skip to main content
US FlagAn official website of the United States government
dot gov icon
Official websites use .gov
A .gov website belongs to an official government organization in the United States.
https lock icon
Secure .gov websites use HTTPS
A lock ( lock ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Explore Research Products in the PAR
It may take a few hours for recently added research products to appear in PAR search results.


Title: The progression of secondary diabetes: A review of modeling studies
Mathematical modeling has provided quantitative information consistent with experimental data, greatly improving our understanding of the progression of type 1 and type 2 diabetes. However, diabetes is a complex metabolic disease and has been found to be involved in crosstalk interactions with diverse endocrine diseases. Mathematical models have also been developed to investigate the quantitative impact of various hormonal disorders on glucose imbalance, advancing the precision treatment for secondary diabetes. Here we review the models established for the study of dysglycemia induced by hormonal disorders, such as excessive glucocorticoids, epinephrine, and growth hormone. To investigate the influence of hyperthyroidism on the glucose regulatory system, we also propose a hyperthyroid-diabetes progression model. Model simulations indicate that timely thyroid treatment can halt the progression of hyperglycemia and prevent beta-cell failure. This highlights the diagnosis of hormonal disorders, together withblood sugar tests, as significant measures for the early diagnosis and treatment of diabetes. The work recapitulates updated biological research on the interactions between the glucose regulatory system and other endocrine axes. Further mathematical modeling of secondary diabetes is desired to promote the quantitative study of the disease and the development of individualized diabetic therapies.  more » « less
Award ID(s):
1950254
PAR ID:
10431828
Author(s) / Creator(s):
; ; ; ;
Date Published:
Journal Name:
Frontiers in Endocrinology
Volume:
13
ISSN:
1664-2392
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. ; ; ; ; (, PLOS Computational Biology)
    Beard, Daniel A. (Ed.)
    Environmentally induced or epigenetic-related beta-cell dysfunction and insulin resistance play a critical role in the progression to diabetes. We developed a mathematical modeling framework capable of studying the progression to diabetes incorporating various diabetogenic factors. Considering the heightened risk of beta-cell defects induced by obesity, we focused on the obesity-diabetes model to further investigate the influence of obesity on beta-cell function and glucose regulation. The model characterizes individualized glucose and insulin dynamics over the span of a lifetime. We then fit the model to the longitudinal data of the Pima Indian population, which captures both the fluctuations and long-term trends of glucose levels. As predicted, controlling or eradicating the obesity-related factor can alleviate, postpone, or even reverse diabetes. Furthermore, our results reveal that distinct abnormalities of beta-cell function and levels of insulin resistance among individuals contribute to different risks of diabetes. This study may encourage precise interventions to prevent diabetes and facilitate individualized patient treatment. 
    more » « less
  2. ; (, Frontiers in Pharmacology)
    BackgroundGlomerular fibrosis is a tissue damage that occurs within the kidneys of chronic and diabetic kidney disease patients. Effective treatments are lacking, and the mechanism of glomerular damage reversal is poorly understood. MethodsA mathematical model suitable for hypothesis-driven systems pharmacology of glomerular fibrosis in diabetes was developed from a previous model of interstitial fibrosis. The adapted model consists of a system of ordinary differential equations that models the complex disease etiology and progression of glomerular fibrosis in diabetes. ResultsWithin the scope of the mechanism incorporated, advanced glycation end products (AGE)—matrix proteins that are modified due to high blood glucose—were identified as major contributors to the delay in the recovery from glomerular fibrosis after glucose control. The model predicted that inhibition of AGE production is not an effective approach for accelerating the recovery from glomerular fibrosis. Further, the model predicted that treatment breaking down accumulated AGE is the most productive at reversing glomerular fibrosis. The use of the model led to the identification that glucose control and aminoguanidine are ineffective treatments for reversing advanced glomerular fibrosis because they do not remove accumulated AGE. Additionally, using the model, a potential explanation was generated for the lack of efficacy of alagebrium in treating advanced glomerular fibrosis, which is due to the inability of alagebrium to reduce TGF- β . ImpactUsing the mathematical model, a mechanistic understanding of disease etiology and complexity of glomerular fibrosis in diabetes was illuminated, and then hypothesis-driven explanations for the lack of efficacy of different pharmacological agents for treating glomerular fibrosis were provided. This understanding can enable the development of more efficacious therapeutics for treating kidney damage in diabetes. 
    more » « less
  3. ; ; (, International Journal of Molecular Sciences)
    null (Ed.)
