Chronic Metabolic Dysfunction Research Articles

Understanding the Complexity of Hyperglycemic Emergencies: Exploring the Influence of the Type and Duration of Diabetes Mellitus and Its Impact on Mortality.

Background Diabetes mellitus remains a pressing global health issue, characterized by chronic metabolic dysfunction and the potential for life-threatening acute hyperglycemic emergencies. These emergencies, known as diabetic ketoacidosis and hyperosmolar hyperglycemic states, trigger a series of physiological disruptions. This article delves deeply into how the type and duration of diabetes mellitus affect the occurrence of hyperglycemic emergencies and mortality rates. Methods The study was conducted at the Institute of Internal Medicine, Rajiv Gandhi General Hospital, affiliated with Madras Medical College, spanning from July 2021 to December 2021. It encompassed both individuals newly diagnosed with diabetic ketoacidosis and patients already undergoing diabetic treatment who developed diabetic ketoacidosis and hyperosmolar hyperglycemic states. Results Within the study cohort of 110 patients, 37.27% were diagnosed with Type 1 diabetes mellitus, while 62.73% were classified as Type 2 diabetes mellitus patients. Among these individuals, 23.60% were newly diagnosed with diabetes, 22.70% had been diabetic for less than one year, 47.30% had a diabetic history of two to five years, and 6.40% had been diabetic for over six years. However, upon investigating the relationship between diabetes duration and mortality rate, no statistically significant findings were observed. Conclusion Hyperglycemic emergencies represent multifaceted clinical challenges influenced by the interplay of various factors, including the type and duration of the disease. By maintaining effective management of hyperglycemia from the outset and sustaining it throughout their lives, people with diabetes can improve their physical and mental health and reduce the likelihood of developing long-term complications that may negatively impact their overall well-being.

Fractional-order modelling and analysis of diabetes mellitus: Utilizing the Atangana-Baleanu Caputo (ABC) operator

This article aims to introduce and analyze a diabetes mellitus model of fractional order, utilizing the ABC derivative. Diabetes mellitus is a prevalent and significant disease worldwide, ranking among the top causes of mortality. It is characterized by chronic metabolic dysfunction, leading to elevated blood glucose levels and subsequent damage to vital organs including the nerves, kidneys, eyes, blood vessels, and heart. The fractional ABC derivative is used in this study to describe and analyze diabetes mellitus mathematically while removing hereditary influences. The investigation begins by exploring the initial points of the diabetes mellitus model. Under the fractional ABC operator, Picard's theorem is used to prove the existence and uniqueness of solutions. For the numerical approximation of solutions in the fractional-order diabetes mellitus model, this study used a specialized technique that combines the principles of fractional calculus and a two-step Lagrange polynomial interpolation. Finally, the obtained results are visually presented through graphical representations, serving as empirical evidence to support our theoretical findings. The numerical experiments showed that the proportion of patients with diabetes mellitus increased as the fractional dimension (θ) reduced. The combination of mathematical modelling, analysis, and numerical simulations provides insights into the dynamics of diabetes mellitus, offering valuable contributions to the understanding and management of this prevalent disease. Additionally, the proposed scheme can be enhanced by incorporating the ABC operator, allowing for the simulation of real-world dynamics and behavior in the coexistence of diabetes mellitus and tuberculosis.

Protective Role of Mitochondrial Uncoupling Proteins against Age-Related Oxidative Stress in Type 2 Diabetes Mellitus.

The accumulation of oxidative damage to DNA and other biomolecules plays an important role in the etiology of aging and age-related diseases such as type 2 diabetes mellitus (T2D), atherosclerosis, and neurodegenerative disorders. Mitochondrial DNA (mtDNA) is especially sensitive to oxidative stress. Mitochondrial dysfunction resulting from the accumulation of mtDNA damage impairs normal cellular function and leads to a bioenergetic crisis that accelerates aging and associated diseases. Age-related mitochondrial dysfunction decreases ATP production, which directly affects insulin secretion by pancreatic beta cells and triggers the gradual development of the chronic metabolic dysfunction that characterizes T2D. At the same time, decreased glucose oxidation in skeletal muscle due to mitochondrial damage leads to prolonged postprandial blood glucose rise, which further worsens glucose homeostasis. ROS are not only highly reactive by-products of mitochondrial respiration capable of oxidizing DNA, proteins, and lipids but can also function as signaling and effector molecules in cell membranes mediating signal transduction and inflammation. Mitochondrial uncoupling proteins (UCPs) located in the inner mitochondrial membrane of various tissues can be activated by ROS to protect cells from mitochondrial damage. Mitochondrial UCPs facilitate the reflux of protons from the mitochondrial intermembrane space into the matrix, thereby dissipating the proton gradient required for oxidative phosphorylation. There are five known isoforms (UCP1-UCP5) of mitochondrial UCPs. UCP1 can indirectly reduce ROS formation by increasing glutathione levels, thermogenesis, and energy expenditure. In contrast, UCP2 and UCP3 regulate fatty acid metabolism and insulin secretion by beta cells and modulate insulin sensitivity. Understanding the functions of UCPs may play a critical role in developing pharmacological strategies to combat T2D. This review summarizes the current knowledge on the protective role of various UCP homologs against age-related oxidative stress in T2D.

