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DYNAMICS OF PANCREATIC BETA CELLS: Evidence for Beta Cell Turnover and Attempted Regeneration in Diabetes from Sources of Beta Cells other than Beta Cell Replication in Rats, Monkeys, and Humans
Full text linkSince the fundamental defect in both type 1 (T1DM) and type 2 diabetes (T2DM) is beta cell failure, there is increasing interest in the capacity, if any, for beta cell regeneration. In this context quantitative analysis of beta cell turnover becomes essential to permit investigation of the mechanisms that regulate it. For example, how does beta cell mass adapt to obesity?
How is beta cell mass preserved during aging? How does beta cell mass expand during childhood?
In collaboration with the Larry Hillblom Islet Research at David Geffen School of Medicine, University of California Los Angeles, we developed a dynamic model to estimate beta cell turnover. Assuming homogeneity of beta cells, the model describes beta cell mass as the balance between beta cell formation and loss. Beta cells are added either by replication of existing beta cells or by other sources of beta cells (OSB), and they are mainly lost through beta cell apoptosis. Since all the model parameters can be quantified with the exception of OSB, it was possible to solve for this unknown.
The resulting components of beta cell turnover, i.e. new beta cell formation (replication of existing beta cells plus other sources of beta cells rather than beta cell replication) and beta cell death (apoptosis), were used to develop a population model to assess the mean age of a beta cell as well as the mean beta cell lifetime. The resulting model is a variation of the classical McKendrick-von Foerster equation and describes beta cells as a variegate population of cells that differ each other by their own age.
The novel insights that emerge by applying the model to different species, i.e. rats, monkeys, and humans are: 1) there is ongoing beta cell turnover in non diabetic rats, monkeys, and humans through adult life; 2) formation and maintenance of the population of adult beta cells largely depend on OSB in non diabetic rats, monkeys, and humans; 3) the formation of new beta cells from other sources of beta cells increases substantially in the face of the increased beta cell apoptosis in the HIP rat model of type 2 diabetes, delaying the decline in beta cell mass. In contrast, beta cell turnover is low in the streptozotocin (STZ) monkey model of T1DM, compared to non diabetic controls. The extent that beta cells are formed in the STZ monkey is again primarily from OSB. 4) Beta cell replication is the primary mechanism subserving the postnatal expansion of beta cell mass in childhood, while in adulthood OSB is the principal mechanism for maintaining beta cell mass in face of an increased beta cell apoptosis; 5) beta cell mass and beta cell turnover increase in response to obesity in humans; 6) the estimated mean age of a beta cell (1-2 months in rats, 2-5 months in monkeys, and 6 months- 2 years in humans) and the mean beta cell lifetime (1-3 months in rats, 2-5 months in monkeys, and 6 months-2 years in humans) potentially permit endogenous regeneration of beta cell mass in diabetes if beta cell turnover could be altered therapeutically.
The presented models provide, for the first time, information about sources of beta cells other than those derived from beta cell replication and estimates of the mean age of a beta cell and the mean beta cell lifetime in rats, monkeys, and humans. The results have an impact from a clinical point of view considering that: a) the origin of beta cells is actively debated, i.e. some propose duplication of existing beta cells, and others suggest formation of new beta cells from a variety of sources; b) restoration of glycemic control in type 1 and type 2 diabetes through endogenous regeneration could be a potential alternative strategy to pancreas transplantation given the insufficient number of pancreases available for transplantation and the risks of prolonged immunosuppression; c) the unique experimental approach to identify other sources of beta cells is the cell-lineage tracing that is not available in humans. Furthermore, the results encourage: a) future studies on beta cell turnover in patients with diabetes; b) the development of ad hoc experiments that identify the possible other sources of beta cells rather than beta cell replication; c) to plan both experiments and mathematical models to establish the forms and the time required for endogenous regeneration of beta cell mass.L’interesse verso una potenziale rigenerazione della massa beta cellulare è in aumento poiché un difetto della stessa caratterizza sia il diabete di tipo 1 che quello di tipo 2. In questo contesto un’analisi quantitativa del turnover beta cellulare diviene essenziale per comprendere la varietà dei meccanismi che lo regolano. Per esempio, la massa beta cellulare si adatta all’obesità?
Si preserva con l'età? Come si espande nell’infanzia?
