Factors predicting the course of diabetes mellitus in hyperthyroid patients

The relationship between changes in glucose tolerance with treatment of hyperthyroidism and various factors that might be relevant to carbohydrate metabolism were investigated in 64 hyperthyroid patients with abnormal glucose tolerance, including 35 cases with fasting plasma glucose (FPG) levels of 140 mg/dl or more. All patients had diffuse toxic goiter. After correction of the hyperthyroidism, glucose intolerance improved in almost all cases, even in cases with fasting hyperglycemia, but diabetes mellitus in patients with FPG above 140 mg/dl and/or delta IRI/delta PG X 30' during a 50-g oral glucose tolerance test below 0.10, persisted. Patients who showed diabetic glucose tolerance even after remission from thyroid dysfunction had significantly lower delta IRI/delta PG X 30' values and a higher incidence of family histories of diabetes mellitus than those not showing diabetic glucose tolerance. There were no significant differences in serum T3 and T4 levels between these two groups of patients. The findings suggest that predisposition to diabetes may be an important factor in persistent glucose intolerance in the hyperthyroidism of Graves' disease. The FPG and delta IRI/delta PG X 30' values may be useful in predicting which patients with hyperthyroidism will have permanent diabetes.     

Metabolic consequences of atenolol and propranolol in treatment of essential hypertension.

A six-month study of triglyceride, cholesterol, free fatty acid (FFA), glucose, insulin, growth hormone, and glucagon concentrations was carried out in asymptomatic hypertensive normal-weight men randomly allocated to treatment with atenolol or propranolol. A highly significant increase in the basal plasma triglyceride concentration was observed in propranolol-treated patients after three and six months'' treatment, with a smaller but significant increase in atenolol-treated subjects after six months'' treatment. The changes in triglyceride concentration could not be ascribed to variations in plasma insulin, growth hormone, or glucagon concentrations. Basal FFA concentrations were reduced during the first three months of treatment in both groups but returned to pretreatment levels after six months. Plasma cholesterol concentrations were unchanged by either agent.     

Hemodynamic and metabolic responses to exercise after adrenoceptor blockade in humans

The effects of acute alpha 1-adrenoceptor blockade with prazosin, beta 1-adrenoceptor blockade with atenolol, and nonselective beta-adrenoceptor blockade with propranolol were compared in a placebo-controlled crossover study of the hemodynamic and metabolic responses to acute exercise 2 h after prolonged prior exercise to induce skeletal muscle glycogen depletion, enhancing the dependence on hepatic glucose output and circulating free fatty acids (FFA). Plasma catecholamines were higher during exercise after, as opposed to before, glycogen depletion and were elevated further by all three drugs. Propranolol failed to produce a significant reduction in systolic blood pressure and elevated diastolic blood pressure. Atenolol reduced systolic blood pressure and did not change diastolic blood pressure. Both beta-blockers reduced FFA levels, but only propranolol lowered plasma glucose relative to placebo during exercise after glycogen depletion. In contrast, prazosin reduced systolic and diastolic blood pressures and resulted in elevated FFA and glucose levels. The results indicate important differences in the hemodynamic effects of beta 1-selective vs. nonselective beta-blockade during exercise after skeletal muscle glycogen depletion. Furthermore they confirm the importance of beta 2-mediated hepatic glucose production in maintaining plasma glucose levels during exercise. Acute alpha 1-blockade with prazosin induces reflex elevation of catecholamines, which in the absence of blockade of hepatic beta 2-receptors produces elevation of plasma glucose. The results suggest there is little role for alpha 1-mediated hepatic glucose production during exercise in humans.     

Continuous 24-h nicotinic acid infusion in rats causes FFA rebound and insulin resistance by altering gene expression and basal lipolysis in adipose tissue

