Original Article
Effect of Troglitazone in Insulin-Treated Patients with Type II Diabetes Mellitus
N Engl J Med 1998; 338:861-866March 26, 1998
- Abstract
Background
Troglitazone is a new oral antidiabetic drug that increases the sensitivity of peripheral tissues to insulin. It may therefore increase the efficacy of exogenous insulin in patients with insulin-resistant diabetes mellitus.
Methods
We studied the effect of troglitazone or placebo in 350 patients with poorly controlled non-insulin-dependent (type II) diabetes mellitus (glycosylated hemoglobin values, 8 to 12 percent; normal, 4.3 to 6.1 percent) despite therapy with at least 30 U of insulin daily. The patients were randomly assigned to receive 200 mg of troglitazone (116 patients), 600 mg of troglitazone (116 patients), or placebo (118 patients) daily for 26 weeks. Insulin doses were not increased and were reduced only to prevent hypoglycemia. Glycosylated hemoglobin, serum glucose while fasting, serum total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides were measured 5 times during an 8-week base-line period and 10 times during the 26-week treatment period. Daily insulin doses were recorded during both periods.
Results
Ninety percent of the patients completed the study. The adjusted mean glycosylated hemoglobin values decreased by 0.8 and 1.4 percentage points, respectively, in the group given 200 mg of troglitazone and the group given 600 mg of troglitazone, and fasting serum glucose concentrations decreased by 35 and 49 mg per deciliter (1.9 and 2.7 mmol per liter), respectively, despite decreases in the insulin dose of 11 percent and 29 percent (P<0.001 for all comparisons with the placebo group). Serum total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol concentrations increased slightly and serum triglyceride concentrations decreased slightly in the troglitazone-treated patients.
Conclusions
When given in conjunction with insulin, troglitazone improves glycemic control in patients with type II diabetes mellitus.
Media in This Article
Figure 1
Mean Glycosylated Hemoglobin Values in Patients with Type II Diabetes during the Base-Line Period and during Treatment with Troglitazone or Placebo.Figure 2
Mean Serum Glucose Concentrations during Fasting in Patients with Type II Diabetes during the Base-Line Period and during Treatment with Troglitazone or Placebo.Article Activity
- Article
Treatment for patients with non-insulin-dependent (type II) diabetes mellitus consists of reducing hyperglycemia through diet, exercise, and therapy with drugs or insulin.1 The longer diabetes has been present, the more likely patients are to require insulin to control their hyperglycemia.2,3 Despite insulin treatment, however, hyperglycemia in these patients is often not well controlled.2
The thiazolidinediones are a class of compounds that reduce insulin resistance in animals with hyperglycemia and hyperinsulinemia.4-8 These drugs have antihyperglycemic effects only in the presence of insulin9 and do not cause hypoglycemia in nondiabetic animals.9,10 In humans, administration of the thiazolidinedione troglitazone increased insulin-stimulated glucose disposal in obese subjects and patients with type II diabetes, demonstrating its ability to ameliorate insulin resistance.11,12 It also normalized impaired glucose tolerance, thus demonstrating the potential to delay or prevent the progression of impaired glucose tolerance to diabetes13; furthermore, in preliminary studies in patients with type II diabetes, troglitazone reduced hyperglycemia and hyperinsulinemia without causing hypoglycemia.11,14,15 We conducted this trial to evaluate the ability of troglitazone to improve glycemic control, as reflected primarily in changes in glycosylated hemoglobin values and fasting serum glucose concentrations, in patients who had poorly controlled type II diabetes despite insulin therapy.
Methods
Study Subjects
A total of 350 patients with type II diabetes were studied. Patients were eligible for the study if they were 18 to 72 years of age, had had diabetes for less than 20 years, were receiving at least 30 U of insulin per day, and had serum glucose concentrations above 140 mg per deciliter (7.8 mmol per liter) while fasting, a glycosylated hemoglobin value between 8.0 and 12.0 percent, and residual insulin secretory capacity as defined by a fasting serum C-peptide concentration of at least 0.8 ng per milliliter (0.3 nmol per liter). The study was conducted at 22 sites in the United States in accordance with the regulatory guidelines of the Food and Drug Administration. The protocol was approved by the institutional review board at each site, and all patients gave written informed consent.
Study Design
The study was divided into three phases: a 2-week screening period; an 8-week single-blind, placebo base-line period; and a 26-week double-blind, randomized comparison of troglitazone and placebo. Patients could enter the trial if they met the fasting serum glucose and glycosylated hemoglobin criteria on either of two assessments during the screening period. Patients were given recommendations for a weight-maintenance diet during this period. After completing the base-line period, the patients were randomly assigned to receive placebo, 200 mg of troglitazone, or 600 mg of troglitazone, each given once daily. The investigators were instructed not to change the insulin doses unless patients had a fasting serum glucose concentration below 90 mg per deciliter (5.0 mmol per liter) at one office visit, a concentration of 90 to 109 mg per deciliter (5.0 to 6.1 mmol per liter) on two consecutive office visits, or a concentration of less than 100 mg per deciliter (5.6 mmol per liter) on two consecutive days during self-monitoring at home. Investigators could then change insulin doses according to their clinical judgment.
Dietary Recommendations
Dietary recommendations, provided by a registered dietitian, were based on the Harris–Benedict equation for calculating basal energy expenditure in kilocalories per day16 and were consistent with the recommendations of the American Diabetes Association.17 The recommended caloric intake was 1.3 times the basal energy expenditure. In calculating this value for patients with a body-mass index of more than 24 (expressed as the weight in kilograms divided by the square of the height in meters), an adjusted body weight ([actual weight - ideal weight] × 0.25 + ideal weight) was used. Dietary compliance was assessed during the study by interviews with the patients.
Evaluation of Efficacy
Glycosylated hemoglobin and fasting serum glucose, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides were measured at 5 visits during the base-line period and 10 visits during the treatment period. Glycosylated hemoglobin was measured by high-performance liquid chromatography with the Bio-Rad Variant analyzer with an intraassay coefficient of variation of 1.2 percent (normal range, 4.3 to 6.1 percent). Fasting serum glucose was measured by the hexokinase method with a Boehringer Mannheim Hitachi automated analyzer. Serum total cholesterol and triglycerides were measured by enzymatic methods with the same automated analyzer. Serum HDL cholesterol was isolated by chemical precipitation and then measured in the same way as total cholesterol. Serum LDL cholesterol was calculated (when the triglyceride value was less than 400 mg per deciliter [4.5 mmol per liter]) with the equation of Friedewald et al.18 All analyses were performed at a central laboratory.
