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Abnormal postprandial suppression of glucagon in Type 2 diabetes (T2DM) has been attributed to impaired insulin secretion. Prior work suggests that insulin and glucagon show an inverse coordinated relationship. However, dysregulation of α-cell function in prediabetes occurs early and independently of changes in ß-cells, which suggests insulin having a less significant role on glucagon control. We therefore, sought to examine whether hepatic vein hormone concentrations provide evidence to further support the modulation of glucagon secretion by insulin. As part of a series of experiments to measure the effect of diabetes-associated genetic variation in TCF7L2 on islet cell function, hepatic vein insulin and glucagon concentrations were measured at 2-minute intervals during fasting and a hyperglycemic clamp. The experiment was performed on 29 nondiabetic subjects (age = 46 ± 2 years, BMI 28 ± 1 Kg/m2 ) and enabled post-hoc analysis, using Cross-Correlation and Cross-Approximate Entropy (Cross-ApEn) to evaluate the interaction of insulin and glucose. Mean insulin concentrations rose from fasting (33 ± 4 vs. 146 ± 12 pmol/L, p < 0.01) while glucagon was suppressed (96 ± 8 vs. 62 ± 5 ng/L, p < 0.01) during the clamp. Cross-ApEn was used to measure pattern reproducibility in the two hormones using glucagon as control mechanism (0.78 ± 0.03 vs. 0.76 ± 0.03, fasting vs. hyperglycemia) and using insulin as a control mechanism (0.78 ± 0.02 vs. 0.76 ± 0.03, fasting vs. hyperglycemia). Values did not differ between the two scenarios. Cross-correlation analysis demonstrated a small in-phase coordination between insulin and glucagon concentrations during fasting, which inverted during hyperglycemia. This data suggests that the interaction between the two hormones is not driven by either. On a minute-to-minute basis, direct control and secretion of glucagon is not mediated (or restrained) by insulin.
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Diabetes Mellitus Tipo 2 , Hiperglicemia , Adulto , Glicemia , Glucagon , Humanos , Insulina , Pessoa de Meia-Idade , Reprodutibilidade dos TestesRESUMO
Introduction: We sought to determine whether chromogranin A-positive hormone-negative (CPHN) endocrine cells are increased in the pancreas of pregnant women, offering potential evidence in support of neogenesis. Methods: Autopsy pancreata from pregnant women (n = 14) and age-matched non-pregnant control women (n = 9) were obtained. Staining of pancreatic sections for chromogranin A, insulin and a cocktail of glucagon, somatostatin, pancreatic polypeptide and ghrelin was undertaken, with subsequent evaluation for CPHN cell frequency. Results: The frequency of clustered ß-cells was increased in pregnant compared to non-pregnant subjects (46.6 ± 5.0 vs. 31.8 ± 5.0% clustered ß-cells of total clustered endocrine cells, pregnant vs. non-pregnant, p < .05). Frequency of endocrine cocktail cells was lower in pregnant women than non-pregnant women (36.2 ± 4.0 vs. 57.0 ± 6.8% clustered endocrine cocktail cells of total clustered endocrine cells, pregnant vs. non-pregnant, p < .01). No difference in frequency of CPHN cells was found in islets, nor in clustered or single cells scattered throughout the exocrine pancreas, between pregnant and non-pregnant women. The frequency of CPHN cells in pregnancy was independent of the number of pregnancies (gravidity). Conclusions: Our findings of no increase in CPHN cell frequency in pancreas of pregnant women suggest that this potential ß-cell regenerative mechanism is not that by which the increased ß-cell mass of pregnancy is achieved. However, an increase in the percentage of clustered ß-cells was found in pregnancy, with decreased frequency of other endocrine cells in clusters, suggesting a compensatory shift from other pancreatic endocrine cell types to ß-cells as a mechanism to meet the increased insulin demands of pregnancy.