In collaborazione con il Larry Hillblom Islet Research at David Geffen School of Medicine, University of California Los Angeles, è stato sviluppato un modello dinamico per la stima del turnover beta cellulare. Assumendo un comportamento omogeneo delle beta cellule in termini di turnover, il modello riesce a descrivere la massa beta cellulare come il bilancio tra la formazione e la morte di beta cellule. Le beta cellule si formano o dalla duplicazione di beta cellule esistenti o da altre sorgenti (abbreviate con OSB, dall’inglese Other Sources of Beta cells) e muoiono principalmente per apoptosi. Dal momento che tutti i parametri del modello possono essere determinati ad eccezione di OSB, dal modello si determina questa quantità incognita. Le componenti del turnover beta cellulare, ovvero la formazione di nuove beta cellule (duplicazione di beta cellule esistenti sommata a OSB) e l’apoptosi, sono state impiegate nello sviluppo di un modello di popolazione per la stima dell’età e dell’aspettativa di vita medie di una beta cellula. Il modello risultante è una variazione della classica equazione di McKendrick-von Foerster e descrive le beta cellule come una popolazione di cellule che differiscono l’una dall’altra per la loro età.
Gli innovativi risultati che emergono dall’applicazione dei modelli a specie differenti, ovvero ratti, scimmie e individui sono: 1) c’è turnover beta cellulare nei ratti, nelle scimmie e negli individui non diabetici in età adulta; 2) la formazione ed il mantenimento della massa beta cellulare dipendono maggiormente da OSB; 3) la formazione di nuove beta cellule da parte di OSB aumenta in modo sostanziale a fronte di un incremento di apoptosi nei ratti di tipo HIP, modello animale del diabete di tipo 2, rallentando in questo modo il declino della massa beta cellulare. In contrasto, il turnover beta cellulare è ridotto nelle scimmie di tipo STZ (ovvero scimmie trattate con streptozotocin), modello animale del diabete di tipo 1, rispetto alle scimmie non diabetiche di controllo. Inoltre la formazione di nuove beta cellule nelle scimmie di tipo STZ è dovuta in gran parte a OSB. 4) La duplicazione di beta cellule esistenti è il meccanismo primario che regola l’espansione della massa beta cellulare nell’infanzia, mentre in età adulta OSB è responsabile del mantenimento della massa beta cellulare a fronte di un incremento dell’apoptosi; 5) la massa ed il turnover beta cellulari aumentano in risposta all’obesità negli individui; 6) le stime ottenute per l’età media di una beta cellula (1-2 mesi nei ratti, 2-5 mesi nelle scimmie e 6 mesi-2 anni negli individui) e per la sua aspettativa di vita media (1-3 mesi nei ratti, 2-5 mesi nelle scimmie e 6 mesi-2 anni negli individui) sono potenzialmente compatibili con la rigenerazione endogena della massa beta cellulare nel diabete, qualora fosse possibile alterare il turnover beta cellulare in modo terapeutico.
I modelli presentati forniscono per la prima volta informazioni sulla presenza di sorgenti di beta cellule diverse dalla duplicazione di beta cellule e stime dell’età e dell’aspettativa di vita medie di una beta cellula nei ratti, nelle scimmie e negli individui. I risultati ottenuti hanno un impatto dal punto di vista clinico considerando che: a) l’origine delle beta cellule è causa di accesi dibattiti: alcuni ricercatori suggeriscono come origine principale la duplicazione delle beta cellule esistenti, altri la formazione di nuove beta cellule da svariate sorgenti diverse dalla duplicazione beta cellulare; b) il ripristino del controllo glicemico sia nel diabete di tipo 1 sia in quello di tipo 2 attraverso una rigenerazione interna potrebbe essere una potenziale strategia alternativa al trapianto di pancreas, dati il numero insufficiente di pancreas disponibili per il trapianto e i rischi di una prolungata terapia immunosoppressiva; c) l’unico approccio sperimentale che consente di identificare le sorgenti di nuove beta cellule diverse dalla duplicazione beta cellulare è la cell-lineage tracing, non disponibile negli studi clinici. In aggiunta i risultati incoraggiano: a) studi futuri sul turnover beta cellulare nei pazienti diabetici; b) lo sviluppo di esperimenti ad hoc atti ad identificare OSB; c) la messa a punto di esperimenti e modelli matematici in grado di stabilire le modalità ed i tempi richiesti per la rigenerazione endogena della massa beta cellulare
