RESUMO
It is known that for a given insulin level glucose clearance depends on glucose concentration. However, a quantitative representation of the concomitant effects of hyperinsulinemia and hyperglycemia on glucose clearance, necessary to describe heterogeneous tests such as euglycemic and hyperglycemic clamps and oral tests, is lacking. Data from five studies (123 subjects) using a glucose tracer and including all the above tests in normal and diabetic subjects were collected. A mathematical model was developed in which glucose utilization was represented as a Michaelis-Menten function of glucose with constant Km and insulin-controlled Vmax, consistently with the basic notions of glucose transport. Individual values for the model parameters were estimated using a population approach. Tracer data were accurately fitted in all tests. The estimated Km was 3.88 (2.83-5.32) mmol/l [median (interquartile range)]. Median model-derived glucose clearance at 600 pmol/l insulin was reduced from 246 to 158 ml·min(-1)·m(-2) when glucose was raised from 5 to 10 mmol/l. The model reproduced the characteristic lack of increase in glucose clearance when moderate hyperinsulinemia was accompanied by hyperglycemia. In all tests, insulin sensitivity was inversely correlated with BMI, as expected (R(2) = 0.234, P = 0.0001). In conclusion, glucose clearance in euglycemic and hyperglycemic clamps and oral tests can be described with a unifying model, consistent with the notions of glucose transport and able to reproduce the suppression of glucose clearance due to hyperglycemia observed in previous studies. The model may be important for the design of reliable glucose homeostasis simulators.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Intolerância à Glucose/metabolismo , Glucose/metabolismo , Hiperglicemia/metabolismo , Hiperinsulinismo/metabolismo , Insulina/metabolismo , Adulto , Idoso , Glicemia/metabolismo , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Técnica Clamp de Glucose , Humanos , Resistência à Insulina , Cinética , Masculino , Pessoa de Meia-Idade , Modelos TeóricosRESUMO
Insulin administration during insulin-modified intravenous glucose tolerance test (IM-IVGTT) can induce transient hypoglycemia in healthy insulin-sensitive subjects. This triggers counterregulatory reflex (CRR) responses, which influence the kinetics of glucose and nonesterified fatty acids (NEFA), and undermines the accuracy of mathematical modeling methods that do not explicitly account for CRR. The aim of this study is to evaluate mathematical models of glucose and NEFA kinetics against experimental data in the presence or absence of CRR. Thirteen healthy nondiabetic subjects underwent a standard IM-IVGTT and a modified test (GC-IM-IVGTT) with a variable glucose infusion preventing hypoglycemia. While model predictions fit very well with glucose and NEFA data from GC-IM-IVGTT, they lagged behind observations from IM-IVGTT during recovery from hypoglycemia, independently of insulinemia, which did not differ significantly between protocols. A modification to the glucose minimal model, using the glucose concentration below a threshold as a signal for CRR, improves model predictions for both glucose and NEFA. The associated increase in endogenous glucose production correlates, among various CRR hormones, mainly with the dynamics of glucagon concentration. The modified minimal models introduce new parameters that quantify strength and duration of CRR following hypoglycemia. Although CRR represents an unwanted side-effect in IM-IVGTT occurring only in insulin-sensitive subjects, this study provides new insights leading to improved procedures for estimating insulin sensitivity from IM-IVGTT, which may also allow for assessing the individual capacity of recovery from hypoglycemic events in patients treated with insulin or insulin-releasing drugs.
Assuntos
Glicemia/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Teste de Tolerância a Glucose , Glucose/farmacologia , Insulina/farmacologia , Modelos Teóricos , Adulto , Glicemia/efeitos dos fármacos , Feminino , Glucose/administração & dosagem , Humanos , Hipoglicemia/metabolismo , Insulina/sangue , Resistência à Insulina/fisiologia , Masculino , Modelos BiológicosRESUMO
UNLABELLED: Increased hepatocellular lipids relate to insulin resistance and are typical for individuals with type 2 diabetes mellitus (T2DM). Steatosis and T2DM have been further associated with impaired muscular adenosine triphosphate (ATP) turnover indicating reduced mitochondrial fitness. Thus, we tested the hypothesis that hepatic energy metabolism could be impaired even in metabolically well-controlled T2DM. We measured hepatic lipid volume fraction (HLVF) and absolute concentrations of gammaATP, inorganic phosphate (Pi), phosphomonoesters and phosphodiesters using noninvasive (1)H/ (31)P magnetic resonance spectroscopy in individuals with T2DM (58 +/- 6 years, 27 +/- 3 kg/m (2)), and age-matched and body mass index-matched (mCON; 61 +/- 4 years, 26 +/- 4 kg/m (2)) and young lean humans (yCON; 25 +/- 3 years, 22 +/- 2 kg/m (2), P < 0.005, P < 0.05 versus T2DM and mCON). Insulin-mediated whole-body glucose disposal (M) and endogenous glucose production (iEGP) were assessed during euglycemic-hyperinsulinemic clamps. Individuals with T2DM had 26% and 23% lower gammaATP (1.68 +/- 0.11; 2.26 +/- 0.20; 2.20 +/- 0.09 mmol/L; P < 0.05) than mCON and yCON individuals, respectively. Further, they had 28% and 31% lower Pi than did individuals from the mCON and yCON groups (0.96 +/- 0.06; 1.33 +/- 0.13; 1.41 +/- 0.07 mmol/L; P < 0.05). Phosphomonoesters, phosphodiesters, and liver aminotransferases did not differ between groups. HLVF was not different between those from the T2DM and mCON groups, but higher (P = 0.002) than in those from the yCON group. T2DM had 13-fold higher iEGP than mCON (P < 0.05). Even after adjustment for HLVF, hepatic ATP and Pi related negatively to hepatic insulin sensitivity (iEGP) (r =-0.665, P = 0.010, r =-0.680, P = 0.007) but not to whole-body insulin sensitivity. CONCLUSION: These data suggest that impaired hepatic energy metabolism and insulin resistance could precede the development of steatosis in individuals with T2DM.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético/fisiologia , Homeostase/fisiologia , Fígado/metabolismo , Trifosfato de Adenosina/metabolismo , Idoso , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/fisiopatologia , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Feminino , Humanos , Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos/fisiologia , Masculino , Pessoa de Meia-Idade , Fosfatos/metabolismo , Fósforo/metabolismoRESUMO
Intravenous infusions of different iron formulations are recognized as a cause of hypophosphatemia. Chronic hypophosphatemia can alter bone metabolism and bone material structure. As a consequence, osteomalacia may develop and lead to bone fragility. Herein, we report a patient with Crohn's disease presenting with persistent hypophosphatemia and insufficiency fractures while receiving regular iron infusions due to chronic gastrointestinal bleeding. Previously, the patient regularly received vitamin D and also zoledronic acid. The patient underwent bone biopsy of the iliac crest that showed typical signs of osteomalacia with dramatically increased osteoid volume and decreased bone formation. Analysis of the bone mineralization density distribution (BMDD) revealed a more complex picture: On the one hand, there was a shift to higher matrix mineralization, presumably owing to low bone turnover; on the other hand, a broadening of the BMDD indicating more heterogeneous mineralization due to osteomalacia was also evident. This is the first report on changes of bone histomorphometry and bone matrix mineralization in iron-induced osteomalacia. © 2017 American Society for Bone and Mineral Research.
Assuntos
Osso e Ossos/patologia , Fraturas de Estresse/etiologia , Fraturas de Estresse/fisiopatologia , Marcha/fisiologia , Hipofosfatemia/fisiopatologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Ferro/efeitos adversos , Dor/fisiopatologia , Administração Intravenosa , Adulto , Biópsia , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/fisiopatologia , Calcificação Fisiológica/efeitos dos fármacos , Fator de Crescimento de Fibroblastos 23 , Fraturas de Estresse/sangue , Fraturas de Estresse/diagnóstico por imagem , Humanos , Hipofosfatemia/sangue , Hipofosfatemia/diagnóstico por imagem , Hipofosfatemia/etiologia , Doenças Inflamatórias Intestinais/sangue , Ferro/administração & dosagem , Ferro/uso terapêutico , Imageamento por Ressonância Magnética , Masculino , Dor/sangue , Dor/etiologia , Fosfatos/sangueRESUMO
Insulin resistance correlates with intramyocellular lipid content (IMCL) and plasma free fatty acids (FFAs) and was recently linked to mitochondrial dysfunction. We examined the underlying relationships by measuring skeletal muscle ATP synthase flux, glucose transport/phosphorylation, and IMCL in response to different plasma insulin and plasma FFA concentrations. Healthy men were studied twice during hyperinsulinemic-euglycemic clamps with (LIP) or without (CON) lipid infusion (plasma FFA: CON approximately 36 vs. LIP approximately 1,034 micromol/l, P < 0.001). ATP synthase flux, glucose-6-phosphate (G6P), and IMCL were determined before and during the clamp in calf muscle using (31)P and (1)H magnetic resonance spectroscopy. Plasma lipid elevation resulted in approximately 46% reduced whole-body glucose metabolism (180-360 min; P < 0.0001 vs. CON) and a 70% lower rise of G6P (P < 0.05 vs. CON) without significant changes in IMCL (LIP 117 +/- 12% vs. CON 93 +/- 3% of basal, P = 0.073). During the clamp, ATP synthase flux increased by approximately 60% under control conditions (P = 0.02 vs. baseline) and was 24% lower during lipid infusion (LIP 11.0 +/- 0.9 vs. CON 14.6 +/- 1.2 micromol . g muscle(-1) . min(-1), P < 0.05). Physiologically increased plasma FFA concentrations reduce insulin-stimulated muscle ATP synthase flux in parallel with induction of insulin resistance.
