RESUMO
Type 2 diabetes is a complex metabolic disorder characterized by peripheral insulin resistance and impaired beta cell function. Insulin resistance is inherited as a non-mendelian trait. In genetically predisposed individuals, resistance of skeletal muscle and adipose tissue to insulin action precedes the onset of clinical diabetes, and is thought to contribute to hyperglycaemia by leading to impaired beta cell function and increased hepatic glucose production. It is not clear whether beta cell and liver defects are also genetically determined. To test the hypothesis that insulin resistance in muscle and fat is sufficient to cause type 2 diabetes in the absence of intrinsic beta cell and liver abnormality, we generated transgenic mice that were insulin-resistant in skeletal muscle and adipose tissue. These mice developed all the prodromal features of type 2 diabetes but, despite the compounded effect of peripheral insulin resistance and a mild impairment of beta cell function, failed to become diabetic. These findings indicate the need for a critical re-examination of the primary site(s) of insulin resistance in diabetes.
Assuntos
Tecido Adiposo/metabolismo , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Resistência à Insulina/genética , Resistência à Insulina/fisiologia , Músculo Esquelético/metabolismo , Animais , Sequência de Bases , Primers do DNA/genética , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Glucose/metabolismo , Intolerância à Glucose/fisiopatologia , Humanos , Técnicas In Vitro , Ilhotas Pancreáticas/patologia , Ilhotas Pancreáticas/fisiopatologia , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Coelhos , Receptor de Insulina/genética , Receptor de Insulina/metabolismoRESUMO
In lipoatrophic diabetes, a lack of fat is associated with insulin resistance and hyperglycemia. This is in striking contrast to the usual association of diabetes with obesity. To understand the underlying mechanisms, we transplanted adipose tissue into A-ZIP/F-1 mice, which have a severe form of lipoatrophic diabetes. Transplantation of wild-type fat reversed the hyperglycemia, dramatically lowered insulin levels, and improved muscle insulin sensitivity, demonstrating that the diabetes in A-ZIP/F-1 mice is caused by the lack of adipose tissue. All aspects of the A-ZIP/F-1 phenotype including hyperphagia, hepatic steatosis, and somatomegaly were either partially or completely reversed. However, the improvement in triglyceride and FFA levels was modest. Donor fat taken from parametrial and subcutaneous sites was equally effective in reversing the phenotype. The beneficial effects of transplantation were dose dependent and required near-physiological amounts of transplanted fat. Transplantation of genetically modified fat into A-ZIP/F-1 mice is a new and powerful technique for studying adipose physiology and the metabolic and endocrine communication between adipose tissue and the rest of the body.
Assuntos
Tecido Adiposo/transplante , Diabetes Mellitus Lipoatrófica/cirurgia , Animais , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Experimental/cirurgia , Diabetes Mellitus Lipoatrófica/sangue , Diabetes Mellitus Lipoatrófica/fisiopatologia , Ácidos Graxos/sangue , Regulação da Expressão Gênica , Técnicas de Transferência de Genes , Resistência à Insulina , Camundongos , Triglicerídeos/sangueRESUMO
Epinephrine is a major stress hormone that plays a central role in the control of metabolic function and energy homeostasis. To evaluate the role of epinephrine and the physiological and pathophysiological consequences of sustained elevation of epinephrine on metabolic and endocrine function, we studied several metabolic parameters and circulating leptin levels in a newly developed transgenic mouse model of phenylethanolamine-N-methyltransferase (PNMT) overexpression. A 100-fold overexpression of PNMT and subsequent elevation of epinephrine levels resulted in a marked suppression of circulating leptin levels in the transgenic animals (1.14 +/- 0.05 vs. 2.17 +/- 0.35 ng/ml; P < 0.01), which correlated negatively with plasma epinephrine (r = -0.82; P < 0.05), thus providing evidence for an inhibitory action of epinephrine on leptin production in vivo. In parallel, we found a marked increase in the body fat content of the transgenic animals (12.54 +/- 1.5 vs. 6.22 +/- 0.2%; P < 0.01) that was accompanied by enlarged adipocytes, indicating an increased lipid storage in PNMT transgenic mice. Interestingly, however, transgenic animals had normal body weight and did not exhibit major alterations in carbohydrate metabolism, as evidenced by analysis of random and fasted blood glucose levels, plasma insulin and C peptide levels, and insulin tolerance test. The metabolic alterations observed were not secondary to changes in food intake or increased activity of the hypothalamic-pituitary-adrenal axis, as there were no differences in these parameters. In summary, sustained primary overproduction of epinephrine resulted in suppression of plasma leptin levels and increased lipid storage in the PNMT transgenic mice. The concerted action of the sympathoadrenal system and reduced leptin may contribute to defending energy reservoirs while maintaining a normal body weight, which may be of vital importance under conditions of stress and energy deficiency.
