Submitted Successfully!
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Ver. Summary Created by Modification Content Size Created at Operation
1 -- 2395 2023-07-10 12:28:50 |
2 format correction Meta information modification 2395 2023-07-12 02:27:35 |

Video Upload Options

Do you have a full video?


Are you sure to Delete?
If you have any further questions, please contact Encyclopedia Editorial Office.
Ciarambino, T.; Crispino, P.; Leto, G.; Minervini, G.; Para, O.; Giordano, M. Microbiota and Glucidic Metabolism. Encyclopedia. Available online: (accessed on 07 December 2023).
Ciarambino T, Crispino P, Leto G, Minervini G, Para O, Giordano M. Microbiota and Glucidic Metabolism. Encyclopedia. Available at: Accessed December 07, 2023.
Ciarambino, Tiziana, Pietro Crispino, Gaetano Leto, Giovanni Minervini, Ombretta Para, Mauro Giordano. "Microbiota and Glucidic Metabolism" Encyclopedia, (accessed December 07, 2023).
Ciarambino, T., Crispino, P., Leto, G., Minervini, G., Para, O., & Giordano, M.(2023, July 10). Microbiota and Glucidic Metabolism. In Encyclopedia.
Ciarambino, Tiziana, et al. "Microbiota and Glucidic Metabolism." Encyclopedia. Web. 10 July, 2023.
Microbiota and Glucidic Metabolism

The global prevalence of overweight and obesity has dramatically increased in the last few decades, with a significant socioeconomic burden. 

diabetes insulin resistance microbiota differences

1. Introduction

From an epidemiological point of view, the pathological conditions related to overweight and obesity are constantly increasing in all geographical areas, with socio-economic repercussions terms of mortality related to diseases such as dyslipidemia, hypertension, and type 2 diabetes mellitus (T2D) [1][2]. In particular, so-called acquired diabetes mellitus or T2D originates in the persistence of high daily glucose levels compared to normal values, due to the resistance of the target tissues to the effect of insulin [3][4]. The pathogenesis of polyfactorial diabetes depends on the mechanisms that determine peripheral insulin resistance, as well as on the distribution of body fat, particularly central body fat, which is correlated more strongly with the metabolic syndrome (MetS) as it actively enters glucose homeostasis, the progressive dysfunction of the pancreatic beta cells [5][6]. Furthermore, there are connections between the metabolic alterations between pancreatic function and hepatic function that are not fully understood, as well as the mechanisms that determine insulin resistance in other peripheral tissues, including skeletal muscle and adipose tissue. The complexity of this relationship between the various organs united by their sensitivity to insulin should favor correct glucose metabolism [7]. From a pathological point of view, however, the first phases of the development of D2T are linked to gradual and progressive insulin resistance, and occur in parallel with the hyperfunction of the pancreatic beta cells, which, in an attempt to compensate for the reduction in the effect of insulin on peripheral tissues, increases their production. Subsequently, however, with the loss of the insulin reserve, the individual reaches the stage of full-blown diabetes and, therefore, a greater risk of organ damage [8][9]. Diabetes, however, should not be considered only a metabolic condition with a relative loss of insulin function; it largely owes its genesis to a low-grade local chronic inflammatory state (meta-inflammation), which is linked to the production and release of multiple inflammatory cytokines, such as interleukins and tumor necrosis factor [10]. Many inflammatory markers have been related to obesity and a large study demonstrated the existence of a link between body composition and systemic inflammatory markers [11]. Other studies have supported similar claims regarding the erythrocyte sedimentation rate [12], plasminogen-activator inhibitor 1 [13], and some inflammatory cytokines [14][15], reinforcing the role of the interaction between inflammation and glucose metabolism. It remains to be established how meta-inflammation influences glucose metabolism and, recently, the answer was complicated by the knowledge obtained from the study of the functions of the human intestinal microbiota. The intestinal microbiota has a symbiotic relationship with the host by acting as a driver of inflammation by mediating the absorption of certain nutrients, which then contributes to metabolic pathologies [16][17]. Evidence of this role of the intestinal microbiota is contained in several studies in which obesity and T2D are associated with alterations in the intestinal microbiota [18][19][20]. At the intestinal level, the microbiota produces a series of metabolites, such as short-chain fatty acids (SCFA), increases the biosynthesis of vitamins and amino acids, and participates in the turnover of bile acids, as well as cell–cell interaction with the other components of the host [21]. Therefore, the balance in the cellular composition of the intestinal microbiota plays an important role in the host’s metabolism and the development of insulin resistance and T2D obesity (Figure 1); on the other hand, the relationships with the main cells of the immune system also change, at the level of the intestinal wall.
Figure 1. Gut microbiome and metabolism.