Validation of whole body C-peptide minimal model during a meal from arteriovenous hepatic catheter measurements
No full textDevelopment of factors to convert frequency to rate for beta-cell replication and apoptosis quantified by time-lapse video microscopy and immunohistochemistry
No full textAn obstacle to development of methods to quantify beta-cell turnover from pancreas tissue is the lack of conversion factors for the frequency of beta-cell replication or apoptosis detected by immunohistochemistry to rates of replication or apoptosis. We addressed this obstacle in islets from 1-mo-old rats by quantifying the relationship between the rate of beta-cell replication observed directly by time-lapse video microscopy (TLVM) and the frequency of beta-cell replication in the same islets detected by immunohistochemistry using antibodies against Ki67 and insulin in the same islets fixed immediately after TLVM. Similarly, we quantified the rate of beta-cell apoptosis by TLVM and then the frequency of apoptosis in the same islets using TdT-mediated dUTP nick-end labeling and insulin. Conversion factors were developed by regression analysis. The conversion factor from Ki67 labeling frequency (%) to actual replication rate (%events/h) is 0.025 +/- 0.003 h(-1). The conversion factor from TdT-mediated dUTP nick-end labeling frequency (%) to actual apoptosis rate (%events/h) is 0.41 +/- 0.05 h(-1). These conversion factors will permit development of models to evaluate beta-cell turnover in fixed pancreas tissue
Aerobic Exercise Increases Peripheral and Hepatic Insulin Sensitivity in Sedentary Adolescents.
No full textCONTEXT:
Data are limited on the effects of controlled aerobic exercise programs (without weight loss) on insulin sensitivity and glucose metabolism in children and adolescents.
OBJECTIVE:
To determine whether a controlled aerobic exercise program (without weight loss) improves peripheral and hepatic insulin sensitivity and affects glucose production (GPR), gluconeogenesis and glycogenolysis in sedentary lean and obese Hispanic adolescents.
PATIENTS AND DESIGN:
Twenty-nine post-pubertal adolescents (14 lean: 15.1 +/- 0.3 y; 20.6 +/- 0.8 kg/m(2); 18.9+/-1.5% body fat and 15 obese: 15.6 +/- 0.4 y; 33.2 +/- 0.9 kg/m(2); 38.4 +/- 1.4% body fat) (mean +/- SE), completed a 12 wk aerobic exercise program (4 x 30 min/week at >or=70% of VO(2) peak). Peripheral and hepatic insulin sensitivity and glucose kinetics were quantified using GCMS pre- and post-exercise.
RESULTS:
No weight loss occurred. Lean and obese participants complied well with the program ( approximately 90% of the exercise sessions attended, resulting in approximately 15% increase in fitness in both groups). Peripheral and hepatic insulin sensitivity were higher in lean than obese adolescents but increased in both groups; peripheral insulin sensitivity by 35 +/- 14% (lean) (p < 0.05) and 59 +/- 19% (obese) (p < 0.01) and hepatic insulin sensitivity by 19 +/- 7% (lean) (p < 0.05) and 23 +/- 4% (obese) (p < 0.01). GPR, gluconeogenesis and glycogenolysis did not differ between the groups. GPR decreased slightly, 3 +/- 1% (lean) (p < 0.05) and 4 +/- 1% (obese) (p < 0.01). Gluconeogenesis remained unchanged, while glycogenolysis decreased slightly in the obese group (p < 0.01).
CONCLUSION:
This well accepted aerobic exercise program, without weight loss, is a promising strategy to improve peripheral and hepatic insulin sensitivity in lean and obese sedentary adolescents. The small decrease in GPR is probably of limited clinical relevance
VLDL-Apo B 100 fractional synthesis rate (FSR) is decreased in type 2 diabetes mellitus patients with diabetic nephropathy and hypertriglyceridaemia: possible defect in VLDL-Apo B 100 removal
No full textStrength exercise improves muscle mass and hepatic insulin sensitivity in obese youth.
No full textINTRODUCTION:
Data on the metabolic effects of resistance exercise (strength training) in adolescents are limited.
PURPOSE:
The objective of this study was to determine whether a controlled resistance exercise program without dietary intervention or weight loss reduces body fat accumulation, increases lean body mass, and improves insulin sensitivity and glucose metabolism in sedentary obese Hispanic adolescents.