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Cromogranina A/metabolismo , Células Secretoras de Insulina/metabolismo , Pâncreas/citologia , Gravidez/metabolismo , Adulto , Contagem de Células , Feminino , Humanos , Insulina/metabolismo , Secreção de Insulina , Adulto JovemRESUMO
OBJECTIVE: Pulsatile insulin secretion is impaired in diseases such as type 2 diabetes that are characterized by insulin resistance. This has led to the suggestion that changes in insulin pulsatility directly impair insulin signaling. We sought to examine the effects of pulse characteristics on insulin action in humans, hypothesizing that a decrease in pulse amplitude or frequency is associated with impaired hepatic insulin action. METHODS: We studied 29 nondiabetic subjects on two occasions. On 1 occasion, hepatic and peripheral insulin action was measured using a euglycemic clamp. The deuterated water method was used to estimate the contribution of gluconeogenesis to endogenous glucose production. On a separate study day, we utilized nonparametric stochastic deconvolution of frequently sampled peripheral C-peptide concentrations during fasting to reconstruct portal insulin secretion. In addition to measuring basal and pulsatile insulin secretion, we used approximate entropy to measure orderliness and Fourier transform to measure the average, and the dispersion of, insulin pulse frequencies. RESULTS: In univariate analysis, basal insulin secretion (R2â =â 0.16) and insulin pulse amplitude (R2â =â 0.09) correlated weakly with insulin-induced suppression of gluconeogenesis. However, after adjustment for age, sex, and weight, these associations were no longer significant. The other pulse characteristics also did not correlate with the ability of insulin to suppress endogenous glucose production (and gluconeogenesis) or to stimulate glucose disappearance. CONCLUSIONS: Overall, our data demonstrate that insulin pulse characteristics, considered independently of other factors, do not correlate with measures of hepatic and peripheral insulin sensitivity in nondiabetic humans.
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Glucose/metabolismo , Secreção de Insulina/fisiologia , Insulina/metabolismo , Adulto , Glicemia/metabolismo , Peptídeo C/metabolismo , Jejum/fisiologia , Feminino , Gluconeogênese/fisiologia , Técnica Clamp de Glucose , Humanos , Resistência à Insulina/fisiologia , Fígado/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUNDMetabolic disorders such as type 2 diabetes have been associated with a decrease in insulin pulse frequency and amplitude. We hypothesized that the T allele at rs7903146 in TCF7L2, previously associated with ß cell dysfunction, would be associated with changes in these insulin pulse characteristics.METHODSTwenty-nine nondiabetic subjects (age 46 ± 2, BMI 28 ± 1 kg/m2) participated in this study. Of these, 16 were homozygous for the C allele at rs7903146 and 13 were homozygous for the T allele. Deconvolution of peripheral C-peptide concentrations allowed the reconstruction of portal insulin secretion over time. These data were used for subsequent analyses. Pulse orderliness was assessed by approximate entropy (ApEn), and the dispersion of insulin pulses was measured by a frequency dispersion index (FDI) after a Fast Fourier Transform (FFT) of individual insulin secretion rates.RESULTSDuring fasting conditions, the CC genotype group exhibited decreased pulse disorderliness compared with the TT genotype group (1.10 ± 0.03 vs. 1.19 ± 0.04, P = 0.03). FDI decreased in response to hyperglycemia in the CC genotype group, perhaps reflecting less entrainment of insulin secretion during fasting.CONCLUSIONDiabetes-associated variation in TCF7L2 is associated with decreased orderliness and pulse dispersion, unchanged by hyperglycemia. Quantification of ApEn and FDI could represent novel markers of ß cell health.FUNDINGThis work was funded by US NIH (DK78646, DK116231), University of Padova research grant CPDA145405, and Mayo Clinic General Clinical Research Center (UL1 TR000135).