2. Visceral Adipose Tissue—Beta-Cell Interaction

Visceral adipose tissue has long been recognized as having a key role in the onset and maintenance of insulin resistance, beta-cell dysfunction, and increases in cardiovascular risk [22], because the adipocytes organized together in the fat deposits of the human body are considered metabolically active cells, capable of influencing the activity of beta cells in the production of insulin, causing the release of adipokines in connection with the presence of an inflammatory state, resulting in lipotoxicity.
Adipose tissue represents a real endocrine gland, and it is an important source of bioactive hormones, which are key factors in beta-cell function and impairment.
Leptin exerts direct effects on pancreatic beta cells, stimulating the Janus-kinase (JAK)/signal transducer of activation (STAT)—the mitogen-activated protein kinase (MAPK) signaling pathway [23]. This adipokine prevents apoptosis and beta-cell dysfunction [24][25].
In addition, leptin can alter beta-cell function and induce apoptosis by stimulating the release of interleukin-1b (IL-1b), inhibiting the expression of the IL-1-receptor antagonist [26], and activating c-Jun N-terminal kinase (JNK) [27]. Other adipokines have also been related to protective and anti-apoptotic effects on beta cells. For example, low levels of adiponectin have been associated with insulin resistance and beta-cell dysfunction [28]. Furthermore, adipsin [29], visfatin [30], irisin [31], omentin [32], and apelin [33] have been shown to have a protective effect on beta cells. On the other hand, some adipokines have a negative impact on pancreatic beta cells. Thus, resistin both induces insulin resistance and impairs insulin secretion in pancreatic beta cells [34], as well as tumor necrosis factor α (TNF-α) [35] and fetuin-A [36]. The novel adipokines asprosin and retinol-binding protein 4 (RBP4) were reported as important features of the pathophysiology of T2D and beta-cell dysfunction in preclinical studies and animal models [37][38].
In addition, visceral adipose tissue is able to release free fatty acids (FFA) into the circulation through the mechanism of lipolysis. These FFAs are important sources of energy during fasting [39]. However, chronically elevated levels of FFAs inhibit glucose-stimulated insulin secretion and lead to beta-cell dysfunction by activating specific signaling pathways involved in glucose metabolism, insulin resistance, and beta-cell function [40] through cytotoxic mechanisms, causing beta-cell apoptosis [41][42].
As mentioned above, diabetes is characterized by a state of chronic low-grade metabolic inflammation (local and systemic), also called meta-inflammation, which has been shown to contribute to the development of insulin resistance and progression to T2D and is characterized by the abnormal expression and production of multiple inflammatory cytokines, such as interleukins [10].
Visceral adipose tissue, through the production of several cytokines and proinflammatory factors such as IL-2, IL-6, IL-8, IL-12A, or monocyte chemoattractant protein-1 (MCP-1), can play a key role in the alteration of beta-cell function [43][44].
Specifically, peripancreatic adipose tissue, due to its close proximity to the islets of Langerhans, is implicated in beta-cell dysfunction through paracrine mechanisms. The most important mediators of this interaction include several factors, such as the chemokine (C-X-Cmotif) ligands (CXCLs)-1, -2, -3, and the induction of the CXCL-5/lipopolysaccharide CXC chemokine by (LIX), which act on the CXC receptor 2 [45].
Activated macrophages infiltrating adipose tissue [46][47] and inflamed adipocytes can also lead to harmful effects and induce beta-cell death [48].
Finally, B2 lymphocytes, adipose-resident immune cells, adipocyte mitochondrial dysfunction, and reactive oxygen species (ROS) can increase insulin resistance [49] and contribute to beta-cell impairment [50].

