RESUMO
Previous studies indicate that CNS administration of oxytocin (OT) reduces body weight in high fat diet-induced obese (DIO) rodents by reducing food intake and increasing energy expenditure (EE). We recently demonstrated that hindbrain (fourth ventricular [4V]) administration of OT elicits weight loss and elevates interscapular brown adipose tissue temperature (TIBAT, a surrogate measure of increased EE) in DIO mice. What remains unclear is whether OT-elicited weight loss requires increased sympathetic nervous system (SNS) outflow to IBAT. We hypothesized that OT-induced stimulation of SNS outflow to IBAT contributes to its ability to activate BAT and elicit weight loss in DIO mice. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on the ability of 4V OT administration to increase TIBAT and elicit weight loss in DIO mice. We first determined whether bilateral surgical SNS denervation to IBAT was successful as noted by ≥ 60% reduction in IBAT norepinephrine (NE) content in DIO mice. NE content was selectively reduced in IBAT at 1-, 6- and 7-weeks post-denervation by 95.9 ± 2.0, 77.4 ± 12.7 and 93.6 ± 4.6% (P<0.05), respectively and was unchanged in inguinal white adipose tissue, pancreas or liver. We subsequently measured the effects of acute 4V OT (1, 5 µg ≈ 0.99, 4.96 nmol) on TIBAT in DIO mice following sham or bilateral surgical SNS denervation to IBAT. We found that the high dose of 4V OT (5 µg ≈ 4.96 nmol) elevated TIBAT similarly in sham mice as in denervated mice. We subsequently measured the effects of chronic 4V OT (16 nmol/day over 29 days) or vehicle infusions on body weight, adiposity and food intake in DIO mice following sham or bilateral surgical denervation of IBAT. Chronic 4V OT reduced body weight by 5.7 ± 2.23% and 6.6 ± 1.4% in sham and denervated mice (P<0.05), respectively, and this effect was similar between groups (P=NS). OT produced corresponding reductions in whole body fat mass (P<0.05). Together, these findings support the hypothesis that sympathetic innervation of IBAT is not necessary for OT-elicited increases in BAT thermogenesis and reductions of body weight and adiposity in male DIO mice.
Assuntos
Tecido Adiposo Marrom , Adiposidade , Dieta Hiperlipídica , Camundongos Endogâmicos C57BL , Obesidade , Ocitocina , Sistema Nervoso Simpático , Animais , Ocitocina/farmacologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/inervação , Masculino , Camundongos , Obesidade/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Adiposidade/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Redução de Peso/efeitos dos fármacos , Camundongos Obesos , Metabolismo Energético/efeitos dos fármacos , Norepinefrina/metabolismoRESUMO
Previous studies indicate that CNS administration of oxytocin (OT) reduces body weight in high fat diet-induced obese (DIO) rodents by reducing food intake and increasing energy expenditure (EE). We recently demonstrated that hindbrain (fourth ventricular [4V]) administration of OT elicits weight loss and elevates interscapular brown adipose tissue temperature (T IBAT , a surrogate measure of increased EE) in DIO mice. What remains unclear is whether OT-elicited weight loss requires increased sympathetic nervous system (SNS) outflow to IBAT. We hypothesized that OT-induced stimulation of SNS outflow to IBAT contributes to its ability to activate BAT and elicit weight loss in DIO mice. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on the ability of 4V OT administration to increase T IBAT and elicit weight loss in DIO mice. We first determined whether bilateral surgical SNS denervation to IBAT was successful as noted by ≥ 60% reduction in IBAT norepinephrine (NE) content in DIO mice. NE content was selectively reduced in IBAT at 1-, 6- and 7-weeks post-denervation by 95.9±2.0, 77.4±12.7 and 93.6±4.6% ( P <0.05), respectively and was unchanged in inguinal white adipose tissue, pancreas or liver. We subsequently measured the effects of acute 4V OT (1, 5 µg ≈ 0.99, 4.96 nmol) on T IBAT in DIO mice following sham or bilateral surgical SNS denervation to IBAT. We found that the high dose of 4V OT (5 µg ≈ 4.96 nmol) elevated T IBAT similarly in sham mice as in denervated mice. We subsequently measured the effects of chronic 4V OT (16 nmol/day over 29 days) or vehicle infusions on body weight, adiposity and food intake in DIO mice following sham or bilateral surgical denervation of IBAT. Chronic 4V OT reduced body weight by 5.7±2.23% and 6.6±1.4% in sham and denervated mice ( P <0.05), respectively, and this effect was similar between groups ( P =NS). OT produced corresponding reductions in whole body fat mass ( P <0.05). Together, these findings support the hypothesis that sympathetic innervation of IBAT is not necessary for OT-elicited increases in BAT thermogenesis and reductions of body weight and adiposity in male DIO mice.