All patients received a Life-Scan One-Touch II glucose meter and were asked to measure fasting capillary-blood glucose at least three times per week and when they had symptoms of hypoglycemia. The results were stored in the meter and downloaded at each visit. The patients recorded the time, amount, and type of each insulin dose on diary cards.
Safety Evaluations
Safety was monitored by assessing symptoms, changes in findings on physical examination (performed by the investigators), 12-lead electrocardiograms, and the results of clinical laboratory tests (hemogram, serum-chemistry panel including liver-function tests, and urinalysis) during the base-line period and at each follow-up visit.
Statistical Analysis
The analyses of efficacy were performed according to the intention-to-treat method and included all patients who received at least one dose of troglitazone or placebo and had at least one follow-up visit. The last observations for patients were carried forward to impute missing values. The safety analyses also included all patients.
Statistical analyses were performed with SAS software, version 6.09. The homogeneity of treatment groups was assessed with Cochran–Mantel–Haenzsel and Fisher's exact tests and F tests as appropriate. Changes from base line (the average of the five measurements during the eight-week base-line period) in glycosylated hemoglobin values and fasting serum glucose, total cholesterol, HDL cholesterol, LDL cholesterol, and triglyceride concentrations were analyzed by analysis of covariance with treatment and study center as factors and the base-line value as the covariate. We compared each troglitazone group with placebo at the midpoint of the study (average of weeks 10 and 12) and at the completion of the study (average of weeks 24 and 26) by performing step-down tests for linear trend.19 Similarly, average daily insulin doses during the last two weeks of the base-line period were compared with the average daily doses between weeks 10 and 12 and weeks 24 and 26. Statistical tests for glycemic end points, lipid measurements, and insulin doses were two-sided. Exploratory analyses to investigate the effect of age, sex, and race were also conducted with analysis of covariance, with center and treatment as factors and the base-line value as the covariate.
Results
Characteristics of the Treatment Groups
The base-line demographic and disease-related characteristics and the degree of glycemic control were similar in the three treatment groups (Table 1Table 1
Base-Line Characteristics of the Patients with Type II Diabetes Mellitus Treated with Troglitazone or Placebo.). Eighty-seven percent of the patients were taking intermediate-acting and short-acting insulin twice daily. Eighty-five percent of the patients took their assigned study medication for 24 or more weeks of the planned 26-week study. A total of 314 of the 350 patients (90 percent) completed the study.Glycemic Control
The mean glycosylated hemoglobin values, fasting serum glucose concentrations, and daily insulin doses during the study are shown in Figure 1Figure 1
Mean Glycosylated Hemoglobin Values in Patients with Type II Diabetes during the Base-Line Period and during Treatment with Troglitazone or Placebo., 2, and 3, respectively. In the troglitazone groups, the glycosylated hemoglobin values reached a nadir at about 16 weeks (Figure 1), whereas fasting serum glucose values reached a nadir at 4 to 8 weeks (Figure 2Figure 2Mean Serum Glucose Concentrations during Fasting in Patients with Type II Diabetes during the Base-Line Period and during Treatment with Troglitazone or Placebo.). The decreases in glycosylated hemoglobin values, fasting serum glucose concentrations, and insulin doses were dose-related and were statistically significant for both troglitazone groups as compared with the placebo group (P<0.001) at both the midpoint and the end of the study (Table 2Table 2
Adjusted Mean Changes from Base Line in Glycosylated Hemoglobin Values, Fasting Serum Glucose Concentrations, and Daily Insulin Dose after 24 to 26 Weeks of Troglitazone Therapy in Patients with Type II Diabetes.). The reductions in glycosylated hemoglobin values and fasting serum glucose concentrations in the troglitazone groups occurred while insulin doses were decreasing. In contrast, the insulin dose in the placebo group did not change (Figure 3Figure 3
Mean Daily Insulin Dose in Patients with Type II Diabetes during the Base-Line Period and during Treatment with Troglitazone or Placebo.). The dose-related effect of troglitazone was similar in men and women and among patients of different ages and racial or ethnic groups (data not shown).Serum Lipid Concentrations
Serum total cholesterol, LDL cholesterol, and HDL cholesterol concentrations increased slightly during treatment in the troglitazone groups (Table 3Table 3
Mean Serum Cholesterol and Triglyceride Concentrations at Base Line and after 24 to 26 Weeks of Troglitazone Therapy in Patients with Type II Diabetes.). The mean serum triglyceride concentrations decreased slightly in all groups.Body Weight
The mean weights at base line, week 8, week 16, and week 26 were 100.5, 100.5, 100.5, and 102.0 kg, respectively, in the placebo group; 98.6, 99.5, 100, and 100.5 kg in the group given 200 mg of troglitazone; and 100.9, 103.2, 104.5, and 104.5 kg in the group given 600 mg of troglitazone. The small increases in body weight at 26 weeks in the troglitazone groups were statistically significant (P< 0.001) as compared with the placebo group.
Adverse Events
Troglitazone was well tolerated. Overall, the incidence and types of adverse events were similar in all three groups, with 94 percent of patients in the combined troglitazone groups and 97 percent of patients in the placebo group reporting at least one adverse event.
Symptoms of hypoglycemia occurred in 41 percent of the patients in the placebo group, 45 percent of those given 200 mg of troglitazone, and 62 percent of those given 600 mg of troglitazone and were associated with concurrent capillary-blood glucose readings of <50 mg per deciliter (2.8 mmol per liter) in 8 percent, 14 percent, and 23 percent of the patients in the respective groups. Of the entire capillary-blood glucose data base of over 30,000 measurements per group, only 0.21 percent of the values in the placebo group were <50 mg per deciliter; the respective values in the group treated with 200 mg of troglitazone and the group treated with 600 mg of troglitazone were 0.26 percent and 0.53 percent. The hypoglycemic events tended to occur early in the course of troglitazone treatment and decreased in frequency after the insulin dose was reduced: 33 episodes and 30 episodes of symptomatic hypoglycemia were reported during the first two weeks of treatment in the group given 200 mg of troglitazone and the group given 600 mg of troglitazone, respectively, as compared with reports of 14 episodes and 17 episodes in the same two groups during the last two weeks of treatment. Except in one patient who lost consciousness and was treated with intravenous glucose, all episodes of symptomatic hypoglycemia were successfully treated with food or glucose tablets. No patient was withdrawn from the study because of hypoglycemic symptoms.