Assuntos
Composição Corporal , Epinefrina/metabolismo , Expressão Gênica , Leptina/metabolismo , Feniletanolamina N-Metiltransferase/genética , Tecido Adiposo/química , Tecido Adiposo/enzimologia , Glândulas Suprarrenais/química , Glândulas Suprarrenais/fisiologia , Animais , Glicemia/metabolismo , Química Encefálica , Peptídeo C/sangue , Ingestão de Alimentos , Epinefrina/análise , Hipotálamo/fisiologia , Imuno-Histoquímica , Insulina/sangue , Camundongos , Camundongos Transgênicos , Feniletanolamina N-Metiltransferase/fisiologia , Hipófise/fisiologia , Reação em Cadeia da Polimerase , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Chromium supplementation may affect various risk factors for coronary artery disease (CAD) and non-insulin-dependent diabetes mellitus (NIDDM), including body weight and composition, basal plasma hormone and substrate levels, and response to an oral glucose load. This study examined the effects of chromium supplementation (400 micrograms.d-1), with or without exercise training, on these risk factors in young, obese women. Chromium picolinate supplementation resulted in significant weight gain in this population, while exercise training combined with chromium nicotinate supplementation resulted in significant weight loss and lowered the insulin response to an oral glucose load. We conclude that high levels of chromium picolinate supplementation are contraindicated for weight loss in young, obese women. Moreover, our results suggest that exercise training combined with chromium nicotinate supplementation may be more beneficial than exercise training alone for modification of certain CAD and NIDDM risk factors.
Assuntos
Terapia por Exercício , Alimentos Fortificados , Quelantes de Ferro/farmacologia , Ácidos Nicotínicos/farmacologia , Obesidade/terapia , Ácidos Picolínicos/farmacologia , Adolescente , Adulto , Glicemia/metabolismo , Doença das Coronárias/prevenção & controle , Diabetes Mellitus Tipo 2/prevenção & controle , Feminino , Humanos , Insulina/metabolismo , Quelantes de Ferro/uso terapêutico , Ácidos Nicotínicos/uso terapêutico , Obesidade/fisiopatologia , Ácidos Picolínicos/uso terapêutico , Fatores de Risco , Aumento de Peso , Redução de PesoRESUMO
Accredited formal educational programs in dental laboratory technology are now under pressures at levels they have never undergone before. Already pushed to the point where many have had to close their doors, the remainder are struggling to survive with already strained resources. Whether or not they will be able to maintain their existence will depend upon their ability to attract quality students, provide them with a good, up to date education, and do so with ever increasing efficiency.
Assuntos
Laboratórios Odontológicos/tendências , Tecnologia Odontológica/educação , Tecnologia Odontológica/tendências , Currículo/tendências , Educação/economia , Humanos , Recursos HumanosRESUMO
The purpose of this investigation was to identify any difference of vertical dimension change that could be attributed to not using a face-bow transfer. Both demonstrations resulted in occlusal changes in vertical dimension. In comparing the demonstrations, where a hinge axis transfer was not taken, a greater amount of change was recorded over that observer in the demonstration where the hinge axis transfer was made. More dedicated research is clearly warranted to establish how much of the change was due to normal technical error. The time spent taking a face-bow transfer (hinge axis) may represent a small portion of the time required to accomplish adjustments on a denture where no transfer was performed. This information will allow the clinician to decide on the time they are willing to dedicate to occlusal corrections at the chair.