RESUMO
This study aimed to investigate the contributions of two factors potentially impairing glucagon response to insulin-induced hypoglycemia (IIH) in insulin-deficient diabetes: 1) loss of paracrine disinhibition by intra-islet insulin and 2) defects in the activation of the autonomic inputs to the islet. Plasma glucagon responses during hyperinsulinemic-hypoglycemic clamps ([Formula: see text]40 mg/dL) were assessed in dogs with spontaneous diabetes (n = 13) and in healthy nondiabetic dogs (n = 6). Plasma C-peptide responses to intravenous glucagon were measured to assess endogenous insulin secretion. Plasma pancreatic polypeptide, epinephrine, and norepinephrine were measured as indices of parasympathetic and sympathoadrenal autonomic responses to IIH. In 8 of the 13 diabetic dogs, glucagon did not increase during IIH (diabetic nonresponder [DMN]; ∆ = -6 ± 12 pg/mL). In five other diabetic dogs (diabetic responder [DMR]), glucagon responses (∆ = +26 ± 12) were within the range of nondiabetic control dogs (∆ = +27 ± 16 pg/mL). C-peptide responses to intravenous glucagon were absent in diabetic dogs. Activation of all three autonomic responses were impaired in DMN dogs but remained intact in DMR dogs. Each of the three autonomic responses to IIH was positively correlated with glucagon responses across the three groups. The study conclusions are as follows: 1) Impairment of glucagon responses in DMN dogs is not due to generalized impairment of α-cell function. 2) Loss of tonic inhibition of glucagon secretion by insulin is not sufficient to produce loss of the glucagon response; impairment of autonomic activation is also required. 3) In dogs with major ß-cell function loss, activation of the autonomic inputs is sufficient to mediate an intact glucagon response to IIH.NEW & NOTEWORTHY In dogs with naturally occurring, insulin-dependent (C-peptide negative) diabetes mellitus, impairment of glucagon responses is not due to generalized impairment of α-cell function. Loss of tonic inhibition of glucagon secretion by insulin is not sufficient, by itself, to produce loss of the glucagon response. Rather, impaired activation of the parasympathetic and sympathoadrenal autonomic inputs to the pancreas is also required. Activation of the autonomic inputs to the pancreas is sufficient to mediate an intact glucagon response to insulin-induced hypoglycemia in dogs with naturally occurring diabetes mellitus. These results have important implications that include leading to a greater understanding and insight into the pathophysiology, prevention, and treatment of hypoglycemia during insulin treatment of diabetes in companion dogs and in human patients.
Assuntos
Sistema Nervoso Autônomo/efeitos dos fármacos , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/veterinária , Doenças do Cão/metabolismo , Glucagon/farmacologia , Hipoglicemia/induzido quimicamente , Hipoglicemia/metabolismo , Hipoglicemiantes , Insulina , Animais , Glicemia/metabolismo , Peptídeo C/metabolismo , Cães , Epinefrina/sangue , Células Secretoras de Glucagon/efeitos dos fármacos , Técnica Clamp de Glucose , Células Secretoras de Insulina/efeitos dos fármacos , Norepinefrina/sangue , Polipeptídeo Pancreático/metabolismoRESUMO
Increasing evidence suggests that, although pancreatic islets can function autonomously to detect and respond to changes in the circulating glucose level, the brain cooperates with the islet to maintain glycaemic control. Here, we review the role of the central and autonomic nervous systems in the control of the endocrine pancreas, including mechanisms whereby the brain senses circulating blood glucose levels. We also examine whether dysfunction in these systems might contribute to complications of type 1 diabetes and the pathogenesis of type 2 diabetes. Graphical abstract.
