Artifactual elevation of serum creatinine level due to fasting.

Abnormal serum creatinine (1.6 mg/dL) and creatinine clearance (33 mL/min) levels found in a 50-year-old woman during fasting were corrected with refeeding. Five healthy subjects who fasted for 96 hours demonstrated an increase in their mean serum creatinine level from 1.0 +/- 0.08 to 1.7 +/- 0.11 mg/dL as determined by Jaffé's method. This increase was probably an artifact caused by the rise in the serum acetoacetate level during fasting. The serum creatinine level determined by an enzymatic method and serum urea nitrogen level did not change substantially during the fast. We conclude that fasting may cause an artifactual increase in the serum creatinine level determined by Jaffé's method, the method used by most clinical laboratories.

Effects of cyclosporine on the renin-angiotensin-aldosterone system and potassium excretion in renal transplant recipients.

To evaluate the mechanism of cyclosporine-induced hyperkalemia, the renin-angiotensin-aldosterone system and renal potassium clearance were compared in ten renal transplant recipients treated with cyclosporine and treated with azathioprine. After stimulation by a low-sodium diet and furosemide, cyclosporine-treated patients demonstrated lower plasma renin activity when supine (1.9 +/- 0.3 v 7.8 +/- 1.4 ng/mL/hr) and after standing (3.0 +/- 0.7 v 12.2 +/- 1.5 ng/mL/hr). Supine plasma aldosterone levels tended to be lower in cyclosporine-treated patients, (4.8 +/- v 10.5 +/- 2.6 ng/dL), although standing plasma aldosterone levels were not different (10.8 +/- 3.0 v 12.3 +/- 2.0 ng/dL). After administration of 0.75 mEq of potassium chloride per kilogram of body weight, cyclosporine-treated patients excreted 52% +/- 7.1% of the potassium load in six hours compared with excretion of 67% +/- 7.0% by the azathioprine-treated patients, although there was no difference in plasma aldosterone levels in response to the potassium load in the two groups. These data suggest that cyclosporine causes suppression of plasma renin activity and a tubular insensitivity to aldosterone, both of which may impair potassium excretion.

Resistance to thyroid hormones. A disorder frequently confused with Graves' disease.

Five patients from two unrelated families were found to have goiter and elevated serum concentrations of thyroxine (T4) and triiodothyronine (T3) without symptoms or signs of hyperthyroidism. All had measurable concentrations of thyroid stimulating hormone (TSH), and in four who were tested, there was an increase in TSH concentration following thyrotropin releasing hormone (TRH) administration. We believe these five patients have general resistance to the effects of thyroid hormones and need elevated concentrations of T4 and T3 to maintain a eumetabolic state. Study of nuclear T3 receptors from cultured fibroblasts of one patient disclosed a normal equilibrium association constant and a maximal binding capacity that was greater than normal control values. These findings suggest that thyroid hormone resistance in this patient is not due to a decrease in either the affinity or the number of specific nuclear T3 receptors. This disorder can easily be confused with Graves' disease and result in inappropriate treatment for hyperthyroidism, as was the case in three of our patients.

Clinical aspects of sucrose and fructose metabolism.

The per capita consumption of sugars in the United States accounts for approximately 21% of total calorie intake. Most Americans eat and enjoy sugar-containing foods every day, but the use of sugars in the diabetic diet has traditionally been proscribed for fear of aggravating hyperglycemia. However, short-term and most longer-term studies demonstrate that dietary sucrose does not cause a greater postprandial rise in plasma glucose than isocaloric amounts of other common carbohydrates. The available evidence suggests that sucrose has a glycemic effect similar to that of bread, potatoes, and rice. Dietary fructose, in contrast, may produce a lesser postprandial rise in plasma glucose than other common carbohydrates. There is considerable controversy about the effects of dietary sucrose and fructose on serum lipids, and their effects on other metabolic events, such as the nonenzymatic glycosylation of proteins, are uncertain. Nevertheless, it is reasonable to allow diabetic patients to consume sugar-containing foods as long as they do so in a controlled fashion.

Effects of the anatomical region used for insulin injections on glycemia in type I diabetes subjects.