Assuntos
Trifosfato de Adenosina/biossíntese , Insulina/farmacologia , Metabolismo dos Lipídeos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Adulto , Transporte Biológico , Glucose/metabolismo , Técnica Clamp de Glucose , Glucose-6-Fosfato/metabolismo , Humanos , Insulina/metabolismo , MasculinoRESUMO
BACKGROUND: Muscular insulin resistance is frequently characterized by blunted increases in glucose-6-phosphate (G-6-P) reflecting impaired glucose transport/phosphorylation. These abnormalities likely relate to excessive intramyocellular lipids and mitochondrial dysfunction. We hypothesized that alterations in insulin action and mitochondrial function should be present even in nonobese patients with well-controlled type 2 diabetes mellitus (T2DM). METHODS AND FINDINGS: We measured G-6-P, ATP synthetic flux (i.e., synthesis) and lipid contents of skeletal muscle with (31)P/(1)H magnetic resonance spectroscopy in ten patients with T2DM and in two control groups: ten sex-, age-, and body mass-matched elderly people; and 11 younger healthy individuals. Although insulin sensitivity was lower in patients with T2DM, muscle lipid contents were comparable and hyperinsulinemia increased G-6-P by 50% (95% confidence interval [CI] 39%-99%) in all groups. Patients with diabetes had 27% lower fasting ATP synthetic flux compared to younger controls (p = 0.031). Insulin stimulation increased ATP synthetic flux only in controls (younger: 26%, 95% CI 13%-42%; older: 11%, 95% CI 2%-25%), but failed to increase even during hyperglycemic hyperinsulinemia in patients with T2DM. Fasting free fatty acids and waist-to-hip ratios explained 44% of basal ATP synthetic flux. Insulin sensitivity explained 30% of insulin-stimulated ATP synthetic flux. CONCLUSIONS: Patients with well-controlled T2DM feature slightly lower flux through muscle ATP synthesis, which occurs independently of glucose transport /phosphorylation and lipid deposition but is determined by lipid availability and insulin sensitivity. Furthermore, the reduction in insulin-stimulated glucose disposal despite normal glucose transport/phosphorylation suggests further abnormalities mainly in glycogen synthesis in these patients.
Assuntos
Trifosfato de Adenosina/biossíntese , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina/fisiologia , Mitocôndrias Musculares/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/fisiologia , Adulto , Idoso , Ácidos Graxos não Esterificados/metabolismo , Feminino , Técnica Clamp de Glucose , Glucose-6-Fosfato/sangue , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismo , Obesidade/fisiopatologia , FosforilaçãoRESUMO
CONTEXT: During insulin-modified frequently sampled iv glucose tolerance tests (IM-FSIGT), which allow assessment of insulin action, plasma glucose can markedly decrease. OBJECTIVE: This study aimed to assess the counterregulatory impact of the insulin-induced fall of glucose on minimal model-derived indices of insulin sensitivity (S(I)) and glucose effectiveness. PARTICIPANTS: Thirteen nondiabetic volunteers (seven males, six females, aged 26 +/- 1 yr, body mass index 22.1 +/- 0.7 kg/m(2)) were studied. DESIGN: All participants were studied in random order during IM-FSIGT (0.3 g/kg glucose; 0.03 U/kg insulin at 20 min) and during identical conditions but with a variable glucose infusion preventing a decrease of plasma glucose concentration below euglycemia (IM-FSIGT-CLAMP). Five participants additionally underwent euglycemic-hyperinsulinemic (1 mU.kg(-1).min(-1)) clamp tests. RESULTS: Plasma glucose declined during IM-FSIGT to its nadir of 50 +/- 3 mg/dl at 60 min in parallel to a rise (P < 0.05 vs. basal) of plasma glucagon, cortisol, epinephrine, and GH. Glucose infusion rates of 4.6 +/- 0.5 mg.kg(-1).min(-1) between 30 and 180 min during IM-FSIGT-CLAMP prevented the decline of plasma glucose and the hypoglycemia counterregulatory hormone response. S(I) was approximately 68% lower during IM-FSIGT (3.40 +/- 0.36 vs. IM-FSIGT-CLAMP: 10.71 +/- 1.06 10(-4).min(-1) per microU/ml, P < 0.0001), whereas glucose effectiveness did not differ between both protocols (0.024 +/- 0.002 vs. 0.021 +/- 0.003 min(-1), P = NS). Compared with the euglycemic hyperinsulinemic clamp test, S(I) expressed in identical units from IM-FSIGT was approximately 66% (P < 0.001) lower but did not differ between the euglycemic hyperinsulinemic clamp test and the IM-FSIGT-CLAMP (P = NS). CONCLUSIONS: The transient fall of plasma glucose during IM-FSIGT results in lower estimates of S(I), which can be explained by hormonal response to hypoglycemia.
Assuntos
Glicemia/análise , Teste de Tolerância a Glucose , Insulina/farmacologia , Adulto , Ácidos Graxos não Esterificados/sangue , Feminino , Glucagon/sangue , Técnica Clamp de Glucose , Humanos , Hidrocortisona/sangue , Insulina/sangue , Masculino , Norepinefrina/sangueRESUMO
To examine the molecular mechanisms by which plasma amino acid elevation impairs insulin action, we studied seven healthy men twice in random order during infusion of an amino acid mixture or saline (total plasma amino acid approximately 6 vs. approximately 2 mmol/l). Somatostatin-insulin-glucose clamps created conditions of low peripheral hyperinsulinemia ( approximately 100 pmol/l, 0-180 min) and prandial-like peripheral hyperinsulinemia ( approximately 430 pmol/l, 180-360 min). At low peripheral hyperinsulinemia, endogenous glucose production (EGP) did not change during amino acid infusion but decreased by approximately 70% during saline infusion (EGP(150-180 min) 11 +/- 1 vs. 3 +/- 1 mumol . kg(-1) . min(-1), P = 0.001). Prandial-like peripheral hyperinsulinemia completely suppressed EGP during both protocols, whereas whole-body rate of glucose disappearance (R(d)) was approximately 33% lower during amino acid infusion (R(d) (330-360 min) 50 +/- 4 vs. 75 +/- 6 mumol . kg(-1) . min(-1), P = 0.002) indicating insulin resistance. In skeletal muscle biopsies taken before and after prandial-like peripheral hyperinsulinemia, plasma amino acid elevation markedly increased the ability of insulin to activate S6 kinase 1 compared with saline infusion ( approximately 3.7- vs. approximately 1.9-fold over baseline). Furthermore, amino acid infusion increased the inhibitory insulin receptor substrate-1 phosphorylation at Ser312 and Ser636/639 and decreased insulin-induced phosphoinositide 3-kinase activity. However, plasma amino acid elevation failed to reduce insulin-induced Akt/protein kinase B and glycogen synthase kinase 3alpha phosphorylation. In conclusion, amino acids impair 1) insulin-mediated suppression of glucose production and 2) insulin-stimulated glucose disposal in skeletal muscle. Our results suggest that overactivation of the mammalian target of rapamycin/S6 kinase 1 pathway and inhibitory serine phosphorylation of insulin receptor substrate-1 underlie the impairment of insulin action in amino acid-infused humans.
