Type 2 diabetes mellitus (T2DM) is characterized by tissue-specific insulin resistance and pancreatic β-cell dysfunction, which result from the interplay of local abnormalities within different tissues and systemic dysregulation of tissue crosstalk. The main local mechanisms comprise metabolic (lipid) signalling, altered mitochondrial metabolism with oxidative stress, endoplasmic reticulum stress and local inflammation. While the role of endocrine dysregulation in T2DM pathogenesis is well established, other forms of inter-organ crosstalk deserve closer investigation to better understand the multifactorial transition from normoglycaemia to hyperglycaemia. This narrative Review addresses the impact of certain tissue-specific messenger systems, such as metabolites, peptides and proteins and microRNAs, their secretion patterns and possible alternative transport mechanisms, such as extracellular vesicles (exosomes). The focus is on the effects of these messengers on distant organs during the development of T2DM and progression to its complications. Starting from the adipose tissue as a major organ relevant to T2DM pathophysiology, the discussion is expanded to other key tissues, such as skeletal muscle, liver, the endocrine pancreas and the intestine. Subsequently, this Review also sheds light on the potential of multimarker panels derived from these biomarkers and related multi-omics for the prediction of risk and progression of T2DM, novel diabetes mellitus subtypes and/or endotypes and T2DM-related complications. 

Inter-organ crosstalk during development and progression of type 2 diabetes mellitus.

Intermuscular adipose tissue in metabolic disease

Adipose tissue secretions are depot-specific and vary based on anatomical location. Considerable attention has been focused on visceral (VAT) and subcutaneous (SAT) adipose tissue with regards to metabolic disease, yet our knowledge of the secretome from these depots is incomplete. We conducted a comprehensive analysis of VAT and SAT secretomes in the context of metabolic function. Conditioned media generated using SAT and VAT explants from individuals with obesity was analyzed using proteomics, mass spectrometry, and multiplex assays. Conditioned media was administered in vitro to rat hepatocytes and myotubes to assess the functional impact of adipose tissue signaling on insulin responsiveness. VAT secreted more cytokines (IL-12p70, IL-13, TNF-α, IL-6 and IL-8), adipokines (MCP-1, PAI-1), and prostanoids (TBX2, PGE2) compared to SAT. Secretome proteomics revealed differences in immune/inflammatory response and extracellular matrix components. In vitro, VAT conditioned media decreased hepatocyte and myotube insulin sensitivity, hepatocyte glucose handling, and increased basal activation of inflammatory signaling in myotubes compared to SAT. Depot-specific differences in adipose tissue secretome composition alter paracrine and endocrine signaling. The unique secretome of VAT has distinct and negative impact on hepatocyte and muscle insulin action.

Exploring visceral and subcutaneous adipose tissue secretomes in human obesity: implications for metabolic disease.

Inflammation is part of the body's innate immune response and is an essential process that not only defends against harmful bacteria and pathogens but also plays a key role in the maintenance and repair of tissues. Under pathological conditions, there is bilateral crosstalk between immune regulation and aberrant metabolism resulting in persistent inflammation in the absence of infection. This phenomenon is referred to as sterile metabolic inflammation (metainflammation) and occurs if the initiating stimulus is not removed or if the resolution process is disrupted. Disruption of this tightly regulated immune response and its failure to resolve as is evident in metabolic disorders and is not only associated with disease progression but also leads to immune senescence and should not be neglected in the clinical management of patients. This review gives an overview of the mechanisms underlying chronic metabolic inflammation, the aberrant metabolic activation of innate immune cells (neutrophils, macrophages, mast cells, dendritic cells) and its role in disease progression using obesity-diabetes as a prime example. Addressing the underlying subclinical metabolic inflammation in addition to achieving glucose control may contribute significantly towards therapeutic interventions aimed at preventing the onset of co-morbidities in diabetic patients.

Immunology of chronic low-grade inflammation: relationship with metabolic function.

Adipose tissue secretes an abundance of lipid and protein mediators, and this secretome is depot‐specific, with local and systemic effects on metabolic regulation. Intermuscular adipose tissue (IMAT) accumulates within the skeletal muscle compartment in obesity, and is associated with insulin resistance and metabolic disease. While the human IMAT secretome decreases insulin sensitivity in vitro, its composition is entirely unknown. The current study was conducted to investigate the composition of the human IMAT secretome, compared to that of the subcutaneous (SAT) and visceral adipose tissue (VAT) depots. IMAT, SAT, and VAT explants from individuals with obesity were used to generate conditioned media. Proteomics analysis of conditioned media was performed using multiplex proximity extension assays, and eicosanoid analysis using liquid chromatography–tandem mass spectrometry. Compared to SAT and/or VAT, IMAT secreted significantly more cytokines (IL2, IL5, IL10, IL13, IL27, FGF23, IFNγ and CSF1) and chemokines (MCP1, IL8, CCL11, CCL20, CCL25 and CCL27). Adipokines hepatocyte growth factor and resistin were secreted significantly more by IMAT than SAT or VAT. IMAT secreted significantly more eicosanoids (PGE2, TXB2, 5‐HETE, and 12‐HETE) compared to SAT and/or VAT. In the context of obesity, IMAT is a distinct adipose tissue with a highly immunogenic and inflammatory secretome, and given its proximity to skeletal muscle, may be critical to glucose regulation and insulin resistance.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.14814/phy2.15424