In the group given 600 mg of troglitazone, the mean red-cell count, hematocrit, and hemoglobin values decreased by 5 percent, 5 percent, and 4 percent, respectively, but the values remained within the normal range. These decreases occurred soon after treatment was begun; thereafter, the mean values did not change, and in most patients the values subsequently increased. The values did not change significantly in the other two groups.
Eight patients (two in the group given 200 mg of troglitazone, three in the group given 600 mg of troglitazone, and three in the placebo group) had serum aminotransferase concentrations that were more than three times the upper limit of the normal range during the 26-week treatment period. Treatment was discontinued in two of the patients in the group treated with 600 mg of troglitazone, because of jaundice and hyperbilirubinemia in one (the patient subsequently recovered) and because of concomitant congestive heart failure in the other. The serum aminotransferase concentrations returned to normal in the third patient in this group during continued therapy. The concentrations returned to normal in the two patients in the group treated with 200 mg of troglitazone after therapy was interrupted. In the three patients in the placebo group, serum aminotransferase concentrations subsequently returned to base-line values without interruption of treatment.
Withdrawal Due to Adverse Events
Five patients in the placebo group, one in the group given 200 mg of troglitazone, and six in the group given 600 mg of troglitazone were withdrawn from the study because of adverse events. The causes of withdrawal were stroke, metabolic myopathy, unintended pregnancy, transient ischemic attack, and exacerbation of depression in the placebo group; myocardial infarction two days before drug treatment was begun in the group given 200 mg of troglitazone; and myocardial infarction, coronary artery disease, congestive heart failure, forgetfulness and lack of concentration, exacerbation of gastric reflux, and jaundice and hyperbilirubinemia in the group given 600 mg of troglitazone.
Discussion
Chronic hyperglycemia in patients with type II diabetes occurs because of resistance to the action of insulin and decreases in insulin secretion. Insulin resistance is a prominent feature, if not the primary defect, in these patients; in some of them insulin-stimulated uptake of glucose is decreased by 60 to 80 percent.20 The results of prospective epidemiologic studies indicate that insulin resistance is detectable before glucose tolerance deteriorates.21-26
Patients with type II diabetes are often treated according to a stepped progression, starting with a regimen of nutrition and exercise and progressing to therapy with a sulfonylurea drug, metformin, or acarbose, alone or in combination. These therapies are often ineffective, and up to 60 percent of patients eventually require insulin,2 often in high doses.
In our study of patients with poorly controlled type II diabetes who were receiving insulin therapy, troglitazone resulted in a significant dose-related decrease in glycosylated hemoglobin values and fasting serum glucose concentrations. The effect of troglitazone on fasting serum glucose concentrations was evident within 4 weeks after treatment was begun and its effect on glycosylated hemoglobin values was maximal at 16 weeks, and the improvement was sustained for the remainder of the study. This improvement occurred despite decreases in the insulin dose of 11 percent in the group given 200 mg of troglitazone and 29 percent in the group given 600 mg of troglitazone. Our study, as well as smaller studies of patients with type II diabetes treated with troglitazone alone, thus demonstrates a significant antihyperglycemic effect of troglitazone.14,15 The 1.4 percent absolute decline in glycosylated hemoglobin values in the group treated with 600 mg of troglitazone represents a decline of approximately 15 percent from the base-line value. If we assume that data from the Diabetes Control and Complications Trial (DCCT) are applicable to patients with type II diabetes, this 15 percent decline translates to a reduction in the risk of progression of diabetic retinopathy of approximately 60 percent.27
We did not study the possibility that an increase in the insulin dose or a change in the insulin regimen to multiple injections of insulin (as in the intensive treatment regimen used in the DCCT) would have improved glycemic control in these patients. However, in most patients in the United States with type II diabetes who are treated with insulin, the disease remains uncontrolled despite the use of large insulin doses.2
Troglitazone was well tolerated, and most adverse events were considered to be related to the underlying diabetes. Several patients had abnormalities in liver function, but therapy was permanently discontinued for this reason in only one patient.
Most of the patients were obese, with a base-line mean body-mass index of about 35. The troglitazone-treated patients had small dose-related increases in body weight. They were instructed to follow a weight-maintenance diet, rather than a weight-reduction diet, so that any improvement in glycemic control induced would not be confounded by the effects of weight loss.
The ratio of serum HDL cholesterol to total cholesterol, a marker of cardiovascular risk, did not change in the patients — the troglitazone-associated increase in serum HDL cholesterol concentrations offset an increase in serum total cholesterol concentrations. Serum triglyceride concentrations decreased slightly in the patients who were treated with troglitazone.
We conclude that the administration of troglitazone results in sustained improvement in glycemic control when given as an adjunct to insulin therapy in patients with type II diabetes. These results are consonant with the findings of physiologic studies that troglitazone increases the sensitivity of peripheral tissues to insulin.
Supported by Sankyo U.S.A., New York, and Parke-Davis Pharmaceutical Research, Division of Warner-Lambert, Ann Arbor, Mich. Drs. Schwartz, Raskin, and Fonseca have served as consultants for Parke-Davis.
Source Information
From the Diabetes and Glandular Diseases Clinic, San Antonio, Tex. (S.S.); the University of Texas Southwestern Medical School, Dallas (P.R.); the University of Arkansas for Medical Sciences and John L. McClellan Memorial Veterans' Hospital, Little Rock (V.F.); and Sankyo U.S.A., New York (J.F.G.).
Address reprint requests to Ms. Graveline at Sankyo U.S.A., 780 Third Ave., Suite 4700, New York, NY 10017.
The other members of the Troglitazone and Exogenous Insulin Study Group are listed in the Appendix.