Assuntos
Aminoácidos/metabolismo , Glucose/metabolismo , Resistência à Insulina/fisiologia , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Adulto , Aminoácidos/administração & dosagem , Aminoácidos/sangue , Células Cultivadas , Ativação Enzimática/fisiologia , Humanos , Masculino , Músculo Esquelético/citologia , FosforilaçãoRESUMO
CONTEXT: Endocrine defensive mechanisms provide for energy supply during hypoglycemia. Intramyocellular lipids (IMCL) were recently shown to contribute to energy supply during exercise. OBJECTIVE: The objective of this study was to assess the contribution of IMCL compared with lipolysis and endogenous glucose production (EGP) to insulin-mediated hypoglycemia counterregulation in patients with type 1 diabetes mellitus (T1DM). DESIGN AND SETTING: This was a prospective explorative study performed in a university research facility. PARTICIPANTS: Six well-controlled T1DM (age, 29 +/- 4 yr; body mass index, 23.4 +/- 1.0 kg/m2; hemoglobin A1c, 6.3 +/- 0.1%) and six nondiabetic humans (controls; age, 28 +/- 2 yr; body mass index, 23.4 +/- 1.0 kg/m2; hemoglobin A1c, 5.1 +/- 0.1%) were studied. INTERVENTIONS: We performed 240-min hypoglycemic (approximately 3 mM)-hyperinsulinemic (0.8 mU/kg x min) clamps on separate days to measure: 1) systemic lipolysis ([2H5]glycerol turnover), EGP ([6,6-(2)H2]glucose), and local lipolysis in abdominal s.c. adipose tissue and gastrocnemius muscle (microdialysis); and 2) IMCL (by 1H nuclear magnetic resonance spectroscopy) in soleus and tibialis anterior muscle. MAIN OUTCOME MEASURES: The main outcome measures were changes in IMCL during prolonged hypoglycemia. RESULTS: At baseline, EGP, glycerol turnover, and IMCL were not different between the groups. During hypoglycemia, hormonal counterregulation was blunted in T1DM (peak: glucagon, 68 +/- 4 vs. 170 +/- 37 pg/ml; cortisol, 16 +/- 2 vs. 24 +/- 2 microg/dl; epinephrine, 274 +/- 84 vs. 597 +/- 212 pg/ml; all P < 0.05 vs. control). T1DM had approximately 50% lower EGP (4.6 +/- 0.6 vs. 10.9 +/- 0.5 micromol/kg x min; P < 0.005), but approximately 40% higher glycerol turnover (374 +/- 21 vs. 272 +/- 19 micromol/kg x min; P < 0.01). Glycerol concentrations in muscle (T1DM, 302 +/- 22 control, 346 +/- 17 micromol/liter) and adipose tissue (264 +/- 25 vs. 318 +/- 25 micromol/liter) did not differ between groups. IMCL in soleus and tibialis anterior muscle did not change from baseline during hypoglycemia. CONCLUSIONS: In well-controlled T1DM, impaired hypoglycemia counterregulation is associated with decreased glucose production and augmented whole body lipolysis, which cannot be explained by either hydrolysis of muscle triglycerides or increased abdominal s.c. adipose tissue lipolysis.
