RESUMO
OBJECTIVE: To assess the role of jejunum in insulin resistance in humans and in experimental animals. DESIGN: Twenty-four subjects undergoing biliopancreatic diversion (BPD) or Roux-en-Y gastric bypass (RYGB) were enrolled. Insulin sensitivity was measured at baseline and at 1 week after surgery using oral glucose minimal model.We excluded the jejunum from intestinal continuity in pigs and created a jejunal loop with its vascular and nerve supply intact accessible from two cutaneous stomas, and reconnected the bowel with an end-to-end anastomosis. Glucose stable isotopes were given in the stomach or in the jejunal loop.In vitro studies using primary porcine and human hepatocytes or myoblasts tested the effects of plasma on gluconeogenesis or glucose uptake and insulin signalling. RESULTS: Whole-body insulin sensitivity (SIâ104: 0.54±0.12 before vs 0.82±0.11 after BPD, p=0.024 and 0.41±0.09 before vs 0.65±0.09/pM/min after RYGB, p=not significant) and Glucose Disposition Index increased only after BPD. In pigs, insulin sensitivity was significantly lower when glucose was administered in the jejunal loop than in the stomach (glucose rate of disappearance (Rd) area under the curve (AUC)/insulin AUCâ10: 1.82±0.31 vs 2.96±0.33 mmol/pM/min, p=0.0017).Metabolomics showed a similar pattern before surgery and during jejunal-loop stimulation, pointing to a higher expression of gluconeogenetic substrates, a metabolic signature of impaired insulin sensitivity.A greater hepatocyte phosphoenolpyruvate-carboxykinase and glucose-6-phosphatase gene expression was elicited with plasma from porcine jejunal loop or before surgery compared with plasma from jejunectomy in pigs or jejunal bypass in humans.Stimulation of myoblasts with plasma from porcine jejunal loop or before surgery reduced glucose uptake, Ser473-Akt phosphorylation and GLUT4 expression compared with plasma obtained during gastric glucose administration after jejunectomy in pigs or after jejunal bypass in humans. CONCLUSION: Proximal gut plays a crucial role in controlling insulin sensitivity through a distinctive metabolic signature involving hepatic gluconeogenesis and muscle insulin resistance. Bypassing the jejunum is beneficial in terms of insulin-mediated glucose disposal in obesity. TRIAL REGISTRATION NUMBER: NCT03111953.
Assuntos
Glucose/metabolismo , Resistência à Insulina , Insulina/metabolismo , Jejuno/metabolismo , Adulto , Animais , Área Sob a Curva , Desvio Biliopancreático , Glicemia/metabolismo , Peptídeo C/sangue , Células Cultivadas , Derivação Gástrica , Peptídeo 1 Semelhante ao Glucagon/sangue , Gluconeogênese , Teste de Tolerância a Glucose , Hepatócitos , Humanos , Fígado/metabolismo , Camundongos , Pessoa de Meia-Idade , Músculo Esquelético/fisiologia , Mioblastos , Obesidade/cirurgia , Fosforilação , Plasma , Período Pós-Operatório , Período Pré-Operatório , Proteínas Proto-Oncogênicas c-akt/metabolismo , SuínosRESUMO
The purpose of this study was to examine the contribution of nonesterified fatty acids (NEFA) and incretin to insulin resistance and diabetes amelioration after malabsorptive metabolic surgery that induces steatorrhea. In fact, NEFA infusion reduces glucose-stimulated insulin secretion, and high-fat diets predict diabetes development. Six healthy controls, 11 obese subjects, and 10 type 2 diabetic (T2D) subjects were studied before and 1 mo after biliopancreatic diversion (BPD). Twenty-four-hour plasma glucose, NEFA, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), and gastric inhibitory polypeptide (GIP) time courses were obtained and analyzed by Granger causality and graph analyses. Insulin sensitivity and secretion were computed by the oral glucose minimal model. Before metabolic surgery, NEFA levels had the strongest influence on the other variables in both obese and T2D subjects. After surgery, GLP-1 and C-peptide levels controlled the system in obese and T2D subjects. Twenty-four-hour GIP levels were markedly reduced after BPD. Finally, not only did GLP-1 levels play a central role, but also insulin and C-peptide levels had a comparable relevance in the network of healthy controls. After BPD, insulin sensitivity was completely normalized in both obese and T2D individuals. Increased 24-h GLP-1 circulating levels positively influenced glucose homeostasis in both obese and T2D subjects who underwent a malabsorptive bariatric operation. In the latter, the reduction of plasma GIP levels also contributed to the improvement of glucose metabolism. It is possible that the combination of a pharmaceutical treatment reducing GIP and increasing GLP-1 plasma levels will contribute to better glycemic control in T2D. The application of Granger causality and graph analyses sheds new light on the pathophysiology of metabolic surgery.
