RESUMO
Fish oils, containing omega-3 fatty acids (omega 3FAs), favorably influence plasma lipoproteins in nondiabetic humans and prevent the development of insulin resistance induced by fat feeding in rats. We studied the effects of fish oils in 10 subjects (aged 42-65 yr) with mild non-insulin-dependent diabetes mellitus (NIDDM). Subjects were fed a standard diabetic diet plus 1) no supplementation (baseline), 2) 10 g fish oil concentrate (30% omega 3FAs) daily, and 3) 10 g safflower oil daily over separate 3-wk periods, the latter two supplements being given in radom order by use of a double-blind crossover design. At the end of each diet period, fasting blood glucose (FBG), insulin, and lipids were measured, and insulin sensitivity was assessed with a hyperinsulinemic-euglycemic clamp performed with [3-3H]glucose. FBG increased 14% during fish oil and 11% during safflower oil supplementation compared with baseline (P less than .05), whereas body weight, fasting serum insulin levels, and insulin sensitivity were unchanged. The absolute increase in FBG during each supplementation period correlated with the baseline FBG (fish oil, r = .83, P less than .005); safflower oil, r = .75, P = .012). Fasting plasma triglyceride levels decreased during fish oil supplementation in the 4 subjects with baseline hypertriglyceridemia (greater than 2 mM) but were not significantly reduced overall. There was no significant change in fasting plasma total, high-density lipoprotein, and low-density lipoprotein cholesterol levels. In summary, dietary fish oil supplementation adversely affected glycemic control in NIDDM subjects without producing significant beneficial effects on plasma lipids. The effect of safflower oil supplementation was not significantly different from fish oil, suggesting that the negative effects on glucose metabolism may be related to the extra energy or fat intake.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Glicemia/metabolismo , Colesterol/sangue , Diabetes Mellitus Tipo 2/sangue , Óleos de Peixe/farmacologia , Triglicerídeos/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Dieta para Diabéticos , Jejum , Feminino , Técnica Clamp de Glucose , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
Insulin-resistant states are associated with accumulation of muscle lipid, suggesting an imbalance between lipid uptake and oxidation. We have employed a new fatty-acid tracer [9,10-3H]-(R)-2-bromopalmitate (3H-R-BrP) to study individual-tissue nonesterified fatty acid (NEFA) uptake in states with diminished or enhanced lipid oxidation. 3H-R-BrP was administered to conscious male Wistar rats (approximately 300 g) during fasting (5, 18, or 36 h), acute blockade of beta-oxidation (etomoxir, 15 micromol/kg), and insulin infusion (0.25 U x kg(-1) x h(-1)). Estimates of NEFA clearance rates (K(f)*) and absolute rates of uptake (R(f)*) were calculated from tissue accumulation of 3H-R-BrP products. In the basal state, NEFA uptake was dependent on the oxidative capacity of tissues: R(f)* in brown adipose tissue (BAT) > heart (HRT) > diaphragm (DPHM) > red quadriceps (RQ) > white quadriceps (WQ) > white adipose tissue (WAT). Fasting increased (P < 0.001) K(f)* in WAT but did not change NEFA clearance in other tissues. However, plasma NEFA levels were raised (P < 0.01), tending to elevate R(f)* in most tissues (P < 0.05: WAT, BAT, WQ, DPHM). Etomoxir reduced (P < 0.01) K(f)* only in oxidative tissues (BAT, RQ, DPHM, HRT). Insulin lowered plasma NEFA levels (P < 0.001) and significantly decreased R(f)* in most tissues (P < 0.05: WAT, RQ, DPHM, HRT). An increased (P < 0.05) clearance was observed in WAT, BAT, and WQ; a decrease (P < 0.01) in K(f)* was observed in HRT. This study is the first to measure tissue-specific NEFA uptake in conscious rats in the postabsorptive, fasted, and insulin-stimulated states. We have demonstrated that tissue NEFA utilization is not exclusively determined by systemic availability, but that the early steps of NEFA uptake or metabolic sequestration can also be rapidly modulated by local processes such as NEFA oxidation.