    Diabetes is one of the leading causes of death globally. Currently, the donor pancreas is the only source of human islets, placing extreme constraints on supply. Hence, it is imperative to develop renewable islets for diabetes research and treatment. To date, extensive efforts have been made to derive insulin-secreting cells from human pluripotent stem cells with substantial success. However, the in vitro generation of functional islet organoids remains a challenge due in part to our poor understanding of the signaling molecules indispensable for controlling differentiation pathways towards the self-assembly of functional islets from stem cells. Since this process relies on a variety of signaling molecules to guide the differentiation pathways, as well as the culture microenvironments that mimic in vivo physiological conditions, this review highlights extracellular matrix proteins, growth factors, signaling molecules, and microenvironments facilitating the generation of biologically functional pancreatic endocrine cells from human pluripotent stem cells. Signaling pathways involved in stepwise differentiation that guide the progression of stem cells into the endocrine lineage are also discussed. The development of protocols enabling the generation of islet organoids with hormone release capacities equivalent to native adult islets for clinical applications, disease modeling, and diabetes research are anticipated. 
    more » « less
  4. ; ; ; ; ; ; (, Current Topics in Medicinal Chemistry)
    Pancreatic Ductal Adenocarcinoma (PDAC) is regarded as one of the most lethal cancer typesfor its challenges associated with early diagnosis and resistance to standard chemotherapeutic agents,thereby leading to a poor five-year survival rate. The complexity of the disease calls for a multidisciplinaryapproach to better manage the disease and improve the status quo in PDAC diagnosis, prognosis,and treatment. To this end, the application of quantitative tools can help improve the understanding ofdisease mechanisms, develop biomarkers for early diagnosis, and design patient-specific treatment strategiesto improve therapeutic outcomes. However, such approaches have only been minimally applied towardsthe investigation of PDAC, and we review the current status of mathematical modeling works inthis field. 
    more » « less
  5. ; ; ; (, The Journal of Clinical Endocrinology & Metabolism)
    Abstract Aims The association of glycemic variability with microvascular disease complications in type 2 diabetes (T2D) has been under-studied and remains unclear. We investigated this relationship using both Action to Control Cardiovascular Risk in Diabetes (ACCORD) and the Veteran Affairs Diabetes Trial (VADT). Methods In ACCORD, fasting plasma glucose (FPG) was measured 1 to 3 times/year for up to 84 months in 10 251 individuals. In the VADT, FPG was measured every 3 months for up to 87 months in 1791 individuals. Variability measures included coefficient of variation (CV) and average real variability (ARV) for fasting glucose. The primary composite outcome was time to either severe nephropathy or retinopathy event and secondary outcomes included each outcome individually. To assess the association, we considered variability measures as time-dependent covariates in Cox proportional hazard models. We conducted a meta-analysis across the 2 trials to estimate the risk of fasting glucose variability as well as to assess the heterogenous effects of FPG variability across treatment arms. Results In both ACCORD and the VADT, the CV and ARV of FPG were associated with development of future microvascular outcomes even after adjusting for other risk factors, including measures of average glycemic control (ie, cumulative average of HbA1c). Meta-analyses of these 2 trials confirmed these findings and indicated FPG variation may be more harmful in those with less intensive glucose control. Conclusions This post hoc analysis indicates that variability of FPG plays a role in, and/or is an independent and readily available marker of, development of microvascular complications in T2D. 
    more » « less
  • Citation Formats
  • MLA
  • APA
  • Chicago
  • BibTeX
  • Save / Share this Record
  • Send to Email