This content will become publicly available on February 27, 2024
- Award ID(s):
- NSF-PAR ID:
- Beard, Daniel A.
- Date Published:
- Journal Name:
- PLOS Computational Biology
- Page Range / eLocation ID:
- Medium: X
- Sponsoring Org:
- National Science Foundation
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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
Abstract Pancreatic islet transplantation can cure diabetes but requires accessible, high-quality islets in sufficient quantities. Cryopreservation could solve islet supply chain challenges by enabling quality-controlled banking and pooling of donor islets. Unfortunately, cryopreservation has not succeeded in this objective, as it must simultaneously provide high recovery, viability, function and scalability. Here, we achieve this goal in mouse, porcine, human and human stem cell (SC)-derived beta cell (SC-beta) islets by comprehensive optimization of cryoprotectant agent (CPA) composition, CPA loading and unloading conditions and methods for vitrification and rewarming (VR). Post-VR islet viability, relative to control, was 90.5% for mouse, 92.1% for SC-beta, 87.2% for porcine and 87.4% for human islets, and it remained unchanged for at least 9 months of cryogenic storage. VR islets had normal macroscopic, microscopic, and ultrastructural morphology. Mitochondrial membrane potential and adenosine triphosphate (ATP) levels were slightly reduced, but all other measures of cellular respiration, including oxygen consumption rate (OCR) to produce ATP, were unchanged. VR islets had normal glucose-stimulated insulin secretion (GSIS) function in vitro and in vivo. Porcine and SC-beta islets made insulin in xenotransplant models, and mouse islets tested in a marginal mass syngeneic transplant model cured diabetes in 92% of recipients within 24–48 h after transplant. Excellent glycemic control was seen for 150 days. Finally, our approach processed 2,500 islets with >95% islets recovery at >89% post-thaw viability and can readily be scaled up for higher throughput. These results suggest that cryopreservation can now be used to supply needed islets for improved transplantation outcomes that cure diabetes.more » « less
Under healthy conditions, the pancreas responds to a glucose challenge by releasing insulin. Insulin suppresses lipolysis in adipose tissue, thereby decreasing plasma glycerol concentration, and it regulates plasma glucose concentration through action in muscle and liver. Insulin resistance (IR) occurs when more insulin is required to achieve the same effects, and IR may be tissue-specific. IR emerges during puberty as a result of high concentrations of growth hormone and is worsened by youth-onset obesity. Adipose, liver, and muscle tissue exhibit distinct dose-dependent responses to insulin in multi-phase hyperinsulinemic-euglycemic (HE) clamps, but the HE clamp protocol does not address potential differences in the dynamics of tissue-specific insulin responses. Changes to the dynamics of insulin responses would alter glycemic control in response to a glucose challenge. To investigate the dynamics of insulin acting on adipose tissue, we developed a novel differential-equations based model that describes the coupled dynamics of glycerol concentrations and insulin action during an oral glucose tolerance test in female adolescents with obesity and IR. We compared these dynamics to the dynamics of insulin acting on muscle and liver as assessed with the oral minimal model applied to glucose and insulin data collected under the same protocol. We found that the action of insulin on glycerol peaks approximately 67 min earlier ( p < 0.001) and follows the dynamics of plasma insulin more closely compared to insulin action on glucose as assessed by the parameters representing the time constants for insulin action on glucose and glycerol ( p < 0.001). These findings suggest that the dynamics of insulin action show tissue-specific differences in our IR adolescent population, with adipose tissue responding to insulin more quickly compared to muscle and liver. Improved understanding of the tissue-specific dynamics of insulin action may provide novel insights into the progression of metabolic disease in patient populations with diverse metabolic phenotypes.more » « less
To study the associations between heterogeneity of gestational diabetes mellitus (GDM) subtype/prepregnancy body mass index (pre‐BMI) and large‐for‐gestational‐age (LGA) infants of Chinese women.
We performed a retrospective case‐control study of 299 women with GDM and 204 women with normal glucose tolerance (NGT), using oral glucose tolerance test‐based indices performed at 24‐25 weeks of gestation. Women with GDM were classified into the following three physiologic subtypes: GDM with a predominant insulin‐secretion defect (GDM‐dysfunction), GDM with a predominant insulin‐sensitivity defect (GDM‐resistance), or GDM with both defects (GDM‐mixed). We then used a binary logistic regression model to evaluate the potential associations of GDM subtypes and pre‐BMI with newborn macrosomia or LGA.
Women with GDM‐resistance had a higher pre‐BMI (
P< 0.001), whereas women in the GDM‐dysfunction and GDM‐mixed groups had pre‐BMIs comparable to the NGT group. In the logistic regression model, women in the GDM‐mixed group exhibited an increased risk of bearing newborns with macrosomia and LGA, and women in the GDM‐dysfunction group tended to have newborns with LGA after adjusting for pre‐BMI and other potential confounders. Women who were overweight or obese prepregnancy manifested an increased risk of having newborns with macrosomia and LGA relative to normal‐weight women, regardless of whether values were unadjusted or adjusted for all potential confounders. There was no significant interaction between GDM subtype and pre‐BMI for any of the studied outcomes. Conclusions
Heterogeneity of GDM (GDM‐dysfunction and GDM‐mixed) and prepregnancy overweight/obesity were independently associated with LGA in Chinese women. There was no significant interaction between GDM subtypes and pre‐BMI for LGA.
Introduction Blood sugar homeostasis relies largely on the action of pancreatic islet hormones, particularly insulin and glucagon. In a prototypical fashion, glucagon is released upon hypoglycemia to elevate glucose by acting on the liver while elevated glucose induces the secretion of insulin which leads to sugar uptake by peripheral tissues. This simplified view of glucagon and insulin does not consider the paracrine roles of the two hormones modulating the response to glucose of α- and β-cells. In particular, glucose-stimulated glucagon secretion by isolated α-cells exhibits a Hill-function pattern, while experiments with intact pancreatic islets suggest a ‘U’-shaped response. Methods To this end, a framework was developed based on first principles and coupled to experimental studies capturing the glucose-induced response of pancreatic α- and β-cells influenced by the two hormones. The model predicts both the transient and steady-state profiles of secreted insulin and glucagon, including the typical biphasic response of normal β-cells to hyperglycemia. Results and discussion The results underscore insulin activity as a differentiating factor of the glucagon secretion from whole islets vs . isolated α-cells, and highlight the importance of experimental conditions in interpreting the behavior of islet cells in vitro . The model also reproduces the hyperglucagonemia, which is experienced by diabetes patients, and it is linked to a failure of insulin to inhibit α-cell activity. The framework described here is amenable to the inclusion of additional islet cell types and extrapancreatic tissue cells simulating multi-organ systems. The study expands our understanding of the interplay of insulin and glucagon for pancreas function in normal and pathological conditions.more » « less