Assuntos
Cirurgia Bariátrica/reabilitação , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/cirurgia , Modelos Teóricos , Obesidade/metabolismo , Obesidade/cirurgia , Adulto , Pesos e Medidas Corporais/normas , Pesos e Medidas Corporais/estatística & dados numéricos , Causalidade , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Obesidade/epidemiologia , Padrões de ReferênciaRESUMO
The mechanisms of type 2 diabetes remission after bariatric surgery is still not fully elucidated. In the present study, we tried to simulate the Roux-en-Y gastric bypass with a canonical or longer biliary limb by infusing a liquid formula diet into different intestinal sections. Nutrients (Nutrison Energy) were infused into mid- or proximal jejunum and duodenum during three successive days in 10 diabetic and 10 normal glucose-tolerant subjects. Plasma glucose, insulin, C-peptide, glucagon, incretins, and nonesterified fatty acids (NEFA) were measured before and up to 360 min following. Glucose rate of appearance (Ra) and insulin sensitivity (SI), secretion rate (ISR), and clearance were assessed by mathematical models. SI increased when nutrients were delivered in mid-jejunum vs. duodenum (SI × 104 min⻹·pM⻹: 1.11 ± 0.44 vs. 0.62 ± 0.22, P < 0.015, in controls and 0.79 ± 0.34 vs. 0.40 ± 0.20, P < 0.05, in diabetic subjects), whereas glucose Ra was not affected. In controls, Sensitivity of NEFA production was doubled in mid-jejunum vs. duodenum (2.80 ± 1.36 vs. 1.13 ± 0.78 × 106, P < 0.005) and insulin clearance increased in mid-jejunum vs. duodenum (2.05 ± 1.05 vs. 1.09 ± 0.38 l/min, P < 0.03). Bypass of duodenum and proximal jejunum by nutrients enhances insulin sensitivity, inhibits lipolysis, and increases insulin clearance. These results may further our knowledge of the effects of bariatric surgery on both insulin resistance and diabetes.
Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Duodeno/metabolismo , Nutrição Enteral/métodos , Resistência à Insulina/fisiologia , Jejuno/metabolismo , Obesidade/fisiopatologia , Adulto , Cirurgia Bariátrica , Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/cirurgia , Carboidratos da Dieta/administração & dosagem , Gorduras na Dieta/administração & dosagem , Proteínas Alimentares/administração & dosagem , Feminino , Alimentos , Intolerância à Glucose/dietoterapia , Intolerância à Glucose/fisiopatologia , Intolerância à Glucose/cirurgia , Humanos , Incretinas/metabolismo , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Intubação Gastrointestinal , Masculino , Pessoa de Meia-Idade , Obesidade/dietoterapia , Obesidade/cirurgiaRESUMO
OBJECTIVE: To elucidate the mechanisms of improvement/reversal of type 2 diabetes after Roux-en-Y gastric bypass (RYGB). METHODS: Fourteen morbidly obese subjects, 7 with normal glucose tolerance and 7 with type 2 diabetes, were studied before and 1 month after RYGB by euglycemic hyperinsulinemic clamp (EHC), by intravenous glucose tolerance test (IVGTT) and by oral glucose tolerance test (OGTT) in 3 different sessions. Intravenous glucose tolerance test IVGTT and OGTT insulin secretion rate (ISR) and sensitivity were obtained by the minimal model. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were measured. Six healthy volunteers were used as controls. RESULTS: Total ISR largely increased in diabetic subjects only when glucose was administered orally (37.8 ± 14.9 vs 68.3 ± 22.8 nmol; P < 0.05, preoperatively vs postoperatively). The first-phase insulin secretion was restored in type 2 diabetic after the IVGTT (Φ1 × 10: 104 ± 54 vs 228 ± 88; P < 0.05, preoperatively vs postoperatively; 242 ± 99 in controls). Insulin sensitivity by EHC (M × 10) was slightly but significantly improved in both normotolerant and diabetic subjects (1.46 ± 0.22 vs 1.37 ± 0.55 mmol·min·kg; P < 0.05 and 1.53 ± 0.23 vs 1.28 ± 0.62 mmol·min·kg; P < 0.05, respectively). Quantitative insulin sensitivity check index was improved in all normotolerant (0.32 ± 0.02 vs 0.30 ± 0.02; P < 0.05) and diabetic subjects (0.33 ± 0.03 vs 0.31 ± 0.02; P < 0.05). GIP and GLP-1 levels increased both at fast and after OGTT mainly in type 2 diabetic subjects. CONCLUSIONS: The large increase of ISR response to the OGTT together with the restoration of the first-phase insulin secretion in diabetic subjects might explain the reversal of type 2 diabetes after RYGB. The large incretin secretion after the oral glucose load might contribute to the increased ISR.