Assuntos
Ácidos Graxos não Esterificados/metabolismo , Palmitatos/farmacocinética , Ácido Palmítico/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Transporte Biológico , Radioisótopos de Carbono , Jejum , Ácidos Graxos não Esterificados/sangue , Hipoglicemiantes/farmacocinética , Masculino , Taxa de Depuração Metabólica , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Especificidade de Órgãos , Ratos , Ratos Wistar , Distribuição Tecidual , TrítioRESUMO
Chronic high-fat feeding in rats induces profound whole-body insulin resistance, mainly due to effects in oxidative skeletal muscle. The mechanisms of this reaction remain unclear, but local lipid availability has been implicated. The aim of this study was to examine the influence of three short-term physiological manipulations intended to lower muscle lipid availability on insulin sensitivity in high-fat-fed rats. Adult male Wistar rats fed a high-fat diet for 3 weeks were divided into four groups the day before the study: one group was fed the normal daily high-fat meal (FM); another group was fed an isocaloric low-fat high-glucose meal (GM); a third group was fasted overnight (NM); and a fourth group underwent a single bout of exercise (2-h swim), then were fed the normal high-fat meal (EX). In vivo insulin action was assessed using the hyperinsulinemic glucose clamp (plasma insulin 745 pmol/l, glucose 7.2 mmol/l). Prior exercise, a single low-fat meal, or fasting all significantly increased insulin-stimulated glucose utilization, estimated at either the whole-body level (P < 0.01 vs. FM) or in red quadriceps muscle (EX 18.2, GM 28.1, and NM 19.3 vs. FM 12.6 +/- 1.1 micromol x 100 g(-1) x min(-1); P < 0.05), as well as increased insulin suppressibility of muscle total long-chain fatty acyl-CoA (LC-CoA), the metabolically available form of fatty acid (EX 24.0, GM 15.5, and NM 30.6 vs. FM 45.4 nmol/g; P < 0.05). There was a strong inverse correlation between glucose uptake and LC-CoA in red quadriceps during the clamp (r = -0.7, P = 0.001). Muscle triglyceride was significantly reduced by short-term dietary lipid withdrawal (GM -22 and NM -24% vs. FM; P < 0.01), but not prior exercise. We concluded that muscle insulin resistance induced by high-fat feeding is readily ameliorated by three independent, short-term physiological manipulations. The data suggest that insulin resistance is an important factor in the elevated muscle lipid availability induced by chronic high-fat feeding.
Assuntos
Gorduras na Dieta/administração & dosagem , Resistência à Insulina , Insulina/sangue , Músculo Esquelético/efeitos dos fármacos , Esforço Físico , Acil Coenzima A/metabolismo , Animais , Glicemia/metabolismo , Carboidratos da Dieta/administração & dosagem , Ingestão de Energia , Jejum , Glucose/administração & dosagem , Técnica Clamp de Glucose , Glicogênio/metabolismo , Masculino , Malonil Coenzima A/metabolismo , Músculo Esquelético/metabolismo , Ratos , Ratos Wistar , Triglicerídeos/metabolismoRESUMO
A semiclosed loop, bedside insulin infusion system using a simple basal infusion algorithm consisting of a linear transition between two insulin delivery rates as blood glucose (BG) increases has been developed. A theoretical study using computer simulation has now been undertaken to examine the effect of BG sampling frequency and algorithm parameters on BG control. A model for BG control by exogenous insulin in the individual with diabetes was developed from a model for healthy subjects and from clinical data in the literature. Results of computer simulation using this model showed a decrease in BG stability as the sampling interval increased from 1 to 4 h. Simulations also showed a decrease in BG stability as the sensitivity of the control algorithm increased. Choice of an appropriate basal control algorithm involved a compromise between stability, sampling interval, and metabolic control. We conclude that satisfactory metabolic control can be obtained using intermittent BG sampling in the basal state; sampling at intervals of 3 h combined with a basal control algorithm whereby insulin delivery rate increases linearly from 0.5 to 2.5 U/h over the BG range 2-12 mmol/L appears suitable for most diabetic persons. Three-hour sampling offers a good compromise between degree of metabolic control and clinical effort involved.