Appendix
In addition to the authors, the Troglitazone and Exogenous Insulin Study Group includes the following investigators: T. Blevins, Austin, Tex.; J. Blodgett, San Antonio, Tex.; P. Dandona, Buffalo, N.Y.; B. Draznin, Denver; J. Drucker and S. Plevin, Palm Harbor, Fla.; L. Fish, Minneapolis; B. Francis, Seattle; R. Guthrie, New Orleans; B. Haag, Springfield, Mass.; B. Henson, Kansas City, Mo.; J. Levine, Nashville; W. Mitchell, Albuquerque, N.M.; W. Nicholas, Jackson, Miss.; M. Nolte, San Francisco; S. Pek, Ann Arbor, Mich.; A. Peters and M. Davidson, Los Angeles; P. Ross, Fairfax, Va.; R. Suwannasri, St. Louis; and R. Teague, Birmingham, Ala.
- References
References
1
American Diabetes Association
Web of Science2
Klein R ,Klein BE ,Moss SE ,Cruickshanks KJ . The medical management of hyperglycemia over a 10-year period in people with diabetes. Diabetes Care 1996;19:744-750
CrossRef | Web of Science | Medline3
Henry RR ,Gumbiner B ,Ditzler T ,Wallace P ,Lyon R ,Glauber HS . Intensive conventional insulin therapy for type II diabetes: metabolic effects during a 6-mo outpatient trial. Diabetes Care 1993;16:21-31
CrossRef | Web of Science | Medline4
Fujita T ,Sugiyama Y ,Taketomi S , et al. Reduction of insulin resistance in obese and/or diabetic animals by 5-[-4-(1-methylcyclohexylmethoxy)benzyl]-thiazolidine-2,4-dione (ADD-3878, U-63,287, ciglitazone), a new antidiabetic agent. Diabetes 1983;32:804-810
CrossRef | Web of Science | Medline5
Fujiwara T ,Yoshioka S ,Yoshioka T , et al. Characterization of new oral antidiabetic agent CS-045: studies in KK and ob/ob mice and Zucker fatty rats. Diabetes 1988;37:1549-1558
CrossRef | Web of Science | Medline6
Stevenson RW ,Hutson NJ ,Krupp MN , et al. Actions of novel antidiabetic agent englitazone in hyperglycemic hyperinsulinemic ob/ob mice. Diabetes 1990;39:1218-1227
CrossRef | Web of Science | Medline7
Lee MK ,Miles PDG ,Khoursheed M ,Gao KM ,Moossa AR ,Olefsky JM . Metabolic effects of troglitazone on fructose-induced insulin resistance in the rat. Diabetes 1994;43:1435-1439
CrossRef | Web of Science | Medline8
Khoursheed M ,Miles PDG ,Gao KM ,Lee MK ,Moossa AR ,Olefsky JM . Metabolic effects of troglitazone on fat-induced insulin resistance in the rat. Metabolism 1995;44:1489-1494
CrossRef | Web of Science | Medline9
Tominaga M ,Igarashi M ,Daimon M , et al. Thiazolidinediones (AD-4833 and CS-045) improve hepatic insulin resistance in streptozotocin-induced diabetic rats. Endocr J 1993;40:343-349
CrossRef | Web of Science | Medline10
Stevenson RW ,McPherson RK ,Genereux BE ,Danbury BH ,Kreutter DK . Antidiabetic agent englitazone enhances insulin action in nondiabetic rats without producing hypoglycemia. Metabolism 1991;40:1268-1274
CrossRef | Web of Science | Medline11
Suter SL ,Nolan JJ ,Wallace P ,Gumbiner B ,Olefsky JM . Metabolic effects of new oral hypoglycemic agent CS-045 in NIDDM subjects. Diabetes Care 1992;15:193-203
CrossRef | Web of Science | Medline12
Nolan JJ ,Ludvik B ,Beerdsen P ,Joyce M ,Olefsky J . Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 1994;331:1188-1193
Full Text | Web of Science | Medline13
Antonucci T ,Whitcomb R ,McLain R ,Lockwood D . Impaired glucose tolerance is normalized by treatment with the thiazolidinedione troglitazone. Diabetes Care 1997;20:188-193
CrossRef | Web of Science | Medline14
Kuzuya T ,Iwamoto Y ,Kosaka K , et al. A pilot clinical trial of a new oral hypoglycemic agent, CS-045, in patients with non-insulin dependent diabetes mellitus. Diabetes Res Clin Pract 1991;11:147-153
CrossRef | Web of Science | Medline15
Iwamoto Y ,Kuzuya T ,Matsuda A , et al. Effect of new oral antidiabetic agent CS-045 on glucose tolerance and insulin secretion in patients with NIDDM. Diabetes Care 1991;11:1083-1086
CrossRef | Web of Science16
Howard LJ. Parenteral and enteral nutrition therapy. In: Wilson JD, Braunwald E, Isselbacher KJ, et al., eds. Harrison's principles of internal medicine. 12th ed. Vol. 1. New York: McGraw-Hill, 1991:427-34.