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/complicações , Derivação Gástrica/métodos , Resistência à Insulina/fisiologia , Insulina/metabolismo , Obesidade Mórbida/cirurgia , Adulto , Diabetes Mellitus Tipo 2/sangue , Feminino , Peptídeo 1 Semelhante ao Glucagon/sangue , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Secreção de Insulina , Masculino , Obesidade Mórbida/sangue , Obesidade Mórbida/complicações , Resultado do TratamentoRESUMO
A high-fat diet increases the risk of insulin resistance, type-2 diabetes, and non-alcoholic steato-hepatitis. Here we identified two heat-shock proteins, Heat-Shock-Protein70 and Glucose-Regulated Protein78, which are increased in the jejunum of rats on a high-fat diet. We demonstrated a causal link between these proteins and hepatic and whole-body insulin-resistance, as well as the metabolic response to bariatric/metabolic surgery. Long-term continuous infusion of Heat-Shock-Protein70 and Glucose-Regulated Protein78 caused insulin-resistance, hyperglycemia, and non-alcoholic steato-hepatitis in rats on a chow diet, while in rats on a high-fat diet continuous infusion of monoclonal antibodies reversed these phenotypes, mimicking metabolic surgery. Infusion of these proteins or their antibodies was also associated with shifts in fecal microbiota composition. Serum levels of Heat-Shock-Protein70 and Glucose-Regulated Protein78were elevated in patients with non-alcoholic steato-hepatitis, but decreased following metabolic surgery. Understanding the intestinal regulation of metabolism may provide options to reverse metabolic diseases.
Assuntos
Hepatite , Hiperglicemia , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Ratos , Animais , Resistência à Insulina/genética , Chaperona BiP do Retículo Endoplasmático , Proteínas de Choque Térmico/metabolismo , Insulina/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Dieta Hiperlipídica/efeitos adversos , Proteínas de Choque Térmico HSP70/metabolismo , Fígado/metabolismo , Hiperglicemia/metabolismo , Glucose/metabolismoRESUMO
The rate of appearance (R(a)) of exogenous glucose in plasma after glucose ingestion is presently measured by tracer techniques that cannot be used in standard clinical testing such as the oral glucose tolerance test (OGTT). We propose a mathematical model that represents in a simple way the gastric emptying, the transport of glucose along the intestinal tract, and its absorption from gut lumen into portal blood. The model gives the R(a) time course in terms of parameters with a physiological counterpart and provides an expression for the release of incretin hormones as related to glucose transit into gut lumen. Glucose absorption was represented by assuming two components related to a proximal and a distal transporter. Model performance was evaluated by numerical simulations. The model was then validated by fitting OGTT glucose and GLP-1 data in healthy controls and type 2 diabetic patients, and useful information was obtained for the rate of gastric emptying, the rate of glucose absorption, the R(a) profile, the insulin sensitivity, and the glucose effectiveness. Model-derived estimates of insulin sensitivity were well correlated (r = 0.929 in controls and 0.886 in diabetic patients) to data obtained from the euglycemic hyperinsulinemic clamp. Although the proposed OGTT analysis requires the measurement of an additional hormone concentration (GLP-1), it appears to be a reasonable choice since it avoids complex and expensive techniques, such as isotopes for glucose R(a) measurement and direct assessment of gastric emptying and intestinal transit, and gives additional correlated information, thus largely compensating for the extra expense.