Assuntos
Articuladores Dentários , Aparelhos de Tração Extrabucal , Dimensão Vertical , Oclusão Dentária , Humanos , Registro da Relação Maxilomandibular/instrumentação , Registro da Relação Maxilomandibular/métodos , Modelos DentáriosRESUMO
The effects of amylin on fiber type-specific muscle glucose metabolism under hyperglycemic (10 mmol/l) and hyperinsulinemic (2.1 nmol/l) conditions were investigated using a rat hindlimb perfusion system. Amylin concentration ranged from 1 to 100 nM. Efficacy for inhibition of glucose uptake traced with 2-deoxyglucose by amylin was demonstrated in all three fiber types. The incorporation of 2-deoxy-[3H]glucose tracer decreased from control values by 41% in fast oxidative (FO), 36% in fast glycolytic (FG), and 37% in slow oxidative (SO) muscle with 100 nM amylin. Amylin increased intracellular glucose 6-phosphate (G-6-P), and G-6-P was negatively correlated with 2-deoxyglucose uptake in both FO (r = -0.65; P < 0.01) and FG (r = -0.53; P < 0.01) muscle. Muscle glycogen concentration increased under control conditions and decreased in the presence of 100 nM amylin. Lactate arteriovenous efflux across the hindlimb increased significantly above control with 100 nM amylin (5.03 +/- 0.81 to 11.28 +/- 0.94 mumol.g-1.h-1). Adenosine 3',5'-cyclic monophosphate (cAMP) increased in FO and FG muscle with amylin. Salmon calcitonin-(8-32), an amylin antagonist, ameliorated the effect of amylin on all responses other than 2-deoxyglucose uptake and G-6-P concentration. These results suggest that amylin may work through at least two independent mechanisms, a cAMP-mediated effect on glycogen metabolism and a non-cAMP-mediated inhibition of glycolysis.
Assuntos
Amiloide/farmacologia , Glucose/metabolismo , Insulina/farmacologia , Músculo Esquelético/metabolismo , Animais , Glicemia/metabolismo , AMP Cíclico/metabolismo , Desoxiglucose/metabolismo , Glicogênio/metabolismo , Membro Posterior , Hiperglicemia , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Lactatos/sangue , Lactatos/metabolismo , Masculino , Fibras Musculares de Contração Rápida/efeitos dos fármacos , Fibras Musculares de Contração Rápida/metabolismo , Fibras Musculares de Contração Lenta/efeitos dos fármacos , Fibras Musculares de Contração Lenta/metabolismo , Músculo Esquelético/efeitos dos fármacos , Perfusão , Ratos , Ratos Sprague-DawleyRESUMO
This investigation used a model of increased skeletal muscle contractile activity to evaluate whether the adenylate cyclase-adenosine 3',5'-cyclic monophosphate (cAMP) pathway and/or the high-energy phosphate state of the muscle might be temporally related to the contraction-induced increase in skeletal muscle GLUT-4 protein concentration. Plantaris and gastrocnemius muscles of Sprague-Dawley rats were subjected to 3, 7, 14, or 28 days of chronic low-frequency electrical stimulation (10 Hz, 24 h/day). GLUT-4 protein concentration was slightly reduced after 3 days of electrical stimulation, similar to control values at 7 days and significantly elevated above control at 14 days (53%, P < 0.05) and 28 days (338%, P < 0.05) of stimulation. ATP, creatine phosphate, creatine, and P, were inversely related to GLUT-4 protein concentration. Adenylate cyclase activity increased with electrical stimulation and was significantly related to the increased GLUT-4 protein. cAMP was significantly increased at 14 days of stimulation and remained elevated through 28 days. These results demonstrate that both the adenylate cyclase-cAMP pathway and the high-energy phosphate state of the muscle are temporally related to elevations in skeletal muscle GLUT-4 protein concentration in response to chronic low-frequency electrical stimulation and, as such, suggest that both may comprise a component of the intracellular signal that regulates the contraction-induced increase in skeletal muscle GLUT-4 protein concentration.
Assuntos
Membranas Intracelulares/fisiologia , Proteínas de Transporte de Monossacarídeos/metabolismo , Contração Muscular/fisiologia , Proteínas Musculares , Músculo Esquelético/metabolismo , Transdução de Sinais , Adenilil Ciclases/metabolismo , Animais , Peso Corporal , AMP Cíclico/metabolismo , Metabolismo Energético , Feminino , Transportador de Glucose Tipo 4 , Músculo Esquelético/anatomia & histologia , Tamanho do Órgão , Concentração Osmolar , Fosfatos/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Thirty-two female Sprague-Dawley rats were assigned to one of four groups: control (CON); exercise training (TR); exercise training + clenbuterol treatment (0.8 mg kg body wt(-1) d(-1)) (TR + CL) or exercise training + clenbuterol treatment + 2% beta-guanidinoproprionic acid diet (TR + CL + beta) to examine whether alterations in the high energy phosphate state of the muscle mediates exercise training-induced increases in skeletal muscle GLUT4 protein concentration and citrate synthase activity. Exercise training consisted of running the rats 5 d week(-1) for 8 weeks on a motor-driven treadmill (32 m min(-1), 15% grade). Gastrocnemius GLUT4 protein concentration and citrate synthase activity were significantly elevated in the TR animals, but these adaptations were attenuated in the TR + CL animals. Providing beta-GPA in combination with clenbuterol enabled training to elevate GLUT4 protein concentration and citrate synthase activity, with the increase in GLUT4 being greater than that observed for the TR animals. Skeletal muscle ATP levels were reduced in the TR + CL + beta animals while ATP levels in the TR + CL animals were significantly elevated compared with CON. An acute 40-min bout of electrical stimulation of the sciatic nerve was found to lower skeletal muscle ATP levels by approximately 50% and elevate cAMP levels in all groups. No difference in post-contraction cAMP levels were observed among groups. However, post-contraction ATP levels in the TR + CL animals were significantly greater than the other groups. Collectively, these findings suggest that exercise training-induced increases in skeletal muscle GLUT4 protein concentration and citrate synthase activity are initiated in response to a reduction in the skeletal muscle ATP concentration.