Heal Thyself: SGLT2 Inhibition Limits Regenerative Cell Exhaustion and Heals Damaged Vessels.

Chronic metabolic dysfunction as a result of type 2 diabetes (T2D) increases susceptibility to the development of ischemic cardiovascular disease (CVD) (1). The search for therapies to improve cardiovascular health in individuals afflicted with T2D has led to the discovery and utilization of a novel class of glucose-lowering drugs called sodium–glucose cotransporter 2 inhibitors (SGLT2i). Located in the proximal tubule of the kidney, the SGLT2 receptor directs the reuptake of glucose and sodium into the circulation (2,3). Inhibition of this pathway results in glucosuria/natriuresis and represents a novel metabolic mechanism to reduce hyperglycemia during T2D. Several randomized clinical trials in people with and without diabetes have now established a critical role for SGLT2i in the reduction of cardiovascular and cardiorenal events (4,5). While direct myocardial and indirect metabolic effects have been proposed to explain these benefits, recent data suggest that SGLT2 inhibition stimulates vascular repair via increased trafficking of bone marrow–derived provascular progenitor cells essential for vessel regeneration (6–9). In this issue of Diabetes , Albiero et al. (10) definitively demonstrate that despite low levels of expression of SGLT2 on hematopoietic cells, SGLT2 inhibition with dapagliflozin improved endothelial repair through enhanced recruitment of hematopoietic stem/progenitor cell (HSPC) progeny from the bone marrow (BM) to the site of vessel injury. In concept, circulating HSPC represent critical intermediates in blood vessel homeostasis via the coordination of angiogenic, arteriogenic, and vasculogenic processes (11). Seminal contributions by the Fadini group and others have previously established a significant depletion in circulating provascular HSPC during T2D, which contributes to …

1380-P: Pregravid A1C and Glucose Measurements to Rule Out Gestational Diabetes and Reduce the Need for Oral Glucose Tolerance Testing in Pregnancy

The recommendation of universal screening for gestational diabetes (GDM) by oral glucose tolerance test (OGTT) in pregnancy may pose a resource challenge for healthcare systems. In light of growing recognition that women who develop GDM have chronic metabolic dysfunction that predates their pregnancy, we hypothesized that pre-gravid measurement of A1c and glucose may provide the capacity to rule out GDM in low-risk women and thereby reduce the overall OGTT burden in pregnancy. To test this hypothesis, we identified all women in Ontario, Canada, with singleton live-birth pregnancies between January 2008 and December 2015 (n=1,001,006, of which 47,180 had GDM), and created derivation and validation cohorts (each n=500,503). In the derivation cohort, pre-gravid A1c (OR=9.72, 95%CI 8.76-10.79), fasting glucose (OR=3.32, 95%CI 3.13-3.51) and random glucose (OR=1.70, 95%CI 1.65-1.75) each predicted subsequent GDM. Area-under-receiver-operating-characteristic curve (AROC) was higher for A1c (0.684) than for fasting glucose (0.647) or random glucose (0.625). Test characteristics revealed that the negative predictive value (NPV) for ruling out GDM was optimized (NPV=98.7%) at pre-gravid A1c ≤4.3%. However, when evaluated in the validation cohort, this pre-gravid A1c threshold would only reduce the need for antepartum OGTT in 0.11% of women. Conversely, if test sensitivity for predicting GDM were set at 95.1% in the derivation cohort, the resultant threshold of pre-gravid A1c ≤5.0% would reduce the need for antepartum OGTT in 7.2% of women but at the cost of missing 2.5% of GDM diagnoses in the validation cohort. In conclusion, pre-gravid A1c and glucose levels can predict a woman’s future risk of GDM. However, their test characteristics are clinically not acceptable for reducing the need for GDM screening by OGTT in pregnancy. Disclosure R. Retnakaran: Consultant; Self; Eli Lilly and Company, Novo Nordisk Inc., Sanofi. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk Inc. B.R. Shah: None.

CSF1R inhibitor PLX5622 and environmental enrichment additively improve metabolic outcomes in middle-aged female mice.