Assuntos
Trânsito Gastrointestinal/fisiologia , Teste de Tolerância a Glucose/métodos , Teste de Tolerância a Glucose/estatística & dados numéricos , Glucose/metabolismo , Incretinas/metabolismo , Adulto , Algoritmos , Glicemia/metabolismo , Composição Corporal/fisiologia , Feminino , Polipeptídeo Inibidor Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/administração & dosagem , Humanos , Infusões Parenterais , Absorção Intestinal/fisiologia , Mucosa Intestinal/metabolismo , Cinética , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Reprodutibilidade dos Testes , Transportador 1 de Glucose-Sódio/metabolismoRESUMO
Although commonly related to nutrient deprivation, the cause of the formation of the necrotic core in the multicellular tumour spheroids is still a controversial issue. We propose a simple model for the cell ATP production that assumes glucose and lactate as the only fuel substrates, and describes the main reactions occurring in the glycolytic and the oxidative pathways. Under the key assumption that cell death occurs when ATP production falls to a critical level, we formulate a multiscale model that integrates the energy metabolism at the cellular level with the diffusive transport of the metabolites in the spheroid mass. The model has been tested by predicting the measurements of the necrotic radius obtained by Freyer and Sutherland (1986a) in EMT6/Ro spheroids under different concentrations of glucose and oxygen in the culture medium. The results appear to be in agreement with the hypothesis that necrosis is caused by ATP deficit.
Assuntos
Trifosfato de Adenosina/deficiência , Carcinoma/patologia , Neoplasias Mamárias Animais/patologia , Esferoides Celulares/patologia , Trifosfato de Adenosina/metabolismo , Animais , Carcinoma/metabolismo , Relação Dose-Resposta a Droga , Metabolismo Energético/fisiologia , Feminino , Glucose/farmacologia , Ácido Láctico/metabolismo , Ácido Láctico/farmacologia , Neoplasias Mamárias Animais/metabolismo , Camundongos , Modelos Teóricos , Necrose/etiologia , Necrose/metabolismo , Oxigênio/farmacologia , Esferoides Celulares/metabolismo , Células Tumorais CultivadasRESUMO
Metabolic surgery improves insulin resistance and is associated with the remission of type 2 diabetes, but the mechanisms involved remain unknown. We find that human jejunal mucosa secretes heat shock proteins (HSPs) in vitro, in particular HSP70 and GRP78. Circulating levels of HSP70 are higher in people resistant to insulin, compared to the healthy and normalize after duodenal-jejunal bypass. Insulin sensitivity negatively correlates with the plasma level of HSP70, while body mass index does not. A high-energy diet increases the circulating levels of HSP70 and insulin resistance. HSP70 stimulates the accumulation of lipid droplets and inhibits Ser473 phosphorylation of Akt and glucose uptake in immortalized liver cells and peripheral blood cells. Serum depleted of HSPs, as well as the serum from the insulin-resistant people subjected to a duodenal-jejunal bypass, reverse these features, identifying gut-secreted HSPs as possible causes of insulin resistance. Duodenal-jejunal bypass might reduce the secretion of HSPs either by shortening the food transit or by decreasing the fat stimulation of endocrine cells.
RESUMO
Intestinal nutrients stimulate insulin secretion more potently than intravenous (IV) glucose administration under similar plasma glucose levels (incretin effect). According to the anti-incretin theory, intestinal nutrients should also cause a reduction of insulin sensitivity and/or secretion (anti-incretin effect) to defend against hyperinsulinemia-hypoglycemia. An exaggerated anti-incretin effect could contribute to insulin resistance/type 2 diabetes, whereas reduction of anti-incretin signals might explain diabetes improvement after bariatric surgery. In this study, we tested some of the predictions made by the anti-incretin theory. Eight healthy volunteers and eight severely obese subjects with insulin resistance were studied. Insulin secretion, insulin sensitivity, Ra, and disposition index were measured after oral glucose tolerance test and isoglycemic IV glucose injection (IGIV). Obese subjects were studied before and after intestinal bypass surgery (biliopancreatic diversion [BPD]). The d-xylose test and lactulose-to-rhamnose ratio were used to test for possible malabsorption of glucose after surgery. Monte Carlo mathematical simulations were used to test whether insulin secretion induced by oral glucose could cause hypoglycemia when coupled with the levels of insulin sensitivity measured during IGIV. Despite isoglycemic conditions, insulin sensitivity was lower during oral than during IV glucose administration. This difference was amplified in obese subjects and reduced to normal after BPD. No evidence of glucose malabsorption was found. Mathematical simulations showed that hypoglycemia would occur if insulin sensitivity were not reduced by oral glucose stimulation. This study demonstrates an anti-incretin effect of intestinal glucose stimulation, which downregulates insulin sensitivity. The findings support a new model for how foodborne factors can induce insulin-resistance and provide a possible explanation for the improvement of insulin resistance/diabetes after gastrointestinal bypass surgery.