3. Gut Microbiome and Metabolism

3.1. Inflammation and Insulin Resistance

The human gastrointestinal tract contains a complex community of trillions of microbe, collectively known as the gut microbiome. These microbes carry out important physiological functions, such as nutrient metabolism, energy harvest, the regulation of immunity, and the maintenance of mucosal defense. Mounting evidence suggests a causal link between altered gut microbiome composition, known as gut dysbiosis, and the development of human diseases such as adipose-tissue dysfunction and insulin resistance/T2D [20][51]. A mild inflammatory state is usually sustained by an increase in circulating pro-inflammatory cytokines in patients with metabolic syndrome, eliciting metabolic effects such as insulin resistance and glucose intolerance; this occurs more frequently in the course of bacterial infections or chronic inflammation of the upper airways [52][53][54]. Results derived from animal and human models have demonstrated that experimental pharmacological treatments obtained from the activity of E. Coli, with anti-inflammatory effects, had positive effects on glucose tolerance [55][56][57][58]. Other anti-inflammatory cytokines, such as IL-4 can increase glucose tolerance and inhibit adipogenesis and macrophage activation [59][60]. The cytokine IL-13 encourages macrophage-alternative activation [61]. Experimentally, it has been shown that both cytokines are elevated in obese and sedentary people, as well as in those with high insulin resistance [62][63]. This anti-inflammatory activity appears to be thwarted by the refractoriness of the receptor of these interleukins, which is frequently found in patients with metabolic syndrome [51]. In adipose tissue, there are two major populations of the macrophages M1, classically activated macrophages, and M2, alternatively activated macrophages. In obese patients, M1-macrophage numbers increase and are correlated with adipose-tissue inflammation and insulin resistance. In contrast, M2 macrophages exert anti-inflammatory effects and utilize oxidative metabolism to maintain adipose-tissue homeostasis. The M1 macrophages are generally responsible for the secretion of pro-inflammatory cytokines and are associated with the development of type II diabetes by altering local and distant tissue functions. Some cytokines can attract immune cells to metabolically active tissues, such as monocyte chemoattractant protein-1 (MCP1), which is increased in the adipose tissues of obese individuals and induces insulin resistance [64][65][66][67].
Therefore, insulin resistance is the determinant event in a chronic inflammatory state that mainly involves the participation of macrophages, which, at the same time, contribute to the development of diabetes [68]. Confirming the role of macrophages in diabetes mellitus, it was observed that the gradual decrease in the functional reserve of beta cells at the level of the pancreatic islets is driven precisely by an inflammatory infiltrate with a prevalent monocyte–macrophage component [69][70][71]. On the other hand, it was shown that by attenuating the intensity of the inflammatory response, with the use of an IL-1 receptor antagonist, there was an improvement in the inflammatory infiltrate affecting the pancreatic islets, improved preservation of beta-cell junctions and, therefore, less insulin resistance [56]. Macrophages also play a crucial role in causing inflammation in the liver during obesity [72]. The pro-inflammatory role of macrophages has not only been demonstrated in the pancreatic islets, but also in other organs involved in glucose metabolism, such as the liver. In fact, the presence of an inflammatory infiltrate specifically linked to the pro-inflammatory activity of the macrophages encourages damage to hepatocytes, causing insulin resistance, hepatic steatosis, and type 2 diabetes [73]. In this process, the role played by macrophages in hepatocytes is not only inflammatory, but also metabolic, as they are also capable of producing insulin-like growth-factor-binding protein 7 (IGFBP7), which competes directly with the insulin receptor, compromising the signal transduction coupled to this receptor [74]. All this suggests that the immune system is involved in the proper functioning of glucose metabolism and, therefore, the pathological conditions related to it. This demonstrates that the chronic low-grade inflammation observed in obesity and type 2 diabetes has harmful consequences for human metabolism and acute inflammatory responses to pathogens further worsen insulin resistance and glycemic control.

3.2. Gut Permeability and Insulin Resistance

Inflammation is a biological response of the immune system, which can be triggered by exposure to pathogens. In particular, bacterial components, such as lipopolysaccharides (LPSs), are sources of metabolic inflammation, as LPS has been found to be increased in the circulation of people with diabetes [75]. The LPSs use increased intestinal permeability to enter the circulation [76]. This not only results in a systemic inflammatory response, but also influences glucose-tolerance mechanisms by inducing hepatic insulin resistance and impairing glucose-stimulated insulin secretion [77]. Two phenomena have been observed in the course of acute inflammation: “metabolic endotoxemia” and “postprandial inflammation” [78][79]. The former is an inflammatory response to increased systemic LPS levels due to a “leaky gut” [77]. Postprandial inflammation is instead the increase in circulating endotoxins and other inflammatory markers after meals, especially high-fat meals [80][81][82][83][84].

3.3. Intestinal Microbiota in Metabolic Diseases

The intestinal microbiota plays a key role in digestion, in the production of metabolites potentially capable of altering human metabolism, and in the development of the immune system; the latter in particular is involved in the genesis, of obesity and type 2 diabetes, as well as predisposing individuals to these conditions [85].
An interesting explanation for the involvement of the intestinal microbiota in the genesis of T2D is given in a recent review [86], which indicates how the bacterial composition plays an important role in the genesis of metabolic diseases through sedentary lifestyles and high-fat diets. The key point is that the development of T2D is a multistep process starting from obesity. In this phase, a diet rich in certain foods, such as fats, tends to shift the balance of the microbiome towards dysbiosis and, therefore, to an increase in insulin resistance and inflammation, which, as stated above, are the two factors determining T2D.
The action elicited by various bacterial species belonging to the intestinal saprophytic flora is to continuously stimulate the biological reactivity of the intestine-associated lymphoid tissues (GALT), stimulating the production of immunoglobulins and their macrophagic activity [87]. This dynamic relationship with the immune system results in an increase in microbial metabolites, such as short-chain fatty acids (SCFAs) or components such as DNA and polysaccharide A (PSA) [51]. In general, there is currently no definition of a “healthy gut microbiota.” Studies deriving from mouse models have shown that mice deprived of intestinal germs showed themselves to be free from obesity despite being subjected to a caloric diet, while, in contrast to this, the introduction of bacterial species related to obesity such as those of the Bacteroides class led to weight gain, and reduced glucose tolerance increased insulin resistance, leading to the accumulation of adipose tissues and a greater acceleration of the atherosclerotic process [88][89][90]. These studies suggest that the transfer of a microbiota related to an obese phenotype in a bacteria-free subject leads to the acquisition of an obese phenotype; therefore there is a causal relationship between the intestinal microbiota and metabolism. Since there is no definition of a healthy microbiota, it is possible to associate some pathologies, such as glucose metabolism disorders, with increases in less beneficial species, such as Bacteroides, or with a loss of diversity among the various species with the expansion of microorganisms that are usually underrepresented (often opportunistic pathogens) [18][91][92]. Diet, lifestyle, and antibiotic use have been identified as triggering events for these changes [93][94]. In the case of type 2 diabetes, an increase in the pro-inflammatory bacterial tiller type was found at the expense of anti-inflammatory bacteria in T2D [18][91][92]. Thus, an increase in all these pro-inflammatory Gram-negative bacterial species could be a plausible source of the meta-inflammation observed in metabolic diseases [95]. The beneficial effects of a saprophytic and balanced bacterial flora are essentially linked to the production of SCFAs [18]. These are derived from the microbial degradation of fibers, and they exert several beneficial effects on host metabolism. In diabetes, SCFA production is reduced [18][96]. A recent study found a causal relationship between a genetic increase in butyrate production and improved insulin response [97].


