A multi-scale in silico mouse model for insulin resistance and humanoid type 2 diabetes

Insulin resistance (IR) causes compensatory insulin production, which in humans eventually progresses to beta-cell failure and type 2 diabetes (T2D). This disease progression involves multi-scale processes, ranging from intracellular signaling to organ-organ and whole-body level regulations, on timescales from minutes to years. T2D progression is commonly studied using overfed and genetically modified rodents. However, rodents do not exhibit human T2D progression, with IR-driven beta-cell failure, and available multi-scale data is too complex to fully comprehend using traditional analysis. To help resolve these issues, we here present an in silico mouse model. This is the first mathematical model that simultaneously explains multi-scale mouse IR data on all three levels – cells, organs, body – ranging from minutes to months. The model correctly predicts new independent multi-scale validation data and provides insights into non-measured processes. Finally, we present a humanoid in silico mouse exhibiting disease progression from IR to IR-driven T2D.

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Targeting type 2 diabetes: lessons from a knockout model of insulin receptor substrate 2

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2014-0114 ◽

2014 ◽

Vol 92 (8) ◽

pp. 613-620 ◽

Cited By ~ 21

Author(s):

Joana Moitinho Oliveira ◽

Sandra A. Rebuffat ◽

Rosa Gasa ◽

Ramon Gomis

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Beta Cell ◽

Insulin Receptor ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Mitogen Activated Protein Kinase ◽

Insulin Receptor Substrate ◽

Beta Cell Failure

Insulin receptor substrate 2 (IRS2) is a widely expressed protein that regulates crucial biological processes including glucose metabolism, protein synthesis, and cell survival. IRS2 is part of the insulin – insulin-like growth factor (IGF) signaling pathway and mediates the activation of the phosphotidylinositol 3-kinase (PI3K)–Akt and the Ras–mitogen-activated protein kinase (MAPK) cascades in insulin target tissues and in the pancreas. The best evidence of this is that systemic elimination of the Irs2 in mice (Irs2−/−) recapitulates the pathogenesis of type 2 diabetes (T2D), in that diabetes arises as a consequence of combined insulin resistance and beta-cell failure. Indeed, work using this knockout mouse has confirmed the importance of IRS2 in the control of glucose homeostasis and especially in the survival and function of pancreatic beta-cells. These studies have shown that IRS2 is critically required for beta-cell compensation in conditions of increased insulin demand. Importantly, islets isolated from T2D patients exhibit reduced IRS2 expression, which supports the likely contribution of altered IRS2-dependent signaling to beta-cell failure in human T2D. For all these reasons, the Irs2−/− mouse has been and will be essential for elucidating the inter-relationship between beta-cell function and insulin resistance, as well as to delineate therapeutic strategies to protect beta-cells during T2D progression.

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Adipsin Prevents Beta-Cell Failure in a Mouse Model of Type 2 Diabetes by Blocking Dedifferentiation and Cell Death

Diabetes ◽

10.2337/db18-272-lb ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 272-LB

Author(s):

NICOLAS GOMEZ-BANOY ◽

TONG CHEN ◽

BREANNE POIRIER ◽

ALFONSO RUBIO-NAVARRO ◽

JAMES LO

Keyword(s):

Type 2 Diabetes ◽

Cell Death ◽

Mouse Model ◽

Beta Cell ◽

Beta Cell Failure

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1734-P: High Dietary Fat Intake Exacerbates Insulin Resistance in a Type 2 Diabetes Genetic Mouse Model

Diabetes ◽

10.2337/db20-1734-p ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 1734-P

Author(s):

AUSTIN REILLY ◽

SHIJUN YAN ◽

ALEXA J. LONCHARICH ◽

HONGXIA REN

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Mouse Model ◽

Dietary Fat ◽

Fat Intake ◽

Dietary Fat Intake ◽

Genetic Mouse Model

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2144-P: Early Administration of Dapagliflozin Preserves Pancreatic Beta-Cell Mass through an Epigenetic Modification in a Mouse Model of Type 2 Diabetes

Diabetes ◽

10.2337/db19-2144-p ◽

2019 ◽

Vol 68 (Supplement 1) ◽

pp. 2144-P

Author(s):

SHUN-ICHIRO ASAHARA ◽

AYUMI KANNO ◽

YOSHIAKI KIDO

Keyword(s):

Type 2 Diabetes ◽

Mouse Model ◽

Beta Cell ◽

Epigenetic Modification ◽

Pancreatic Beta Cell ◽

Cell Mass ◽

Beta Cell Mass ◽

Early Administration ◽

Pancreatic Beta Cell Mass

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Comparison of Sleeve Gastrectomy and Conservatory Treatment Effect on Biochemical and Hormonal Profile of Obese Type 2 Diabetes Subjects: CREDOR Randomized Controlled Study Results

Revista de Chimie ◽

10.37358/rc.17.7.5730 ◽

2017 ◽

Vol 68 (7) ◽

pp. 1622-1627 ◽

Cited By ~ 1

Author(s):