Assuntos
Regulação para Baixo , Glucose/farmacologia , Incretinas/metabolismo , Resistência à Insulina , Administração Oral , Adulto , Simulação por Computador , Feminino , Glucose/administração & dosagem , Glucose/metabolismo , Humanos , Hipoglicemia , Masculino , Pessoa de Meia-Idade , Obesidade , Redução de PesoRESUMO
Insulin resistance is the common denominator of several diseases including type 2 diabetes and cancer, and investigating the mechanisms responsible for insulin signaling impairment is of primary importance. A mathematical model of the insulin signaling network (ISN) is proposed and used to investigate the dose-response curves of components of this network. Experimental data of C2C12 myoblasts with phosphatase and tensin homologue (PTEN) suppressed and data of L6 myotubes with induced insulin resistance have been analyzed by the model. We focused particularly on single and double Akt phosphorylation and pointed out insulin signaling changes related to insulin resistance. Moreover, a new characterization of the upstream signaling of the mammalian target of rapamycin complex 2 (mTORC2) is presented. As it is widely recognized that ISN proteins have a crucial role also in cell proliferation and death, the ISN model was linked to a cell population model and applied to data of a cell line of acute myeloid leukemia treated with a mammalian target of rapamycin inhibitor with antitumor activity. The analysis revealed simple relationships among the concentrations of ISN proteins and the parameters of the cell population model that characterize cell cycle progression and cell death.
Assuntos
Resistência à Insulina , Insulina/metabolismo , Modelos Teóricos , Neoplasias/metabolismo , Transdução de Sinais , Animais , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismoRESUMO
The present study was aimed at evaluating the feasibility and reliability of lower limb skeletal muscle (SM) mass estimates obtained by bioimpedance analysis (BIA). BIA estimates were compared with the estimates obtained by dual-energy X-ray absorptiometry (DXA). Ten normal weight and 10 obese women had BIA and DXA evaluations. Lower limb SM mass was then derived from DXA appendicular lean soft tissue estimates. Lower limb SM mass and SM distribution were also estimated from BIA modeling that fits measured resistance values along the leg. SM mass (mean +/- SD) was 5.8 +/- 1.0 kg by BIA vs. 5.8 +/- 1.1 kg by DXA in normal weight subjects and 7.2 +/- 1.4 kg by BIA vs. 7.2 +/- 1.2 kg by DXA in obese subjects. Mean +/- SD of the absolute value of the relative error was 7.0 +/- 3.4 and 5.9 +/- 3.4% in the two groups, respectively. Similar results were obtained by using five resistance values for the analysis. In conclusion, the proposed BIA model provides an adequate means of evaluating appendicular SM mass.
Assuntos
Composição Corporal , Impedância Elétrica , Perna (Membro)/anatomia & histologia , Músculo Esquelético/anatomia & histologia , Obesidade/patologia , Absorciometria de Fóton , Anatomia Transversal , Estudos de Viabilidade , Feminino , Humanos , Perna (Membro)/diagnóstico por imagem , Modelos Anatômicos , Músculo Esquelético/diagnóstico por imagem , Obesidade/diagnóstico por imagem , Reprodutibilidade dos TestesRESUMO
A mathematical model is developed that describes the proliferative behaviour at the stationary state of the cell population within a tumour cord, i.e. in a cylindrical arrangement of tumour cells growing around a blood vessel and surrounded by necrosis. The model, that represents the tumour cord as a continuum, accounts for the migration of cells from the inner to the outer zone of the cord and describes the cell cycle by a sequence of maturity compartments plus a possible quiescent compartment. Cell-to-cell variability of cycle phase transit times and changes in the cell kinetic parameters within the cord, related to changes of the microenvironment, can be represented in the model. The theoretical predictions are compared against literature data of the time course of the labelling index and of the fraction of labelled mitoses in an experimental tumour after pulse labelling with 3H-thymidine. It is shown that the presence of cell migration within the cord can lead to a marked underestimation of the actual changes along cord radius of the kinetics of cell cycle progression.