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Alelos , Diabetes Mellitus Tipo 2/genética , Secreção de Insulina/genética , Polimorfismo Genético , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Adulto , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Células Secretoras de Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismoRESUMO
PURPOSE: Abnormal glucagon concentrations are a feature of prediabetes but it is uncertain if α-cell dysfunction contributes to a longitudinal decline in ß-cell function. We therefore sought to determine if a decline in ß-cell function is associated with a higher nadir glucagon in the postprandial period or with higher fasting glucagon. METHODS: This was a longitudinal study in which 73 non-diabetic subjects were studied on 2 occasions 6.6⯱â¯0.3â¯years apart using a 2-hour, 7-sample oral glucose tolerance test. Disposition Index (DI) was calculated using the oral minimal model applied to the measurements of glucose, insulin, C-peptide concentrations during the studies. We subsequently examined the relationship of glucagon concentrations at baseline with change in DI (used as a measure of ß-cell function) after adjusting for changes in weight and the baseline value of DI. RESULTS: After adjusting for covariates, nadir postprandial glucagon concentrations were not associated with changes in ß-cell function as quantified by DI. On the other hand, fasting glucagon concentrations during the baseline study were inversely correlated with longitudinal changes in DI. CONCLUSIONS: Defects in α-cell function, manifest as elevated fasting glucagon, are associated with a subsequent decline in ß-cell function. It remains to be ascertained if abnormal α-cell function contributes directly to loss of ß-cell secretory capacity in the pathogenesis of type 2 diabetes.
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Glucagon/sangue , Células Secretoras de Insulina/fisiologia , Adulto , Glicemia/análise , Peptídeo C/sangue , Jejum , Feminino , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pâncreas/citologia , Pâncreas/crescimento & desenvolvimento , Período Pós-Prandial , Estado Pré-Diabético/metabolismoRESUMO
Bone remodeling consists of resorption by osteoclasts followed by formation by osteoblasts, and osteoclasts are a source of bone formation-stimulating factors. Here we utilize osteoclast ablation by denosumab (DMAb) and RNA-sequencing of bone biopsies from postmenopausal women to identify osteoclast-secreted factors suppressed by DMAb. Based on these analyses, LIF, CREG2, CST3, CCBE1, and DPP4 are likely osteoclast-derived coupling factors in humans. Given the role of Dipeptidyl Peptidase-4 (DPP4) in glucose homeostasis, we further demonstrate that DMAb-treated participants have a significant reduction in circulating DPP4 and increase in Glucagon-like peptide (GLP)-1 levels as compared to the placebo-treated group, and also that type 2 diabetic patients treated with DMAb show significant reductions in HbA1c as compared to patients treated either with bisphosphonates or calcium and vitamin D. Thus, our results identify several coupling factors in humans and uncover osteoclast-derived DPP4 as a potential link between bone remodeling and energy metabolism.
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Osso e Ossos/metabolismo , Metabolismo Energético , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Remodelação Óssea , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Denosumab/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , Metabolismo Energético/efeitos dos fármacos , Feminino , Humanos , Pessoa de Meia-Idade , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Estudos Prospectivos , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
AIM: To establish pancreatic alpha-cell mass in lean, non-diabetic humans over the adult lifespan, performed as a follow-up study to beta-cell mass across the adult human lifespan. METHODS: We examined human pancreatic autopsy tissue from 66 lean, non-diabetic individuals aged from 30 to 102 years, grouped into deciles: 3rd (30-39 years), 4th (40-49 years), 5th (50-59 years), 6th (60-69 years), 7th (70-79 years), 8th (80-89 years) and 9th deciles (90+ years). Sections of pancreas were immunostained for glucagon and analyzed for fractional alpha-cell area. Population-based pancreatic volume data were used to calculate alpha-cell mass. RESULTS: With advanced age, the exocrine pancreas undergoes atrophy demonstrated by increased fat area (as % exocrine area) (0.05 ± 0.01 vs 1.6 ± 0.7% fat area of total exocrine pancreas, 3rd vs 9th decile, P < 0.05). Consequently, islet density increases with age (2.7 ± 0.4 vs 10.5 ± 3.3 islets/mm2, 3rd vs 9th decile, P < 0.05). Alpha-cell fractional area increases with advanced age (0.34 ± 0.05% vs 0.73 ± 0.26%, 3rd vs 9th decile, P < 0.05). However, alpha-cell