17
Nutritional recommendations and principles for individuals with diabetes mellitusDiabetes Care 1991;14:Suppl 2:20-27
CrossRef | Web of Science | Medline18
Friedewald WT ,Levy RI ,Fredrickson DS . Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499-502
Web of Science | Medline19
Tukey JW ,Ciminera JL ,Heyse JF . Testing the statistical certainty of a response to increasing doses of a drug. Biometrics 1985;41:295-301
CrossRef | Web of Science | Medline20
Saltiel AR ,Olefsky JM . Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 1996;45:1661-1669
CrossRef | Web of Science | Medline21
Lillioja S ,Mott DM ,Spraul M , et al. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus: prospective studies of Pima Indians. N Engl J Med 1993;329:1988-1992
Full Text | Web of Science | Medline22
Vaag A ,Henriksen JE ,Madsbad S ,Holm N ,Beck-Nielsen H . Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin-dependent diabetes mellitus. J Clin Invest 1995;95:690-698
CrossRef | Web of Science | Medline23
Eriksson J ,Franssila-Kallunki A ,Ekstrand A , et al. Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. N Engl J Med 1989;321:337-343
Full Text | Web of Science | Medline24
Warram JH ,Martin BC ,Krolewski AS ,Soeldner JS ,Kahn CR . Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Intern Med 1990;113:909-915
Web of Science | Medline25
Pimenta W ,Korytkowski M ,Mitrakou A , et al. Pancreatic beta-cell dysfunction as the primary genetic lesion in NIDDM: evidence from studies in normal glucose-tolerant individuals with a first-degree NIDDM relative. JAMA 1995;273:1855-1861
CrossRef | Web of Science | Medline26
O'Rahilly S ,Turner RC ,Matthews DR . Impaired pulsatile secretion of insulin in relatives of patients with non-insulin-dependent diabetes. N Engl J Med 1988;318:1225-1230
Full Text | Web of Science | Medline27
The absence of a glycemic threshold for the development of long-term complications: the perspective of the Diabetes Control and Complications Trial
CrossRef | Web of Science | Medline
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CrossRef2
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CrossRef3
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CrossRef4
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CrossRef14
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CrossRef15
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CrossRef17
Boris Mankovsky, Ramaz B. Kurashvili. (2007) Glitazones: Beyond glucose lowering!. Diabetes and Metabolic Syndrome: Clinical Research and Reviews 1:3, 197-207
CrossRef18
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CrossRef20
Ronald B. Goldberg. (2006) Impact of thiazolidenediones on serum lipoprotein levels. Current Atherosclerosis Reports 8:5, 397-404
CrossRef21
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Kayoko Goya, Satoru Sumitani, Michio Otsuki, Xin Xu, Hiroyasu Yamamoto, Shogo Kurebayashi, Hiroshi Saito, Haruhiko Kouhara, Soji Kasayama. (2006) The thiazolidinedione drug troglitazone up-regulates nitric oxide synthase expression in vascular endothelial cells. Journal of Diabetes and its Complications 20:5, 336-342
CrossRef23
Udaya M. Kabadi, Mary Kabadi. (2006) Comparative efficacy of glimepiride and/or metformin with insulin in type 2 diabetes. Diabetes Research and Clinical Practice 72:3, 265-270
CrossRef24
Sheila A Doggrell. (2006) Muraglitazar: beneficial or detrimental in the treatment of Type 2 diabetes?. Expert Opinion on Pharmacotherapy 7:9, 1229-1233
CrossRef25
Julius Enoru-Eta, Lilian G. Yengi, John Kao, JoAnn Scatina. (2006) A reporter gene cellular model for evaluating induction of CYP3A4 by new chemical entities. Drug Development Research 67:5, 470-475
CrossRef26
Jennifer L Miller, Janet H Silverstein. (2006) The Treatment of Type 2 Diabetes Mellitus in Youth. Treatments in Endocrinology 5:4, 201-210
CrossRef27
Suzanne M. Strowig, Philip Raskin. (2005) Combination therapy using metformin or thiazolidinediones and insulin in the treatment of diabetes mellitus. Diabetes, Obesity and Metabolism 7:6, 633-641
CrossRef28
Simona Bruno, Dario Cattaneo, Norberto Perico, Giuseppe Remuzzi. (2005) Emerging drugs for diabetic nephropathy. Expert Opinion on Emerging Drugs 10:4, 747-771
CrossRef29
Teresa Yuk-Hwa Wong, Cheuk-Chun Szeto, Kai-Ming Chow, Chi-Bong Leung, Christopher Wai-Kei Lam, Philip Kam-Tao Li. (2005) Rosiglitazone Reduces Insulin Requirement and C-Reactive Protein Levels in Type 2 Diabetic Patients Receiving Peritoneal Dialysis. American Journal of Kidney Diseases 46:4, 713-719
CrossRef30
Himanshu P. Raikwar, Gladson Muthian, Johnson Rajasingh, Caroline Johnson, John J. Bright. (2005) PPARγ antagonists exacerbate neural antigen-specific Th1 response and experimental allergic encephalomyelitis. Journal of Neuroimmunology 167:1-2, 99-107
CrossRef31
S. A. Amiel, S. R. Heller, I. A. Macdonald, S. L. Schwartz, L. J. Klaff, J. A. Ruggles, C. Weyer, O. G. Kolterman, D. G. Maggs. (2005) The effect of pramlintide on hormonal, metabolic or symptomatic responses to insulin-induced hypoglycaemia in patients with type 1 diabetes. Diabetes, Obesity and Metabolism 7:5, 504-516
CrossRef32
M C Carmona, K Louche, M Nibbelink, B Prunet, A Bross, M Desbazeille, C Dacquet, P Renard, L Casteilla, L Pénicaud. (2005) Fenofibrate prevents Rosiglitazone-induced body weight gain in ob/ob mice. International Journal of Obesity 29:7, 864-871
CrossRef33
Steven V. Edelman, Candis M. Morello. (2005) Strategies for Insulin Therapy in Type 2 Diabetes. Southern Medical Journal 98:3, 363-371
CrossRef34
Mario Chojkier. (2005) Troglitazone and liver injury: In search of answers. Hepatology 41:2, 237-246
CrossRef35
Alvin Huang, Philip Raskin. (2005) Thiazolidinediones and Insulin. Treatments in Endocrinology 4:4, 205-220
CrossRef36
Hiroyuki OSE, Michiaki FUKUI, Yoshihiro KITAGAWA, Chizuko HIRATA, Naoko ICHIO, Mayuko KADONO, Shin-ichi MOGAMI, Masayoshi ONISHI, Yukiko ICHIDA, Toshiki NAKAJIMA, Goji HASEGAWA, Toshikazu YOSHIKAWA, Naoto NAKAMURA. (2005) Efficacy of Glimepiride in Patients with Poorly Controlled Insulin-treated Type 2 Diabetes Mellitus. Endocrine Journal 52:5, 563-569
CrossRef37
Mitsuo Tanimoto, Qiuling Fan, Tomohito Gohda, Toshihide Shike, Yuichiro Makita, Yasuhiko Tomino. (2004) Effect of pioglitazone on the early stage of type 2 diabetic nephropathy in KK/Ta mice. Metabolism 53:11, 1473-1479
CrossRef38
Alex N Goudswaard, Niall J Furlong, Gerlof D Valk, Ronald P Stolk, Guy EHM Rutten, Alex N Goudswaard. 2004. Insulin monotherapy versus combinations of insulin with oral hypoglycaemic agents in patients with type 2 diabetes mellitus. .
CrossRef39
Ouliana Ziouzenkova, Jorge Plutzky. (2004) Lipolytic PPAR activation: new insights into the intersection of triglycerides and inflammation?. Current Opinion in Clinical Nutrition and Metabolic Care 7:4, 369-375
CrossRef40
Mandeep Bajaj, Ralph A. DeFronzo. 2004. Combination Therapy in Type 2 Diabetes. .
