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Glucose infusion in mice: a new model to induce beta-cell replication.

ABSTRACT: Developing new techniques to induce beta-cells to replicate is a major goal in diabetes research. Endogenous beta-cells replicate in response to metabolic changes, such as obesity and pregnancy, which increase insulin requirement. Mouse genetic models promise to reveal the pathways responsible for compensatory beta-cell replication. However, no simple, short-term, physiological replication stimulus exists to test mouse models for compensatory replication. Here, we present a new tool to induce beta-cell replication in living mice. Four-day glucose infusion is well tolerated by mice as measured by hemodynamics, body weight, organ weight, food intake, and corticosterone level. Mild sustained hyperglycemia and hyperinsulinemia induce a robust and significant fivefold increase in beta-cell replication. Glucose-induced beta-cell replication is dose and time dependent. Beta-cell mass, islet number, beta-cell size, and beta-cell death are not altered by glucose infusion over this time frame. Glucose infusion increases both the total protein abundance and nuclear localization of cyclin D2 in islets, which has not been previously reported. Thus, we have developed a new model to study the regulation of compensatory beta-cell replication, and we describe important novel characteristics of mouse beta-cell responses to glucose in the living pancreas.

SUBMITTER: Alonso LC

PROVIDER: S-EPMC2921922 | biostudies-literature | 2007 Jul

REPOSITORIES: biostudies-literature

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Glucose infusion in mice: a new model to induce beta-cell replication.

Alonso Laura C LC Yokoe Takuya T Zhang Pili P Scott Donald K DK Kim Seung K SK O'Donnell Christopher P CP Garcia-Ocaña Adolfo A

Diabetes 20070330 7

Developing new techniques to induce beta-cells to replicate is a major goal in diabetes research. Endogenous beta-cells replicate in response to metabolic changes, such as obesity and pregnancy, which increase insulin requirement. Mouse genetic models promise to reveal the pathways responsible for compensatory beta-cell replication. However, no simple, short-term, physiological replication stimulus exists to test mouse models for compensatory replication. Here, we present a new tool to induce be ...[more]

PMID: 17400928

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Project description:Type 2 diabetes (T2D) is a pathophysiology that is characterized by insulin resistance, beta- and alpha-cell dysfunction. Mathematical models of various glucose challenge experiments have been developed to quantify the contribution of insulin and beta-cell dysfunction to the pathophysiology of T2D. There is a need for effective extended models that also capture the impact of alpha-cell dysregulation on T2D. In this paper a delay differential equation-based model is developed to describe the coupled glucose-insulin-glucagon dynamics in the isoglycemic intravenous glucose infusion (IIGI) experiment. As the glucose profile in IIGI is tailored to match that of a corresponding oral glucose tolerance test (OGTT), it provides a perfect method for studying hormone responses that are in the normal physiological domain and without the confounding effect of incretins and other gut mediated factors. The model was fit to IIGI data from individuals with and without T2D. Parameters related to glucagon action, suppression, and secretion as well as measures of insulin sensitivity, and glucose stimulated response were determined simultaneously. Significant impairment in glucose dependent glucagon suppression was observed in patients with T2D (duration of T2D: 8 (6-36) months) relative to weight matched control subjects (CS) without diabetes (k1 (mM)-1: 0.16 ± 0.015 (T2D, n = 7); 0.26 ± 0.047 (CS, n = 7)). Insulin action was significantly lower in patients with T2D (a1 (10 pM min)-1: 0.000084 ± 0.0000075 (T2D); 0.00052 ± 0.00015 (CS)) and the Hill coefficient in the equation for glucose dependent insulin response was found to be significantly different in T2D patients relative to CS (h: 1.4 ± 0.15; 1.9 ± 0.14). Trends in parameters with respect to fasting plasma glucose, HbA1c and 2-h glucose values are also presented. Significantly, a negative linear relationship is observed between the glucagon suppression parameter, k1, and the three markers for diabetes and is thus indicative of the role of glucagon in exacerbating the pathophysiology of diabetes (Spearman Rank Correlation: (n = 12; (-0.79, 0.002), (-0.73,.007), (-0.86,.0003)) respectively).

Project description:The pancreas plays a critical role in maintaining glucose homeostasis through the secretion of hormones from the islets of Langerhans. Glucose-stimulated insulin secretion (GSIS) by the pancreatic β-cell is the main mechanism for reducing elevated plasma glucose. Here we present a systematic modeling workflow for the development of kinetic pathway models using the Systems Biology Markup Language (SBML). Steps include retrieval of information from databases, curation of experimental and clinical data for model calibration and validation, integration of heterogeneous data including absolute and relative measurements, unit normalization, data normalization, and model annotation. An important factor was the reproducibility and exchangeability of the model, which allowed the use of various existing tools. The workflow was applied to construct a novel data-driven kinetic model of GSIS in the pancreatic β-cell based on experimental and clinical data from 39 studies spanning 50 years of pancreatic, islet, and β-cell research in humans, rats, mice, and cell lines. The model consists of detailed glycolysis and phenomenological equations for insulin secretion coupled to cellular energy state, ATP dynamics and (ATP/ADP ratio). Key findings of our work are that in GSIS there is a glucose-dependent increase in almost all intermediates of glycolysis. This increase in glycolytic metabolites is accompanied by an increase in energy metabolites, especially ATP and NADH. One of the few decreasing metabolites is ADP, which, in combination with the increase in ATP, results in a large increase in ATP/ADP ratios in the β-cell with increasing glucose. Insulin secretion is dependent on ATP/ADP, resulting in glucose-stimulated insulin secretion. The observed glucose-dependent increase in glycolytic intermediates and the resulting change in ATP/ADP ratios and insulin secretion is a robust phenomenon observed across data sets, experimental systems and species. Model predictions of the glucose-dependent response of glycolytic intermediates and biphasic insulin secretion are in good agreement with experimental measurements. Our model predicts that factors affecting ATP consumption, ATP formation, hexokinase, phosphofructokinase, and ATP/ADP-dependent insulin secretion have a major effect on GSIS. In conclusion, we have developed and applied a systematic modeling workflow for pathway models that allowed us to gain insight into key mechanisms in GSIS in the pancreatic β-cell.

Dataset Information

Glucose infusion in mice: a new model to induce beta-cell replication.

Publications

Glucose infusion in mice: a new model to induce beta-cell replication.

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