mass remains constant at ~190 mg throughout the adult lifespan in lean, non-diabetic humans. Within islets, alpha-cell distribution between mantle and core is unchanged across deciles (1862 ± 220 vs 1945 ± 200 vs 1948 ± 139 alpha cells in islet mantle/mm2, 3rd vs 6th vs 9th decile, P = 0.93 and 1912 ± 442 vs 1449 ± 123 vs 1514 ± 168 alpha cells in islet core/mm2, 3rd vs 6th vs 9th decile, P = 0.47), suggesting that human islets retain their structural organization in the setting of age-related exocrine atrophy. CONCLUSIONS: Consistent with our previous findings for beta-cell mass, alpha-cell mass remains constant in humans, even with advanced age. Pancreatic endocrine cells are much more robustly preserved than exocrine cells in aged humans, and islets maintain their structural integrity throughout life.
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Células Secretoras de Glucagon/patologia , Pâncreas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Longevidade , Masculino , Pessoa de Meia-IdadeRESUMO
The characteristics of pulsatile insulin secretion are important determinants of type 2 diabetes pathophysiology, but they are understudied due to the difficulties in measuring pulsatile insulin secretion noninvasively. Deconvolution of either peripheral C-peptide or insulin concentrations offers an appealing alternative to hepatic vein catheterization. However, to do so, there are a series of methodological challenges to overcome. C-peptide has a relatively long half-life and accumulates in the circulation. On the other hand, peripheral insulin concentrations reflect relatively fast clearance and hepatic extraction as it leaves the portal circulation to enter the systemic circulation. We propose a method based on nonparametric stochastic deconvolution of C-peptide concentrations, using individually determined C-peptide kinetics, to overcome these limitations. The use of C-peptide (instead of insulin) concentrations allows estimation of portal (and not post-hepatic) insulin pulses, whereas nonparametric stochastic deconvolution allows evaluation of pulsatile signals without any a priori assumptions of pulse shape and occurrence. The only assumption required is the degree of smoothness of the (unknown) secretion rate. We tested this method first on simulated data and then on 29 nondiabetic subjects studied during euglycemia and hyperglycemia and compared our estimates with the profiles obtained from hepatic vein insulin concentrations. This method produced satisfactory results both in the ability to fit the data and in providing reliable estimates of pulsatile secretion, in agreement with hepatic vein measurements. In conclusion, the proposed method enables reliable and noninvasive measurement of pulsatile insulin secretion. Future studies will be needed to validate this method in people with type 2 diabetes.
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Peptídeo C/sangue , Hiperglicemia/sangue , Secreção de Insulina/fisiologia , Insulina/sangue , Adulto , Peptídeo C/metabolismo , Simulação por Computador , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Glucose/metabolismo , Voluntários Saudáveis , Veias Hepáticas , Humanos , Hiperglicemia/metabolismo , Insulina/metabolismo , Cinética , Masculino , Pessoa de Meia-Idade , Estatísticas não ParamétricasRESUMO
Context: In subjects with normal fasting glucose (NFG) and normal glucose tolerance (NGT), glucose concentrations >155 mg/dL 1 hour after 75 g of oral glucose predict increased risk of progression to diabetes. Recently, it has been suggested that the mechanism underlying this abnormality is increased gut absorption of glucose. Objective: We sought to determine the rate of systemic appearance of meal-derived glucose in subjects classified by their 1-hour glucose after a 75-g oral glucose challenge. Design: This was a cross-sectional study. Participating subjects underwent a 75-g oral glucose challenge and a labeled mixed meal test. Setting: An inpatient clinical research unit at an academic medical center. Participants: Thirty-six subjects with NFG/NGT participated in this study. Interventions: Subjects underwent an oral glucose tolerance test. Subsequently, they underwent a labeled mixed meal to measure fasting and postprandial glucose metabolism. Main Outcome Measures: We examined ß-cell function and the rate of meal appearance (Meal Ra) in NFG/NGT subjects. Subsequently, we examined the relationship of peak postchallenge glucose with Meal Ra and indices of ß-cell function. Results: Peak glucose concentrations correlated inversely with ß-cell function. No relationship of Meal Ra with peak postchallenge glucose concentrations was observed. Conclusion: In subjects with NFG/NGT, elevated 1-hour peak postchallenge glucose concentrations reflect impaired ß-cell function rather than increased systemic meal appearance.