Assuntos
Ciclo Celular/fisiologia , Modelos Biológicos , Neoplasias/patologia , Animais , Carcinoma/irrigação sanguínea , Carcinoma/patologia , Feminino , Neoplasias Mamárias Experimentais/irrigação sanguínea , Neoplasias Mamárias Experimentais/patologia , Camundongos , Neoplasias/irrigação sanguíneaRESUMO
Gastric bypass surgery can dramatically improve type 2 diabetes. It has been hypothesized that by excluding duodenum and jejunum from nutrient transit, this procedure may reduce putative signals from the proximal intestine that negatively influence insulin sensitivity (SI). To test this hypothesis, resection or bypass of different intestinal segments were performed in diabetic Goto-Kakizaki and Wistar rats. Rats were randomly assigned to five groups: duodenal-jejunal bypass (DJB), jejunal resection (jejunectomy), ileal resection (ileectomy), pair-fed sham-operated, and nonoperated controls. Oral glucose tolerance test was performed within 2 weeks after surgery. Baseline and poststimulation levels of glucose, insulin, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) were measured. Minimal model analysis was used to assess SI. SI improved after DJB (SI = 1.14 ± 0.32 × 10(-4) min(-1) â pM(-1)) and jejunectomy (SI = 0.80 ± 0.14 × 10(-4) min(-1) â pM(-1)), but not after ileectomy or sham operation/pair feeding in diabetic rats. Both DJB and jejunal resection normalized SI in diabetic rats as shown by SI levels equivalent to those of Wistar rats (SI = 1.01 ± 0.06 × 10(-4) min(-1) â pM(-1); P = NS). Glucose effectiveness did not change after operations in any group. While ileectomy increased plasma GIP levels, no changes in GIP or GLP-1 were observed after DJB and jejunectomy. These findings support the hypothesis that anatomic alterations of the proximal small bowel may reduce factors associated with negative influence on SI, therefore contributing to the control of diabetes after gastric bypass surgery.
Assuntos
Diabetes Mellitus Tipo 2/cirurgia , Duodeno/cirurgia , Incretinas/metabolismo , Resistência à Insulina , Insulina/metabolismo , Jejuno/cirurgia , Animais , Área Sob a Curva , Glicemia/análise , Diabetes Mellitus Tipo 2/metabolismo , Derivação Gástrica , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Secreção de Insulina , Masculino , Ratos , Ratos WistarRESUMO
Mathematical modeling of the glucose-insulin feedback system is necessary to the understanding of the homeostatic control, to analyze experimental data, to identify and quantify relevant biophysical parameters, to design clinical trials and to evaluate diabetes prevention or disease modification therapies. Much work has been made over the last 30years, and the time now seems ripe to provide a comprehensive review. The one here proposed is focused on the most important clinical/experimental tests performed to understand the mechanism of glucose homeostasis. The review proceeds from models of pancreatic insulin production, with a coarser/finer level of detail ranging over cellular and subcellular scales, to short-term organ/tissue models accounting for the intra-venous and the oral glucose tolerance tests as well as for the euglycemic hyperinsulinemic clamp, to total-body, long-term diabetes models aiming to represent disease progression in terms of ß-cell population dynamics over a long period of years.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus/fisiopatologia , Insulina/metabolismo , Modelos Teóricos , Animais , Diabetes Mellitus/sangue , Humanos , Insulina/sangue , Secreção de InsulinaRESUMO
BACKGROUND: Two recent studies demonstrated that bariatric surgery induced remission of type 2 diabetes very soon after surgery and far too early to be attributed to weight loss. In this study, we sought to explore the mechanism/s of this phenomenon by testing the effects of proteins from the duodenum-jejunum conditioned-medium (CM) of db/db or Swiss mice on glucose uptake in vivo in Swiss mice and in vitro in both Swiss mice soleus and L6 cells. We studied the effect of sera and CM proteins from insulin resistant (IR) and insulin-sensitive subjects on insulin signaling in human myoblasts. METHODOLOGY/PRINCIPAL FINDINGS: db/db proteins induced massive IR either in vivo or in vitro, while Swiss proteins did not. In L6 cells, only db/db proteins produced a noticeable increase in basal (473)Ser-Akt phosphorylation, lack of GSK3ß inhibition and a reduced basal (389)Thr-p70-S6K1 phosphorylation. Human IR serum markedly increased basal (473)Ser-Akt phosphorylation in a dose-dependent manner. Human CM IR proteins increased by about twofold both basal and insulin-stimulated (473)Ser-Akt. Basal (9)Ser-GSK3ß phosphorylation was increased by IR subjects serum with a smaller potentiating effect of insulin. CONCLUSIONS: These findings show that jejunal proteins either from db/db mice or from insulin resistant subjects impair muscle insulin signaling, thus inducing insulin resistance.