OBJECTIVE: Subcutaneous insulin is absorbed at different rates from different anatomical regions, but it is not clear how much the varying rates of absorption affect plasma glucose concentrations in diabetic subjects. To address this issue, subcutaneous injections of insulin in the abdomen were compared with subcutaneous injections of insulin in the thigh. RESEARCH DESIGN AND METHODS: In a crossover trial, 22 type I diabetic subjects received, in random order, a test dose of regular insulin injected subcutaneously in the abdomen on one morning and in a thigh on another morning. The subjects also received, in random order, usual morning doses of NPH and regular insulins injected subcutaneously in the abdomen on one morning and in a thigh on another morning. The study was performed in the University of Minnesota General Clinical Research Center. Main outcome measures were plasma glucose and serum free insulin. RESULTS: After injections of regular insulin in the abdomen, the peak postprandial increment in plasma glucose was 3.1 mM or 29% lower (P < 0.001), the peak increment in serum free insulin was 54 pM or 38% higher (P = 0.017), and the length of time required to achieve peak serum free insulin was significantly shorter than after injections of regular insulin in the thigh. After injections of NPH and regular insulins in the abdomen, the morning peak increment in plasma glucose was 2.5 mM or 18% lower (P = 0.008) than after injections of NPH and regular insulins in a thigh. However, no significant difference was observed in the afternoon peak increment in plasma glucose. CONCLUSIONS: A subcutaneous injection of regular insulin in the abdomen produced a substantially greater reduction in plasma glucose than an injection of regular insulin in the thigh. Changing the injection site of regular insulin from the abdomen to the thigh had an effect equivalent to reducing the dose administered. With injections of NPH and regular insulin in combination, the influence of the region used for injection was less but still potentially important.

Comparison of predictive capabilities of diabetic exchange lists and glycemic index of foods.

To determine whether the diabetic exchange lists or the glycemic index of foods better predicts postprandial responses to carbohydrate-containing foods eaten as part of a mixed meal, three test meals were developed and fed to 12 subjects with non-insulin-dependent diabetes mellitus (NIDDM) and 13 healthy subjects. Each test meal contained exactly the same exchanges (1 milk, 4 starch, 2 fruit, 2 meat, 3 fat, 1 vegetable). In one meal, foods of high glycemic index (GI) were used, in a second meal, foods of intermediate GI were used, and in a third meal foods of low GI were used. The total GIs of the meals were: high, 184; intermediate, 131; and low, 107, thus predicting responses to intermediate and low GI, which were 71 and 58%, respectively, of the responses to high GI. Although some of the observed differences in the glycemic responses to the test meals were statistically significant, primarily in healthy subjects, the differences were usually much less than predicted by the GIs of the meals. In NIDDM subjects, peak postprandial plasma glucose, plasma glucose area, plasma glucose area increment, and mean plasma glucose responses after intermediate and low GI were greater than 90% of the corresponding responses to high GI. In healthy subjects, only the plasma glucose area increment after the low-GI meal was close to the predicted response. High GI produced significantly greater insulin responses than low GI in healthy subjects. We conclude that the diabetic exchange lists more accurately predict postprandial responses to carbohydrate-containing foods eaten as part of a mixed meal than does the GI of foods.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic effects of dietary fructose in diabetic subjects.

OBJECTIVE: To assess the metabolic effects of chronic dietary fructose consumption in diabetic subjects. RESEARCH DESIGN AND METHODS: Six type I and 12 type II diabetic subjects consumed, in random order, two isocaloric study diets for 28 days. In one diet, 20% of energy was derived from fructose. In the other diet, < 3% of energy came from fructose, and carbohydrate energy was derived primarily from starch. Both study diets were composed of common foods. All meals were prepared in a metabolic kitchen where all foods were weighed during meal preparation. RESULTS: Mean plasma glucose, urine glucose, and serum glycosylated albumin values were lower during the fructose diet than during the starch diet, but the differences achieved only marginal statistical significance. The day-28 value for mean plasma glucose was 12.5% lower (P = 0.03) during the fructose diet than during the starch diet. At days 14, 21, and 28, fasting serum cholesterol and LDL cholesterol were both significantly higher during the fructose diet than during the starch diet. The day-28 values for serum cholesterol and LDL cholesterol during the fructose diet were 6.9% (P = 0.008) and 10.9% (P = 0.002) higher, respectively, than the corresponding values during the starch diet. No differences were observed between the study diets in fasting serum HDL cholesterol, fasting serum triglycerides, peak postprandial serum triglycerides, or fasting serum lactate. Peak postprandial serum lactate was significantly higher during the fructose diet. Type I and type II diabetic subjects responded to the diets in a consistent way, but type I subjects experienced significantly more hypoglycemia during the fructose diet than during the starch diet. CONCLUSIONS: A high-fructose diet may result in reduced glycemia in diabetic subjects but at the expense of increased fasting serum total and LDL cholesterol.