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Glucagon-Like Peptide-1 (GLP-1) is an insulin secretagogue which is elevated after Roux-en-Y Gastric Bypass (RYGB). However, its contribution to glucose metabolism after RYGB remains uncertain. AIMS: We tested the hypothesis that GLP-1 lowers postprandial glucose concentrations and improves ß-cell function after RYGB. MATERIALS AND METHODS: To address these questions we used a labeled mixed meal to assess glucose metabolism and islet function in 12 obese subjects with type 2 diabetes studied before and four weeks after RYGB. During the post-RYGB study subjects were randomly assigned to receive an infusion of either saline or Exendin-9,39 a competitive antagonist of GLP-1 at its receptor. Exendin-9,39 was infused at 300â¯pmol/kg/min for 6â¯h. All subjects underwent RYGB for medically-complicated obesity. RESULTS: Exendin-9,39 resulted in increased integrated incremental postprandial glucose concentrations (181⯱â¯154 vs. 582⯱â¯129â¯mmol per 6â¯h, pâ¯=â¯0.02). In contrast, this was unchanged in the presence of saline (275⯱â¯88 vs. 315⯱â¯66â¯mmol per 6â¯h, pâ¯=â¯0.56) after RYGB. Exendin-9,39 also impaired ß-cell responsivity to glucose but did not alter Disposition Index (DI). CONCLUSIONS: These data indicate that the elevated GLP-1 concentrations that occur early after RYGB improve postprandial glucose tolerance by enhancing postprandial insulin secretion.
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Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Derivação Gástrica , Peptídeo 1 Semelhante ao Glucagon/fisiologia , Células Secretoras de Insulina/metabolismo , Adulto , Diabetes Mellitus Tipo 2/cirurgia , Feminino , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Masculino , Obesidade/cirurgia , Período Pós-Operatório , Período Pós-PrandialRESUMO
We sought to establish whether an increase in chromogranin A-positive, hormone-negative (CPHN) endocrine cells occurs in the pancreas of patients with cystic fibrosis (CF), as potential evidence of neogenesis. Pancreata were obtained at autopsy from nondiabetic patients with CF (n = 12) and age-matched nondiabetic control subject (CS) individuals without CF (n = 12). In addition, pancreas from three diabetic patients with CF was obtained. Pancreas sections were stained for chromogranin A, insulin, and a cocktail of glucagon, somatostatin, pancreatic polypeptide, and ghrelin and evaluated for the frequency of CPHN cells. There was a higher frequency of CPHN cells in islets of the patients with CF compared with the CS group. Moreover, CPHN cells occurring as single cells or clusters scattered in the exocrine pancreas were also more frequent in patients with CF. The increased frequency of CPHN cells in pancreas of patients with CF may indicate an attempt at endocrine cell regeneration.