Assuntos
Diabetes Mellitus Experimental/patologia , Resistência à Insulina , Insulina/metabolismo , Jejuno/metabolismo , Proteínas/metabolismo , Transdução de Sinais , Adulto , Animais , Diferenciação Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Desoxiglucose/metabolismo , Diabetes Mellitus Experimental/enzimologia , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Fosforilação/efeitos dos fármacos , Fosfosserina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismoRESUMO
OBJECTIVE: The purpose of this study was to elucidate the mechanisms of diabetes reversibility after malabsorptive bariatric surgery. RESEARCH DESIGN AND METHODS: Peripheral insulin sensitivity and beta-cell function after either intravenous (IVGTT) or oral glucose tolerance (OGTT) tests and minimal model analysis were assessed in nine obese, type 2 diabetic subjects before and 1 month after biliopancreatic diversion and compared with those in six normal-weight control subjects. Insulin-dependent whole-body glucose disposal was measured by the euglycemic clamp, and glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were also measured. RESULTS: The first phase of insulin secretion after the IVGTT was fully normalized after the operation. The disposition index from OGTT data was increased about 10-fold and became similar to the values found in control subjects, and the disposition index from IVGTT data increased about 3.5-fold, similarly to what happened after the euglycemic clamp. The area under the curve (AUC) for GIP decreased about four times (from 3,000 +/- 816 to 577 +/- 155 pmol x l(-1) x min, P < 0.05). On the contrary, the AUC for GLP1 almost tripled (from 150.4 +/- 24.4 to 424.4 +/- 64.3 pmol x l(-1) . min, P < 0.001). No significant correlation was found between GIP or GLP1 percent changes and modification of the sensitivity indexes independently of the route of glucose administration. CONCLUSIONS: Restoration of the first-phase insulin secretion and normalization of insulin sensitivity in type 2 diabetic subjects after malabsorptive bariatric surgery seem to be related to the reduction of the effect of some intestinal factor(s) resulting from intestinal bypass.
Assuntos
Cirurgia Bariátrica , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/cirurgia , Vias de Administração de Medicamentos , Glucose/metabolismo , Insulina/metabolismo , Adulto , Feminino , Polipeptídeo Inibidor Gástrico/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Teste de Tolerância a Glucose , Humanos , Secreção de Insulina , Masculino , Pessoa de Meia-Idade , Modelos TeóricosRESUMO
A mathematical model that represents the dynamics of intracellular insulin granules in beta-cells is proposed. Granule translocation and exocytosis are controlled by signals assumed to be essentially related to ATP-to-ADP ratio and cytosolic Ca(2+) concentration. The model provides an interpretation of the roles of the triggering and amplifying pathways of glucose-stimulated insulin secretion. Values of most of the model parameters were inferred from available experimental data. The numerical simulations represent a variety of experimental conditions, such as the stimulation by high K(+) and by different time courses of extracellular glucose, and the predicted responses agree with published experimental data. Model capacity to represent data measured in a hyperglycemic clamp was also tested. Model parameter changes that may reflect alterations of beta-cell function present in type 2 diabetes are investigated, and the action of pharmacological agents that bind to sulfonylurea receptors is simulated.
