The Effects of Empagliflozin, an SGLT2 Inhibitor, on Pancreatic β-Cell Mass and Glucose Homeostasis in Type 1 Diabetes

Type-1 diabetes mellitus (T1DM) is an autoimmune disease that has an impact on mortality due to the destruction of insulin-producing pancreatic β -cells in the islets of Langerhans. Over the past few years, the interest in analyzing this type of disease, either in a biological or mathematical sense, has relied on the search for a treatment that guarantees full control of glucose levels. Mathematical models inspired by natural phenomena, are proposed under the prey–predator scheme. T1DM fits in this scheme due to the complicated relationship between pancreatic β -cell population growth and leukocyte population growth via the immune response. In this scenario, β -cells represent the prey, and leukocytes the predator. This paper studies the global dynamics of T1DM reported by Magombedze et al. in 2010. This model describes the interaction of resting macrophages, activated macrophages, antigen cells, autolytic T-cells, and β -cells. Therefore, the localization of compact invariant sets is applied to provide a bounded positive invariant domain in which one can ensure that once the dynamics of the T1DM enter into this domain, they will remain bounded with a maximum and minimum value. Furthermore, we analyzed this model in a closed-loop scenario based on nonlinear control theory, and proposed bases for possible control inputs, complementing the model with them. These entries are based on the existing relationship between cell–cell interaction and the role that they play in the unchaining of a diabetic condition. The closed-loop analysis aims to give a deeper understanding of the impact of autolytic T-cells and the nature of the β -cell population interaction with the innate immune system response. This analysis strengthens the proposal, providing a system free of this illness—that is, a condition wherein the pancreatic β -cell population holds and there are no antigen cells labeled by the activated macrophages.

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Distinct Roles of β-Cell Mass and Function During Type 1 Diabetes Onset and Remission

Diabetes ◽

10.2337/db14-1055 ◽

2015 ◽

Vol 64 (6) ◽

pp. 2148-2160 ◽

Cited By ~ 30

Author(s):

Helena Chmelova ◽

Christian M. Cohrs ◽

Julie A. Chouinard ◽

Cathleen Petzold ◽

Matthias Kuhn ◽

...

Keyword(s):

Type 1 Diabetes ◽

Cell Mass ◽

Β Cell ◽

Diabetes Onset ◽

And Function

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Harnessing immune cells to enhance β-cell mass in type 1 diabetes

Journal of Investigative Medicine ◽

10.1136/jim-d-15-00196 ◽

2016 ◽

Vol 64 (1) ◽

pp. 14-20 ◽

Cited By ~ 2

Author(s):

Ercument Dirice ◽

Rohit N Kulkarni

Keyword(s):

Type 1 Diabetes ◽

Mononuclear Cells ◽

Islet Cells ◽

Cell Mass ◽

Cell Loss ◽

Cell Types ◽

Β Cells ◽

Β Cell ◽

Autoimmune Attack

Type 1 diabetes is characterized by early β-cell loss leading to insulin dependence in virtually all patients with the disease in order to maintain glucose homeostasis. Most studies over the past few decades have focused on limiting the autoimmune attack on the β cells. However, emerging data from patients with long-standing diabetes who continue to harbor functional insulin-producing cells in their diseased pancreas have prompted scientists to examine whether proliferation of existing β cells can be enhanced to promote better glycemic control. In support of this concept, several studies indicate that mononuclear cells that infiltrate the islets have the capacity to trigger proliferation of islet cells including β cells. These observations indicate the exciting possibility of identifying those mononuclear cell types and their soluble factors and harnessing their ability to promote β-cell growth concomitant with autoimmune therapy to prevent the onset and/or halt the progression of the disease.

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The Constitutive Lack of α7 Nicotinic Receptor Leads to Metabolic Disorders in Mouse

Biomolecules ◽

10.3390/biom10071057 ◽

2020 ◽

Vol 10 (7) ◽

pp. 1057

Author(s):

Blandine Gausserès ◽

Junjun Liu ◽

Ewout Foppen ◽

Cécile Tourrel-Cuzin ◽

Ana Rodriguez Sanchez-Archidona ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Homeostasis ◽