Metabolic effects of dietary sucrose in type II diabetic subjects.

OBJECTIVE: To assess in diabetic subjects the effects of dietary sucrose on glycemia and lipemia. RESEARCH DESIGN AND METHODS: Twelve type II diabetic subjects consumed, in random order, two isocaloric, 55% carbohydrate study diets for 28 days. In one diet, 19% of energy was derived from sucrose. In the other diet, < 3% of energy was derived from sucrose, and carbohydrate energy came primarily from starch. Both study diets were composed of common foods. All meals were prepared in a metabolic kitchen where foods were weighed during meal preparation. RESULTS: No significant differences were noted between the study diets at any time point in mean plasma glucose. At day 28, mean plasma glucose values for the sucrose diet were 9.6 +/- 0.5 mM and for the starch diet were 9.4 +/- 0.6 mM (P = 0.63). Also, no significant differences were observed between the study diets in urine glucose, fasting serum total, HDL, or LDL cholesterol; fasting serum TG; or peak postprandial serum TG. CONCLUSIONS: A high sucrose diet did not adversely affect glycemia or lipemia in type II diabetic subjects.

Urinary C-peptide as a measure of beta-cell function after a mixed meal in healthy subjects: comparison of four-hour urine C-peptide with serum insulin and plasma C-peptide.

Urinary C-peptide (UCP) is a noninvasive measure of integrated insulin production, and the usefulness of 24-h collections has been previously reported. Only small numbers of subjects have been studied using shorter urine collections. To see how well 4-h urine collections for C-peptide (UCP) correlate with serum immunoreactive insulin (SI) and plasma C-peptide (PCP), we studied 41 healthy subjects (19 men, 22 women) using as a stimulus a 600-kcal mixed meal and the same mixed meal after oral prednisone. UCP values correlated best with the area under the curves for SI (r = 0.457, P less than 0.001) and PCP (r = 0.557, P less than 0.001). UCP was also significantly correlated with peak SI (r = 0.382, P less than 0.001), peak PCP (r = 0.496, P less than 0.001), fasting SI (r = 0.297, P = 0.007), and fasting PCP (r = 0.341, P = 0.007) values. Urinary C-peptide was significantly correlated with SI and PCP concentrations in a broad range of physiologic values for SI and PCP supporting the usefulness of UCP as a simple, noninvasive measure of beta-cell function. Four-hour collections for UCP may be useful in further studies of beta-cell function.

Pharmacologic induction of weight loss to treat type 2 diabetes.

OBJECTIVE: Most individuals with type 2 diabetes are overweight, and weight loss for them is an important therapeutic objective. However, usual weight-loss strategies have generally not produced sustained weight loss. Pharmacologic agents to assist weight loss might be useful, but no long-term data on their effectiveness and safety in patients with type 2 diabetes are available. We therefore initiated a 2-year placebo-controlled trial of the weight-loss medications fenfluramine and phentermine in type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: A total of 44 overweight (> 120% ideal body weight) subjects with type 2 diabetes were enrolled in a randomized, placebo-controlled, double-blind trial of fenfluramine and phentermine. All subjects received intensive nutrition counseling, an exercise prescription, and instruction in behavior modification. Subjects were randomly assigned to 20 mg fenfluramine three times a day and 37.5 mg phentermine daily (n = 23) or dual placebos (n = 21). Diabetes medications were adjusted as necessary to achieve glycemic goals. Changes in weight, glycemia, lipemia, and blood pressure were assessed every 2 months, as were adverse events. In September 1997, when fenfluramine was withdrawn from the U.S. market, fenfluramine was stopped in all subjects. Thus the length of drug treatment varied, but 16 subjects (8 in each group) reached 12 months of treatment. Only data obtained before the withdrawal of fenfluramine are included in this report. RESULTS: A study termination, diabetes medications had been reduced in 1 subject in the placebo group (5%) and 11 subjects in the drug treatment group (52%) (P = 0.005). Drug treatment resulted in significant reductions in body weight, BMI, and HbA1c at all time points through 6 months. Changes in weight at 6 months were -2.7 +/- 1.4 kg (mean +/- SEM) with placebo treatment and -9.6 +/- 1.5 kg with drug treatment (P = 0.003). Even though more subjects in the drug treatment group required reductions in diabetes medications, at 6 months, changes in HbA1c were -0.3 +/- 0.2% with placebo treatment and -1.6 +/- 0.3% with drug treatment (P = 0.002). Fasting plasma glucose and triglycerides were significantly reduced at some time points with drug treatment. No serious adverse events attributable to study medications were observed. CONCLUSIONS: Premature study termination decreased the power of our study at later time points. However, our data suggest that weight loss medications are an effective treatment for type 2 diabetes during active weight loss. Whether the benefit persists after weight loss has stopped remains to be determined.