CrossRef41
Andr?? J Scheen. (2004) Combined Thiazolidinedione-Insulin Therapy. Drug Safety 27:12, 841-856
CrossRef42
(2004) The Effects of Rosiglitazone on in vivo Synthesis of Bone Collagen in Mice. Journal of the Korean Society of Food Science and Nutrition 33:1, 218-221
CrossRef43
Rukmini Rajagopalan, Alfonso Perez, Zhan Ye, Mehmood Khan, Frederick T Murray. (2004) Pioglitazone is Effective Therapy for Elderly Patients with Type 2 Diabetes Mellitus. Drugs & Aging 21:4, 259-271
CrossRef44
William L Isley. (2003) Hepatotoxicity of thiazolidinediones. Expert Opinion on Drug Safety 2:6, 581-586
CrossRef45
Silvio E. Inzucchi. (2003) Glycemic Management of Diabetes in the Perioperative Setting. International Anesthesiology Clinics 40:2, 77-93
CrossRef46
Cora Weigert, Katrin Brodbeck, Angelika Bierhaus, Hans U Häring, Erwin D Schleicher. (2003) c-Fos-driven transcriptional activation of transforming growth factor β-1: inhibition of high glucose-induced promoter activity by thiazolidinediones. Biochemical and Biophysical Research Communications 304:2, 301-307
CrossRef47
J. L. Chan, M. J. Abrahamson. (2003) Pharmacological Management of Type 2 Diabetes Mellitus: Rationale for Rational Use of Insulin. Mayo Clinic Proceedings 78:4, 459-467
CrossRef48
Enzo Ragucci, Joel Zonszein, William H. Frishman. (2003) Pharmacotherapy of Diabetes Mellitus: Implications for the Prevention and Treatment of Cardiovascular Disease. Heart Disease 5:1, 18-33
CrossRef49
Elena Izkhakov, Eyal Meltzer, Ardon Rubinstein. (2003) Pathogenesis and Management of Diabetic Dyslipidemia. Treatments in Endocrinology 2:4, 231-245
CrossRef50
Janice C Parker. (2002) Troglitazone: the discovery and development of a novel therapy for the treatment of Type 2 diabetes mellitus. Advanced Drug Delivery Reviews 54:9, 1173-1197
CrossRef51
Nathan, David M., . (2002) Initial Management of Glycemia in Type 2 Diabetes Mellitus. New England Journal of Medicine 347:17, 1342-1349
Full Text52
Jan WA Smit, Michaela Diamant. (2002) Genetically defined pancreatic beta cell failure. Pharmacogenomics 3:5, 669-678
CrossRef53
Frédéric Picard, Johan Auwerx. (2002) PPARγ
AND GLUCOSE HOMEOSTASIS . Annual Review of Nutrition 22:1, 167-197
CrossRef54
H. N. Buch, V. Baskar, D. M. Barton, D. Kamalakannan, C. Akarca, B. M. Singh. (2002) Combination of insulin and thiazolidinedione therapy in massively obese patients with Type 2 diabetes. Diabetic Medicine 19:7, 572-574
CrossRef55
L. R. Reynolds, E. C. Konz, R. C. Frederich, J. W. Anderson. (2002) Rosiglitazone amplifies the benefits of lifestyle intervention measures in long-standing type 2 diabetes mellitus. Diabetes, Obesity and Metabolism 4:4, 270-275
CrossRef56
Jue Li, Takashi Kaneko, Yuan Wang, Li-Qiang Qin, Pei-Yu Wang, Akio Sato. (2002) Troglitazone enhances the hepatotoxicity of acetaminophen by inducing CYP3A in rats. Toxicology 176:1-2, 91-100
CrossRef57
Helen Vosper, Guennadi A Khoudoli, Tracey L Graham, Colin N.A Palmer. (2002) Peroxisome proliferator-activated receptor agonists, hyperlipidaemia, and atherosclerosis. Pharmacology & Therapeutics 95:1, 47-62
CrossRef58
Andrew S Greenberg, Anastassios G Pittas. (2002) Thiazolidinediones in the treatment of Type 2 diabetes. Expert Opinion on Pharmacotherapy 3:5, 529-540
CrossRef59
Priscilla Hollander. (2002) Insulin therapy in type 2 diabetes. Current Opinion in Endocrinology & Diabetes 9:2, 139-144
CrossRef60
Alicja Jozkowicz, J. Dulak, J. Nanobashvili, M. Prager, I. Huk. (2002) Role of Peroxisome Proliferator-Activated Receptor gamma Ligands in the Vessel Wall. European Surgery-Acta Chirurgica Austriaca 34:2, 121-126
CrossRef61
Barry J. Goldstein. (2002) Differentiating members of the thiazolidinedione class: a focus on efficacy. Diabetes/Metabolism Research and Reviews 18:S2, S16-S22
CrossRef62
Harold E. Lebovitz. (2002) Differentiating members of the thiazolidinedione class: a focus on safety. Diabetes/Metabolism Research and Reviews 18:S2, S23-S29
CrossRef63
Arlan L. Rosenbloom. (2002) Increasing Incidence of Type 2 Diabetes in Children and Adolescents. Pediatric Drugs 4:4, 209-221
CrossRef64
Fabrice M.A.C. Martens, Frank L.J. Visseren, Jacinthe Lemay, Eelco J.P. de Koning, Ton J. Rabelink. (2002) Metabolic and Additional Vascular Effects of Thiazolidinediones. Drugs 62:10, 1463-1480
CrossRef65
Tadashi Nakamura, Tohru Funahashi, Shizuya Yamashita, Makoto Nishida, Yoshiharu Nishida, Masahiko Takahashi, Kikuko Hotta, Hiroshi Kuriyama, Shinji Kihara, Noriyuki Ohuchi, Takamichi Nishimura, Bun-ichiro Kishino, Katsunori Ishikawa, Toshiharu Kawamoto, Katsuto Tokunaga, Chisa Nakagawa, Ikuo Mineo, Fumiko Watanabe, Seiichiro Tarui, Yuji Matsuzawa. (2001) Thiazolidinedione derivative improves fat distribution and multiple risk factors in subjects with visceral fat accumulation—double-blind placebo-controlled trial. Diabetes Research and Clinical Practice 54:3, 181-190
CrossRef66