Metabolic Disorders ◽

Late Onset ◽

Cell Mass ◽

Chow Diet ◽

Pancreatic Β Cell ◽

Β Cell ◽

Α7 Nachr ◽

Old Mice

Objective: Type 2 diabetes (T2D) occurs by deterioration in pancreatic β-cell function and/or progressive loss of pancreatic β-cell mass under the context of insulin resistance. α7 nicotinic acetylcholine receptor (nAChR) may contribute to insulin sensitivity but its role in the pathogenesis of T2D remains undefined. We investigated whether the systemic lack of α7 nAChR was sufficient to impair glucose homeostasis. Methods: We used an α7 nAChR knock-out (α7−/−) mouse model fed a standard chow diet. The effects of the lack of α7 nAChR on islet mass, insulin secretion, glucose and insulin tolerance, body composition, and food behaviour were assessed in vivo and ex vivo experiments. Results: Young α7−/− mice display a chronic mild high glycemia combined with an impaired glucose tolerance and a marked deficit in β-cell mass. In addition to these metabolic disorders, old mice developed adipose tissue inflammation, elevated plasma free fatty acid concentrations and presented glycolytic muscle insulin resistance in old mice. Finally, α7−/− mice, fed a chow diet, exhibited a late-onset excessive gain in body weight through increased fat mass associated with higher food intake. Conclusion: Our work highlights the important role of α7 nAChR in glucose homeostasis. The constitutive lack of α7 nAChR suggests a novel pathway influencing the pathogenesis of T2D.

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Dendritic Cell-Directed CTLA-4 Engagement during Pancreatic β Cell Antigen Presentation Delays Type 1 Diabetes

The Journal of Immunology ◽

10.4049/jimmunol.0903130 ◽

2010 ◽

Vol 184 (12) ◽

pp. 6695-6708 ◽

Cited By ~ 15

Author(s):

Subha Karumuthil-Melethil ◽

Nicolas Perez ◽

Ruobing Li ◽

Bellur S. Prabhakar ◽

Mark J. Holterman ◽

...

Keyword(s):

Type 1 Diabetes ◽

Dendritic Cell ◽

Antigen Presentation ◽

Pancreatic Β Cell ◽

Β Cell ◽

Cell Antigen

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Insulitis and β-Cell Mass in the Natural History of Type 1 Diabetes

Diabetes ◽

10.2337/db15-0779 ◽

2015 ◽

Vol 65 (3) ◽

pp. 719-731 ◽

Cited By ~ 150

Author(s):

Martha Campbell-Thompson ◽

Ann Fu ◽

John S. Kaddis ◽

Clive Wasserfall ◽

Desmond A. Schatz ◽

...

Keyword(s):

Type 1 Diabetes ◽

Natural History ◽

Cell Mass ◽

Β Cell ◽

History Of

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Prevention of Diabetes in db/db Mice by Dietary Soy Is Independent of Isoflavone Levels

Endocrinology ◽

10.1210/en.2012-1490 ◽

2012 ◽

Vol 153 (11) ◽

pp. 5200-5211 ◽

Cited By ~ 19

Author(s):

Céline Zimmermann ◽

Christopher R. Cederroth ◽

Lucie Bourgoin ◽

Michelangelo Foti ◽

Serge Nef

Keyword(s):

Glucose Homeostasis ◽

Cell Function ◽

Hepatic Glucose Production ◽

Cell Mass ◽

Glucose Production ◽

Metabolic Effects ◽

Pancreatic Β Cell ◽

Β Cell ◽

Glucose Levels ◽

Hepatic Glucose

Abstract Recent evidence points towards the beneficial use of soy proteins and isoflavones to improve glucose control and slow the progression of type 2 diabetes. Here, we used diabetic db/db mice fed a high soy-containing diet (SD) or a casein soy-free diet to investigate the metabolic effects of soy and isoflavones consumption on glucose homeostasis, hepatic glucose production, and pancreatic islet function. Male db/db mice fed with a SD exhibited a robust reduction in hyperglycemia (50%), correlating with a reduction in hepatic glucose production and preserved pancreatic β-cell function. The rapid decrease in fasting glucose levels resulted from an inhibition of gluconeogenesis and an increase in glycolysis in the liver of db/db mice. Soy consumption also prevented the loss of pancreatic β-cell mass and thus improved glucose-stimulated insulin secretion (3-fold), which partly accounted for the overall improvements in glucose homeostasis. Comparison of SD effects on hyperglycemia with differing levels of isoflavones or with purified isoflavones indicate that the beneficial physiological effects of soy are not related to differences in their isoflavone content. Overall, these findings suggest that consumption of soy is beneficial for improving glucose homeostasis and delaying the progression of diabetes in the db/db mice but act independently of isoflavone concentration.

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