  1. GBD2015 Obesity Collaborators; Afshin, A.; Forouzanfar, M.H.; Reitsma, M.B.; Sur, P.; Estep, K. Health Effects of Overweight and Obesity in 195 Countries Over 25 Years. N. Engl. J. Med. 2017, 377, 13–27.
  2. Saeedi, P.; Petersohn, I.; Salpea, P.; Malanda, B.; Karuranga, S.; Unwin, N.; Colagiuri, S.; Guariguata, L.; Motala, A.A.; Ogurtsova, K.; et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res. Clin. Pract. 2019, 157, 107843.
  3. Lin, Y.; Sun, Z. Current views on type 2 diabetes. J. Endocrinol. 2010, 204, 1.
  4. Vu, B.G.; Stach, C.S.; Kulhankova, K.; Salgado-Pabòn, W.; Klingelhutz, A.J.; Schlievert, P.M. Chronic superantigen exposure induces systemic inflammation, elevated bloodstream endotoxin, and abnormal glucose tolerance in rabbits: Possible role in diabetes. MBio 2015, 6, e02554-14.
  5. Eizirik, D.L.; Pasquali, L.; Cnop, M. Pancreatic b-Cells in Type 1 and Type 2 Diabetes Mellitus: Different Pathways to Failure. Nat. Rev. Endocrinol. 2020, 16, 349–362.
  6. Gastaldelli, A.; Miyazaki, Y.; Pettiti, M.; Matsuda, M.; Mahankali, S.; Santini, E.; DeFronzo, R.A.; Ferrannini, E. Metabolic Effects of Visceral Fat Accumulation in Type 2 Diabetes. J. Clin. Endocrinol. Metab. 2002, 87, 5098–5103.
  7. Morigny, P.; Houssier, M.; Mouise, L.E.; Langin, D. Adipocyte lipolysis and insulin resistance. Biochimie 2016, 125, 259–266.
  8. DeFronzo, R.A. From the triumvirate to the ominous octet: A new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009, 58, 773–795.
  9. Heine, R.J.; Diamant, M.; Mbanya, J.C.; Nathan, D.M. Management of hyperglycemia in type 2 diabetes: The end of recurrent failure? BMJ 2006, 333, 1200–1204.
  10. Dandona, P.; Aljada, A.; Bandyopadhyay, A. Inflammation: The link between insulin resistance, obesity, and diabetes. Trends Immunol. 2004, 25, 4–7.
  11. Choi, J.; Joseph, L.; Pilote, L. Obesity and C-reactive protein in various populations: A systematic review and meta-analysis. Obes. Rev. 2013, 14, 232–244.
  12. De Rooij, S.R.; Nijpels, G.; Nilsson, P.M.; Nolan, J.J.; Gabriel, R.; Bobbioni-Harsch, E.; Mingrone, G.; Dekker, J.M.; Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) Investigators. Low-grade chronic inflammation in the relationship between insulin sensitivity and cardiovascular disease (RISC) population: Associations with insulin resistance and cardiometabolic risk profile. Diabetes Care 2009, 32, 1295–1301.
  13. Mavri, A.; Alessi, M.C.; Geel-Georgelin, O.; Fina, F.; Sentocnik, J.T.; Bastelica, D.; Stegnar, M.; Juhan-Vague, I. Subcutaneous abdominal, but not femoral fat expression of plasminogen activator inhibitor-1 (PAI-1) is related to plasma PAI-1 levels and insulin resistance and decreases after weight loss. Diabetologia 2001, 44, 2025–2031.
  14. Bahceci, M.; Gokalp, D.; Bahceci, S.; Tuzcu, A.; Atmaca, S.; Arikan, S. The correlation between adiposity and adiponectin, tumor necrosis factor-α, interleukin-6 and high sensitivity C-reactive protein levels. Is adipocyte size associated with inflammation in adults? J. Endocrinol. Investig. 2007, 30, 210–214.
  15. Marques-Vidal, P.; Bochud, M.; Bastardot, F. Association between inflammatory and obesity markers in a Swiss population-based sample (Co Laus Study). Obes. Facts 2012, 5, 734–744.
  16. Fan, Y.; Pedersen, O. Gut Microbiota in Human Metabolic Health and Disease. Nat. Rev. Microbiol. 2021, 19, 55–71.
  17. Lloyd-Price, J.; Abu-Ali, G.; Huttenhower, C. The Healthy Human Microbiome. Genome Med. 2016, 8, 51.
  18. Qin, J.; Li, Y.; Cai, Z.; Li, S.; Zhu, J.; Zhang, F.; Liang, S.; Zhang, W.; Guan, Y.; Shen, D.; et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 2012, 490, 55–60.