Assuntos
Glicemia/análise , Computadores , Diabetes Mellitus/tratamento farmacológico , Sistemas de Infusão de Insulina , Modelos Biológicos , HumanosRESUMO
OBJECTIVE: Subjects with IDDM should take carbohydrate before exercise to avoid hypoglycemia. However, there is little information on the glycemic effect of recommended supplementation. This study is aimed to determine the glycemic effects of oral glucose or bread (30 g carbohydrate) before 45 min of moderate exercise. RESEARCH DESIGN AND METHODS: Nine subjects with uncomplicated IDDM did 45 min of bicycle ergometer exercise at 60% VO2max in the morning before insulin injection on three occasions: 1) with no carbohydrate supplement, 2) with 30 g glucose in water at -5 min, and 3) with 30 g carbohydrate as white bread with water at -20 min. The glycemic responses were determined. The glycemic responses to glucose and bread were also determined without exercise in six subjects. RESULTS: Without carbohydrate, exercise caused a small fall (-1.2 +/- 0.6 mmol/l, mean +/- SE) in plasma glucose (PG). With either glucose or bread, PG rose (the change in plasma glucose relative to basal [delta PG] = 5.1 +/- 0.8 and 2.6 +/- 0.8, respectively). The rise was greater (P < 0.01) without exercise (delta PG = 6.9 +/- 0.7 and 4.5 +/- 0.7, respectively). During exercise, glucose increased PG levels more than bread increased glucose levels P < 0.05). CONCLUSIONS: Before morning insulin injection, the fall in PG during moderate exercise in IDDM subjects is generally small or absent. The glycemic effects of complex carbohydrate are slightly less than glucose before exercise. Under these circumstances, the usually recommended amount of carbohydrate tends to cause an unwanted elevation of PG; thus, IDDM subjects should anticipate reducing or even omitting carbohydrate supplementation after monitoring their individual glycemic response.
Assuntos
Glicemia/metabolismo , Pão , Diabetes Mellitus Tipo 1/fisiopatologia , Carboidratos da Dieta , Teste de Esforço , Glucose , Esforço Físico , Adolescente , Adulto , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Feminino , Frequência Cardíaca , Humanos , Insulina/uso terapêutico , Masculino , Consumo de Oxigênio , Descanso , Fatores de TempoRESUMO
OBJECTIVE: To examine the mechanisms by which weight loss improves glycemic control in overweight subjects with NIDDM, particularly the relationships between energy restriction, improvement in insulin sensitivity, and regional and overall adipose tissue loss. RESEARCH DESIGN AND METHODS: Hyperinsulinemic glucose clamps were performed in 20 subjects (BMI = 32.0 +/- 0.5 [SEM] kg/m2, age = 48.4 +/- 2.7 years) with normal glucose tolerance (NGT) (n = 10) or mild NIDDM (n = 10) before and on the 4th (d4) and 28th (d28) days of a reduced-energy (1,100 +/- 250 [SD] kcal/day) formula diet. Body composition changes were assessed by dual energy x-ray absorptiometry and insulin secretory changes were measured by insulin response to intravenous glucose before and after weight loss. RESULTS: In both groups, energy restriction (d4) reduced fasting plasma glucose (FPG) (delta FPG: NGT = -0.4 +/- 0.2 mmol/l and NIDDM = -1.1 +/- 0.03 mmol/l, P = 0.002), which was independently related to reduced carbohydrate intake (partial r = 0.64, P = 0.003). There was a marked d4 increase in percent of insulin suppression of hepatic glucose output (HGO) in both groups (delta HGO suppression: NGT = 28 +/- 15% and NIDDM = 32 +/- 8%, P = 0.002). By d28, with 6.3 +/- 0.4 kg weight loss, FPG was further reduced (d4 vs. d28) in NIDDM only (P = 0.05), and insulin sensitivity increased in both groups (P = 0.02). Only loss of abdominal fat related to improvements in FPG (r = 0.51, P = 0.03) and insulin sensitivity after weight loss (r = 0.48, P = 0.05). In contrast to insulin action, there were only small changes in insulin secretion. CONCLUSIONS: Both energy restriction and weight loss have beneficial effects on insulin action and glycemic control in obesity and mild NIDDM. The effect of energy restriction is related to changes in individual macronutrients, whereas weight loss effects relate to changes in abdominal fat.