Assuntos
Sistema Nervoso Autônomo/metabolismo , Glicemia/metabolismo , Sistema Nervoso Central/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucagon/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/inervação , Animais , Sistema Nervoso Autônomo/fisiopatologia , Sistema Nervoso Central/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Células Receptoras SensoriaisAssuntos
Diabetes Mellitus Tipo 2/etiologia , Endocrinologia , Resistência à Insulina/fisiologia , Liderança , Obesidade/etiologia , Pesquisa Biomédica/história , Glicemia/metabolismo , Cardiologia/história , Diabetes Mellitus Tipo 2/metabolismo , Endocrinologia/história , História do Século XX , História do Século XXI , Humanos , Insulina/metabolismo , Secreção de Insulina/fisiologia , Cidade de Nova Iorque , Obesidade/metabolismo , MédicosRESUMO
Dynamic adjustment of insulin secretion to compensate for changes of insulin sensitivity that result from alteration of nutritional or metabolic status is a fundamental aspect of glucose homeostasis. To investigate the role of the brain in this coupling process, we used cold exposure as an experimental paradigm because the sympathetic nervous system (SNS) helps to coordinate the major shifts of tissue glucose utilization needed to ensure that increased thermogenic needs are met. We found that glucose-induced insulin secretion declined by 50% in rats housed at 5°C for 28 h, and yet, glucose tolerance did not change, owing to a doubling of insulin sensitivity. These potent effects on insulin secretion and sensitivity were fully reversed by returning animals to room temperature (22°C) for 4 h or by intravenous infusion of the α-adrenergic receptor antagonist phentolamine for only 30 min. By comparison, insulin clearance was not affected by cold exposure or phentolamine infusion. These findings offer direct evidence of a key role for the brain, acting via the SNS, in the rapid, highly coordinated, and reciprocal changes of insulin secretion and insulin sensitivity that preserve glucose homeostasis in the setting of cold exposure.
Assuntos
Glicemia/metabolismo , Temperatura Baixa , Resistência à Insulina , Insulina/metabolismo , Sistema Nervoso Simpático/metabolismo , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Glicemia/efeitos dos fármacos , Técnica Clamp de Glucose , Secreção de Insulina , Masculino , Fentolamina/farmacologia , Ratos , Ratos Long-Evans , Ratos Wistar , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
This review outlines the current state of knowledge regarding a unique neural defect of the pancreatic islet in autoimmune diabetes, one that we have termed early sympathetic islet neuropathy (eSIN). We begin with the findings that a majority of islet sympathetic nerves are lost near the onset of type 1, but not type 2, diabetes and that this nerve loss is restricted to the islet. We discuss later work demonstrating that while the loss of islet sympathetic nerves and the loss of islet beta cells in type 1 diabetes both require infiltration of the islet by lymphocytes, their respective mechanisms of tissue destruction differ. Uniquely, eSIN requires the activation of a specific neurotrophin receptor and we propose two possible pathways for activation of this receptor during the immune attack on the islet. We also outline what is known about the functional consequences of eSIN, focusing on impairment of sympathetically mediated glucagon secretion and its application to the clinical problem of insulin-induced hypoglycaemia. Finally, we offer our view on the important remaining questions regarding this unique neural defect.
Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/patologia , Sistema Nervoso Simpático/metabolismo , Sistema Nervoso Simpático/patologia , Autoimunidade/fisiologia , Diabetes Mellitus Tipo 1/imunologia , Neuropatias Diabéticas/imunologia , Glucagon/metabolismo , Humanos , Fatores de Crescimento Neural/metabolismo , Sistema Nervoso Simpático/imunologiaRESUMO
In humans, the glucagon response to moderate-to-marked insulin-induced hypoglycemia (IIH) is largely mediated by the autonomic nervous system. Because this glucagon response is impaired early in type 1 diabetes, we sought to determine if these patients, like animal models of autoimmune diabetes, have an early and severe loss of islet sympathetic nerves. We also tested whether this nerve loss is a permanent feature of type 1 diabetes, is islet-selective, and is not seen in type 2 diabetes. To do so, we quantified pancreatic islet and exocrine sympathetic nerve fiber area from autopsy samples of patients with type 1 or 2 diabetes and control subjects without diabetes. Our central finding is that patients with either very recent onset (<2 weeks) or long duration (>10 years) of type 1 diabetes have a severe loss of islet sympathetic nerves (Δ = -88% and Δ = -79%, respectively). In contrast, patients with type 2 diabetes lose no islet sympathetic nerves. There is no loss of exocrine sympathetic nerves in either type 1 or type 2 diabetes. We conclude that patients with type 1, but not type 2, diabetes have an early, marked, sustained, and islet-selective loss of sympathetic nerves, one that may impair their glucagon response to IIH.