Quantifying the inflammatory secretome of human intermuscular adipose tissue

Glycerol is a substrate for gluconeogenesis and fatty acid esterification in the liver, processes which are upregulated in obesity and may contribute to excess fat accumulation. Glycine and glutamate, in addition to cysteine, are components of glutathione, the major antioxidant in the liver. In principle, glycerol could be incorporated into glutathione via the TCA cycle or 3-phosphoglycerate, but it is unknown whether glycerol contributes to hepatic de novo glutathione biosynthesis.Glycerol metabolism to hepatic metabolic products including glutathione was examined in the liver from adolescents undergoing bariatric surgery. Participants received oral [U-13C3]glycerol (50 mg/kg) prior to surgery and liver tissue (0.2-0.7g) was obtained during surgery. Glutathione, amino acids, and other water-soluble metabolites were extracted from the liver tissue and isotopomers were quantified with nuclear magnetic resonance spectroscopy.Data were collected from 8 participants (2 male, 6 female; age 17.1 years [range 14-19]; BMI 47.4 kg/m2 [range 41.3-63.3]). The concentrations of free glutamate, cysteine, and glycine were similar among participants, and so were the fractions of 13C-labeled glutamate and glycine derived from [U-13C3]glycerol. The signals from all component amino acids of glutathione - glutamate, cysteine and glycine - were strong and analyzed to obtain the relative concentrations of the antioxidant in the liver. The signals from glutathione containing [13C2]glycine or [13C2]glutamate derived from the [U-13C3]glycerol drink were readily detected, and 13C-labelling patterns in the moieties were consistent with the patterns in corresponding free amino acids from the de novo glutathione synthesis pathway. The newly synthesized glutathione with [U-13C3]glycerol trended to be lower in obese adolescents with liver pathology.This is the first report of glycerol incorporation into glutathione through glycine or glutamate metabolism in human liver. This could represent a compensatory mechanism to increase glutathione in the setting of excess glycerol delivery to the liver. 

https://doi.org/10.1016/j.redox.2023.102749

Glycerol as a precursor for hepatic de novo glutathione synthesis in human liver

Abstract Disclosure: E. Finn: None. K.N. Fuller: None. L.A. Knaub: None. Y. Garcia Reyes: None. S.C. Derderian: None. J. Schoen: None. T. Inge: None. J.E. Reusch: Advisory Board Member; Self; Medtronic Diabetes. K. Nadeau: None. M. Cree: None. Introduction: The severity of metabolic disease in youth with obesity is varied and determinants of disease progression are not known. Non-alcoholic fatty liver disease appears to be central to the development of cardiometabolic disease in youth with severe obesity. We tested the hypothesis that hepatic mitochondrial respiratory capacity would correlate with cardiometabolic measures in youth with severe obesity and a range of glycemia. Methods: Adolescents with severe obesity and a range of dysglycemia undergoing bariatric surgery were enrolled. Participants underwent anthropomorphic assessments, fasting labs, and a 4-hour mixed meal tolerance test (MMTT, 45 g carbs, 14 g protein, and 14 g fat) over 30 minutes followed by serial measures of glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), and free fatty acids. Liver biopsies obtained at time of vertical sleeve gastrectomy surgery were analyzed for mitochondrial respiration. Permeabilized liver tissue was assessed for mitochondrial oxygen consumption by respirometry (Oxygraph-2k, OROBOROS) under both pyruvate (carbohydrate) and palmitoyl-carnitine (lipids) substrate conditions. Results: Fifteen youth with severe obesity (female=60%, mean age 16.9 ± 1.5 years, mean BMI 47.4 ± 7.2 kg/m2) were enrolled. Lower hepatic carbohydrate-supported respiration relates to higher serum glucose concentrations throughout the 4-hr MMTT (P=< 0.001 to 0.05) as well as higher fasting serum triglycerides (p =<0.001-0.05). Lower liver lipid-supported respiration is associated with higher C-peptide levels (p =0.001-0.01) throughout MMTT, increased Matsuda Index (p =0.001-0.05), and higher fasting hepatic transaminases, alanine aminotransferase (p =0.006-0.04), aspartame aminotransferase (p =0.007-0.02), and gamma-glutamyl transferase (p =0.01-0.03). Insulin, GLP-1, and free fatty acids are not correlated with mitochondrial respiration. Conclusion: Consistent with findings in adults and animals, youth with severe obesity have lower hepatic mitochondrial respiration which correlates with markers of poorer cardiometabolic health including higher triglycerides, higher glucose concentraions, lower insulin sensitivity, higher insulin secretion (C-peptide), and higher liver transaminases. Based on these findings, dysregulated hepatic mitochondrial respiration should be further explored as a possible contributor to the development of early liver disease and glucose dysregulation. Presentation: Friday, June 16, 2023

OR15-03 Lower Hepatic Mitochondrial Respiration Relates To Dysmetabolism In Adolescents With Severe Obesity

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Exploring visceral and subcutaneous adipose tissue secretomes in human obesity: implications for metabolic disease.

Quantifying the inflammatory secretome of human intermuscular adipose tissue

Glycerol as a precursor for hepatic de novo glutathione synthesis in human liver

OR15-03 Lower Hepatic Mitochondrial Respiration Relates To Dysmetabolism In Adolescents With Severe Obesity