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Mellitus/fisiopatologia , Dieta para Diabéticos , Obesidade , Redução de Peso/fisiologia , Antropometria , Composição Corporal/fisiologia , Diabetes Mellitus/dietoterapia , Diabetes Mellitus/metabolismo , Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/metabolismo , Dieta com Restrição de Gorduras , Ingestão de Energia/fisiologia , Metabolismo Energético/fisiologia , Jejum , Ácidos Graxos não Esterificados/metabolismo , Feminino , Glucose/metabolismo , Teste de Tolerância a Glucose , Humanos , Hiperglicemia/fisiopatologia , Hiperglicemia/prevenção & controle , Insulina/metabolismo , Resistência à Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Valores de ReferênciaRESUMO
Controversy exists about rates of bone mineral loss from the lumbar spine at the menopause. Cross-sectional studies of lumbar bone mineral against age have been interpreted as evidence for or against a menopause-related change in lumbar bone loss, depending on their goodness of fit to either linear or nonlinear equations. To investigate the ability of cross-sectional studies to detect accelerated lumbar bone loss at the menopause, we constructed models of different patterns of loss and evaluated the findings in cross-sectional analyses of computer-simulated populations of normal women. A sample size of greater than 300 was needed to distinguish between linear and nonlinear patterns of bone loss with a power of 90% when the data was analyzed throughout life. Examining for differences between the slopes of the regressions of pre- and postmenopausal women was more useful for detecting nonlinear bone loss under some circumstances. A difference between slopes was apparent in studies containing 100 subjects if lumbar bone density (BMD) was assumed to be unchanged prior to the menopause, but a larger study size was needed (greater than 1000) if BMD was assumed to fall before the menopause. We also measured lumbar BMD by dual photon absorptiometry in 141 normal females. When the data was analyzed against age throughout life, a nonlinear pattern of bone loss was found, and comparison of pre- and postmenopausal subjects showed a significant difference in the slopes of the linear regressions. Our patient data support the concept of a relatively stable lumbar BMD prior to the menopause with a rapid but transient decline postmenopausally.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Envelhecimento , Osso e Ossos/anatomia & histologia , Menopausa , Simulação por Computador , Feminino , HumanosRESUMO
Peroxisome proliferator-activated receptor gamma (PPAR-gamma) activation in adipose tissue is known to regulate genes involved in adipocyte differentiation and lipid metabolism. However, the role of PPAR-gamma in muscle remains unclear. To examine the potential regulation of genes by PPAR-gamma in human skeletal muscle, we used semiquantitative RT-PCR to determine the expression of PPAR-gamma, lipoprotein lipase (LPL), muscle carnitine palmitoyl transferase-1 (mCPT1), fatty acid-binding protein (FABP), carnitine acylcarnitine transferase (CACT), and glucose transporter-4 (GLUT4) in freeze-dried muscle samples from 14 male subjects. These samples were dissected free of adipose and other tissue contamination, as confirmed by minimal or absent adipsin expression. Between individuals, the messenger ribonucleic acid concentration of PPAR-gamma varied up to 3-fold, whereas LPL varied up to 6.5-fold, mCPT1 13-fold, FABP 4-fold, CACT 4-fold, and GLUT4 up to 3-fold. The expression of LPL (r2 = 0.54; P = 0.003), mCPT1 (r2 = 0.42; P = 0.012), and FABP (r2 = 0.324; P = 0.034) all correlated significantly with PPAR-gamma expression in the same samples. No significant correlation was observed between the expression of CACT and PPAR-gamma or between GLUT4 and PPAR-gamma. These findings demonstrate a relationship between PPAR-gamma expression and the expression of other genes of lipid metabolism in muscle and support the hypothesis that PPAR-gamma activators such as the antidiabetic thiazolidinediones may regulate fatty acid metabolism in skeletal muscle as well as in adipose tissue.