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Hipoglicemia/tratamento farmacológico , Hipoglicemia/metabolismo , Hipoglicemiantes/uso terapêutico , Metabolismo dos Lipídeos , Células Musculares/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Adulto , Glicemia/metabolismo , Epinefrina/sangue , Ácidos Graxos não Esterificados/sangue , Glucagon/sangue , Glucose/administração & dosagem , Glucose/farmacologia , Glicerol/metabolismo , Humanos , Hidrocortisona/sangue , Infusões Intravenosas , Insulina/sangue , Insulina/uso terapêutico , Cinética , Lipólise/efeitos dos fármacos , Masculino , Microdiálise , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismoRESUMO
The gastric peptide ghrelin augments and the adipocyte-derived hormone leptin reduces appetite and food intake. In the central nervous system, insulin directly decreases hunger sensation but could also act indirectly by modulating ghrelin and leptin secretion. This study examines dose-dependent effects of insulin on plasma ghrelin and leptin concentrations during hyperinsulinemic (1, 2, and 4 mU x kg(-1) x min(-1))-euglycemic clamp tests in six nondiabetic (control subjects) and six type 2 diabetic patients. Type 2 diabetic patients were studied before and after prolonged (12-h and 67-h) variable intravenous insulin treatment aiming at near-normoglycemia (115 +/- 4 mg/dl). Nondiabetic subjects were also studied during saline infusion, which did not affect ghrelin but decreased leptin by 19 +/- 6% (P < 0.03). In control subjects, plasma ghrelin decreased at all clamp steps (-17 +/- 1, -27 +/- 6, and -33 +/- 4%, respectively; P < 0.006 vs. baseline), whereas leptin increased by 35 +/- 11% (P < 0.05). In type 2 diabetic patients without insulin treatment, ghrelin decreased by 18 +/- 7% (P < 0.05) only after 4 mU x kg(-1) x min(-1) insulin infusion and leptin increased by 19 +/- 6% (P < 0.05). After prolonged insulin treatment and near-normoglycemia, ghrelin and leptin remained unchanged in type 2 diabetic patients during the clamps. In conclusion, insulin reduces plasma ghrelin in nondiabetic patients and, to a lesser extent, in type 2 diabetic patients before insulin therapy. These findings indicate an indirect effect of insulin via ghrelin on the suppression of hunger sensation and appetite.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Insulina/sangue , Leptina/sangue , Hormônios Peptídicos/sangue , Idoso , Ácidos Graxos não Esterificados/sangue , Feminino , Grelina , Técnica Clamp de Glucose , Hemoglobinas Glicadas/metabolismo , Hormônio do Crescimento Humano/sangue , Humanos , Hiperinsulinismo/sangue , Insulina/farmacologia , Cinética , Masculino , Pessoa de Meia-Idade , Valores de Referência , Análise de RegressãoRESUMO
Insulin resistance is frequently associated with increased lipid content in muscle and liver. Insulin excess stimulates tissue lipid accumulation. To examine the effects of insulin and improved glycemia on insulin sensitivity and intracellular lipids, we performed stepped (1, 2, and 4 mU x min(-1) x kg(-1)) hyperinsulinemic-euglycemic clamps in eight type 2 diabetic and six nondiabetic control subjects at baseline and after 12 and 67 h of insulin-mediated near-normoglycemia (118 +/- 7 mg/dl). Intrahepatocellular lipids (IHCLs) and intramyocellular lipids (IMCLs) of soleus (IMCL-S) and tibialis anterior muscle (IMCL-TA) were measured with (1)H nuclear magnetic resonance spectroscopy. At baseline, nondiabetic subjects had an approximate twofold higher insulin sensitivity (P < 0.02) and lower IHCLs than diabetic patients (5.8 +/- 1.2 vs. 18.3 +/- 4.2%, P < 0.03), in whom IMCL-TA negatively correlated with insulin sensitivity (r = -0.969, P < 0.001). After a 67-h insulin infusion in diabetic patients, IMCL-S and IHCLs were increased (P < 0.05) by approximately 36 and approximately 18%, respectively, and correlated positively with insulin sensitivity (IMCL-S: r = 0.982, P < 0.0005; IHCL: r = 0.865, P < 0.03), whereas fasting glucose production, measured with D-[6,6-(2)H(2)]glucose, decreased by approximately 10% (P < 0.04). In conclusion, these results indicate that IMCLs relate to insulin resistance in type 2 diabetic patients at baseline and that insulin-mediated near-normoglycemia for approximately 3 days reduces fasting glucose production but stimulates lipid accumulation in liver and muscle without affecting insulin sensitivity.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Idoso , Glicemia/metabolismo , Feminino , Humanos , Resistência à Insulina , Fígado/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismoRESUMO
Plasma concentrations of amino acids are frequently elevated in insulin-resistant states, and a protein-enriched diet can impair glucose metabolism. This study examined effects of short-term plasma amino acid (AA) elevation on whole-body glucose disposal and cellular insulin action in skeletal muscle. Seven healthy men were studied for 5.5 h during euglycemic (5.5 mmol/l), hyperinsulinemic (430 pmol/l), fasting glucagon (65 ng/l), and growth hormone (0.4 microg/l) somatostatin clamp tests in the presence of low (approximately 1.6 mmol/l) and increased (approximately 4.6 mmol/l) plasma AA concentrations. Glucose turnover was measured with D-[6,6-(2)H(2)]glucose. Intramuscular concentrations of glycogen and glucose-6-phosphate (G6P) were monitored using (13)C and (31)P nuclear magnetic resonance spectroscopy, respectively. A approximately 2.1-fold elevation of plasma AAs reduced whole-body glucose disposal by 25% (P < 0.01). Rates of muscle glycogen synthesis decreased by 64% (180--315 min, 24 plus minus 3; control, 67 plus minus 10 micromol center dot l(-1) center dot min(-1); P < 0.01), which was accompanied by a reduction in G6P starting at 130 min (DeltaG6P(260--300 min), 18 plus minus 19; control, 103 plus minus 33 micromol/l; P < 0.05). In conclusion, plasma amino acid elevation induces skeletal muscle insulin resistance in humans by inhibition of glucose transport/phosphorylation, resulting in marked reduction of glycogen synthesis.
