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Validating a dimensionless number for glucose homeostasis in humans.

ABSTRACT: Understanding type 2 diabetes is challenged by the diversity of patient phenotypes. Translating data across species and among individuals is a barrier for understanding the genetic loci that underpin this multifactorial disease. Dynamic scaling, based upon dimensional analysis, is a common technique in engineering used to translate data among different systems. The objective of this study was to gain insight using dimensional analysis into the relative changes in insulin production capacity vs. insulin-dependent glucose metabolism in patient groups that represent distinct stages of disease progression. A dimensionless number was derived using variables involved in the production of insulin and in the sensitivity of glucose metabolism to insulin. The resulting dynamic scaling relationship was validated against patient data obtained for over 2000 individuals that range in phenotype from normal to severe type 2 diabetes. Individuals were identified in the third National Health and Nutrition Evaluation Survey. Patient groups clustered in different regions based upon the severity of clinical symptoms. The cross-sectional comparison among patient groups shows that progression from normal to clinical onset of type 2 diabetes exhibits a non-linear change in the ratio of insulin production to insulin-dependent glucose metabolism: normals are balanced, pre-diabetic individuals exhibit an increase, and individuals with clinical type 2 diabetes exhibit a decrease in this ratio. This dimensionless number provides a method for discriminating between patient groups from first principles. By analogy with other dimensionless numbers, this number may be used to monitor basic physiological variables responsible for glucose homeostasis. In addition, a similar dynamic trajectory to the clinical populations could provide a criterion for selecting relevant animal models for diabetes.

SUBMITTER: Klinke DJ

PROVIDER: S-EPMC4402237 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Validating a dimensionless number for glucose homeostasis in humans.

Klinke David J DJ

Annals of biomedical engineering 20090610 9

Understanding type 2 diabetes is challenged by the diversity of patient phenotypes. Translating data across species and among individuals is a barrier for understanding the genetic loci that underpin this multifactorial disease. Dynamic scaling, based upon dimensional analysis, is a common technique in engineering used to translate data among different systems. The objective of this study was to gain insight using dimensional analysis into the relative changes in insulin production capacity vs. ...[more]

PMID: 19513847

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Project description:Chronic inflammation is a driving force for the development of metabolic disease including diabetes and obesity. However, the functional characteristics of T-cell senescence in the abnormal glucose homeostasis are not fully understood. We studied the patients visiting a hospital for routine health check-ups, who were divided into two groups: normal controls and people with prediabetes. Gene expression profiling of peripheral blood mononuclear cells from normal controls and patients with type 2 diabetes was undertaken using microarray analysis. We also investigated the immunometabolic characteristics of peripheral and hepatic senescent T cells in the normal subjects and patients with prediabetes. Moreover, murine senescent T cells were tested functionally in the liver of normal or mice with metabolic deterioration caused by diet-induced obesity. Human senescent (CD28-CD57+) CD8+ T cells are increased in the development of diabetes and proinflammatory cytokines and cytotoxic molecules are highly expressed in senescent T cells from patients with prediabetes. Moreover, we demonstrate that patients with prediabetes have higher concentrations of reactive oxygen species (ROS) in their senescent CD8+ T cells via enhancing capacity to use glycolysis. These functional properties of senescent CD8+ T cells contribute to the impairment of hepatic insulin sensitivity in humans. Furthermore, we found an increase of hepatic senescent T cells in mouse models of aging and diet-induced obesity. Adoptive transfer of senescent CD8+ T cells also led to a significant deterioration in systemic abnormal glucose homeostasis, which is improved by ROS scavengers in mice. This study defines a new clinically relevant concept of T-cell senescence-mediated inflammatory responses in the pathophysiology of abnormal glucose homeostasis. We also found that T-cell senescence is associated with systemic inflammation and alters hepatic glucose homeostasis. The rational modulation of T-cell senescence would be a promising avenue for the treatment or prevention of diabetes.

Project description:BACKGROUNDBeige adipose tissue is associated with improved glucose homeostasis in mice. Adipose tissue contains β3-adrenergic receptors (β3-ARs), and this study was intended to determine whether the treatment of obese, insulin-resistant humans with the β3-AR agonist mirabegron, which stimulates beige adipose formation in subcutaneous white adipose tissue (SC WAT), would induce other beneficial changes in fat and muscle and improve metabolic homeostasis.METHODSBefore and after β3-AR agonist treatment, oral glucose tolerance tests and euglycemic clamps were performed, and histochemical analysis and gene expression profiling were performed on fat and muscle biopsies. PET-CT scans quantified brown adipose tissue volume and activity, and we conducted in vitro studies with primary cultures of differentiated human adipocytes and muscle.RESULTSThe clinical effects of mirabegron treatment included improved oral glucose tolerance (P < 0.01), reduced hemoglobin A1c levels (P = 0.01), and improved insulin sensitivity (P = 0.03) and β cell function (P = 0.01). In SC WAT, mirabegron treatment stimulated lipolysis, reduced fibrotic gene expression, and increased alternatively activated macrophages. Subjects with the most SC WAT beiging showed the greatest improvement in β cell function. In skeletal muscle, mirabegron reduced triglycerides, increased the expression of PPARγ coactivator 1 α (PGC1A) (P < 0.05), and increased type I fibers (P < 0.01). Conditioned media from adipocytes treated with mirabegron stimulated muscle fiber PGC1A expression in vitro (P < 0.001).CONCLUSIONMirabegron treatment substantially improved multiple measures of glucose homeostasis in obese, insulin-resistant humans. Since β cells and skeletal muscle do not express β3-ARs, these data suggest that the beiging of SC WAT by mirabegron reduces adipose tissue dysfunction, which enhances muscle oxidative capacity and improves β cell function.TRIAL REGISTRATIONClinicaltrials.gov NCT02919176.FUNDINGNIH: DK112282, P30GM127211, DK 71349, and Clinical and Translational science Awards (CTSA) grant UL1TR001998.

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Validating a dimensionless number for glucose homeostasis in humans.

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Validating a dimensionless number for glucose homeostasis in humans.

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