Nicotinic acid (NA) has been used as a lipid drug for five decades. The lipid-lowering effects of NA are attributed to its ability to suppress lipolysis in adipocytes and lower plasma FFA levels. However, plasma FFA levels often rebound during NA treatment, offsetting some of the lipid-lowering effects of NA and/or causing insulin resistance, but the underlying mechanisms are unclear. The present study was designed to determine whether a prolonged, continuous NA infusion in rats produces a FFA rebound and/or insulin resistance. NA infusion rapidly lowered plasma FFA levels (>60%, P < 0.01), and this effect was maintained for ≥5 h. However, when this infusion was extended to 24 h, plasma FFA levels rebounded to the levels of saline-infused control rats. This was not due to a downregulation of NA action, because when the NA infusion was stopped, plasma FFA levels rapidly increased more than twofold (P < 0.01), indicating that basal lipolysis was increased. Microarray analysis revealed many changes in gene expression in adipose tissue, which would contribute to the increase in basal lipolysis. In particular, phosphodiesterase-3B gene expression decreased significantly, which would increase cAMP levels and thus lipolysis. Hyperinsulinemic glucose clamps showed that insulin's action on glucose metabolism was improved during 24-h NA infusion but became impaired with increased plasma FFA levels after cessation of NA infusion. In conclusion, a 24-h continuous NA infusion in rats resulted in an FFA rebound, which appeared to be due to altered gene expression and increased basal lipolysis in adipose tissue. In addition, our data support a previous suggestion that insulin resistance develops as a result of FFA rebound during NA treatment. Thus, the present study provides an animal model and potential molecular mechanisms of FFA rebound and insulin resistance, observed in clinical studies with chronic NA treatment.     

Insulin secretion and sensitivity in hyperthyroidism

To examine the effect of hyperthyroidism on carbohydrate metabolism, we studied glucose-stimulated insulin secretion and glucose utilization in 8 subjects with Graves' disease before and after treatment for hyperthyroidism and 8 age-, sex- and weight-matched normal subjects. Subjects with Graves' disease had significant elevated serum levels of thyroxine (24.81 +/- 2.44 micrograms/dl, mean +/- SEM) and triiodothyronine (459 +/- 5.5 ng/dl, mean +/- SEM). Simultaneous measurement of plasma glucose, serum insulin and C-peptide levels during fasting and every 30 minutes up to 180 minutes after 75 g oral glucose loading was determined. In addition, plasma glucose, serum insulin and serum C-peptide were measured during euglycemic glucose clamp with insulin infusion of 40 mU/m2 min-1. Mean fasting plasma glucose (P less than 0.05, serum insulin (P less than 0.005) and serum C-peptide (P less than 0.005) levels were significantly higher in the hyperthyroid patients. After glucose loading, the plasma glucose (P less than 0.05), serum insulin (P less than 0.05) and C-peptide (P less than 0.05) responses were significantly higher in hyperthyroid patients at all times up to 180 minutes. During euglycemic clamp studies, the steady-state serum insulin levels were identical in the two groups. The glucose disposal rate was lower in hyperthyroid patients before treatment (P less than 0.01) than in normal subjects. After thyroid function had been normalized for 2 to 4 weeks, the glucose disposal rate increased significantly (P less than 0.05), but was still significantly lower than those of normal subjects (P less than 0.05). Our data show that patients with Graves' hyperthyroidism manifest glucose intolerance, hyperinsulinemia and insulin resistance.     

Metabolic effects of chronic prazosin treatment

The effects of chronic (3 mg/day for 1 week) administration of the vasodilator drug prazosin on several metabolic and endocrine variables were evaluated in 12 hypertensive patients, 6 with normal and 6 with abnormal oral glucose tolerance test (OGTT). After 1 week prazosin treatment there were no significant modifications in fasting plasma glucose, serum free fatty acids (FFA), cholesterol, triglycerides, insulin (IRI), growth hormone (GH), prolactin (PRL) and gastrin levels; oral glucose tolerance and IRI response to glucose were unchanged in normal subjects, while in chemical diabetics there was a significant improvement in glucose tolerance and a slight increse in IRI secretion. Therefore, the untoward metabolic effects of acute prazosin administration, i.e. increased plasma glucose and serum FFA, are not sustained during chronic treatment, which may even improve glucose metabolism in diabetic patients.     