Assuntos
Carnitina Aciltransferases/genética , Proteínas de Transporte/genética , Regulação da Expressão Gênica , Lipase Lipoproteica/genética , Proteínas de Transporte de Monossacarídeos/genética , Proteínas Musculares , Músculo Esquelético/metabolismo , Proteínas de Neoplasias , Receptores Citoplasmáticos e Nucleares/fisiologia , Fatores de Transcrição/fisiologia , Proteínas Supressoras de Tumor , Idoso , Glicemia/metabolismo , Fator D do Complemento , Proteína 7 de Ligação a Ácidos Graxos , Proteínas de Ligação a Ácido Graxo , Ácidos Graxos não Esterificados/sangue , Transportador de Glucose Tipo 4 , Humanos , Insulina/sangue , Metabolismo dos Lipídeos , Masculino , Pessoa de Meia-Idade , Receptores Citoplasmáticos e Nucleares/genética , Valores de Referência , Análise de Regressão , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serina Endopeptidases/genética , Fatores de Transcrição/genética , Triglicerídeos/sangueRESUMO
A common observation in animal models and in humans is that accumulation of muscle triglyceride is associated with the development of insulin resistance. In animals, this is true of genetic models of obesity and nutritional models of insulin resistance generated by high-fat feeding, infusion of lipid, or infusion of glucose. Although there is a strong link between the accumulation of triglycerides (TG) in muscle and insulin resistance, it is unlikely that TG are directly involved in the generation of muscle insulin resistance. There are now other plausible mechanistic links between muscle lipid metabolites and insulin resistance, in addition to the classic substrate competition proposed by Randle's glucose-fatty acid cycle. The first step in fatty acid metabolism (oxidation or storage) is activation to the long-chain fatty acyl CoA (LCACoA). This review covers the evidence suggesting that cytosolic accumulation of this active form of lipid in muscle can lead to impaired insulin signaling, impaired enzyme activity, and insulin resistance, either directly or by conversion to other lipid intermediates that alter the activity of key kinases and phosphatases. Actions of fatty acids to bind specific nuclear transcription factors provide another mechanism whereby different lipids could influence metabolism.
Assuntos
Acil Coenzima A/metabolismo , Resistência à Insulina , Músculos/metabolismo , Animais , Ésteres , Humanos , Metabolismo dos LipídeosRESUMO
Glycogen depletion is thought to be a potent stimulus for the substantially increased glucose fluxes observed in skeletal muscle following exercise. The aim of this study was to establish the relationships between the glycogen mass and the rates of glucose uptake (Rg') and glucose incorporation into glycogen (Rgly) in individual muscles of conscious adult Wistar rats following moderate nonexhausting treadmill exercise (15 m/min at a 10 degree slope for 45 minutes, approximately 65% VO2max). Muscle glycogen content was determined at 0, 20, 45, 90, or 135 minutes following exercise and compared with Rg' and Rgly measurements at matched times. Muscle types varied in the rate of glycogen resynthesis. Glycogen depots of glycolytic muscle (white gastrocnemius) were still significantly (P < .01) lower than preexercise levels after 135 minutes; red oxidative muscles (soleus and red gastrocnemius) were essentially repleted by 90 minutes. Immediately following exercise, Rg' and Rgly in red gastrocnemius and soleus were 42 +/- 4 and 42 +/- 5 and 36 +/- 2 and 33 +/- 7 micromol/(min . 100 g), greater than the rates induced by maximal insulin stimulation in previous studies. In red muscles, there was a strong inverse relationship between Rgly and tissue glycogen content, consistent with a dominant role for the glycogen mass in the regulation of glycogen resynthesis.