Assuntos
Glucose/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Modelos Teóricos , Vesículas Secretórias/metabolismo , Animais , Peptídeo C/metabolismo , Simulação por Computador , Técnica Clamp de Glucose , Humanos , Secreção de Insulina , Modelos Biológicos , Vesículas Secretórias/efeitos dos fármacosRESUMO
There is experimental evidence that a source of fatty acids (FAs) that is either exogenous or endogenous is necessary to support normal insulin secretion. Therefore, FAs comodulate the glucose-induced pancreatic insulin secretion. To assess the role of FAs, 16 morbidly obese nondiabetic patients and 6 healthy volunteers were studied. The controls and the obese subjects, before and after diet-induced weight loss, spent 24 h in a calorimetric chamber, where they consumed standardized meals. Hourly blood samples were drawn from a central venous catheter for the measurement of glucose, C-peptide, and nonesterified fatty acid (NEFA) concentrations. Insulin sensitivity was measured (as the M value) by euglycemic hyperinsulinemic clamp. In the present study, we propose a mathematical model in which insulin secretion rate (ISR) is expressed as a function of both plasma glucose and NEFA concentrations. Model parameters, obtained by fitting the individual experimental data of plasma C-peptide concentration, gave an estimated ISR comparable with that obtained by the deconvolution method. To evaluate the performance of the model in an experimental condition in which incretin effect was minimized, previous data on insulin secretion following a butter load and subsequent hyperglycemic clamp were reanalyzed. This model of nutrient-stimulated insulin secretion is the first attempt to represent in a simple way the interaction between glucose and NEFA in the regulation of insulin secretion in the beta-cell and explains, at least in part, the "potentiation factor" used in previous models to account for other control factors different from glucose after either an intravenous infusion of glucose or a mixed meal.
Assuntos
Glicemia/metabolismo , Ritmo Circadiano , Ingestão de Alimentos , Ácidos Graxos não Esterificados/sangue , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Modelos Biológicos , Obesidade Mórbida/fisiopatologia , Peptídeo C/sangue , Técnica Clamp de Glucose , Humanos , Hiperglicemia/fisiopatologia , Secreção de Insulina , Obesidade Mórbida/dietoterapia , Concentração Osmolar , Redução de PesoRESUMO
Metabolically healthy skeletal muscle possesses the ability to switch easily between glucose and fat oxidation in response to homeostatic signals. In type 2 diabetes mellitus and obesity, the skeletal muscle shows a great reduction in this metabolic flexibility. A substrate like dodecanedioic acid (C-12), able to increase skeletal muscle glycogen stores via succinyl-CoA formation, might both postpone the fatigue and increase fatty acid utilization, since it does not affect insulin secretion. In healthy volunteers and in type 2 diabetic subjects, the effect of an oral C-12 load was compared with a glucose or water load during prolonged, moderate-intensity, physical exercise. C-12 metabolism was analyzed by a mathematical model. After C-12, diabetics were able to complete the 2 h of exercise. Nonesterified fatty acids increased both during and after the exercise in the C-12 session. C-12 oxidation provided 14% of total energy expenditure, and the sum of C-12 plus lipids oxidized after the C-12 meal was significantly greater than lipids oxidized after the glucose meal (P < 0.025). The fraction of C-12 that entered the central compartment was 47% of that ingested. During the first phase of the exercise ( approximately 60 min), the mean C-12 clearance from the central compartment toward tissues was 2.57 and 1.30 l/min during the second phase of the exercise. In conclusion, C-12 seems to be a suitable energy substrate during exercise, since it reduces muscle fatigue, is rapidly oxidized, and does not stimulate insulin secretion, which implies that lipolysis is not inhibited as reported after glucose ingestion.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Ácidos Dicarboxílicos/administração & dosagem , Metabolismo Energético/efeitos dos fármacos , Modelos Biológicos , Administração Oral , Adulto , Glicemia/metabolismo , Ácidos Graxos não Esterificados/sangue , Glicogênio/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fadiga Muscular/efeitos dos fármacos , Fadiga Muscular/fisiologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Oxirredução , Esforço Físico/fisiologiaRESUMO
This work illustrates the behavior of the interstitial pressure and of the interstitial fluid motion in tumor cords (cylindrical arrangements of tumor cells growing around blood vessels of the tumor) by means of numerical simulations on the basis of a mathematical model previously developed. The model describes the steady state of a tumor cord surrounded by necrosis and its time evolution following cell killing. The most relevant aspects of the dynamics of extracellular fluid are by computing the longitudinal average of the radial fluid velocity and of the pressure field. In the present paper, the necrotic region is treated as a mixture of degrading dead cells and fluid.