Assuntos
Diabetes Mellitus Tipo 1/patologia , Sistema Nervoso Simpático/patologia , Adolescente , Adulto , Sistema Nervoso Autônomo/metabolismo , Sistema Nervoso Autônomo/patologia , Sistema Nervoso Autônomo/fisiopatologia , Criança , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Glucagon/metabolismo , Humanos , Hipoglicemia/metabolismo , Hipoglicemia/patologia , Hipoglicemia/fisiopatologia , Imuno-Histoquímica , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Ilhotas Pancreáticas/fisiopatologia , Masculino , Pessoa de Meia-Idade , Pâncreas/metabolismo , Pâncreas/patologia , Pâncreas/fisiopatologia , Sistema Nervoso Simpático/metabolismo , Sistema Nervoso Simpático/fisiopatologia , Adulto JovemRESUMO
OBJECTIVE: Central administration of ligands for fibroblast growth factor receptors (FGFRs) such as fibroblast growth factor-19 (FGF19) and FGF21 exert glucose-lowering effects in rodent models of obesity and type 2 diabetes (T2D). Conversely, intracerebroventricular (icv) administration of the non-selective FGFR inhibitor (FGFRi) PD173074 causes glucose intolerance, implying a physiological role for neuronal FGFR signaling in glucose homeostasis. The current studies were undertaken to identify neuroendocrine mechanisms underlying the glucose intolerance induced by pharmacological blockade of central FGFRs. METHODS: Overnight fasted, lean, male, Long-Evans rats received icv injections of either PD173074 or vehicle (Veh) followed 30 min later by performance of a frequently sampled intravenous glucose tolerance test (FSIGT). Minimal model analysis of glucose and insulin data from the FSIGT was performed to estimate insulin-dependent and insulin-independent components of glucose disposal. Plasma levels of lactate, glucagon, corticosterone, non-esterified free fatty acids (NEFA) and catecholamines were measured before and after intravenous (iv) glucose injection. RESULTS: Within 20 min of icv PD173074 injection (prior to the FSIGT), plasma levels of lactate, norepinephrine and epinephrine increased markedly, and each returned to baseline rapidly (within 8 min) following the iv glucose bolus. In contrast, plasma glucagon levels were not altered by icv FGFRi at either time point. Consistent with a previous report, glucose tolerance was impaired following icv PD173074 compared to Veh injection and, based on minimal model analysis of FSIGT data, this effect was attributable to reductions of both insulin secretion and the basal insulin effect (BIE), consistent with the inhibitory effect of catecholamines on pancreatic ß-cell secretion. By comparison, there were no changes in glucose effectiveness at zero insulin (GEZI) or the insulin sensitivity index (SI). To determine if iv glucose (given during the FSIGT) contributed to the rapid resolution of the sympathoadrenal response induced by icv FGFRi, we performed an additional study comparing groups that received iv saline or iv glucose 30 min after icv FGFRi. Our finding that elevated plasma catecholamine levels returned rapidly to baseline irrespective of whether rats subsequently received an iv bolus of saline or glucose indicates that the rapid reversal of sympathoadrenal activation following icv FGFRi was unrelated to the subsequent glucose bolus. CONCLUSIONS: The effect of acute inhibition of central FGFR signaling to impair glucose tolerance likely involves a stress response associated with pronounced, but transient, sympathoadrenal activation and an associated reduction of insulin secretion. Whether this effect is a true consequence of FGFR blockade or involves an off-target effect of the FGFR inhibitor requires additional study.