METHODS:
Twelve obese adolescents (age = 15.5 ± 0.5 yr, body mass index = 35.3 ± 0.8 kg·m; 40.8% ± 1.5% body fat) completed a 12-wk resistance exercise program (two times 1 h·wk, exercising all major muscle groups). At baseline and on completion of the program, body composition was measured by dual-energy x-ray absorptiometry, abdominal fat distribution was measured by magnetic resonance imaging, hepatic and intramyocellular fat was measured by magnetic resonance spectroscopy, peripheral insulin sensitivity was measured by the stable-label intravenous glucose tolerance test, and hepatic insulin sensitivity was measured by the hepatic insulin sensitivity index = 1000/(GPR × fasting insulin). Glucose production rate (GPR), gluconeogenesis, and glycogenolysis were quantified using stable isotope gas chromatography/mass spectrometry techniques.
RESULTS:
All participants were normoglycemic. The exercise program resulted in significant strength gain in both upper and lower body muscle groups. Body weight increased from 97.0 ± 3.8 to 99.6 ± 4.2 kg (P < 0.01). The major part (∼80%) was accounted for by increased lean body mass (55.7 ± 2.8 to 57.9 ± 3.0 kg, P ≤ 0.01). Total, visceral, hepatic, and intramyocellular fat contents remained unchanged. Hepatic insulin sensitivity increased by 24% ± 9% (P < 0.05), whereas peripheral insulin sensitivity did not change significantly. GPR decreased by 8% ± 1% (P < 0.01) because of a 12% ± 5% decrease in glycogenolysis (P < 0.05).
CONCLUSIONS:
We conclude that a controlled resistance exercise program without weight loss increases strength and lean body mass, improves hepatic insulin sensitivity, and decreases GPR without affecting total fat mass or visceral, hepatic, and intramyocellular fat contents
Shortened beta-cell lifespan leads to beta-cell deficit in a rodent model of type 2 diabetes
No full textSince the fundamental defect in both type 1 and type 2 diabetes is β-cell failure, there is increasing interest in the capacity, if any, for β-cell regeneration. Insights into typical β-cell age and lifespan during normal development and how these are influenced in diabetes is desirable to realistically establish the prospects for β-cell regeneration as means to reverse the deficit in β-cell mass in diabetes. We assessed the mean β-cell age and lifespan by the classical McKendrick-von Foester equation that describes the age-based heterogeneity of β-cells in terms of the time-varying β-cell formation and loss estimated by a β-cell turnover model. This modeling approach was applied to evaluate β-cell lifespan in a rodent model of type 2 diabetes in comparison with nondiabetic controls. When rats were 10 mo old, mean β-cell lifespan was 1 mo vs. 6 mo in rats with type 2 diabetes vs. controls. A shortened β-cell lifespan in a rat model of type 2 diabetes results in a decrease in mean β-cell age and thus contributes to decreased β-cell mass
Dynamics of beta-cell turnover: evidence for beta-cell turnover and regeneration from sources of beta-cells other than beta-cell replication in the HIP rat
No full textype 2 diabetes is characterized by hyperglycemia, a deficit in beta-cells, increased beta-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). These characteristics are recapitulated in the human IAPP transgenic (HIP) rat. We developed a mathematical model to quantify beta-cell turnover and applied it to nondiabetic wild type (WT) vs. HIP rats from age 2 days to 10 mo to establish 1) whether beta-cell formation is derived exclusively from beta-cell replication, or whether other sources of beta-cells (OSB) are present, and 2) to what extent, if any, there is attempted beta-cell regeneration in the HIP rat and if this is through beta-cell replication or OSB. We conclude that formation and maintenance of adult beta-cells depends largely ( approximately 80%) on formation of beta-cells independent from beta-cell duplication. Moreover, this source adaptively increases in the HIP rat, implying attempted beta-cell regeneration that substantially slows loss of beta-cell mass.ype 2 diabetes is characterized by hyperglycemia, a deficit in beta-cells, increased beta-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). These characteristics are recapitulated in the human IAPP transgenic (HIP) rat. We developed a mathematical model to quantify beta-cell turnover and applied it to nondiabetic wild type (WT) vs. HIP rats from age 2 days to 10 mo to establish 1) whether beta-cell formation is derived exclusively from beta-cell replication, or whether other sources of beta-cells (OSB) are present, and 2) to what extent, if any, there is attempted beta-cell regeneration in the HIP rat and if this is through beta-cell replication or OSB. We conclude that formation and maintenance of adult beta-cells depends largely ( approximately 80%) on formation of beta-cells independent from beta-cell duplication. Moreover, this source adaptively increases in the HIP rat, implying attempted beta-cell regeneration that substantially slows loss of beta-cell mass
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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