Use of the dexamethasone-adrenocorticotropin test to assess the requirement for continued glucocorticoid replacement therapy after pituitary surgery.

We assessed the need for continued glucocorticoid replacement therapy in postsurgical pituitary tumor patients using a dexamethasone-ACTH test. The patients received 1 mg dexamethasone, orally, at 2300 h and 250 micrograms synthetic ACTH (Cosyntropin), iv, at 0800 h the next morning. The mean +/- SD integrated cortisol response for a 2-h period of the 31 pituitary tumor patients [1264 +/- 924 micrograms X min/dl (34.87 +/- 25.49 mumol X min/liter)] was significantly less (P less than 0.005) than that of 25 normal subjects [3331 +/- 544 micrograms X min/dl (91.90 +/- 17.04 mumol X min/liter)]. Replacement glucocorticoids were abruptly discontinued in 11 patients with responses above 1450 micrograms X min/dl (40.01 mumol X min/liter). No clinical or laboratory evidence of adrenal insufficiency occurred as long as 15 months after discontinuation. Metyrapone tests, however, in the 11 glucocorticoid-withdrawn patients revealed a reduced mean +/- SD serum 11-deoxycortisol level compared with that of 10 normal subjects [8.9 +/- 4.7 vs. 15.6 +/- 5.0 micrograms/dl (0.26 +/- 0.13 vs. 0.45 +/- 0.16 mumol/liter); P less than 0.005]. Our results indicate that the dexamethasone-ACTH test is useful in identifying patients in whom replacement glucocorticoid therapy can be safely withdrawn under nonstressed conditions. The test can be simplified to one plasma cortisol level determined 30 min after ACTH administration.

Metabolic and endocrine investigations in women of normal weight with the bulimia syndrome.

Bulimia is a disorder characterized by episodes of binge-eating. Patients with this problem consume large amounts of food when binge-eating and, subsequently, to avoid weight gain, usually self-induce vomiting or induce diarrhea with laxatives. Metabolic and endocrine investigations in six bulimic subjects of normal weight are reported. Normal fasting plasma glucose concentrations and glucose tolerance were present in all. Five subjects had normal serum T4 and T3 concentrations. Only one subject had depressed serum T4 and T3 concentrations and this subject had a normal serum TSH level. Menstrual irregularities were present in all patients and, in three, were associated with modestly elevated serum prolactin levels. In four subjects there was an abnormal increase in serum growth hormone following TRH administration and in three, growth hormone failed to suppress normally after oral glucose. Two subjects were found to have a hypokalimic metabolic alkalosis, presumably due to vomiting. Urinary 17-OH steroid excretion and urinary concentrating ability were normal or nearly so in all subjects.

Metabolic effects of dietary fructose in healthy subjects.

To determine if dietary fructose causes adverse metabolic effects, we used a crossover design to compare a diet containing 20% of energy from fructose with an isoenergic high-starch diet that contained less than 3% fructose. Fourteen healthy subjects consumed each diet for 28 d. There were no significant differences between the diets in the mean values of hemoglobin A1C, serum glycosylated albumin, fasting plasma glucose, peak postprandial plasma glucose, integrated plasma glucose, fasting serum lactate, or fasting serum triglycerides. Peak postprandial serum lactate was significantly higher during the fructose diet at days 1, 7, and 14 but not at days 21 or 28. Peak postprandial serum triglycerides were significantly higher only at day 1 of the fructose diet. Day-28 fasting serum total and LDL cholesterol for the fructose diet were 9.0% and 11.0% higher, respectively, than the corresponding values for the starch diet. A high-fructose diet compared with a high-starch diet resulted in significantly higher fasting serum total and LDL cholesterol and also caused transient changes in postprandial serum lactate and triglycerides.