  19. Karlsson, F.H.; Tremaroli, V.; Nookaew, I.; Bergstrom, G.; Behre, C.J.; Fagerberg, B.; Nielsen, J.; Bäckhed, F. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 2013, 498, 99–103.
  20. Le Chatelier, E.; Nielsen, T.; Qin, J.; Prifti, E.; Hildebrand, F.; Falony, G.; Almeida, M.; Arumugam, M.; Batto, J.-M.; Kennedy, S.; et al. Richness of human gut microbiome correlates with metabolic markers. Nature 2013, 500, 541–546.
  21. Almeida, M.; Arumugam, M.; Batto, J.-M.; Kennedy, S. Inflammatory cytokines and the risk to develop type 2 diabetes. Diabetes 2003, 52, 812.
  22. Livingston, E.H. Lower Body Subcutaneous Fat Accumulation and Diabetes Mellitus Risk. Surg. Obes. Relat. Dis. 2006, 2, 362–368.
  23. Frühbeck, G. Intracellular Signalling Pathways Activated by Leptin. Biochem. J. 2006, 393, 7–20.
  24. Brown, J.E.P.; Dunmore, S.J. Leptin Decreases Apoptosis and Alters BCL-2: Bax Ratio in Clonal Rodent Pancreatic Beta-Cells. Diabetes Metab. Res. Rev. 2007, 23, 497–502.
  25. Lee, Y.; Magkos, F.; Mantzoros, C.S.; Kang, E.S. Effects of Leptin and Adiponectin on Pancreatic b-Cell Function. Metabolism 2011, 60, 1664–1672.
  26. Maedler, K.; Sergeev, P.; Ehses, J.A.; Mathe, Z.; Bosco, D.; Berney, T.; Dayer, J.M.; Reinecke, M.; Halban, P.A.; Donath, M.Y. Leptin Modulates β Cell Expression of IL-1 Receptor Antagonist and Release of IL-1β in Human Islets. Proc. Natl. Acad. Sci. USA 2004, 101, 8138–8143.
  27. Maedler, K.; Schulthess, F.T.; Bielman, C.; Berney, T.; Bonny, C.; Prentki, M.; Donath, M.Y.; Roduit, R. Glucose and leptin induce apoptosis in human β-cells and impair glucose-stimulated insulin secretion through activation of c-Jun N-terminal kinases. FASEB J. 2008, 22, 1905–1913.
  28. Bacha, F.; Saad, R.; Gungor, N.; Arslanian, S.A. Adiponectin in Youth: Relationship to visceral Adiposity, Insulin Sensitivity, and Beta-Cell Function. Diabetes Care 2004, 27, 547–552.
  29. Lo, J.C.; Ljubicic, S.; Leibiger, B.; Kern, M.; Leibiger, I.B.; Moede, T.; Kelly, M.E.; Bhowmick, D.C.; Murano, I.; Cohen, P.; et al. Adipsin Is an Adipokine That Improves β Cell Function in Diabetes. Cell 2014, 158, 41–53.
  30. Cheng, Q.; Dong, W.; Qian, L.; Wu, J.; Peng, Y. Visfatin Inhibits Apoptosis of Pancreatic b-Cell Line, MIN6, via the Mitogen-Activated Protein Kinase/Phosphoinositide 3-Kinase Pathway. J. Mol. Endocrinol. 2011, 47, 13–21.
  31. Zhang, D.; Xie, T.; Leung, P.S. Irisin Ameliorates Glucolipotoxicity-Associated b-Cell Dysfunction and Apoptosis via AMPK Signaling and Anti-Inflammatory Actions. Cell. Physiol. Biochem. 2018, 51, 924–937.
  32. Pan, X.; Kaminga, A.C.; Wen, S.W.; Acheampong, K.; Liu, A. Omentin-1 in Diabetes Mellitus: A Systematic Review and Meta-Analysis. PLoS ONE 2019, 14, e0226292.
  33. Feng, J.; Zhao, H.; Du, M.; Wu, X. The Effect of Apelin-13 on Pancreatic Islet Beta Cell Mass and Myocardial Fatty Acid and Glucose Metabolism of Experimental Type 2 Diabetic Rats. Peptides 2019, 114, 1–7.
  34. Nakata, M.; Okada, T.; Ozawa, K.; Yada, T. Resistin Induces Insulin Resistance in Pancreatic Islets to Impair Glucose-Induced Insulin Release. Biochem. Biophys. Res. Commun. 2007, 353, 1046–1051.
  35. Parkash, J.; Chaudhry, M.A.; Rhoten, W.B. Tumor Necrosis Factor-α-Induced Changes in Insulin-Producing β-Cells. Anat. Rec. Part A 2005, 286, 982–993.
  36. Shen, X.; Yang, L.; Yan, S.; Zheng, H.; Liang, L.; Cai, X.; Liao, M. Fetuin A Promotes Lipotoxicity in β Cells through the TLR4 Signaling Pathway and the Role of Pioglitazone in Anti-Lipotoxicity. Mol. Cell. Endocrinol. 2015, 412, 1–11.
  37. Wang, R.; Hu, W. Asprosin Promotes b-Cell Apoptosis by Inhibiting the Autophagy of b-Cell via AMP K-mTOR Pathway. J. Cell. Physiol. 2021, 236, 215–221.