Assuntos
Aminoácidos/farmacologia , Resistência à Insulina , Músculo Esquelético/efeitos dos fármacos , Difosfato de Adenosina/análise , Adulto , Aminoácidos/sangue , Glicemia/análise , Glicemia/metabolismo , Deutério , Epinefrina/sangue , Jejum , Glucagon/sangue , Técnica Clamp de Glucose , Glucose-6-Fosfato/análise , Glicogênio/análise , Glicogênio/biossíntese , Hormônio do Crescimento Humano/sangue , Humanos , Hidrocortisona/sangue , Concentração de Íons de Hidrogênio , Insulina/sangue , Insulina/farmacologia , Cinética , Espectroscopia de Ressonância Magnética , Masculino , Músculo Esquelético/química , Músculo Esquelético/metabolismo , Fosfatos/análise , Fosfocreatina/análise , Fosforilação , Somatostatina/sangueRESUMO
Decreased skeletal muscle glucose disposal and increased endogenous glucose production (EGP) contribute to postprandial hyperglycemia in type 2 diabetes, but the contribution of hepatic glycogen metabolism remains uncertain. Hepatic glycogen metabolism and EGP were monitored in type 2 diabetic patients and nondiabetic volunteer control subjects (CON) after mixed meal ingestion and during hyperglycemic-hyperinsulinemic-somatostatin clamps applying 13C nuclear magnetic resonance spectroscopy (NMRS) and variable infusion dual-tracer technique. Hepatocellular lipid (HCL) content was quantified by 1H NMRS. Before dinner, hepatic glycogen was lower in type 2 diabetic patients (227 +/- 6 vs. CON: 275 +/- 10 mmol/l liver, P < 0.001). After meal ingestion, net synthetic rates were 0.76 +/- 0.16 (type 2 diabetic patients) and 1.36 +/- 0.15 mg x kg(-1) x min(-1) (CON, P < 0.02), resulting in peak concentrations of 283 +/- 15 and 360 +/- 11 mmol/l liver. Postprandial rates of EGP were approximately 0.3 mg x kg(-1) x min(-1) (30-170 min; P < 0.05 vs. CON) higher in type 2 diabetic patients. Under clamp conditions, type 2 diabetic patients featured approximately 54% lower (P < 0.03) net hepatic glycogen synthesis and approximately 0.5 mg x kg(-1) x min(-1) higher (P < 0.02) EGP. Hepatic glucose storage negatively correlated with HCL content (R = -0.602, P < 0.05). Type 2 diabetic patients exhibit 1) reduction of postprandial hepatic glycogen synthesis, 2) temporarily impaired suppression of EGP, and 3) no normalization of these defects by controlled hyperglycemic hyperinsulinemia. Thus, impaired insulin sensitivity and/or chronic glucolipotoxicity in addition to the effects of an altered insulin-to-glucagon ratio or increased free fatty acids accounts for defective hepatic glycogen metabolism in type 2 diabetic patients.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Glicogênio Hepático/metabolismo , Glicemia/metabolismo , Ácidos Graxos não Esterificados/sangue , Feminino , Técnica Clamp de Glucose , Humanos , Hiperinsulinismo , Glicogênio Hepático/biossíntese , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Valores de ReferênciaRESUMO
OBJECTIVE: Muscle insulin resistance has been implicated in the development of steatosis and dyslipidemia by changing the partitioning of postprandial substrate fluxes. Also, insulin resistance may be due to reduced mitochondrial function. We examined the association between mitochondrial activity, insulin sensitivity, and steatosis in a larger human population. RESEARCH DESIGN AND METHODS: We analyzed muscle mitochondrial activity from ATP synthase flux (fATP) and ectopic lipids by multinuclei magnetic resonance spectroscopy from 113 volunteers with and without diabetes. Insulin sensitivity was assessed from M values using euglycemic-hyperinsulinemic clamps and/or from oral glucose insulin sensitivity (OGIS) using oral glucose tolerance tests. RESULTS: Muscle fATP correlated negatively with hepatic lipid content and HbA1c. After model adjustment for study effects and other confounders, fATP showed a strong negative correlation with hepatic lipid content and a positive correlation with insulin sensitivity and fasting C-peptide. The negative correlation of muscle fATP with age, HbA1c, and plasma free fatty acids was weakened after adjustment. Body mass, muscle lipid contents, plasma lipoproteins, and triglycerides did not associate with fATP. CONCLUSIONS: The association of impaired muscle mitochondrial activity with hepatic steatosis supports the concept of a close link between altered muscle and liver energy metabolism as early abnormalities promoting insulin resistance.