Assuntos
Trifosfato de Adenosina/metabolismo , Citrato (si)-Sintase/metabolismo , Proteínas de Transporte de Monossacarídeos/metabolismo , Proteínas Musculares , Músculo Esquelético/metabolismo , Condicionamento Físico Animal/fisiologia , Adenilil Ciclases/metabolismo , Animais , Clembuterol/farmacologia , AMP Cíclico/metabolismo , Dieta , Estimulação Elétrica , Feminino , Transportador de Glucose Tipo 4 , Guanidinas/farmacologia , Músculo Esquelético/efeitos dos fármacos , Propionatos/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
The present study investigated whether alterations in the muscle high energy phosphate state initiates the contraction-induced increase in skeletal muscle GLUT4 protein concentration. Sprague-Dawley rats were provided either a normal or a 2% beta-guanidinoproprionic acid (beta-GPA) diet for 8 weeks and then the gastrocnemius of one hind limb was subjected to 0, 14 or 28 days of chronic (24 h day-1) low-frequency electrical stimulation (10 Hz). The beta-GPA diet, in the absence of electrical stimulation, significantly reduced ATP, creatine phosphate, creatine and inorganic phosphate and elevated GLUT4 protein concentration by 60% without altering adenylate cyclase activity or cAMP concentration. Following 14 days of electrical stimulation, GLUT4 protein concentration was elevated above non-stimulated muscle in both groups but was significantly more elevated in the beta-GPA group. Concurrent with this greater rise in GLUT4 protein concentration was a greater decline in the high energy phosphates and a greater rise in cAMP. After 28 days of electrical stimulation, GLUT4 protein concentration and cAMP stabilized and was not different between diet treatments. However, the high energy phosphates were significantly higher in the normal diet rats as opposed to the beta-GPA rats. These findings therefore suggest that a reduction in cellular energy supply initiates the contraction-induced increase in muscle GLUT4 protein concentration, but that a rise in cAMP may potentiate this effect.
Assuntos
Guanidinas/farmacologia , Proteínas de Transporte de Monossacarídeos/metabolismo , Músculo Esquelético/fisiologia , Propionatos/farmacologia , Trifosfato de Adenosina/metabolismo , Adenilil Ciclases/metabolismo , Animais , Peso Corporal/fisiologia , AMP Cíclico/metabolismo , Dieta , Estimulação Elétrica , Feminino , Transportador de Glucose Tipo 4 , Proteínas Musculares/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Tamanho do Órgão/fisiologia , Fosfatos/metabolismo , Fosfocreatina/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
We examined the effects of amylin on 3-O-methyl-D-glucose (3-O-MG) transport in perfused rat hindlimb muscle under hyperinsulinemic (350 microU/ml, 2,100 pmol/l) conditions. Amylin at 100 nmol/l concentration inhibited 3-O-MG transport relative to control in all three basic muscle fiber types. Transport decreased in slow-twitch oxidative (from 5.65 +/- 1.13 to 3.46 +/- 0.71 micromol . g-1 . h-1), fast-twitch oxidative (from 6.84 +/- 0.90 to 4.84 +/- 0.76 micromol . g-1 . h-1), and fast-twitch glycolytic (from 1.27 +/- 0.20 to 0.60 +/- 0.05 micromol . g-1 . h-1) muscle. Amylin inhibition of insulin-stimulated glucose transport in skeletal muscle was accompanied by a 433 +/- 72% increase in intracellular glucose 6-phosphate (G-6-P) despite the absence of extracellular glucose. The source of hexose units for the formation and maintenance of G-6-P was likely glycogen. Amylin increased glycogenolysis, increased lactate formation, and decreased glycogen synthase activity. Furthermore, the kinetics of glycogen synthase suggest that this enzyme may control intracellular G-6-P concentration. Despite the large increase in G-6-P, no detectable increase in uridine diphosphate-N-acetylhexosamines occurred, suggesting that the proposed glucosamine pathway may not be involved in transport inhibition. However, decreases in uridine diphosphate hexoses were detected. Therefore, uridine or hexosamine-based metabolites may be involved in amylin action.