Effects of dietary fructose on plasma lipids in healthy subjects.

BACKGROUND: About 9% of average dietary energy intake in the United States comes from fructose. Such a high consumption raises concern about the metabolic effects of this sugar. OBJECTIVE: The objective of this study was to determine the effect of dietary fructose on plasma lipids. DESIGN: The study was conducted in the General Clinical Research Center at Fairview-University of Minnesota Medical Center. The participants were 24 healthy adult volunteers (12 men and 12 women; 6 of each sex were aged <40 y and 6 of each sex were aged >/=40 y). All subjects received 2 isoenergetic study diets assigned by using a randomized, balanced crossover design. One diet provided 17% of energy as fructose. The other diet was sweetened with glucose and was nearly devoid of fructose. Each diet was fed for 6 wk. Both diets were composed of common foods and contained nearly identical amounts of carbohydrate, protein, fat, fiber, cholesterol, and saturated, monounsaturated, and polyunsaturated fatty acids. All meals were prepared in the metabolic kitchen of the General Clinical Research Center. RESULTS: The responses to the study diets differed by sex. In men, the fructose diet produced significantly higher fasting, postprandial, and daylong plasma triacylglycerol concentrations than did the glucose diet. The daylong plasma triacylglycerol concentration after 6 wk of the fructose diet was 32% greater in men than the corresponding concentration during the glucose diet (P: < 0.001). The fructose diet had no significant effect on fasting or postprandial plasma triacylglycerol concentrations in women. The fructose diet also had no persistent effect on fasting plasma cholesterol, HDL cholesterol, or LDL cholesterol in either men or women. CONCLUSIONS: Dietary fructose was associated with increased fasting and postprandial plasma triacylglycerol concentrations in men. Diets high in added fructose may be undesirable, particularly for men. Glucose may be a suitable replacement sugar.

Treatment of type III hyperlipoproteinemia with four different treatment regimens.

The efficacy of clofibrate (CPIB) and nicotinic acid (NA) in the treatment of type III hyperlipoproteinemia was evaluated in 5 male subjects in a randomized cross-over study with clofibrate 1 g b.i.d. and NA 3 g/day (given either b.i.d. or t.i.d.). Following a baseline period of 6 weeks, each drug was given for 12 weeks with samples for lipid and lipoprotein determinations obtained at 6, 9, and 12 weeks. Both clofibrate and NA resulted in a significant reduction from baseline of total cholesterol (23% and 28%), VLDL cholesterol (49% and 56%), total triglycerides (40% and 43%), and VLDL triglycerides (46% and 48%), as well as a significant increase in HDL cholesterol (22% and 28%) and HDL/LDL ratio (31% and 62%). The HDL/LDL ratio was higher on NA than clofibrate (0.47 +/- 0.19 vs. 0.38 +/- 0.09, P less than 0.05). Four subjects were continued in the study and treated sequentially with NA 3.0 g/day (alternate to the previous schedule) and gemfibrozil 1.2 g/d in divided doses. Each of the 4 regimens resulted in a significant change from baseline of each of the measured lipid and lipoprotein determinations except LDL cholesterol. Comparison among the treatment regimens revealed no differences except for significantly higher HDL cholesterol and HDL/LDL ratio with NA given t.i.d.

Suppression of plasma renin activity by cyclosporine.

Cyclosporine treatment is associated with hypertension and suppression of plasma renin activity, the causes of which are unclear. To determine whether suppressed plasma renin activity is due to extracellular fluid volume expansion, 10 cyclosporine-treated renal transplant recipients were compared with 10 azathioprine-treated renal transplant recipients and seven patients with renal insufficiency. Glomerular filtration rate and effective renal plasma flow were significantly lower in cyclosporine-treated patients than in azathioprine-treated patients. Upright plasma renin activity was suppressed in cyclosporine-treated patients (cyclosporine 2.9 +/- 0.9, azathioprine 4.7 +/- 0.9, renal insufficiency 5.2 +/- 1.9 ng/ml/hour) but could be stimulated by a four-day period of dietary sodium restriction and diuretic administration (cyclosporine 15.8 +/- 4.4 ng/ml/hour). Extracellular fluid volume tended to be higher in cyclosporine-treated patients (cyclosporine 30.7 +/- 2.3, azathioprine 26.7 +/- 2.5, renal insufficiency 25.5 +/- 1.4 percent lean body mass), although the difference between cyclosporine-treated and azathioprine-treated patients did not attain statistical significance. There were no differences in the urinary excretion of prostaglandin E2 or 6-keto prostaglandin F1 alpha between the two groups of renal transplant recipients. It is concluded that suppression of plasma renin activity by cyclosporine is physiologic and may reflect expansion of extracellular fluid volume, which can be reversed by sodium depletion.