Assuntos
Jejum , Fígado Gorduroso/metabolismo , Mitocôndrias Musculares/metabolismo , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Adulto , Feminino , Humanos , Resistência à Insulina , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mitocôndrias Musculares/enzimologia , Adulto JovemAssuntos
Fraturas de Estresse , Hipofosfatemia , Doenças Inflamatórias Intestinais , Marcha , Humanos , Ferro , DorRESUMO
BACKGROUND: Liver biopsy is the standard method for diagnosis of hepatic steatosis, but is invasive and carries some risk of morbidity. AIMS AND METHODS: Quantification of hepatocellular lipid content (HCL) with non-invasive single voxel (1)H magnetic resonance spectroscopy (MRS) at 3T was compared with histological grading and biochemical analysis of liver biopsies in 29 patients with chronic hepatitis C. Body mass index, indices of insulin resistance (homeostasis model assessment index, HOMA-IR), serum lipids and serum liver transaminases were also quantified. RESULTS: HCL as assessed by (1)H MRS linearly correlated (r=0.70, p<0.001) with histological evaluation of liver biopsies and was in agreement with histological steatosis staging in 65% of the patients. Biochemically assessed hepatic triglyceride contents correlated with HCL measured with (1)H MRS (r=0.63, p<0.03) and allowed discriminating between none or mild steatosis versus moderate or severe steatosis. Patients infected with hepatitis C virus genotype 3 had a higher prevalence of steatosis (62%) which was not explained by differences in body mass or whole body insulin resistance. When these patients were excluded from correlation analysis, hepatic fat accumulation positively correlated with insulin resistance in the remaining hepatitis C patients (HCL vs. HOMA-IR, r=0.559, p<0.020, n=17). CONCLUSION: Localized (1)H MRS is a valid and useful method for quantification of HCL content in patients with chronic hepatitis C and can be easily applied to non-invasively monitoring of steatosis during repeated follow-up measurements in a clinical setting.
Assuntos
Tecido Adiposo/metabolismo , Fígado Gorduroso/diagnóstico , Fígado Gorduroso/metabolismo , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/metabolismo , Lipídeos/análise , Espectroscopia de Ressonância Magnética/métodos , Adulto , Fígado Gorduroso/etiologia , Feminino , Hepatite C Crônica/complicações , Humanos , Masculino , Prótons , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: Statins may exert pleiotropic effects on insulin action that are still controversial. We assessed effects of high-dose simvastatin therapy on peripheral and hepatic insulin sensitivity, as well as on ectopic lipid deposition in patients with hypercholesterolemia and type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed a randomized, double-blind, placebo-controlled, single-center study. Twenty patients with type 2 diabetes received 80 mg simvastatin (BMI 29 +/- 4 kg/m2, age 55 +/- 6 years) or placebo (BMI 27 +/- 4 kg/m2, age 58 +/- 8 years) daily for 8 weeks and were compared with 10 healthy humans (control subjects; BMI 27 +/- 4 kg/m2, age 55 +/- 7 years). Euglycemic-hyperinsulinemic clamp tests combined with D-[6,6-d2]glucose infusion were used to assess insulin sensitivity (M) and endogenous glucose production (EGP). 1H magnetic resonance spectroscopy was used to quantify intramyocellular and hepatocellular lipids. RESULTS: High-dose simvastatin treatment lowered plasma total and LDL cholesterol levels by approximately 33 and approximately 48% (P < 0.005) but did not affect M, intracellular lipid deposition in soleus and tibialis anterior muscles and liver, or basal and insulin-suppressed EGP. In simvastatin-treated patients, changes in LDL cholesterol related negatively to changes in M (r = -0.796, P < 0.01). Changes in fasting free fatty acids (FFAs) related negatively to changes in M (r = -0.840, P < 0.01) and positively to plasma retinol-binding protein-4 (r = 0.782, P = 0.008). CONCLUSIONS: High-dose simvastatin treatment has no direct effects on whole-body or tissue-specific insulin action and ectopic lipid deposition. A reduction in plasma FFAs probably mediates alterations in insulin sensitivity in vivo.
Assuntos
Glicemia/metabolismo , LDL-Colesterol/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipídeos/fisiologia , Sinvastatina/uso terapêutico , Adulto , Glicemia/efeitos dos fármacos , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Método Duplo-Cego , Ácidos Graxos não Esterificados/sangue , Glucose/metabolismo , Humanos , Insulina/sangue , Fígado/metabolismo , Espectroscopia de Ressonância Magnética , Pessoa de Meia-Idade , Placebos , Valores de ReferênciaRESUMO
Liver fatty acid-binding protein (L-FABP) is a highly conserved key factor in lipid metabolism. Amino acid replacements in L-FABP might alter its function and thereby affect glucose metabolism in lipid-exposed subjects, as indicated by studies in L-FABP knockout mice. Amino acid replacements in L-FABP were investigated in a cohort of 1,453 Caucasian subjects. Endogenous glucose production (EGP), gluconeogenesis, and glycogenolysis were measured in healthy carriers of the only common Thr(94)-to-Ala amino acid replacement (Ala/Ala(94)) vs. age-, sex-, and BMI-matched wild-type (Thr/Thr(94)) controls at baseline and after 320-min lipid/heparin-somatostatin-insulin-glucagon clamps (n = 18). Whole body glucose disposal was further investigated (subset; n = 13) using euglycemic-hyperinsulinemic clamps without and with lipid/heparin infusion. In the entire cohort, the only common Ala/Ala(94) mutation was significantly associated with reduced body weight, which is in agreement with a previous report. In lipid-exposed, individually matched subjects there was a genotype vs. lipid-treatment interaction for EGP (P = 0.009) driven mainly by reduced glycogenolysis in Ala/Ala(94) carriers (0.46 +/- 0.05 vs. 0.59 +/- 0.05 mgxkg(-1)xmin(-1), P = 0.013). The lipid-induced elevation of plasma glucose levels was smaller in Ala/Ala(94) carriers compared with wild types (P < 0.0001). Whole body glucose disposal was not different between lipid-exposed L-FABP genotypes. In summary, the Ala/Ala(94)-mutation contributed significantly to reduced glycogenolysis and less severe hyperglycemia in lipid-exposed humans and was further associated with reduced body weight in a large cohort. Data clearly show that investigation of L-FABP phenotypes in the basal overnight-fasted state yielded incomplete information, and a challenge test was essential to detect phenotypical differences in glucose metabolism between L-FABP genotypes.