Assuntos
3-O-Metilglucose/farmacocinética , Amiloide/farmacologia , Insulina/farmacologia , Fibras Musculares de Contração Rápida/metabolismo , Fibras Musculares de Contração Lenta/metabolismo , Músculo Esquelético/metabolismo , Amiloide/fisiologia , Análise de Variância , Animais , Transporte Biológico/efeitos dos fármacos , Glucose-6-Fosfato/metabolismo , Glicogênio/metabolismo , Glicogênio Sintase/metabolismo , Glicólise/efeitos dos fármacos , Glicólise/fisiologia , Membro Posterior , Insulina/fisiologia , Antagonistas da Insulina/farmacologia , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Lactatos/metabolismo , Fibras Musculares de Contração Rápida/efeitos dos fármacos , Fibras Musculares de Contração Lenta/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Consumo de Oxigênio , Perfusão , Ratos , Ratos Sprague-DawleyRESUMO
Peripheral insulin resistance and impaired insulin action are the primary characteristics of type 2 diabetes. The first observable defect in this major disorder occurs in muscle, where glucose disposal in response to insulin is impaired. We have developed a transgenic mouse with a dominant-negative insulin-like growth factor-I receptor (KR-IGF-IR) specifically targeted to the skeletal muscle. Expression of KR-IGF-IR resulted in the formation of hybrid receptors between the mutant and the endogenous IGF-I and insulin receptors, thereby abrogating the normal function of these receptors and leading to insulin resistance. Pancreatic beta-cell dysfunction developed at a relative early age, resulting in diabetes. These mice provide an excellent model to study the molecular mechanisms underlying the development of human type 2 diabetes.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Glucose/metabolismo , Resistência à Insulina/genética , Músculo Esquelético/metabolismo , Receptor IGF Tipo 1/fisiologia , Receptor de Insulina/fisiologia , Envelhecimento , Animais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Ácidos Graxos não Esterificados/sangue , Técnica Clamp de Glucose , Humanos , Hiperinsulinismo , Insulina/metabolismo , Insulina/farmacologia , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Transgênicos , Músculo Esquelético/efeitos dos fármacos , Mutagênese Sítio-Dirigida , Estado Pré-Diabético/sangue , Estado Pré-Diabético/genética , Estado Pré-Diabético/fisiopatologia , Receptor IGF Tipo 1/genética , Receptor de Insulina/genética , Triglicerídeos/sangue , Triglicerídeos/metabolismoRESUMO
We tested the effect of chronic leptin treatment on fasting-induced torpor in leptin-deficient A-ZIP/F-1 and ob/ob mice. A-ZIP/F-1 mice have virtually no white adipose tissue and low leptin levels, whereas ob/ob mice have an abundance of fat but no leptin. These two models allowed us to examine the roles of adipose tissue and leptin in the regulation of entry into torpor. Torpor is a short-term hibernation-like state that allows conservation of metabolic fuels. We first characterized the A-ZIP/F-1 animals, which have a 10-fold reduction in total body triglyceride stores. Upon fasting, A-ZIP/F-1 mice develop a lower metabolic rate and decreased plasma glucose, insulin, and triglyceride levels, with no increase in free fatty acids or beta-hydroxybutyrate. Unlike control mice, by 24 hr of fasting, they have nearly exhausted their triglycerides and are catabolizing protein. To conserve energy supplies during fasting, A-ZIP/F-1 (but not control) mice entered deep torpor, with a minimum core body temperature of 24 degrees C, 2 degrees C above ambient. In ob/ob mice, fasting-induced torpor was completely reversed by leptin treatment. In contrast, neither leptin nor thyroid hormone prevented torpor in A-ZIP/F-1 mice. These data suggest that there are at least two signals for entry into torpor in mice, a low leptin level and another signal that is independent of leptin and thyroid hormone levels. Studying rodent torpor provides insight into human torpor-like states such as near drowning in cold water and induced hypothermia for surgery.