Assuntos
Glucose/metabolismo , Glicogênio/metabolismo , Músculo Esquelético/metabolismo , Esforço Físico/fisiologia , Animais , Membro Posterior , Masculino , Ratos , Ratos WistarRESUMO
In normal subjects during moderate exercise there is a strong negative correlation between plasma glucose and hepatic glucose output (HGO) suggesting a negative feedback regulation of HGO by plasma glucose. Little information is available about HGO responses to exercise in non-insulin-dependent diabetes mellitus (NIDDM). To determine whether the same feedback relationship is operative, we have compared the glucose turnover responses to moderate exercise (50% Vo2max for 60 minutes) of nonobese non-insulin-dependent diabetic subjects (NIDDM, n = 7) with a group of age-matched controls (n = 5). Glucose turnover responses to exercise in NIDDM were heterogeneous. Plasma glucose showed sustained falls, no change, or sustained rises in different individuals. Similarly, HGO responses ranged from undetectable to responses comparable to those of normal subjects. The mean integrated HGO response in NIDDM was significantly reduced compared with controls (11 +/- 6 [SEM] v 33 +/- 7 mmol/h/70 kg, P less than .05); mean glucose utilization response was also reduced but not significantly different from controls (NIDDM 18 +/- 5 v control 35 +/- 6). In NIDDM there was no significant feedback-control relationship between plasma glucose and HGO (r = -0.20, P = NS) in contrast to controls (r = -0.87, P less than .01). We conclude that feedback control of HGO by plasma glucose during moderate exercise is impaired in NIDDM. This impairment may be due to defective nonpancreatic glucoregulatory mechanisms.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Exercício Físico , Glucose/farmacocinética , Fígado/metabolismo , Idoso , Retroalimentação , Humanos , Insulina/metabolismo , Secreção de Insulina , Masculino , Pessoa de Meia-IdadeRESUMO
The presence and physiologic importance of cephalic phase insulin release in humans remains controversial. The aim of these studies was to determine whether cephalic phase insulin release could be demonstrated in normal weight subjects and whether it would be associated with changes in blood glucose, free fatty acid, and pancreatic polypeptide levels. The studies were followed by a hyperglycemic clamp to determine whether cephalic responses would alter overall glucose disposal or glucose-stimulated insulin secretion. In all, 17 subjects were studied on two occasions with and without (control study) presentation of food stimuli. Tease-feeding alone (n = 6), or the administration of a sweet taste alone (aspartame, n = 5) failed to stimulate cephalic responses. However, the presentation of the combined stimuli (tease meals plus sweet taste, n = 7) resulted in a significant fall (P less than .005) in blood glucose levels and a variable rise in serum insulin (% insulin rise 38 +/- 15%, P less than .05) and C-peptide levels (7 +/- 6%, NS) within five minutes of the food presentation when compared with control studies, with no change seen in free fatty acid or pancreatic polypeptide levels. The blood glucose fall correlated strongly (r = .90, P less than .01) with a score of the subjective response to the food and taste.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Alimentos , Insulina/metabolismo , Sensação/fisiologia , Adulto , Glicemia/metabolismo , Peso Corporal , Peptídeo C/sangue , Ácidos Graxos não Esterificados/sangue , Feminino , Humanos , Insulina/sangue , Secreção de Insulina , Masculino , Olfato/fisiologia , Paladar/fisiologia , Percepção Visual/fisiologiaRESUMO
Thiazolidinediones are oral insulin-sensitizing agents that may be useful for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). BRL 49653 ameliorates insulin resistance and improves glucoregulation in high-fat-fed (HF) rats. It is known that thiazolidinediones bind to the peroxisome proliferator-activated receptor (PPAR gamma) in fat cells, but the extent to which the improved glucoregulation and hypolipidemic effects relate to adipose tissue requires clarification. We therefore examined BRL 49653 effects on lipid metabolism in HF and control (high-starch-fed [HS]) rats. The diet period was 3 weeks, with BRL 49653 (10 mumol/kg/d) or vehicle gavage administered over the last 4 days. Studies were performed on animals in the conscious fasted state. In HF rats, rate constants governing 3H-palmitate clearance were unaffected by BRL 49653. This finding, taken with a concurrent decrease of fasting plasma nonesterified fatty acids (NEFA) (P < .01, ANOVA), demonstrated that systemic NEFA supply and hence absolute utilization are reduced by BRL 49653. Hepatic triglyceride (TG) production (HTGP) assessed using Triton WR1339 was unaffected by diet or BRL 49653. In liver, BRL 49653 increased insulin-stimulated conversion of glucose into fatty acid in both HF (by 270%) and HS (by 30%) groups (P < .05). Relative to HS rats, HF animals had substantially elevated levels of muscle diglyceride (diacylglycerol[DG] by 240%, P < .001). BRL 49653 significantly reduced muscle DG in HF (by 30%, P < .05) but not in HS rats. The agent did not reduce the intake of dietary lipid. In conclusion, these results are consistent with a primary action of BRL 49653 in adipose tissue to conserve lipid by reducing systemic lipid supply and subsequent utilization. The parallel effects of diet and BRL 49653 treatment on insulin resistance and muscle acylglyceride levels support the involvement of local lipid oversupply in the generation of muscle insulin resistance.