Assuntos
Glicemia/efeitos dos fármacos , Proteínas de Ligação a Ácido Graxo/genética , Glicogenólise/genética , Lipídeos/farmacologia , Fígado/metabolismo , Mutação , Alanina/genética , Glicemia/metabolismo , Peso Corporal/genética , Estudos de Coortes , Feminino , Genótipo , Técnica Clamp de Glucose , Glicogenólise/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Mutação/fisiologia , Treonina/genéticaRESUMO
The nutrient-sensitive kinase mammalian target of rapamycin (mTOR) and its downstream target S6 kinase (S6K) are involved in amino acid-induced insulin resistance. Whether the mTOR/S6K pathway directly modulates glucose metabolism in humans is unknown. We studied 11 healthy men (29 years old, BMI 23 kg/m(2)) twice in random order after oral administration of 6 mg rapamycin, a specific mTOR inhibitor, or placebo. An amino acid mixture was infused to activate mTOR, and somatostatin-insulin-glucose clamps created conditions of low peripheral hyperinsulinemia (approximately 100 pmol/l, 0-180 min) and prandial-like peripheral hyperinsulinemia (approximately 450 pmol/l, 180-360 min). Glucose turnover was assessed using d-[6,6-(2)H(2)]glucose infusion (n = 8). Skeletal muscle biopsies were performed at baseline and during prandial-like peripheral hyperinsulinemia (n = 3). At low peripheral hyperinsulinemia, whole-body glucose uptake was not affected by rapamycin. During prandial-like peripheral hyperinsulinemia, rapamycin increased glucose uptake compared with placebo by 17% (R(d 300-360 min), 75 +/- 5 vs. 64 +/- 5 micromol x kg(-1) x min(-1), P = 0.0008). Rapamycin affected endogenous glucose production neither at baseline nor during low or prandial-like peripheral hyperinsulinemia. Combined hyperaminoacidemia and prandial-like hyperinsulinemia increased S6K phosphorylation and inhibitory insulin receptor substrate-1 (IRS-1) phosphorylation at Ser312 and Ser636 in the placebo group. Rapamycin partially inhibited this increase in mTOR-mediated S6K phosphorylation and IRS-1 Ser312 and Ser636 phosphorylation. In conclusion, rapamycin stimulates insulin-mediated glucose uptake in man under conditions known to activate the mTOR/S6K pathway.
Assuntos
Glucose/metabolismo , Proteínas Quinases/metabolismo , Adulto , Aminoácidos/sangue , Transporte Biológico/efeitos dos fármacos , Glicemia/metabolismo , Peptídeo C/sangue , Ácidos Graxos não Esterificados/sangue , Glucagon/sangue , Hormônio do Crescimento Humano/sangue , Humanos , Insulina/sangue , Masculino , Valores de Referência , Sirolimo/farmacologia , Serina-Treonina Quinases TORRESUMO
BACKGROUND: The fasting serum lipid profile [triglycerides (TGs), total cholesterol (TC), and LDL- and HDL-cholesterol (LDL-C and HDL-C)] is used to calculate lipid ratios (TC/HDL-C, LDL-C/HDL-C, TG/HDL-C) that allow identification of individuals at increased risk for cardiovascular disease. Because these individuals are also frequently insulin resistant, this study analyzed the relationships between lipid ratios and insulin sensitivity. METHODS: In 132 obese [mean (SE) body mass index, 37.5 (0.6) kg/m(2)] outpatients without known diabetes mellitus, fasting serum lipid profiles and 75-g oral glucose tolerance tests were performed. Insulin sensitivity was assessed from surrogate estimates for fasting (QUICKI) and dynamic (OGIS) conditions. RESULTS: After exclusion of other endocrine diseases (n = 35), the remaining patients were classified as glucose tolerant (n = 56), glucose intolerant (n = 22), or as having type 2 diabetes (n = 19). QUICKI and OGIS indicated severe insulin resistance in all individuals with type 2 diabetes and impaired glucose tolerance compared with glucose-tolerant individuals: QUICKI, glucose tolerant, 0.302 (0.002); glucose intolerant, 0.290 (0.002); type 2 diabetes, 0.281 (0.005); P <0.001; OGIS (mL . m(-2) . min(-1)), glucose tolerant, 343 (7), glucose intolerant, 293 (9); type 2 diabetes, 256 (12); P <0.001. Serum TG (P <0.005) and TG/HDL-C ratios (P <0.05) were increased in individuals with impaired glucose tolerance. TG/HDL-C ratios negatively correlated with QUICKI (r = -0.370; P < 0.001) and OGIS (r = -0.333; P < 0.005) in nondiabetic individuals (glucose tolerant plus glucose intolerant), but not in patients with type 2 diabetes (not significant). CONCLUSIONS: This study demonstrates that the TG/HDL-C ratio positively correlates with insulin resistance in severely obese nondiabetic individuals.