RESUMO
Short-term hyperglycemia suppresses superior cervical ganglia neurotransmission. If this ganglionic dysfunction also occurs in the islet sympathetic pathway, sympathetically mediated glucagon responses could be impaired. Our objectives were 1) to test for a suppressive effect of 7 days of streptozotocin (STZ) diabetes on celiac ganglia (CG) activation and on neurotransmitter and glucagon responses to preganglionic nerve stimulation, 2) to isolate the defect in the islet sympathetic pathway to the CG itself, and 3) to test for a protective effect of the WLD(S) mutation. We injected saline or nicotine in nondiabetic and STZ-diabetic rats and measured fos mRNA levels in whole CG. We electrically stimulated the preganglionic or postganglionic nerve trunk of the CG in nondiabetic and STZ-diabetic rats and measured portal venous norepinephrine and glucagon responses. We repeated the nicotine and preganglionic nerve stimulation studies in nondiabetic and STZ-diabetic WLD(S) rats. In STZ-diabetic rats, the CG fos response to nicotine was suppressed, and the norepinephrine and glucagon responses to preganglionic nerve stimulation were impaired. In contrast, the norepinephrine and glucagon responses to postganglionic nerve stimulation were normal. The CG fos response to nicotine, and the norepinephrine and glucagon responses to preganglionic nerve stimulation, were normal in STZ-diabetic WLD(S) rats. In conclusion, short-term hyperglycemia's suppressive effect on nicotinic acetylcholine receptors of the CG impairs sympathetically mediated glucagon responses. WLD(S) rats are protected from this dysfunction. The implication is that this CG dysfunction may contribute to the impaired glucagon response to insulin-induced hypoglycemia seen early in type 1 diabetes.
Assuntos
Diabetes Mellitus Tipo 1/fisiopatologia , Regulação para Baixo , Gânglios Simpáticos/fisiopatologia , Glucagon/metabolismo , Hiperglicemia/etiologia , Ilhotas Pancreáticas/metabolismo , Transmissão Sináptica , Animais , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Regulação para Baixo/efeitos dos fármacos , Estimulação Elétrica , Gânglios Simpáticos/efeitos dos fármacos , Gânglios Simpáticos/metabolismo , Estimulantes Ganglionares/farmacologia , Glucagon/sangue , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/inervação , Masculino , Proteínas Mutantes/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Agonistas Nicotínicos/farmacologia , Norepinefrina/sangue , Norepinefrina/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Sprague-Dawley , Ratos Transgênicos , Ratos Wistar , Receptores Nicotínicos/química , Receptores Nicotínicos/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Degeneração Walleriana/complicaçõesRESUMO
Several lines of evidence implicate excess glucagon secretion in the elevated rates of hepatic glucose production (HGP), hyperglycemia, and ketosis characteristic of uncontrolled insulin-deficient diabetes (uDM), but whether hyperglucagonemia is required for hyperglycemia in this setting is unknown. To address this question, adult male Wistar rats received either streptozotocin (STZ) to induce uDM (STZ-DM) or vehicle and remained nondiabetic. Four days later, animals received daily subcutaneous injections of either the synthetic GLP-1 receptor agonist liraglutide in a dose-escalating regimen to reverse hyperglucagonemia or its vehicle for 10 days. As expected, plasma glucagon levels were elevated in STZ-DM rats, and although liraglutide treatment lowered glucagon levels to those of nondiabetic controls, it failed to attenuate diabetic hyperglycemia, elevated rates of glucose appearance (Ra), or increased hepatic gluconeogenic gene expression. In contrast, it markedly reduced levels of both plasma ketone bodies and hepatic expression of the rate-limiting enzyme involved in ketone body production. To independently confirm this finding, in a separate study, treatment of STZ-DM rats with a glucagon-neutralizing antibody was sufficient to potently lower plasma ketone bodies but failed to normalize elevated levels of either blood glucose or Ra. These data suggest that in rats with uDM, hyperglucagonemia is required for ketosis but not for increased HGP or hyperglycemia.