Effect of Acipimox on Plasma Lipids and Glucose/Insulin in Pregnant Rats

To determine how a reduction in maternal hypertriglyceridemia during late pregnancy may affect glucose/insulin relationships, pregnant and virgin rats were orally treated with acipimox, a potent antilipolytic agent. In 20-day pregnant rats receiving 80 mg of acipimox, plasma triglycerides (TG), free fatty acids (FFA), and glycerol decreased more than in virgin rats shortly after the drug (up to 7 hours), when compared with animals treated with distilled water, whereas plasma glucose level was unaffected by the treatment in either group of rats. When acipimox was given every 12 hours from day 17 to day 20 of pregnancy, plasma TG, FFA, and glycerol levels progressively increased, whereas they either decreased or did not change in virgin rats receiving the same treatment, with no effect in plasma glucose levels in either group. Fetal body weight was lower than in controls in 20-day pregnant rats that received acipimox for 3 days. On day 20 of pregnancy, 3 hours after receiving acipimox or distilled water, rats received a 2 g glucose/kg oral load and it was found that the change in plasma glucose was similar in both groups, whereas the increase in plasma insulin was greater in pregnant rats treated with acipimox. However, no difference was found in either variable after the oral glucose load in virgin rats receiving acipimox or distilled water. No differences in plasma glucose levels were found after intravenous (IV) administration of insulin in pregnant rats treated or not treated with acipimox. In conclusion, present results show that administration of acipimox during the last days of gestation inhibited lipolysis and decreased fetal weight. Over a short period of time, in pregnant rats, reductions of plasma FFA and TG after acipimox treatment improved the glucose-induced insulin release, but did not seem to have any effect in peripheral insulin resistance.     

Changes in plasma glucose, insulin (IRI), glucagon (IRG) and free fatty acids (FFA) following alanine loading in hyperthyroid patients

The responses of plasma glucose, insulin (IRI), glucagon (IRG) and free fatty acids (FFA) following alanine loading (0.1 g/kg) were observed in 9 control subjects and 7 hyperthyroid patients, before and after restoration of thyroid function to normal. Despite the persistence of impaired glucose response to alanine, the blunted IRI and IRG responses in the hyperthyroid state were improved with a significant reduction in fasting IRI and IRG after treatment. Markedly increased FFA following alanine loading in hyperthyroid patients was reduced after treatment, but the FFA concentration remained greater than in the control subjects. We tentatively conclude that the impaired alpha and beta-cell responses to alanine were temporarily induced by the direct and/or indirect effects of thyroid hormone excess.     

NO-1886改善糖尿病小型猪的糖代谢

合成化合物NO-1886是一种脂蛋白脂酶活化剂,已被证明其可降低血浆TG并能升高HDLC的浓度．后又发现其还有降低高脂高蔗糖诱发糖尿病兔血浆葡萄糖浓度的作用．对高脂高蔗糖饲料喂养的小型猪脂肪细胞大小、血浆TNF—α和FFA的水平以及NO-1886对其影响进行了研究,结果发现,脂肪细胞明显肥大．血浆TNF-α和FFA以及空腹血糖水平均增高,且引起胰岛素抵抗．添加了l％NO-1886后．脂肪细胞增大被抑制,血浆TNF—α、FFA和空腹血糖的浓度均显著降低,血浆葡萄糖清除率和胰岛素分泌急性相都有了明显改善．以上结果说明,NO-1886可能通过抑制脂肪蓄积、降低血浆TNF-α和FFA的浓度而改善高脂高蔗糖饲料引起的小型猪的糖代谢紊乱．     

Effect of meal and propranolol on whole body and splanchnic oxygen consumption in patients with cirrhosis

Our aim was to measure whole body energy expenditure after a mixed liquid meal, with and without simultaneous propranolol infusion, in patients with cirrhosis. We also wanted to investigate the effect of propranolol on substrate fluxes and oxygen uptake in the tissues drained by the hepatic vein and azygos vein in the postprandial period in these patients. Whole-body oxygen uptake, hepatic blood flow, hepatic venous pressure gradient and net-hepatic fluxes of oxygen, lactate, glucose, glycerol, and free fatty acids (FFA) were measured in 12 patients with alcoholic cirrhosis before and for 2 h after ingestion of a mixed liquid meal (700 kcal). Half of the patients (n = 6) were randomized to a treatment group receiving intravenous infusion of propranolol in combination with the meal. The meal-induced energy expenditure was significantly lower in patients given propranolol [15.0 +/- 18.9 vs. 67.0 +/- 26.1 kJ/120 min (means +/- SD), P < 0.01]. Meal-induced whole body oxygen uptake was lower in patients receiving propranolol (19.2 +/- 38 vs. 135.7 +/- 61 mmol/120 min, P < 0.01), and the meal-induced increase in splanchnic oxygen uptake was nonexistent when propranolol was administered in combination (-13.2 +/- 34.8 vs. 110.4 +/- 34.8 mmol/120 min, P = 0.04). Postprandially, the propranolol group had a tendency toward a reduced splanchnic glucose output, and the FFA uptake was significantly reduced. Propranolol reduces meal-induced whole body oxygen uptake and energy expenditure as well as splanchnic oxygen uptake. The splanchnic reduction in oxygen consumption can explain almost the entire reduction in whole body oxygen consumption.     