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Context: A better understanding of nocturnal regulation of glucose homeostasis will provide the framework for designing rational therapeutic strategies to improve the management of overnight glucose in patients with type 2 diabetes (T2D). Objective: To establish the nocturnal pattern and regulation of glucose production (EGP) in humans and to determine whether the pattern is dysregulated in people with T2D. Design: Subjects were infused with [3-3H] glucose overnight. Arterial blood samples were drawn for hormones and analytes to estimate EGP throughout the night. Deuterium-labeled water was provided to measure gluconeogenesis (GNG) using the hexamethylenetetramine method of Landau. Setting: Mayo Clinic Clinical Research Trials Unit, Rochester, MN, USA. Participants and Interventions: A total of 43 subjects [23 subjects with T2D and 20 nondiabetic (ND) subjects comparable for age and body mass index] were included in this study. Main Outcome(s) Measure(s): Glucose and EGP. Results: Plasma glucose, C-peptide, and glucagon concentrations were higher throughout the night, whereas insulin concentrations were higher in subjects with T2D vs ND subjects at 1:00 and 4:00 am but similar at 7:00 am. EGP was higher in the subjects with T2D than in the ND subjects throughout the night (P < 0.001). Glycogenolysis (GGL) fell and GNG rose, resulting in significantly higher (P < 0.001) rates of GNG at 4:00 and 7:00 am and significantly (P < 0.001) higher rates of GGL at 1:00, 4:00, and 7:00 am in T2D as compared with ND. Conclusions: These data imply that optimal therapies for T2D for nocturnal/fasting glucose control should target not only the absolute rates of EGP but also the contributing pathways of GGL and GNG sequentially.
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Biomarcadores/sangue , Glicemia/análise , Peptídeo C/análise , Ritmo Circadiano , Diabetes Mellitus Tipo 2/prevenção & controle , Glucagon/análise , Insulina/análise , Automonitorização da Glicemia , Índice de Massa Corporal , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Seguimentos , Homeostase , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Sono/fisiologiaRESUMO
Context: Chronic pancreatitis (CP) is characterized by inflammation, fibrosis, and a loss of pancreatic acinar cells, which can result in exocrine and eventually endocrine deficiency. Pancreatitis has been reported to induce formation of new endocrine cells (neogenesis) in mice. Our recent data have implicated chromogranin A-positive hormone-negative (CPHN) cells as potential evidence of neogenesis in humans. Objective: We sought to establish if CPHN cells were more abundant in CP in humans. Design, Setting, and Participants: We investigated the frequency and distribution of CPHN cells and the expression of the chemokine C-X-C motif ligand 10 (CXCL10) and its receptor chemokine C-X-C motif receptor 3 in pancreas of nondiabetic subjects with CP. Results: CPHN cell frequency in islets was increased sevenfold in CP [2.1% ± 0.67% vs 0.35% ± 0.09% CPHN cells in islets, CP vs nonpancreatitis (NP), P < 0.01], as were the CPHN cells found as scattered cells in the exocrine areas (17.4 ± 2.9 vs 4.2 ± 0.6, CP vs NP, P < 0.001). Polyhormonal endocrine cells were also increased in CP (2.7 ± 1.2 vs 0.1 ± 0.04, CP vs NP, % of polyhormonal cells of total endocrine cells, P < 0.01), as was expression of CXCL10 in α and ß cells. Conclusion: There is increased islet endogenous expression of the inflammation marker CXCL10 in islets in the setting of nondiabetic CP and an increase in polyhormonal (insulin-glucagon expressing) cells. The increase in CPHN cells in CP, often in a lobular distribution, may indicate foci of attempted endocrine cell regeneration.