Assuntos
Ácidos Graxos/metabolismo , Hipoglicemiantes/farmacologia , Metabolismo dos Lipídeos , Tiazóis/farmacologia , Tiazolidinedionas , Análise de Variância , Animais , Diglicerídeos/metabolismo , Ácidos Graxos não Esterificados/sangue , Fígado/metabolismo , Masculino , Músculos/metabolismo , Ratos , Ratos Wistar , Rosiglitazona , Triglicerídeos/metabolismoRESUMO
Because of a failure to detect significant quantities of intracellular glucose, it has been generally accepted that transport rather than phosphorylation is the rate-limiting process of muscle glucose metabolism under most (but not all) physiological conditions. Here, we have measured tissue free levels of the glucose analog 2-deoxy-D-glucose (2DG) in red quadriceps muscle of rats fed a high-fat diet (59% of energy from fat) for 3 weeks, to identify the barrier to insulin-stimulated glucose uptake previously seen in such animals. Measurements were performed on pentobarbital-anesthetized rats following exogenous infusion of radiolabeled 2DG. A glucose clamp was used to maintain plasma insulin at high physiological levels (approximately 120 mU/L). Three other treatment groups representing normal insulin action (chow-fed), extreme glucose uptake (maximal insulin stimulation + hyperglycemia), and insulin resistance with elevated free intracellular glucose (epinephrine infusion) were also studied for comparison. In chow-fed animals, no muscle free 2DG was detected, confirming transport as the rate-limiting process. In fat-fed animals, a significant elevation in muscle free 2DG was observed (P < .01 v chow-fed controls). The elevation was similar in magnitude to that in epinephrine-infused rats, and implied a limitation of insulin action at a posttransport step. This result was confirmed with a more complex modeling analysis. We conclude that posttransport steps influence insulin-stimulated in vivo muscle glucose metabolism in long-term high-fat-fed rats.
Assuntos
Gorduras na Dieta/administração & dosagem , Glucose/metabolismo , Insulina/farmacologia , Músculo Esquelético/metabolismo , Animais , Transporte Biológico , Desoxiglucose/farmacocinética , Gorduras na Dieta/farmacologia , Epinefrina/farmacologia , Técnica Clamp de Glucose , Hiperglicemia/metabolismo , Resistência à Insulina , Masculino , Ratos , Ratos Wistar , Distribuição TecidualRESUMO
This review considers evidence for, and putative mechanisms of, lipid-induced muscle insulin resistance. Acute free fatty acid elevation causes muscle insulin resistance in a few hours, with similar muscle lipid accumulation as accompanies more prolonged high fat diet-induced insulin resistance in rodents. Although causal relations are not as clearcut in chronic human insulin resistant states such as obesity and type 2 diabetes, it is now recognised that muscle lipids also accumulate in these states. The classic Randle glucose-fatty acid cycle is only one of a number of mechanisms by which fatty acids might influence muscle glucose metabolism and insulin action. A key factor is seen to be accumulation of muscle long chain acyl CoAs, which could alter insulin action via several mechanisms including chronic activation of protein kinase C isoforms or ceramide accumulation. These interactions are fundamental to understanding metabolic effects of new insulin "sensitizers", e.g. thiazolidinediones, which alter lipid metabolism and improve muscle insulin sensitivity in insulin resistant states. Recent work has also pointed to a possible role of lipids in beta cell deterioration ("lipotoxicity") associated with type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Resistência à Insulina , Ilhotas Pancreáticas/fisiopatologia , Lipídeos/fisiologia , Músculo Esquelético/fisiopatologia , Obesidade/fisiopatologia , Animais , HumanosRESUMO
Subcutaneous insulin absorption is a complex process, whose quantitative aspects have important clinical implications. In this review we briefly discuss the rationale of modelling techniques before introducing some of the more common types of models (empirical vs mechanistic, simple vs complex, compartmental) found in the biological literature. The various approaches are compared regarding their suitability to model subcutaneous absorption of insulin. Methods are described (monitoring residual depot activity or the appearance of insulin in the systemic circulation) which allow the determination of model parameters from experimental data. The degree to which current model predictions describe the available experimental data is discussed. Since the absorption of insulin involves a number of poorly understood events it would be difficult, at this time, to construct a complex model which completely describes all aspects of the absorption process. Although the simpler techniques (such as the use of a one-pool model) provide only an approximate description of subcutaneous kinetics they are likely to remain useful tools in routine investigation.