Comparison of effectiveness of thyrotropin-suppressive doses of D- and L-thyroxine in treatment of hypercholesterolemia.

In an attempt to compare the cholesterol-lowering effects of equivalent doses of D- and L-thyroxine, 10 euthyroid, hypercholesterolemic subjects were treated with graded doses of each medication in a cross-over design using thyrotropin suppression following thyrotropin-releasing hormone administration as the end-point. The mean thyrotropin-suppressive dose of D-thyroxine was 2.4 +/- 0.66 mg per day, which resulted in mean reductions of 10 percent in total plasma cholesterol, 10 percent in plasma low-density lipoprotein cholesterol, and 11 percent in plasma high-density lipoprotein cholesterol. The mean thyrotropin-suppressive dose of L-thyroxine was 135 +/- 46 micrograms per day, which resulted in mean reductions of 7 percent in total plasma cholesterol, 6 percent in plasma low-density lipoprotein cholesterol, and 14 percent in plasma high-density lipoprotein cholesterol. The reductions in total, low-density, and high-density cholesterol achieved with D-thyroxine were not significantly different from those achieved with L-thyroxine. Neither medication produced a significant increase in heart rate or ventricular ectopy as determined by Holter monitoring. These data do not support the belief that D-thyroxine has a preferential cholesterol-lowering effect in humans when compared with equivalent doses of L-thyroxine. In addition, both D- and L-thyroxine reduced plasma high-density lipoprotein cholesterol.

Thyroxine administration during radiation therapy to the neck does not prevent subsequent thyroid dysfunction.

In an attempt to reduce the incidence of hypothyroidism following irradiation of the neck, we administered oral L-thyroxine in doses sufficient to suppress serum TSH to 20 patients receiving radiation therapy for Hodgkin's disease or other lymphomas. L-thyroxine was discontinued when radiation therapy was completed. Twenty similar patients who did not receive L-thyroxine during radiation therapy served as a control group. After a mean follow-up period of 33 months, seven patients (35%) in the L-thyroxine group developed elevation of serum TSH and were started on chronic L-thyroxine therapy. In the control group, after mean follow-up of 19 months, five patients (25%) developed elevation of TSH and were started on chronic L-thyroxine. We conclude that suppression of serum TSH during neck irradiation does not prevent subsequent thyroid dysfunction.

Chronic treatment with phentermine combined with fenfluramine lowers plasma serotonin.

As expected on the basis of published research in both humans and animals, treatment with phentermine/fenfluramine lowers plasma 5-hydroxytryptamine [corrected], whereas treatment with phentermine had no significant effect. In light of these findings, future research should focus on mechanisms other than increased plasma 5-hydroxytryptamine [corrected] to explain how fenfluramine increases the risk of primary pulmonary hypertension and valvular heart disease.

TSH response to TRH in euthyroid, hypercholesterolemic patients treated with graded doses of dextrothyroxine.

In an attempt to determine the minimum dose of D-Thyroxine (D-T4) which will suppress pituitary TSH response to TRH, we have treated 6 euthyroid, hypercholesterolemic patients with graded doses of D-T4. TSH response was suppressed in 3 patients with 3 mg and in the remaining 3 patients with 4 mg D-T4 administered once daily. The mean TSH suppressive dose of 3.5 mg, as determined in this study, is considerably less than the 6 mg daily dose given to patients treated with D-T4 in the Coronary Drug Project. This suggests that the adverse effects observed with D-T4 treatment in the Coronary Drug Project may have been due to mild, undetected hyperthryroidism. D-T4 treatment in our patients was not associated with an increase in heart rate or ventricular ectopic beats as determined by Holter monitoring. However, bile samples obtained at the time of TSH suppression showed a significant increase in lithogenic index. In four patients, TSH suppressive doses of D-T4 were associated with a 12% decrease in mean cholesterol and a 17% decrease in mean LDL cholesterol concentrations.