  38. Huang, R.; Bai, X.; Li, X.; Wang, X.; Zhao, L. Retinol-Binding Protein 4 Activates STRA6, Provoking Pancreatic b-Cell Dysfunction in Type 2 Diabetes. Diabetes 2021, 70, 449–463.
  39. Lafontan, M.; Langin, D. Lipolysis and Lipid Mobilization in Human Adipose Tissue. Prog. Lipid Res. 2009, 48, 275–297.
  40. Boden, G. Effects of Free Fatty Acids (FFA) on Glucose Metabolism: Significance for Insulin Resistance and Type 2 Diabetes. Exp. Clin. Endocrinol. Diabetes 2003, 111, 121–124.
  41. Eitel, K.; Staiger, H.; Rieger, J.; Mischak, H.; Brandhorst, H.; Brendel, M.D.; Bretzel, R.G.; Häring, H.U.; Kellerer, M. Protein Kinase C δ Activation and Translocation to the Nucleus Are Required for Fatty Acid-Induced Apoptosis of Insulin-Secreting Cells. Diabetes 2003, 52, 991–997.
  42. El-Assaad, W.; Buteau, J.; Peyot, M.L.; Nolan, C.; Roduit, R.; Hardy, S.; Joly, E.; Dbaibo, G.; Rosenberg, L.; Prentki, M. Saturated Fatty Acids Synergize with Elevated Glucose to Cause Pancreatic β-Cell Death. Endocrinology 2003, 144, 4154–4163.
  43. Kochumon, S.; Al Madhoun, A.; Al-Rashed, F.; Thomas, R.; Sindhu, S.; Al-Ozairi, E.; Al-Mulla, F.; Ahmad, R. Elevated Adipose Tissue Associated IL-2 Expression in Obesity Correlates with Metabolic Inflammation and Insulin Resistance. Sci. Rep. 2020, 10, 163–164.
  44. Daniele, G.; Guardado Mendoza, R.; Winnier, D.; Fiorentino, T.V.; Pengou, Z.; Cornell, J.; Andreozzi, F.; Jenkinson, C.; Cersosimo, E.; Federici, M.; et al. The Inflammatory Status Score Including IL-6, TNF-α, Osteopontin, Fractalkine, MCP-1 and Adiponectin Underlies Whole-Body Insulin Resistance and Hyperglycemia in Type 2 Diabetes Mellitus. Acta Diabetol. 2014, 51, 123–131.
  45. Rebuffat, S.A.; Sidot, E.; Guzman, C.; Azay-Milhau, J.; Jover, B.; Lajoix, A.-D.; Peraldi-Roux, S. Adipose Tissue Derived-Factors Impaired Pancreatic β-Cell Function in Diabetes. Biochim. Biophys. Acta Mol. Basis Dis. 2018, 1864, 3378–3387.
  46. Ying, W.; Riopel, M.; Bandyopadhyay, G.; Dong, Y.; Birmingham, A.; Seo, J.B.; Ofrecio, J.M.; Wollam, J.; Hernandez-Carretero, A.; Fu, W.; et al. Adipose Tissue Macrophage-Derived Exosomal miRNAs Can Modulate In Vivo and In Vitro Insulin Sensitivity. Cell 2017, 171, 372–384.e12.
  47. Gao, H.; Luo, Z.; Jin, Z.; Ji, Y.; Ying, W. Adipose Tissue Macrophages Modulate Obesity-Associated β Cell Adaptations through Secreted miRNA-Containing Extracellular Vesicles. Cells 2021, 10, 2451.
  48. Gesmundo, I.; Pardini, B.; Gargantini, E.; Gamba, G.; Birolo, G.; Fanciulli, A.; Banfi, D.; Congiusta, N.; Favaro, E.; Deregibus, M.C.; et al. Adipocyte-Derived Extracellular Vesicles Regulate Survival and Function of Pancreatic β Cells. JCI Insight 2021, 6, e141962.
  49. Ying, W.; Wollam, J.; Ofrecio, J.M.; Bandyopadhyay, G.; El Ouarrat, D.; Lee, Y.S.; Li, P.; Osborn, O.; Olefsky, J.M. Adipose Tissue B2 Cells Promote Insulin Resistance Through Leukotriene LTB4/LTB4R1 Signaling. J. Clin. Investig. 2017, 127, 1019–1030.
  50. He, F.; Huang, Y.; Song, Z.; Zhou, H.J.; Zhang, H.; Perry, R.J.; Shulman, G.I.; Min, W. Mitophagy-Mediated Adipose Inflammation Contributes to Type 2 Diabetes with Hepatic Insulin Resistance. J. Exp. Med. 2021, 218, e20201416.
  51. Scheithauer, T.P.M.; Rampanelli, E.; Nieuwdorp, M.; Vallance, B.A.; Verchere, C.B.; van Raalte, D.H.; Herrema, H. Gut Microbiota as a Trigger for Metabolic Inflammation in Obesity and Type 2 Diabetes. Front. Immunol. 2020, 11, 571731.
  52. Liu, C.; Feng, X.; Li, Q.; Wang, Y.; Li, Q.; Hua, M. Adiponectin, TNF-α and inflammatory cytokines and risk of type 2 diabetes: A systematic review and meta-analysis. Cytokine 2016, 86, 100–109.