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Quimiocina CXCL10/metabolismo , Cromogranina A/metabolismo , Pâncreas/metabolismo , Pancreatite Crônica/metabolismo , Receptores CXCR3/metabolismo , Idoso , Feminino , Humanos , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Masculino , Pessoa de Meia-Idade , Pâncreas/patologia , Pancreatite Crônica/patologiaRESUMO
AIMS: To compare the performance of population-based kinetics with that of directly measured C-peptide kinetics when used to calculate ß-cell responsivity indices, and to study people with and without acute insulin resistance to ensure that population-based kinetics apply to all conditions where ß-cell function is measured. METHODS: Somatostatin was used to inhibit endogenous insulin secretion in 56 people without diabetes. Subsequently, a C-peptide bolus was administered and the changing concentrations were used to calculate individual kinetic measures of C-peptide clearance. In addition, the participants were studied on 2 occasions in random order using an oral glucose tolerance test (OGTT). On one occasion, free fatty acid elevation, to cause insulin resistance, was achieved by infusion of Intralipid + heparin. The Disposition Index (DI) was then estimated by the oral minimal model using either population-based or individual C-peptide kinetics. RESULTS: There were marked differences in the exchange variables (k 12 and k 21 ) of the model describing C-peptide kinetics, but smaller differences in the fractional clearance; that is, the irreversible loss from the accessible compartment (k 01 ), obtained from population-based estimates compared with experimental measurement. Because it is predominantly influenced by k 01 , DI estimated using individual kinetics correlated well with DI estimated using population-based kinetics. CONCLUSIONS: These data support the use of population-based measures of C-peptide kinetics to estimate ß-cell function during an OGTT.
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Peptídeo C/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/fisiologia , Feminino , Glucose/farmacologia , Teste de Tolerância a Glucose , Glicerol/farmacologia , Hormônios/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Solventes/farmacologia , Somatostatina/farmacologia , Edulcorantes/farmacologiaRESUMO
Context: Previously, we identified chromograninA positive hormone-negative (CPHN) cells in high frequency in human fetal and neonatal pancreas, likely representing nascent endocrine precursor cells. Here, we characterize the putative endocrine fate and replicative status of these newly formed cells. Objective: To establish the replicative frequency and transcriptional identity of CPHN cells, extending our observation on CPHN cell frequency to a larger cohort of fetal and infant pancreas. Design, Setting, and Participants: 8 fetal, 19 infant autopsy pancreata were evaluated for CPHN cell frequency; 12 fetal, 24 infant/child pancreata were evaluated for CPHN replication and identity. Results: CPHN cell frequency decreased 84% (islets) and 42% (clusters) from fetal to infant life. Unlike the beta-cells at this stage, CPHN cells were rarely observed to replicate (0.2 ± 0.1 vs. 4.7 ± 1.0%, CPHN vs. islet hormone positive cell replication, p < 0.001), indicated by the lack of Ki67 expression in CPHN cells whether located in the islets or in small clusters, and with no detectable difference between fetal and infant groups. While the majority of CPHN cells express (in overall compartments of pancreas) the pan-endocrine transcription factor NKX2.2 and beta-cell specific NKX6.1 in comparable frequency in fetal and infant/child cases (81.9 ± 6.3 vs. 82.8 ± 3.8% NKX6.1+-CPHN cells of total CPHN cells, fetal vs. infant/child, p = 0.9; 88.0 ± 4.7 vs. 82.1 ± 5.3% NKX2.2+-CPHN cells of total CPHN cells, fetal vs. infant/child, p = 0.4), the frequency of clustered CPHN cells expressing NKX6.1 or NKX2.2 is lower in infant/child vs. fetal cases (1.2 ± 0.3 vs. 16.7 ± 4.7 clustered NKX6.1+-CPHN cells/mm2, infant/child vs. fetal, p < 0.01; 2.7 ± 1.0 vs. 16.0 ± 4.0 clustered NKX2.2+-CPHN cells/mm2, infant/child vs. fetal, p < 0.01). Conclusions: The frequency of CPHN cells declines steeply from fetal to infant life, presumably as they differentiate to hormone-expressing cells. CPHN cells represent a non-replicative pool of endocrine precursor cells, a proportion of which are likely fated to become beta-cells. Precis : CPHN cell frequency declines steeply from fetal to infant life, as they mature to hormone expression. CPHN cells represent a non-replicative pool of endocrine precursor cells, a proportion of which are likely fated to become beta-cells.