The relation between free fatty acid levels and tolerance for glucose in a triple glucose tolerance test

The improved glucose tolerance observed in a multiple glucose tolerance test (Staub-Traugott effect) has been observed in dogs with concomitant measurement of immunoreactive insulin (IRI) and plasma free fatty acid (FFA). It was possible to reduce and in one experiment eliminate the improved glucose tolerance observed in the Staub-Traugott procedure. This was done in successive experiments in which the glucose challenge dose was 1 × BW^{0 period; 7} grams: (1) by injecting octanoate (0.1 mmoles/kg each hour) at the same time as the glucose; (2) by supplementing the injections with the infusion of octanoate (0.1 mmoles/kg/15 mins) during the second and third hours; (3) by repeating this last procedure after a seven day fast. Similar experiments were carried out with a larger glucose challenge dose (1 g/kg).Glucose tolerance appeared to depend as strongly on FFA levels as it did on IRI levels, and improvement in glucose tolerance occurred only when there was an associated reduction in FFA for a given glucose challenge. A measure of the Staub-Traugott effect was defined in terms of the different glucose utilizations during a multiple glucose tolerance test. An increase in the mean FFA levels achieved before or during a multiple glucose tolerance test lessened or eliminated the Staub-Traugott effect.     

Hyperthyroidism is associated with higher plasma endothelin-1 concentrations

The objective of this study was to determine the change of plasma endothelin (ET)-1 concentrations and insulin resistance index after therapy for hyperthyroidism. We studied 20 patients with hyperthyroidism (15 women and 5 men; age, 34.0 +/- 2.8 years), and 31 patients with euthyroid goiters as controls (27 women, 4 men; age, 37.0 +/- 2.4 years). All hyperthyroid patients were treated with antithyroid drugs. The patients received evaluations before and after normalization of thyroid function. The evaluations included body mass index (BMI), body fat, and measurement of circulating concentrations of thyroid hormones, glucose, insulin, and ET-1. Hyperthyroid subjects had higher plasma ET-1 concentrations than the control group (P < 0.001). No significant differences in serum glucose and insulin concentrations or insulin resistance index estimated by the R value of the homeostasis model assessment (HOMA-R) were noted between the groups. Plasma ET-1 concentrations decreased after correction of hyperthyroidism compared with pretreatment (P = 0.006). Serum glucose concentrations decreased after correction of hyperthyroidism (P = 0.005). Moreover, both body weight-adjusted insulin concentrations and the HOMA-R index were also decreased after correction of hyperthyroidism compared with pretreatment (P = 0.026 and P = 0.019, respectively). Pearson's correlation revealed that plasma ET-1 levels positively correlated with serum triiodothyronine (T3) and free thyroxine (FT4) levels. Serum insulin levels and the HOMA-R index positively correlated with BMI and body fat. The HOMA-R index also positively correlated with serum T3 and FT4 levels. Neither insulin levels nor the HOMA-R index correlated with ET-1 levels. Hyperthyroidism is associated with higher plasma ET-1 concentrations. In addition, correction of hyperthyroidism is also associated with a decrease of plasma ET-1 levels as well as the insulin resistance index calculated by HOMA-R.     