  53. Zhou, W.; Sailani, M.R.; Contrepois, K.; Zhou, Y.; Ahadi, S.; Leopold, S.R.; Zhang, M.J.; Rao, V.; Avina, M.; Mishra, T.; et al. Longitudinal multi-omics of host–microbe dynamics in prediabetes. Nature 2019, 569, 663–671.
  54. Michalovich, D.; Rodriguez-Perez, N.; Smolinska, S.; Pirozynski, M.; Mayhew, D.; Uddin, S.; Van Horn, S.; Sokolowska, M.; Altunbulakli, C.; Eljaszewicz, A.; et al. Obesity and disease severity magnify disturbed microbiome-immune interactions in asthma patients. Nat. Commun. 2019, 10, 5711.
  55. Sabapathy, V.; Stremska, M.E.; Mohammad, S.; Corey, R.L.; Sharma, P.R.; Sharma, R. Novel immunomodulatory cytokine regulates inflammation, diabetes, and obesity to protect from diabetic nephropathy. Front. Pharmacol. 2019, 10, 572.
  56. Larsen, C.M.; Faulenbach, M.; Vaag, A.; Vølund, A.; Ehses, J.A.; Seifert, B.; Mandrup-Poulsen, T.; Donath, M.Y. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 2007, 356, 1517–1526.
  57. Fleischman, A.; Shoelson, S.E.; Bernier, R.; Goldfine, A.B. Salsalate improves glycemia and inflammatory parameters in obese young adults. Diabetes Care 2008, 31, 289–294.
  58. Dominguez, H.; Storgaard, H.; Rask-Madsen, C.; Hermann, T.S.; Ihlemann, N.; Nielsen, D.B.; Spohr, C.; Kober, L.; Vaag, A.; Torp-Pedersen, C. Metabolic and vascular effects of tumor necrosis factor-α blockade with etanercept in obese patients with type 2 diabetes. J. Vasc. Res. 2005, 42, 517–525.
  59. Luzina, I.G.; Keegan, A.D.; Heller, N.M.; Rook, G.A.W.; Shea-Donohue, T.; Atamas, S.P. Regulation of inflammation by interleukin-4: A review of “alternatives”. J. Leukoc. Biol. 2012, 92, 753–764.
  60. Tsao, C.-H.; Shiau, M.-Y.; Chuang, P.-H.; Chang, Y.-H.; Hwang, J. Interleukin-4 regulates lipid metabolism by inhibiting adipogenesis and promoting lipolysis. J. Lipid Res. 2014, 55, 385–397.
  61. Van Dyken, S.J.; Locksley, R.M. Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: Roles in homeostasis and disease. Annu. Rev. Immunol. 2013, 31, 317–343.
  62. Schmidt, F.M.; Weschenfelder, J.; Sander, C.; Minkwitz, J.; Thormann, J.; Chittka, T.; Mergl, R.; Kirkby, K.C.; Faßhauer, M.; Stumvoll, M.; et al. Inflammatory cytokines in general and central obesity and modulating effects of physical activity. PLoS ONE 2015, 10, e0121971.
  63. Martínez-Reyes, C.P.; Gómez-Arauz, A.Y.; Torres-Castro, I.; Manjarrez-Reyna, A.N.; Palomera, L.F.; Olivos-García, A.; Mendoza-Tenorio, E.; Sánchez-Medina, G.A.; Islas-Andrade, S.; Melendez-Mier, G.; et al. Serum levels of interleukin-13 increase in subjects with insulin resistance but do not correlate with markers of low-grade systemic inflammation. J. Diabetes Res. 2018, 2018, 7209872.
  64. Castoldi, A.; Naffah De Souza, C.; Câmara, N.O.S.; Moraes-Vieira, P.M. The macrophage switch in obesity development. Front. Immunol. 2016, 6, 637.
  65. Kang, Y.E.; Kim, J.M.; Joung, K.H.; Lee, J.H.; You, B.R.; Choi, M.J.; Ryu, M.J.; Ko, Y.B.; Lee, M.A.; Lee, J.; et al. The roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in obesity-associated insulin resistance in modest obesity and early metabolic dysfunction. PLoS ONE 2016, 11, e0154003.
  66. Inouye, K.E.; Shi, H.; Howard, J.K.; Daly, C.H.; Lord, G.M.; Rollins, B.J.; Flier, J.S. Absence of CC chemokine ligand 2 does not limit obesity-associated infiltration of macrophages into adipose tissue. Diabetes 2007, 56, 2242.
  67. Griffith, J.W.; Sokol, C.L.; Luster, A.D. Chemokines and chemokine receptors: Positioning cells for host defense and immunity. Annu. Rev. Immunol. 2014, 32, 659–702.
  68. Shimobayashi, M.; Albert, V.; Wölnerhanssen, B.; Frei, I.C.; Weissenberger, D.; Meyer-Gerspach, A.C.; Clement, N.; Moes, S.; Colombi, M.; Meier, J.A.; et al. Insulin resistance causes inflammation in adipose tissue. J. Clin. Investig. 2018, 128, 1538–1550.