As the elderly population grows, chronic metabolic dysfunction including obesity and diabetes are becoming increasingly common comorbidities. Hypothalamic inflammation through CNS resident microglia serves as a common pathway between developing obesity and developing systemic aging pathologies. Despite understanding aging as a life-long process involving interactions between individuals and their environment, limited studies address the dynamics of environment interactions with aging or aging therapeutics. We previously demonstrated environmental enrichment (EE) is an effective model for studying improved metabolic health and overall healthspan in mice, which acts through a brain-fat axis. Here we investigated the CSF1R inhibitor PLX5622 (PLX), which depletes microglia, and its effects on metabolic decline in aging in interaction with EE. PLX in combination with EE substantially improved metabolic outcomes in middle-aged female mice over PLX or EE alone. Chronic PLX treatment depleted 75% of microglia from the hypothalamus and reduced markers of inflammation without affecting brain-derived neurotrophic factor levels induced by EE. Adipose tissue remodeling and adipose tissue macrophage modulation were observed in response to CSF1R inhibition, which may contribute to the combined benefits seen in EE with PLX. Our study suggests benefits exist from combined drug and lifestyle interventions in aged animals.

HDAC3 inhibition prevents blood-brain barrier permeability through Nrf2 activation in type 2 diabetes male mice

BackgroundType 2 diabetes mellitus (T2DM) is a chronic metabolic dysfunction characterized by progressive insulin resistance and hyperglycaemia. Increased blood-brain barrier (BBB) permeability is a critical neurovascular complication of T2DM that adversely affects the central nervous system homeostasis and function. Histone deacetylase 3 (HDAC3) has been reported to be elevated in T2DM animals and may promote neuroinflammation; however, its involvement in the BBB permeability of T2DM has not been investigated. In this study, we tested our hypothesis that HDAC3 expression and activity are increased in the T2DM mouse brain. Inhibition of HDAC3 may ameliorate T2DM-induced BBB permeability through Nrf2 activation.MethodsT2DM (db/db, leptin receptor-deficient), genetic non-hyperglycemic control (db/+), and wild-type male mice at the age of 16 weeks were used in this study. HDAC3 expression and activity, Nrf2 activation, and BBB permeability and junction protein expression were examined. The effects of HDAC3 activity on BBB permeability were tested using highly selective HDAC3 inhibitor RGFP966. In primary cultured human brain microvascular endothelial cells (HBMEC), hyperglycemia (25 mM glucose) plus interleukin 1 beta (20 ng/ml) (HG-IL1β) served as T2DM insult in vitro. The effects of HDAC3 on transendothelial permeability were investigated by FITC-Dextran leakage and trans-endothelial electrical resistance, and the underlying molecular mechanisms were investigated using Western blot, q-PCR, co-immunoprecipitation, and immunocytochemistry for junction protein expression, miR-200a/Keap1/Nrf2 pathway regulation.ResultsHDAC3 expression and activity were significantly increased in the hippocampus and cortex of db/db mice. Specific HDAC3 inhibition significantly ameliorated BBB permeability and junction protein downregulation in db/db mice. In cultured HBMEC, HG-IL1β insult significantly increased transendothelial permeability and reduced junction protein expression. HDAC3 inhibition significantly attenuated the transendothelial permeability and junction protein downregulation. Moreover, we demonstrated the underlying mechanism was at least in part attributed by HDAC3 inhibition-mediated miR-200a/Keap1/Nrf2 signaling pathway and downstream targeting junction protein expression in T2DM db/db mice.ConclusionsOur experimental results show that HDAC3 might be a new therapeutic target for BBB damage in T2DM.

Adipose Tissue Hypoxia: Effects on Metabolism and Insulin Sensitivity

Obesity is associated with an increased risk of insulin resistance and type 2 diabetes. These risks have been correlated with a chronic inflammatory response of the adipose tissue that affects glucose and lipid metabolism. Hypoxia, stemming from inadequate adipose tissue blood flow in obesity, has been shown to be an important contributor to this inflammatory response. The response to hypoxia includes changes in gene expression that affect glucose uptake, glycolysis, lipid metabolism, inflammation, and angiogenesis. This review describes the effects of obesity on chronic and intermittent hypoxia in white adipose tissue and highlights the resulting effects on gene expression and cell metabolism that can affect the onset of systemic insulin resistance and the development of chronic metabolic dysfunction in type 2 diabetes.