Comparative effectiveness of carvedilol and propranolol on glycemic control and insulin resistance associated with L-thyroxin-induced hyperthyroidism--an experimental study

The present study was undertaken to investigate the effectiveness of adrenergic antagonists carvedilol and propranolol on L-thyroxin-induced cardiovascular and metabolic disturbances in rats. Treatment with L-thyroxin sodium (75 mg/kg body mass, s.c., every alternate day for 3 weeks), produced a significant increase in food and water intake, body temperature, heart rate, systolic blood pressure, along with an increase in serum T3, T4, and triglyceride levels. Besides a significant reduction in body mass, serum levels of TSH and cholesterol were also reduced following L-thyroxin treatment. Carvedilol (10 mg/kg body mass, orally) and propranolol (10 mg/kg body mass, i.p.) administered daily in the third week to 2 separate groups of L-thyroxin-treated animals reversed thyroxin-induced loss in body mass and rise in body temperature, blood pressure, and heart rate. Propranolol treatment increased TSH levels and decreased T3 and T4 levels in hyperthyroid animals, whereas carvedilol did not produce any effect on thyroid hormones. Carvedilol treatment reversed thyroxin induced hypertriglyceridemia, whereas propranolol treatment had no effect. Both carvedilol and propranolol prevented decrease in cholesterol levels induced by thyroxine. Compared with normal animals, L-thyroxin-treated animals showed a state of hyperglycemia, hyperinsulinaemia, impaired glucose tolerance, and insulin resistance, as inferred from elevated fasting serum glucose and insulin levels, higher area under the curve over 120 min for glucose, and decreased insulin sensitivity index (KITT). Propranolol and carvedilol treatment significantly decreased fasting serum glucose levels. Treatment with propranolol did not alter serum insulin levels, area-under-the-curve glucose, or KITT values. However, treatment with carvedilol significantly reduced area-under-the-curve glucose, decreased fasting serum insulin levels and significantly increased KITT values. In conclusion, carvedilol appears to produce favorable effects on insulin sensitivity and glycemic control and can therefore be considered as more efficacious adjunctive treatment than propranolol in hyperthyroidism.     

Thiazolidinediones improve beta-cell function in type 2 diabetic patients

Thiazolidinediones (TZDs) improve glycemic control and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). There is growing evidence from in vivo and in vitro studies that TZDs improve pancreatic beta-cell function. The aim of this study was to determine whether TZD-induced improvement in glycemic control is associated with improved beta-cell function. We studied 11 normal glucose-tolerant and 53 T2DM subjects [age 53+/-2 yr; BMI 29.4+/-0.8 kg/m2; fasting plasma glucose (FPG) 10.3+/-0.4 mM; Hb A1c 8.2+/-0.3%]. Diabetic patients were randomized to receive placebo or TZD for 4 mo. Subjects received 1) 2-h OGTT with determination of plasma glucose, insulin, and C-peptide concentrations and 2) two-step euglycemic insulin (40 and 160 mU.m-2.min-1) clamp with [3-(3)H]glucose. T2DM patients were then randomized to receive 4 mo of treatment with pioglitazone (45 mg/day), rosiglitazone (8 mg/day), or placebo. Pioglitazone and rosiglitazone similarly improved FPG, mean plasma glucose during OGTT, Hb A1c, and insulin-mediated total body glucose disposal (Rd) and decreased mean plasma FFA during OGTT (all P<0.01, ANOVA). The insulin secretion/insulin resistance (disposition) index [DeltaISR(AUC)/Deltaglucose(AUC)/IR] was significantly improved in all TZD-treated groups: +1.8+/-0.7 (PIO+drug-na?ve diabetics), +0.7+/-0.3 (PIO+sulfonylurea-treated diabetics), and 0.7+/-0.2 (ROSI+sulfonylurea-withdrawn diabetics) vs. -0.2+/-0.3 in the two placebo groups (P<0.01, all TZDs vs. placebo, ANOVA). Improved insulin secretion correlated positively with increased body weight, fat mass, and Rd and inversely with decreased plasma glucose and FFA during the OGTT. In T2DM patients, TZD treatment leads to improved beta-cell function, which correlates strongly with improved glycemic control.     