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Context: Abnormal glucagon concentrations contribute to hyperglycemia, but the mechanisms of α-cell dysfunction in prediabetes are unclear. Objective: We sought to determine the relative contributions of insulin secretion and action to α-cell dysfunction in nondiabetic participants across the spectrum of glucose tolerance. Design: This was a cross-sectional study. A subset of participants (n = 120) was studied in the presence and absence of free fatty acid (FFA) elevation, achieved by infusion of Intralipid (Baxter Healthcare, Deerfield, IL) plus heparin, to cause insulin resistance. Setting: An inpatient clinical research unit at an academic medical center. Participants: A total of 310 nondiabetic persons participated in this study. Interventions: Participants underwent a seven-sample oral glucose tolerance test. Subsequently, 120 participants were studied on two occasions. On one day, infusion of Intralipid plus heparin raised FFA. On the other day, participants received glycerol as a control. Main Outcome Measure(s): We examined the relationship of glucagon concentration with indices of insulin action after adjusting for the effects of age, sex, and weight. Subsequently, we sought to determine whether an acute decrease in insulin action, produced by FFA elevation, altered glucagon concentrations in nondiabetic participants. Results: Fasting glucagon concentrations correlated positively with fasting insulin and C-peptide concentrations and inversely with insulin action. Fasting glucagon was not associated with any index of ß-cell function in response to an oral challenge. As expected, FFA elevation decreased insulin action and also raised glucagon concentrations. Conclusions: In nondiabetic participants, glucagon secretion was altered by changes in insulin action.
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Células Secretoras de Glucagon/patologia , Glucagon/sangue , Hiperglicemia/fisiopatologia , Resistência à Insulina , Insulina/farmacologia , Estado Pré-Diabético/fisiopatologia , Biomarcadores/sangue , Glicemia/metabolismo , Peptídeo C/sangue , Estudos Transversais , Feminino , Seguimentos , Células Secretoras de Glucagon/efeitos dos fármacos , Células Secretoras de Glucagon/metabolismo , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/farmacologia , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
AIMS/HYPOTHESIS: We sought to establish whether the increased incidence of diabetes associated with Down syndrome was due to a congenital deficit in ß cells. METHODS: The pancreas was obtained at autopsy from nondiabetic subjects with Down syndrome (n = 29) and age-matched nondiabetic control subjects without Down syndrome (n = 28). The pancreas sections were evaluated for the fractional ß-cell area. RESULTS: No difference was found in the fractional ß-cell area between the subjects with Down syndrome and the control subjects. CONCLUSIONS/INTERPRETATIONS: The increased incidence and prevalence of diabetes in individuals with Down syndrome is not due to an underlying congenital deficiency of ß cells.
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AIMS/HYPOTHESIS: Shift-work is associated with circadian rhythm disruption and an increased risk of obesity and type 2 diabetes. We sought to determine the effect of rotational shift-work on glucose metabolism in humans. METHODS: We studied 12 otherwise healthy nurses performing rotational shift-work using a randomised crossover study design. On each occasion, participants underwent an isotope-labelled mixed meal test during a simulated day shift and a simulated night shift, enabling simultaneous measurement of glucose flux and beta cell function using the oral minimal model. We sought to determine differences in fasting and postprandial glucose metabolism during the day shift vs the night shift. RESULTS: Postprandial glycaemic excursion was higher during the night shift (381±33 vs 580±48 mmol/l per 5 h, p<0.01). The time to peak insulin and C-peptide and nadir glucagon suppression in response to meal ingestion was also delayed during the night shift. While insulin action did not differ between study days, the beta cell responsivity to glucose (59±5 vs 44±4 × 10-9 min-1; p<0.001) and disposition index were decreased during the night shift. CONCLUSIONS/INTERPRETATION: Impaired beta cell function during the night shift may result from normal circadian variation, the effect of rotational shift-work or a combination of both. As a consequence, higher postprandial glucose concentrations are observed during the night shift.