.
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Paradisi, G., Steinberg, H. O., Shepard, M. K., Hook, G., Baron, A. D.
(2003). Troglitazone Therapy Improves Endothelial Function to Near Normal Levels in Women with Polycystic Ovary Syndrome. J. Clin. Endocrinol. Metab.
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Andrews, R. C., Rooyackers, O., Walker, B. R.
(2003). Effects of the 11{beta}-Hydroxysteroid Dehydrogenase Inhibitor Carbenoxolone on Insulin Sensitivity in Men with Type 2 Diabetes. J. Clin. Endocrinol. Metab.
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Wagner, J. A.
(2002). Early Clinical Development of Pharmaceuticals for Type 2 Diabetes Mellitus: From Preclinical Models to Human Investigation. J. Clin. Endocrinol. Metab.
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Willi, S. M., Kennedy, A., Wallace, P., Ganaway, E., Rogers, N. L., Garvey, W. T.
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(2002). Troglitazone Treatment Increases Protein Kinase B Phosphorylation in Skeletal Muscle of Normoglycemic Subjects at Risk for the Development of Type 2 Diabetes. Diabetes
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(2002). Peroxisome Proliferator-activated Receptor gamma Agonists Inhibit HIV-1 Replication in Macrophages by Transcriptional and Post-transcriptional Effects. J. Biol. Chem.
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(2002). Induction of Adipocyte Complement-Related Protein of 30 Kilodaltons by PPAR{gamma} Agonists: A Potential Mechanism of Insulin Sensitization. Endocrinology
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Arima, S., Kohagura, K., Takeuchi, K., Taniyama, Y., Sugawara, A., Ikeda, Y., Abe, M., Omata, K., Ito, S.
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Inzucchi, S. E.
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(2001). PPAR{gamma}/RXR{alpha} Heterodimers Control Human Trophoblast Invasion. J. Clin. Endocrinol. Metab.
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Yokoyama, I., Yonekura, K., Moritan, T., Tateno, M., Momose, T., Ohtomo, K., Inoue, Y., Nagai, R.
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(2001). Pioglitazone Ameliorates Tumor Necrosis Factor-{alpha}-Induced Insulin Resistance by a Mechanism Independent of Adipogenic Activity of Peroxisome Proliferator-Activated Receptor-{gamma}. Diabetes
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Yonemitsu, S., Nishimura, H., Shintani, M., Inoue, R., Yamamoto, Y., Masuzaki, H., Ogawa, Y., Hosoda, K., Inoue, G., Hayashi, T., Nakao, K.
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Chen, Z., Ishibashi, S., Perrey, S., Osuga, J.-i., Gotoda, T., Kitamine, T., Tamura, Y., Okazaki, H., Yahagi, N., Iizuka, Y., Shionoiri, F., Ohashi, K., Harada, K., Shimano, H., Nagai, R., Yamada, N.
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