Arterial hypertension associated with hyper and hypothyroidism]

45 patients with hyper and hypothyroidism in the time 1989-1990 were observed. The Graves' disease was diagnosed in 29 and rather in the younger patients, but 16 had the toxic nodular goiter and those were elderly. In 27 the hypertension was secondary (symptomatic) and after the successful treatment of the hyperthyroidism was completely controlled. In 14 cases the hypertension was primary (essential) and the application of the hypotensive drugs was also necessary. Among 4 patients with primary hypothyroidism and associated hypertension and coronary insufficiency the early treatment by the thyroid preparation was successful: the blood pressure was lowered and the coronary insufficiency was improved; but if the replacement therapy was stopped and the hypothyroidism was relapsed, the blood pressure was increases and the coronary insufficiency was aggravated. Conclusions: 1. The secondary (symptomatic) hypertension associated with the hyperthyroidism may be controlled by successful treatment of the thyrotoxicosis, but the primary (essential) must be treated by the hypotensive drugs also. 2. The early treatment of the hypothyroidism may control the associated hypertension and the coronary insufficiency. 3. Graves' disease is associated mostly with symptomatic hypertension, in nodular toxic goiter in most of the cases the essential hypertension was established.     

Metabolic responses to catecholamines in dogs injected with a single dose of triiodothyronine.

Lipolytic and glycogenolytic responses to catecholamine infusions were studied in resting dogs before and 20 h following administration of a single dose (0.1 mg/kg) of triiodothyronine (T3). In the dogs pretreated with T3 much higher increases in the plasma FFA concentration were found both during noradrenaline and adrenaline infusions in comparison with control experiments. Adrenaline-induced increases in blood LA and glucose levels were also significantly higher in T3-pretreated dogs than in controls. The blockade of beta-adrenergic receptors with propranolol prevented the increases in blood FFA and LA concentrations during subsequent adrenaline infusion. Phentolamine -- the alpha-adrenergic blocking agent -- infused to the T3-pretreated dog inhibited the adrenaline-induced rise in blood glucose level. The observed changes in the metabolic responses to catecholamines induced by triiodothyronine pretreatment indicate that at least in the dog this hormone potentiates both the lipolytic and glycogenolytic effects of catecholamines acting on appropriate adrenergic receptors.     

Diabetogenic effect of triamcinolone in man with impaired thyroid function: serum free fatty acids, inorganic phosphorus, calcium and total protein pattern after an oral glucose load.

In a group of 35 subjects (12 hypothyroid, 11 euthyroid and 12 hyperthyroid) the changes of FFA, inorganic phosphorus, calcium and total proteins were investigated during glucose tolerance test with (TGTT) or without (OGTT) triamcinolone pretreatment. In hypothyroidism the decrease of FFA during TGTT was blunted, whereas the pattern of phosphatemia was unaltered and total proteins were increased. In euthyroidism triamcinolone exerts the opposite effect on the behaviour of FFA (decline was smaller and shorter) and phosphatemia (decline was pronounced and persists for longer period). In hyperthyroidism the fasting level of FFA decreased in TGTT but during the test no significant differences in FFA and phosphatemia patterns were observed. The calcemia was not influenced by triamcinolone in any subgroup. Our results suggest the importance of thyroid function as modifying factor in some metabolic effects of triamcinolone in man. Changes in hypothyroidism are in good agreement with changes of blood glucose and insulinemia, as described previously. Opposite effect of triamcinolone on FFA and phosphatemia pattern in euthyroidism may suggest the changes of sensitivity of some peripheral tissues to insulin action. The decline of fasting level of FFA after triamcinolone in hyperthyroidism is surprising and might be of importance in maintaining unaltered glucose tolerance after triamcinolone in this subgroup.     

Tesaglitazar, a dual PPAR{alpha}/{gamma} agonist, ameliorates glucose and lipid intolerance in obese Zucker rats

Insulin resistance, impaired glucose tolerance, high circulating levels of free fatty acids (FFA), and postprandial hyperlipidemia are associated with the metabolic syndrome, which has been linked to increased risk of cardiovascular disease. We studied the metabolic responses to an oral glucose/triglyceride (TG) (1.7/2.0 g/kg lean body mass) load in three groups of conscious 7-h fasted Zucker rats: lean healthy controls, obese insulin-resistant/dyslipidemic controls, and obese rats treated with the dual peroxisome proliferator-activated receptor alpha/gamma agonist, tesaglitazar, 3 mumol.kg(-1).day(-1) for 4 wk. Untreated obese Zucker rats displayed marked insulin resistance, as well as glucose and lipid intolerance in response to the glucose/TG load. The 2-h postload area under the curve values were greater for glucose (+19%), insulin (+849%), FFA (+53%), and TG (+413%) compared with untreated lean controls. Treatment with tesaglitazar lowered fasting plasma glucose, improved glucose tolerance, substantially reduced fasting and postload insulin levels, and markedly lowered fasting TG and improved lipid tolerance. Fasting FFA were not affected, but postprandial FFA suppression was restored to levels seen in lean controls. Mechanisms of tesaglitazar-induced lowering of plasma TG were studied separately using the Triton WR1339 method. In anesthetized, 5-h fasted, obese Zucker rats, tesaglitazar reduced hepatic TG secretion by 47%, increased plasma TG clearance by 490%, and reduced very low-density lipoprotein (VLDL) apolipoprotein CIII content by 86%, compared with obese controls. In conclusion, the glucose/lipid tolerance test in obese Zucker rats appears to be a useful model of the metabolic syndrome that can be used to evaluate therapeutic effects on impaired postprandial glucose and lipid metabolism. The present work demonstrates that tesaglitazar ameliorates these abnormalities and enhances insulin sensitivity in this animal model.     