Assuntos
Diabetes Mellitus Experimental/complicações , Glucagon/sangue , Glucose/metabolismo , Hiperglicemia/etiologia , Cetose/etiologia , Fígado/metabolismo , Animais , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/fisiologia , Glucagon/fisiologia , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Hiperglicemia/sangue , Insulina/farmacologia , Corpos Cetônicos/sangue , Cetose/sangue , Liraglutida , Masculino , Ratos Wistar , Receptores de Glucagon/fisiologia , EstreptozocinaRESUMO
Our goal was to determine the role of the p75 neurotrophin receptor (p75NTR) in the loss of islet sympathetic nerves that occurs during the autoimmune attack of the islet. The islets of transgenic (Tg) mice in which ß-cells express a viral glycoprotein (GP) under the control of the insulin promotor (Ins2) were stained for neuropeptide Y before, during, and after virally induced autoimmune attack of the islet. Ins2-GP(Tg) mice injected with lymphocytic choriomeningitis virus (LCMV) lost islet sympathetic nerves before diabetes development but coincident with the lymphocytic infiltration of the islet. The nerve loss was marked and islet-selective. Similar nerve loss, chemically induced, was sufficient to impair sympathetically mediated glucagon secretion. In contrast, LCMV-injected Ins2-GP(Tg) mice lacking the p75NTR retained most of their islet sympathetic nerves, despite both lymphocytic infiltration and development of diabetes indistinguishable from that of p75NTR wild-type mice. We conclude that an inducible autoimmune attack of the islet causes a marked and islet-selective loss of sympathetic nerves that precedes islet collapse and hyperglycemia. The p75NTR mediates this nerve loss but plays no role in mediating the loss of islet ß-cells or the subsequent diabetes. p75NTR-mediated nerve loss may contribute to the impaired glucose counterregulation seen in type 1 diabetes.
Assuntos
Autoimunidade/fisiologia , Diabetes Mellitus Tipo 1/imunologia , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/inervação , Receptores de Fator de Crescimento Neural/fisiologia , Sistema Nervoso Simpático/patologia , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Feminino , Glicoproteínas/genética , Insulina/genética , Ilhotas Pancreáticas/patologia , Ilhotas Pancreáticas/virologia , Vírus da Coriomeningite Linfocítica/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Sistema Nervoso Simpático/virologia , Proteínas Virais/genéticaRESUMO
In rodent models of type 1 diabetes, leptin administration into brain ventricles normalizes blood glucose at doses that have no effect when given peripherally. The ventromedial nucleus of the hypothalamus (VMN) is a potential target for leptin's antidiabetic effects because leptin-sensitive neurons in this brain area are implicated in glucose homeostasis. To test this hypothesis, we injected leptin directly into the bilateral VMN of rats with streptozotocin-induced uncontrolled diabetes mellitus. This intervention completely normalized both hyperglycemia and the elevated rates of hepatic glucose production and plasma glucagon levels but had no effect on tissue glucose uptake in the skeletal muscle or brown adipose tissue as measured using tracer dilution techniques during a basal clamp. To determine whether VMN leptin signaling is required for leptin-mediated normalization of diabetic hyperglycemia, we studied mice in which the leptin receptor gene was deleted in VMN steroidogenic factor 1 neurons using cre-loxP technology. Our findings indicate leptin action within these neurons is not required for the correction of diabetic hyperglycemia by central leptin infusion. We conclude that leptin signaling in the VMN is sufficient to mediate leptin's antidiabetic action but may not be necessary for this effect. Leptin action within a distributed neuronal network may mediate its effects on glucose homeostasis.
Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Hiperglicemia/prevenção & controle , Leptina/metabolismo , Neurônios/metabolismo , Receptores para Leptina/metabolismo , Transdução de Sinais , Núcleo Hipotalâmico Ventromedial/metabolismo , Animais , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/patologia , Glucagon/sangue , Glucagon/metabolismo , Células Secretoras de Glucagon/efeitos dos fármacos , Células Secretoras de Glucagon/metabolismo , Gluconeogênese/efeitos dos fármacos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/metabolismo , Hipoglicemiantes/uso terapêutico , Infusões Intraventriculares , Injeções Intraventriculares , Leptina/administração & dosagem , Leptina/genética , Leptina/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ratos , Ratos Wistar , Receptores para Leptina/agonistas , Receptores para Leptina/genética , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacos , Núcleo Hipotalâmico Ventromedial/patologiaRESUMO