Assuntos
Insulina/farmacocinética , Modelos Teóricos , Absorção , Humanos , Injeções Subcutâneas , Insulina/administração & dosagemRESUMO
Despite its increasing use in physiological animal investigations, there has been no systematic study of the whole body kinetics of 2-deoxy-D-glucose (2DG) or its modification by insulin. A previously proposed model that included processes representing transport across cell walls and intracellular phosphorylation of 2DG was investigated. The model predictions were compared with the plasma disappearance of 2DG observed in the rat following intravenous bolus injection. Experiments were performed during euglycemia at varying levels of hyperinsulinemia. The model was adequate to describe empirically the experimental data after a correction was made for urine loss. However, the variation in model parameters with plasma insulin concentration was not consistent with the expected action of insulin on cellular efflux. A possible explanation could be a shift in the rate-limiting step from glucose transport to another prephosphorylation process under conditions of high tissue uptake. This suggests that either intracellular or extracellular diffusion may constitute a significant barrier to 2DG (and glucose) uptake under some conditions.
Assuntos
Desoxiaçúcares/metabolismo , Desoxiglucose/metabolismo , Insulina/farmacologia , Animais , Cinética , Masculino , Matemática , Modelos Teóricos , Técnica de Diluição de Radioisótopos , Ratos , Ratos Endogâmicos , Valores de Referência , TrítioRESUMO
The nature of and rates of loss of products of systemic radiolabelled 2-deoxy-D-glucose in rat tissues in vivo were investigated to validate the use of this tracer to measure rates of metabolism of circulating glucose by tissues in vivo. Apparent first order rate constants for loss of products ranged from 8.0 +/- 0.10 (SD) X 10(-3) min-1 (liver) to 2.2 +/- 0.8 X 10(-3) min-1 (skeletal muscle). 2-deoxyglucose 6-phosphate was the major product found in all tissues examined except liver; all tissues contained other minor products. Products were effectively trapped by rat tissues in vivo allowing the use of this tracer for the measurement of rates of circulating glucose utilisation by tissues in vivo.
Assuntos
Desoxiaçúcares/metabolismo , Desoxiglucose/metabolismo , Animais , Radioisótopos de Carbono , Técnicas In Vitro , Cinética , Masculino , Músculos/metabolismo , Especificidade de Órgãos , Técnica de Diluição de Radioisótopos , Ratos , Ratos Endogâmicos , TrítioRESUMO
We have tested the hypothesis that hepatic glucose output (Ra) during exercise in humans is subject to feedback control by circulating glucose within a control range that is determined by the circulating insulin concentration. Three exercise protocols based on 60-min cycle ergometer exercise at 55% maximal O2 consumption were used: 1) control, 2) insulin infusion with a euglycemic clamp, and 3) insulin infusion with a fixed-rate glucose infusion. Ra was measured using a constant infusion of [3H]glucose. During the glucose clamp there was no Ra response to exercise. There were significant inverse relationships between Ra and plasma glucose during control exercise (r = -0.73, P less than 0.001) and exercise with fixed-rate glucose and insulin infusion (r = -0.96, P less than 0.001). During the fixed-rate glucose and insulin infusion, plasma glucose fell from the commencement of exercise but stabilized at a lower level. These results are interpreted in terms of a simple difference controller where Ra is proportional to the deviation of plasma glucose from a defined set point. Insulin affects Ra and regulates the steady-state glucose level by altering the sensitivity of this control system.