The longitudinal effect of inhibiting fatty acid oxidation in diabetic rats fed a high fat diet.

This study was designed to examine the time-course of response to inhibition of fatty acid (FA) oxidation in rats rendered mildly diabetic with streptozotocin and fed a high fat diet (50% of energy derived from fat). Etomoxir, a specific carnitine palmitoyltransferase (CPT-1) inhibitor, was administered subcutaneously (12.5 mg/kg) to inhibit long chain fatty acid oxidation. Diabetic and non-diabetic control rats were maintained on the high fat diet. Following an overnight fast, glucose, free fatty acid (FFA) and triglyceride (TG) concentrations were determined after three days, one week and four weeks of treatment. The effect of Etomoxir treatment in reducing fasting glucose concentrations was not evident until after one week, while fasting FFA and TG concentrations were already reduced after three days treatment. All of these changes were maintained over the four week period (P less than 0.001), resulting in reduced levels of fasting plasma glucose (17.6 +/- 2.4 vs 22.3 +/- 1.9 mmol/l), fasting plasma TG (0.32 +/- 0.07 vs 0.98 +/- 0.14 mmol/l) and fasting serum FFA (1.52 +/- 0.26 vs 3.51 +/- 0.69 mEq/l). In addition, the improvements in glucose and lipid levels were accompanied by restored rates of growth towards that of non-diabetic control rats. These results suggest that the short term inhibition of FA oxidation improves fasting glucose, FFA and TG concentrations in diabetic rats fed a high fat diet.     

Effects of beta-adrenergic receptor stimulation and blockade on substrate metabolism during submaximal exercise

We used beta-adrenergic receptor stimulation and blockade as a tool to study substrate metabolism during exercise. Eight moderately trained subjects cycled for 60 min at 45% of VO(2 peak) 1) during a control trial (CON); 2) while epinephrine was intravenously infused at 0.015 microg. kg(-1) x min(-1) (beta-STIM); 3) after ingesting 80 mg of propranolol (beta-BLOCK); and 4) combining beta-BLOCK with intravenous infusion of Intralipid-heparin to restore plasma fatty acid (FFA) levels (beta-BLOCK+LIPID). beta-BLOCK suppressed lipolysis (i.e., glycerol rate of appearance) and fat oxidation while elevating carbohydrate oxidation above CON (135 +/- 11 vs. 113 +/- 10 micromol x kg(-1) x min(-1); P < 0.05) primarily by increasing rate of disappearance (R(d)) of glucose (36 +/- 2 vs. 22 +/- 2 micromol x kg(-1) x min(-1); P < 0.05). Plasma FFA restoration (beta-BLOCK+LIPID) attenuated the increase in R(d) glucose by more than one-half (28 +/- 3 micromol x kg(-1) x min(-1); P < 0.05), suggesting that part of the compensatory increase in muscle glucose uptake is due to reduced energy from fatty acids. On the other hand, beta-STIM markedly increased glycogen oxidation and reduced glucose clearance and fat oxidation despite elevating plasma FFA. Therefore, reduced plasma FFA availability with beta-BLOCK increased R(d) glucose, whereas beta-STIM increased glycogen oxidation, which reduced fat oxidation and glucose clearance. In summary, compared with control exercise at 45% VO(2 peak) (CON), both beta-BLOCK and beta-STIM reduced fat and increased carbohydrate oxidation, albeit through different mechanisms.