Recent evidence suggests that central leptin administration fully normalizes hyperglycemia in a rodent model of uncontrolled insulin-deficient diabetes by reducing hepatic glucose production (HGP) and by increasing glucose uptake. The current studies were undertaken to determine whether brain-derived neurotrophic factor (BDNF) action in the brain lowers blood glucose in uncontrolled insulin-deficient diabetes and to investigate the mechanisms mediating this effect. Adult male rats implanted with cannulas to either the lateral cerebral ventricle or the ventromedial hypothalamic nucleus (VMN) received either vehicle or streptozotocin to induce uncontrolled insulin-deficient diabetes. Three days later, animals received daily intracerebroventricular or intra-VMN injections of either BDNF or its vehicle. We found that repeated daily intracerebroventricular administration of BDNF attenuated diabetic hyperglycemia independent of changes in food intake. Instead, using tracer dilution techniques during a basal clamp, we found that BDNF lowered blood glucose levels by potently suppressing HGP, without affecting tissue glucose uptake, an effect associated with normalization of both plasma glucagon levels and hepatic expression of gluconeogenic genes. Moreover, BDNF microinjection directly into the VMN also lowered fasting blood glucose levels in uncontrolled insulin-deficient diabetes, but this effect was modest compared with intracerebroventricular administration. We conclude that central nervous system BDNF attenuates diabetic hyperglycemia via an insulin-independent mechanism. This action of BDNF likely involves the VMN and is associated with inhibition of glucagon secretion and a decrease in the rate of HGP.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Gluconeogênese , Hiperglicemia/prevenção & controle , Fígado/metabolismo , Neurônios/metabolismo , Núcleo Hipotalâmico Ventromedial/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/administração & dosagem , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Comportamento Alimentar/efeitos dos fármacos , Glucagon/sangue , Glucagon/metabolismo , Gluconeogênese/efeitos dos fármacos , Glucose/metabolismo , Hipoglicemiantes/uso terapêutico , Injeções Intraventriculares , Insulina/uso terapêutico , Ventrículos Laterais/efeitos dos fármacos , Ventrículos Laterais/metabolismo , Fígado/efeitos dos fármacos , Masculino , Neurônios/efeitos dos fármacos , Ratos , Ratos Wistar , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacosRESUMO
In type 1 diabetes, the impairment of the glucagon response to hypoglycemia increases both its severity and duration. In nondiabetic individuals, hypoglycemia activates the autonomic nervous system, which in turn mediates the majority of the glucagon response to moderate and marked hypoglycemia. The first goal of this minireview is therefore to illustrate and document these autonomic mechanisms. Specifically we describe the hypoglycemic thresholds for activating the three autonomic inputs to the islet (parasympathetic nerves, sympathetic nerves, and adrenal medullary epinephrine) and their magnitudes of activation as glucose falls from euglycemia to near fatal levels. The implication is that their relative contributions to this glucagon response depend on the severity of hypoglycemia. The second goal of this minireview is to discuss known and suspected down-regulation or damage to these mechanisms in diabetes. We address defects in the central nervous system, the peripheral nervous system, and in the islet itself. They are categorized as either functional defects caused by glucose dysregulation or structural defects caused by the autoimmune attack of the islet. In the last section of the minireview, we outline approaches for reversing these defects. Such reversal has both scientific and clinical benefit. Scientifically, one could determine the contribution of these defects to the impairment of glucagon response seen early in type 1 diabetes. Clinically, restoring this glucagon response would allow more aggressive treatment of the chronic hyperglycemia that is linked to the debilitating long-term complications of this disease.
Assuntos
Sistema Nervoso Autônomo/fisiologia , Glucagon/química , Glucagon/metabolismo , Hipoglicemia/metabolismo , Animais , Autoimunidade , Sistema Nervoso Central/metabolismo , Diabetes Mellitus/fisiopatologia , Diabetes Mellitus Tipo 1/metabolismo , Regulação da Expressão Gênica , Glucose/metabolismo , Humanos , Resistência à Insulina , Ilhotas Pancreáticas/citologia , Modelos Biológicos , Sistema Nervoso Periférico/metabolismoRESUMO
The autonomic nervous system influences insulin and glucagon secretion. In this issue, Rodriguez-Diaz et al. (2011) show that mouse and human islets differ in their innervation patterns, yet the effect of neural activation on islet hormone secretion is similar. Key questions raised by this species difference have potential relevance to diabetic therapeutics.
RESUMO
The brain has emerged as a target for the insulin-sensitizing effects of several hormonal and nutrient-related signals. The current studies were undertaken to investigate mechanisms whereby leptin lowers circulating blood glucose levels independently of insulin. After extending previous evidence that leptin infusion directly into the lateral cerebral ventricle ameliorates hyperglycemia in rats with streptozotocin-induced uncontrolled diabetes mellitus, we showed that the underlying mechanism is independent of changes of food intake, urinary glucose excretion, or recovery of pancreatic ß-cells. Instead, leptin action in the brain potently suppresses hepatic glucose production while increasing tissue glucose uptake despite persistent, severe insulin deficiency. This leptin action is distinct from its previously reported effect to increase insulin sensitivity in the liver and offers compelling evidence that the brain has the capacity to normalize diabetic hyperglycemia in the presence of sufficient amounts of central nervous system leptin.