Diana Simona Stefan ◽

Andrada Mihai ◽

Daiana Bajko ◽

Daniela Lixandru ◽

Laura Petcu ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Weight Loss ◽

Sleeve Gastrectomy ◽

Beta Cell ◽

Beta Cell Dysfunction ◽

Control Group ◽

Cell Dysfunction ◽

Randomized Controlled

Metabolic surgery is the most efficacious method for the treatment of morbid obesity and was recently included among the antidiabetes treatments recommended in obese type 2 diabetes (T2D) patients. The aim of this study was to compare in a randomized controlled trial the effect of sleeve gastrectomy (SG) to that of intensive lifestyle intervention plus pharmacologic treatment on some markers of insulin resistance and beta cell function as well as some appetite controlling hormones in a group of male obese T2D subjects. The study groups comprised 20 subjects for SG and 21 control subjects. Fasting blood glucose, insulin, proinsulin, adiponectin, leptin, ghrelin, HOMA-IR, HOMA-%B, proinsulin-to-insulin ratio and proinsulin-to-adiponectin ratio were evaluated at baseline and after one year follow-up. Overall, patients in the SG group lost 78.98% of excess weight loss (%EWL) in comparison with 9.45% in the control group. This was accompanied by a significant improvement of insulin resistance markers, including increase of adiponectin and decrease of HOMA-IR, while no changes were recorded in the control group. Weight loss was also associated with a significant improvement of proinsulin-to-insulin and proinsulin-to-adiponectin ratio, both surrogate markers of beta cell dysfunction. These also improved in the control group, but were only marginally significant. Our findings suggest that improved insulin resistance and decreased beta cell dysfunction after sleeve gastrectomy might explain diabetes remission associated with metabolic surgery.

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Development of a Nongenetic Mouse Model of Type 2 Diabetes

Experimental Diabetes Research ◽

10.1155/2011/416254 ◽

2011 ◽

Vol 2011 ◽

pp. 1-12 ◽

Cited By ~ 64

Author(s):

Elizabeth R. Gilbert ◽

Zhuo Fu ◽

Dongmin Liu

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Mouse Model ◽

Serum Insulin ◽

Cell Mass ◽

Low Fat ◽

Β Cell ◽

Islet Mass ◽

Metabolic Characteristics

Insulin resistance and loss of β-cell mass cause Type 2 diabetes (T2D). The objective of this study was to generate a nongenetic mouse model of T2D. Ninety-six 6-month-old C57BL/6N males were assigned to 1 of 12 groups including (1) low-fat diet (LFD; low-fat control; LFC), (2) LFD with 1 i.p. 40 mg/kg BW streptozotocin (STZ) injection, (3), (4), (5), (6) LFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively, (7) high-fat diet (HFD), (8) HFD with 1 STZ injection, (9), (10), (11), (12) HFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively. After 4 weeks, serum insulin levels were reduced in HFD mice administered at least 2 STZ injections as compared with HFC. Glucose tolerance was impaired in mice that consumed HFD and received 2, 3, or 4 injections of STZ. Insulin sensitivity in HFD mice was lower than that of LFD mice, regardless of STZ treatment. Islet mass was not affected by diet but was reduced by 50% in mice that received 3 STZ injections. The combination of HFD and three 40 mg/kg STZ injections induced a model with metabolic characteristics of T2D, including peripheral insulin resistance and reduced β-cell mass.

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Obesity, Type 2 Diabetes and Beta Cell Failure: An Asian Perspective

Journal of Molecular and Genetic Medicine ◽

10.4172/1747-0862.s1-008 ◽

2014 ◽

Vol s1 (01) ◽

Cited By ~ 5

Author(s):

Yoshifumi Saisho

Keyword(s):

Type 2 Diabetes ◽

Beta Cell ◽

Beta Cell Failure

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Pathophysiology of type 2 diabetes mellitus in youth: the evolving chameleon

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302009000200008 ◽

2009 ◽

Vol 53 (2) ◽

pp. 165-174 ◽

Cited By ~ 22

Author(s):

Hala Tfayli ◽

Silva Arslanian

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Beta Cell ◽

Polycystic Ovary ◽

Significant Proportion ◽

Public Health Problem ◽

Family History Of Diabetes ◽

Beta Cell Failure

Type 2 diabetes mellitus (T2DM) in children and adolescents is an important Public Health problem against the backdrop of the epidemic of childhood obesity. The clinical presentation of T2DM in youth is heterogeneous from minimal symptomatology to diabetic ketoacidosis. The increasing rates of youth T2DM have paralleled the escalating rates of obesity, which is the major risk factor impacting insulin sensitivity. Additional risk factors include minority race, family history of diabetes mellitus, maternal diabetes during pregnancy, pubertal age group and conditions associated with insulin resistance (IR) - such as polycystic ovary syndrome (PCOS). The pathophysiology of T2DM has been studied extensively in adults, and it is widely accepted that IR together with beta-cell failure are necessary for the development of clinical diabetes mellitus in adulthood. However, pathophysiologic studies in youth are limited and in some cases conflicting. Similar to adults, IR is a prerequisite, but beta-cell failure is necessary for progression from normal glucose tolerance to prediabetes and frank diabetes in youth. Even though rates of T2DM in youth are increasing, the overall prevalence remains low if compared with type 1 diabetes mellitus (T1DM). However, as youth with T1DM are becoming obese, the clinical distinction between T2DM and obese T1DM has become difficult, because of the overlapping clinical picture with evidence of islet cell autoimmunity in a significant proportion of clinically diagnosed youth with T2DM. The latter are most likely obese children with autoimmune T1DM who carry a misdiagnosis of T2DM. Further research is needed to probe the pathophysiological, immunological, and metabolic differences between these two groups in the hopes of assigning appropriate therapeutic regimens. These challenges combined with the evolving picture of youth T2DM and its future complications provide unending opportunities for acquisition of new knowledge in the field of childhood diabetes.

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