Sustainable Three-Dimensional Tissue Model of Human Adipose Tissue

The need for physiologically relevant sustainable human adipose tissue models is crucial for understanding tissue development, disease progression, in vitro drug development and soft tissue regeneration. The coculture of adipocytes differentiated from human adipose-derived stem cells, with endothelial cells, on porous silk protein matrices for at least 6 months is reported, while maintaining adipose-like outcomes. Cultures were assessed for structure and morphology (Oil Red O content and CD31 expression), metabolic functions (leptin, glycerol production, gene expression for GLUT4, and PPARγ) and cell replication (DNA content). The cocultures maintained size and shape over this extended period in static cultures, while increasing in diameter by 12.5% in spinner flask culture. Spinner flask cultures yielded improved adipose tissue outcomes overall, based on structure and function, when compared to the static cultures. This work establishes a tissue model system that can be applied to the development of chronic metabolic dysfunction systems associated with human adipose tissue, such as obesity and diabetes, due to the long term sustainable functions demonstrated here.

Capacidade funcional em pacientes com diabetes mellitus no município de Matinhos, Paraná

O diabetes mellitus (DM) é decorrente de um inadequado funcionamento metabólico crônico, caracterizado por hiperglicemia com distúrbio dos carboidratos, gordura e metabolismo da proteína. O DM tem impacto substancial no perfil físico-funcional dos pacientes, entre os quais se destaca o teste de caminhada de seis minutos (TC6'). O objetivo do estudo foi analisar a capacidade funcional, por meio da distância percorrida no TC6', dos pacientes com DM tipo 1 (DM1) e 2 (DM2) cadastrados em Estratégias de Saúde da Família (ESFs) e Programas de Agentes Comunitários de Saúde (PACS) do município de Matinhos, Paraná. De 800 pacientes cadastrados nas ESF e PACS, foram contatados 497, e 153 participaram do estudo, sendo 1,30% com DM1 e 98,69% com DM2. Os avaliados tiveram média de 60,49±11,24 anos, a glicemia foi 173,18 mg/dL e as médias de massa corporal, estatura e índice de massa corpórea foram respectivamente: 76,69±14,07 kg, 1,62±0,08 m e 29,11±4,61 kg/m². Não houve correlação entre nível glicêmico e idade (r=0,023), entre idade e TC6' (r=-0,056), e nível glicêmico e TC6' (r=0,11). Observou-se que 28,10% apresentavam doença cardiovascular, 60,13% eram hipertensos e 16,99% tabagistas. O tratamento medicamentoso prevaleceu sobre os tratamentos dieta e exercício. Houve diferença estatística (p<0,0001) entre a distância prevista e a percorrida no TC6', indicando que os pacientes com DM não atingiram os níveis esperados neste teste. Seria necessário realizar um programa multidisciplinar direcionado a essa população, com ações em atividade física e dieta, com o intuito de minimizar os efeitos do DM sobre os aspectos funcionais desses pacientes.

Discordant white matter N-acetylasparate and diffusion MRI measures suggest that chronic metabolic dysfunction contributes to axonal pathology in multiple sclerosis

Diffusion MRI and magnetic resonance spectroscopic measurements of selectively neuronally localised N-acetylaspartate (NAA) both have been used widely to assess white matter integrity and axonal loss. We have tested directly the relationship between changes in diffusion MRI parameters and NAA concentrations in the corpus callosum (CC) in an in vivo study of patients with MS. Fifteen MS patients (median EDSS 2.5, range 1–4) were studied with T1 anatomical, T2-weighted, and diffusion-sensitised MRI and PRESS single-voxel MRS. A recently described method, tract-based spatial statistics (TBSS) [Smith, S.M., Jenkinson, M., Johansen-Berg, H., Rueckert, D., Nichols, T.E., Mackay, C.E. et al., 2006. Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage 31, 1487–1505] also was used to perform exploratory voxelwise whole-brain analysis of white matter diffusion fractional anisotropy (FA). We found a strong correlation between callosal size and both mean FA (r=0.68, p<0.005) (related specifically to changes in the radial tensor component) and mean inter-hemispheric motor tract connectivity probability (r=0.74, p<0.001). TBSS confirmed that the diffusion anisotropies of white matter voxels specifically within the callosum were correlated with the callosal size. Individual patient global T2 lesion volumes were correlated with both the probability of callosal connectivity (r=−0.69, p<0.005) and fractional anisotropy across the callosum (r=−0.76, p<0.001). However, absolute concentrations of NAA from the voxel showed no correlation with callosal cross-sectional area, mean connectivity or fractional anisotropy within the callosal pathway. We conclude that diffusion MRI shows changes consistent with sensitivity to axonal loss, but that relative NAA changes are not necessarily related directly to this. Axonal metabolic function, independent of structural integrity, may be a major determinant of NAA measures in MS.