Satoko Maruyama, Keiko Yanagisawa, Reiko Kanamuro, Shinichi Teno, Yasuhiko Iwamoto. (2001) Serum leptin level as an indicator to predict the clinical efficacy of troglitazone in patients with type 2 diabetes mellitus. Diabetes Research and Clinical Practice 53:3, 161-164
CrossRef67
BO Zhang, Masashi Shiomi, Hiroaki Tanaka, Junru Mei, Ping Fan, Yoshio Tsujita, Hiroyoshi Horikoshi, Keijiro Saku. (2001) Effects of high-dose troglitazone on insulin sensitivity and β-cell function in watanabe heritable hyperlipidemic rabbits. European Journal of Drug Metabolism and Pharmacokinetics 26:3, 185-192
CrossRef68
Felicity Kaplan, Khulood Al-Majali, D. Betteridge. (2001) Journal of Cardiovascular Risk 8:4, 211-217
CrossRef69
John A Papadakis, Haralampos J Milionis, Martin Press, Dimitri P Mikhailidis. (2001) Treating dyslipidaemia in non-insulin-dependent diabetes mellitus — a special reference to statins. Journal of Diabetes and its Complications 15:4, 211-226
CrossRef70
Edwin AM Gale. (2001) Lessons from the glitazones: a story of drug development. The Lancet 357:9271, 1870-1875
CrossRef71
Maureen D. Passaro, Robert E. Ratner. (2001) Combination oral agent and insulin therapy for type 2 diabetes mellitus. Current Diabetes Reports 1:2, 106-111
CrossRef72
P.J. Palumbo. (2001) Glycemic Control, Mealtime Glucose Excursions, and Diabetic Complications in Type 2 Diabetes Mellitus. Mayo Clinic Proceedings 76:6, 609-618
CrossRef73
P J Palumbo. (2001) Gycemic control, mealtime glucose excursions, and diabetic complications in type 2 diabetes mellitus.. Mayo Clinic Proceedings 76:6, 609-618
CrossRef74
F Bosquet, A Heurtier, N Chastang, S Jacqueminet. (2001) Place et modalités de lˈinsulinothérapie chez le diabétique de type 2. La Revue de Médecine Interne 22:3, 265-273
CrossRef75
Pongamorn Bunnag, Gobchai Puavilai, Suwannee Chanprasertyotin, Sunitaya Chandraprasert, Sompong Suwanwalaikorn, Ampha Suthijumroon, Yupin Benjasuratwong, Apasanee Boonyavaraku, Wannee Nitiyanant, Sutin Sriussadaporn, Chaichan Deerochanawong. (2001) Effects of troglitazone in patients with type 2 diabetes mellitus not adequately controlled by sulfonylureas. Diabetes Research and Clinical Practice 51:2, 151-153
CrossRef76
Amy Smith, Leon Fogelfeld, George Bakris. (2000) New therapies in diabetes – thiazolidinediones. Expert Opinion on Emerging Drugs 5:4, 441-456
CrossRef77
Gregory J Murphy, Julie C Holder. (2000) PPAR-γ agonists: therapeutic role in diabetes, inflammation and cancer. Trends in Pharmacological Sciences 21:12, 469-474
CrossRef78
Kyoko Shimizu, Keiko Shiratori, Naoaki Hayashi, Toshihide Fujiwara, Hiroyoshi Horikoshi. (2000) Effect of Troglitazone on Exocrine Pancreas in Rats with Streptozotocin-Induced Diabetes Mellitus. Pancreas 21:4, 421-426
CrossRef79
Tsutomu Takagi, Takashi Akasaka, Atsushi Yamamuro, Yasuhiro Honda, Takeshi Hozumi, Shigefumi Morioka, Kiyoshi Yoshida. (2000) Troglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with non–insulin dependent diabetes mellitus. Journal of the American College of Cardiology 36:5, 1529-1535
CrossRef80
Vidushi Sood, Kathleen Colleran, Mark R. Burge. (2000) Thiazolidinediones: A Comparative Review of Approved Uses. Diabetes Technology & Therapeutics 2:3, 429-440
CrossRef81
Leifsparre Hermann. (2000) Optimising Therapy for Insulin-Treated Type 2 Diabetes Mellitus. Drugs & Aging 17:4, 283-294
CrossRef82
Hannele Yki-Järvinen. (2000) Comparison of insulin regimens for patients with type 2 diabetes. Current Opinion in Endocrinology & Diabetes 7:4, 175-183
CrossRef83
Satoshi Sunayama, Yoshiro Watanabe, Hiroyuki Daida, Hiroshi Yamaguchi. (2000) Thiazolidinediones, dyslipidaemia and insulin resistance syndrome. Current Opinion in Lipidology 11:4, 397-402
CrossRef84
Joe M. Chehade, Arshag D. Mooradian. (2000) A Rational Approach to Drug Therapy of Type 2 Diabetes Mellitus. Drugs 60:1, 95-113
CrossRef85
James M. May, Zhi-Chao Qu. (2000) Troglitazone Protects Human Erythrocytes from Oxidant Damage. Antioxidants & Redox Signaling 2:2, 243-250
CrossRef86
Elaine Murphy, John J Nolan. (2000) Insulin sensitiser drugs. Expert Opinion on Investigational Drugs 9:6, 1347-1361
CrossRef87
(2000) The rise and fall of troglitazone. Diabetic Medicine 17:6, 414-415
CrossRef88
Alan O. Marcus. (2000) Safety of Drugs Commonly Used to Treat Hypertension, Dyslipidemia, and Type 2 Diabetes (The Metabolic Syndrome): Part 2. Diabetes Technology & Therapeutics 2:2, 275-281
CrossRef89
Alan J. Garber. (2000) Using dose-response characteristics of therapeutic agents for treatment decisions in type 2 diabetes. Diabetes, Obesity and Metabolism 2:3, 139-147
CrossRef90
Saul Genuth. (2000) Implications of the United Kingdom Prospective Diabetes Study for Patients with Obesity and Type 2 Diabetes. Obesity 8:2, 198-201
CrossRef91
Akiyoshi Shimaya, Eiji Kurosaki, Ryosuke Nakano, Reiko Hirayama, Masayuki Shibasaki, Hisataka Shikama. (2000) The novel hypoglycemic agent YM440 normalizes hyperglycemia without changing body fat weight in diabetic db/db mice. Metabolism 49:3, 411-417
CrossRef92
Kristina Schoonjans, Johan Auwerx. (2000) Thiazolidinediones: an update. The Lancet 355:9208, 1008-1010