Assuntos
Glicemia/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Diabetes Mellitus Experimental , Hiperglicemia , Insulina/farmacologia , Leptina/farmacologia , Animais , Composição Corporal/efeitos dos fármacos , Corticosterona/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Glucagon/sangue , Teste de Tolerância a Glucose , Hiperglicemia/sangue , Hiperglicemia/tratamento farmacológico , Masculino , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
This short review outlines the physiology of glucagon in vivo, with an emphasis on its neural control, the author's area of interest. Glucagon is secreted from alpha cells, which are a minority of the pancreatic islet. Anatomically, they are down stream from the majority islet beta cells. Beta-cell secretory products restrain glucagon secretion. Activation of the autonomic nerves, which innervate the islet, increases glucagon secretion. Glucagon is secreted into the portal vein and thus has its major physiologic action at the liver to break down glycogen. Glucagon thereby maintains hepatic glucose production during fasting and increases hepatic glucose production during stress, including the clinically important stress of hypoglycemia. Three different mechanisms proposed to stimulate glucagon secreted during hypoglycemia are discussed: (1) a stimulatory effect of low glucose directly on the alpha cell, (2) withdrawal of an inhibitory effect of adjacent beta cells, and (3) a stimulatory effect of autonomic activation. In type 1 diabetes (T1DM), increased glucagon secretion contributes to the elevated ketones and acidosis present in diabetic ketoacidosis (DKA). It also contributes to the hyperglycemia seen with or without DKA. The glucagon response to insulin-induced hypoglycemia is impaired soon after the development of T1DM. The mediators of this impairment include loss of beta cells and loss of sympathetic nerves from the autoimmune diabetic islet.
Assuntos
Células Secretoras de Glucagon/metabolismo , Glucagon/metabolismo , Ilhotas Pancreáticas/metabolismo , Fígado/metabolismo , Animais , Sistema Nervoso Autônomo/fisiopatologia , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Glicogênio/metabolismo , Homeostase , Humanos , Hipoglicemia/metabolismo , Hipoglicemia/fisiopatologia , Insulina/metabolismo , Ilhotas Pancreáticas/inervaçãoRESUMO
OBJECTIVE: Depletion of body fat stores during uncontrolled, insulin-deficient diabetes (uDM) results in markedly reduced plasma leptin levels. This study investigated the role of leptin deficiency in the genesis of severe insulin resistance and related metabolic and neuroendocrine derangements induced by uDM. RESEARCH DESIGN AND METHODS: Adult male Wistar rats remained nondiabetic or were injected with the beta-cell toxin, streptozotocin (STZ) to induce uDM and subsequently underwent subcutaneous implantation of an osmotic minipump containing either vehicle or leptin at a dose (150 microg/kg/day) designed to replace leptin at nondiabetic plasma levels. To control for leptin effects on food intake, another group of STZ-injected animals were pair fed to the intake of those receiving leptin. Food intake, body weight, and blood glucose levels were measured daily, with body composition and indirect calorimetry performed on day 11, and an insulin tolerance test to measure insulin sensitivity performed on day 16. Plasma hormone and substrate levels, hepatic gluconeogenic gene expression, and measures of tissue insulin signal transduction were also measured. RESULTS: Physiologic leptin replacement prevented insulin resistance in uDM via a mechanism unrelated to changes in food intake or body weight. This effect was associated with reduced total body fat and hepatic triglyceride content, preservation of lean mass, and improved insulin signal transduction via the insulin receptor substrate-phosphatidylinositol-3-hydroxy kinase pathway in the liver, but not in skeletal muscle or adipose tissue. Although physiologic leptin replacement lowered blood glucose levels only slightly, it fully normalized elevated plasma glucagon and corticosterone levels and reversed the increased hepatic expression of gluconeogenic enzymes characteristic of rats with uDM. CONCLUSIONS: We conclude that leptin deficiency plays a key role in the pathogenesis of severe insulin resistance and related endocrine disorders in uDM. Treatment of diabetes in humans may benefit from correction of leptin deficiency as well as insulin deficiency.