CrossRef93
Miya Fukano, Shigeru Amano, Jin Sato, Kazuo Yamamoto, Hideyoshi Adachi, Hidetoshi Okabe, Yoshihide Fujiyama, Tadao Bamba. (2000) Subacute hepatic failure associated with a new antidiabetic agent, troglitazone: A case report with autopsy examination. Human Pathology 31:2, 250-253
CrossRef94
J. Jaime Caro, Wendy S. Klittich, Gabriel Raggio, Patricia L. Kavanagh, Judith A. O'Brien, Lori A. Shomphe, Kenneth M. Flegel, Catherine Copley-Merriman, Cathy Sigler. (2000) Economic assessment of troglitazone as an adjunct to sulfonylurea therapy in the treatment of type 2 diabetes. Clinical Therapeutics 22:1, 116-127
CrossRef95
Douglas A Greene. (1999) Rosiglitazone: a new therapy for Type 2 diabetes. Expert Opinion on Investigational Drugs 8:10, 1709-1719
CrossRef96
Michiko Asano, Toshiaki Nakajima, Kuniaki Iwasawa, Toshihiro Morita, Fumitaka Nakamura, Hiroyuki Imuta, Keigo Chisaki, Nobuhiro Yamada, Masao Omata, Yukichi Okuda. (1999) Troglitazone and pioglitazone attenuate agonist-dependent Ca 2+ mobilization and cell proliferation in vascular smooth muscle cells. British Journal of Pharmacology 128:3, 673-683
CrossRef97
Toshihide Kawai, Izumi Takei, Yuko Oguma, Norimi Ohashi, Mikiya Tokui, Shuji Oguchi, Fuminori Katsukawa, Hiroshi Hirose, Akira Shimada, Kiyoaki Watanabe, Takao Saruta. (1999) Effects of troglitazone on fat distribution in the treatment of male type 2 diabetes. Metabolism 48:9, 1102-1107
CrossRef98
A MAVANDADI, W GONG. (1999) Effects of troglitazone in hispanic patients with type 2 diabetes mellitus. Current Therapeutic Research 60:9, 494-501
CrossRef99
Akhil A. Parulkar, Vivian A. Fonseca. (1999) Recent advances in pharmacological treatment of type 2 diabetes mellitus. Comprehensive Therapy 25:8-10, 418-426
CrossRef100
Mark R. Burge, Vidushi Sood, Taher A. Sobhy, Amer G. Rassam, David S. Schade. (1999) Sulphonylurea-induced hypoglycaemia in type 2 diabetes mellitus: a review. Diabetes, Obesity and Metabolism 1:4, 199-206
CrossRef101
Oi Lian Kon, Sasirekha Sivakumar, Khay Lin Teoh, Serene HL Lok, Yun Chau Long. (1999) Naked plasmid-mediated gene transfer to skeletal muscle ameliorates diabetes mellitus. The Journal of Gene Medicine 1:3, 186-194
CrossRef102
William Mayoral, James H. Lewis, Hyman Zimmerman. (1999) Drug-induced liver disease. Current Opinion in Gastroenterology 15:3, 208-216
CrossRef103
David Kerr, David Cavan. (1999) Treating obese patients with poorly controlled diabetes: confessions of an insulin therapist. Diabetes/Metabolism Research and Reviews 15:3, 219-225
CrossRef104
Hedley C. Freake. (1999) A Genetic Mutation in PPARγ Is Associated with Enhanced Fat Cell Differentiation: Implications for Human Obesity. Nutrition Reviews 57:5, 154-156
CrossRef105
EDWARD LIPKIN. (1999) New Strategies for the Treatment of Type 2. Journal of the American Dietetic Association 99:3, 329-334
CrossRef106
M. Buysschaert, E. Bobbioni, M. Starkie, L. Frith, for the Troglitazone Study Group. (1999) Troglitazone in combination with sulphonylurea improves glycaemic control in Type 2 diabetic patients inadequately controlled by sulphonylurea therapy alone. Diabetic Medicine 16:2, 147-153
CrossRef107
J H O'Keefe, J M Miles, W H Harris, R M Moe, B D McCallister. (1999) Improving the adverse cardiovascular prognosis of type 2 diabetes.. Mayo Clinic Proceedings 74:2, 171-180
CrossRef108
Mauricio J Reginato, Mitchell A Lazar. (1999) Mechanisms by which Thiazolidinediones Enhance Insulin Action. Trends in Endocrinology & Metabolism 10:1, 9-13
CrossRef109
Kurt Preininger, Harald Stingl, Rainer Englisch, Clemens Fürnsinn, Jürg Graf, Werner Waldhäusl, Michael Roden. (1999) Acute troglitazone action in isolated perfused rat liver. British Journal of Pharmacology 126:1, 372-378
CrossRef110
Ristow, Michael, Müller-Wieland, Dirk, Pfeiffer, Andreas, Krone, Wilhelm, Kahn, C. Ronald, . (1998) Obesity Associated with a Mutation in a Genetic Regulator of Adipocyte Differentiation. New England Journal of Medicine 339:14, 953-959
Full Text111
(1998) Effect of Troglitazone in Type 2 Diabetes Mellitus. New England Journal of Medicine 339:6, 406-406
Full Text112
Athanasios G Papavassiliou. (1998) Transcription-factor-modulating agents: precision and selectivity in drug design. Molecular Medicine Today 4:8, 358-366
CrossRef113
Nikolaus Marx, Galina Sukhova, Curran Murphy, Peter Libby, Jorge Plutzky. (1998) Macrophages in Human Atheroma Contain PPARγ. The American Journal of Pathology 153:1, 17-23
CrossRef114
Colin Perry, John R Petrie. (1998) Insulin-sensitising agents. Expert Opinion on Emerging Drugs 3:1, 247-260
CrossRef115
Watkins, Paul B., , Whitcomb, Randall W., . (1998) Hepatic Dysfunction Associated with Troglitazone. New England Journal of Medicine 338:13, 916-917
Full Text116
Imura, Hiroo, . (1998) A Novel Antidiabetic Drug, Troglitazone — Reason for Hope and Concern. New England Journal of Medicine 338:13, 908-909
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