  69. Eguchi, K.; Manabe, I.; Oishi-Tanaka, Y.; Ohsugi, M.; Kono, N.; Ogata, F.; Yagi, N.; Ohto, U.; Kimoto, M.; Miyake, K.; et al. Saturated fatty acid and TLR signaling link β cell dysfunction and islet inflammation. Cell Metab. 2012, 15, 518–533.
  70. Westwell-Roper, C.; Nackiewicz, D.; Dan, M.; Ehses, J.A. Toll-like receptors and NLRP3 as central regulators of pancreatic islet inflammation in type 2 diabetes. Immunol. Cell Biol. 2014, 92, 314–323.
  71. Donath, M.Y. Targeting inflammation in the treatment of type 2 diabetes: Time to start. Nat. Rev. Drug Discov. 2014, 13, 465–476.
  72. Lefere, S.; Tacke, F. Macrophages in obesity and non-alcoholic fatty liver disease: Crosstalk with metabolism. JHEP Rep. 2019, 1, 30–43.
  73. Morgantini, C.; Jager, J.; Li, X.; Levi, L.; Azzimato, V.; Sulen, A.; Barreby, E.; Xu, C.; Tencerova, M.; Näslund, E.; et al. Liver macrophages regulate systemic metabolism through non-inflammatory factors. Nat. Metab. 2019, 1, 445–459.
  74. Huang, W.; Metlakunta, A.; Dedousis, N.; Zhang, P.; Sipula, I.; Dube, J.J.; Scott, D.K.; O’Doherty, R.M. Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes 2010, 59, 347–357.
  75. Gomes, J.M.G.; Costa, J.A.; Alfenas, R.C.G. Metabolic endotoxemia and diabetes mellitus: A systematic review. Metabolism 2017, 68, 133–144.
  76. Ghoshal, S.; Witta, J.; Zhong, J.; De Villiers, W.; Eckhardt, E. Chylomicrons promote intestinal absorption of lipopolysaccharides. J. Lipid Res. 2009, 50, 90–97.
  77. Cani, P.D.; Amar, J.; Iglesias, M.A.; Poggi, M.; Knauf, C.; Bastelica, D.; Neyrinck, A.M.; Fava, F.; Tuohy, K.M.; Chabo, C.; et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007, 56, 1761–1772.
  78. Harte, A.L.; Varma, M.C.; Tripathi, G.; McGee, K.C.; Al-Daghri, N.M.; Al-Attas, O.S.; Sabico, S.; O’hare, J.P.; Ceriello, A.; Saravanan, P.; et al. High fat intake leads to acute postprandial exposure to circulating endotoxin in type 2 diabetic subjects. Diabetes Care 2012, 35, 375–382.
  79. Burcelin, R. Gut microbiota and immune crosstalk in metabolic disease. Mol. Metab. 2016, 5, 771–781.
  80. Van Oostrom, A.J.; Sijmonsma, T.P.; Rabelink, T.J.; Van Asbeck, B.S.; Cabezas, M.C. Postprandial leukocyte increase in healthy subjects. Metabolism 2003, 52, 199–202.
  81. Erridge, C.; Attina, T.; Spickett, C.M.; Webb, D.J. A high-fat meal induces low-grade endotoxemia: Evidence of a novel mechanism of postprandial inflammation. Am. J. Clin. Nutr. 2007, 86, 1286–1292.
  82. Pendyala, S.; Walker, J.M.; Holt, P.R. A high-fat diet is associated with endotoxemia that originates from the gut. Gastroenterology 2012, 142, 1100–1101.
  83. Bakker, G.J.; Schnitzler, J.G.; Bekkering, S.; De Clercq, N.C.; Koopen, A.M.; Hartstra, A.V.; Meessen, E.C.E.; Scheithauer, T.P.; Winkelmeijer, M.; Dallinga-Thie, G.M.; et al. Oral vancomycin treatment does not alter markers of postprandial inflammation in lean and obese subjects. Physiol. Rep. 2019, 7, e14199.
  84. Lancaster, G.I.; Langley, K.G.; Berglund, N.A.; Kammoun, H.L.; Reibe, S.; Estevez, E.; Weir, J.; Mellett, N.A.; Pernes, G.; Conway, J.R.W.; et al. Evidence that TLR4 is not a receptor for saturated fatty acids but mediates lipid-induced inflammation by reprogramming macrophage metabolism. Cell Metab. 2018, 27, 1096–1110.
  85. Thaiss, C.A.; Zmora, N.; Levy, M.; Elinav, E. The microbiome and innate immunity. Nature 2016, 535, 65–74.
  86. Sikalidis, A.K.; Maykish, A. The Gut Microbiome and Type 2 Diabetes Mellitus: Discussing a Complex Relationship. Biomedicines 2020, 8, 8.
  87. Khosravi, A.; Yáñez, A.; Price, J.G.; Chow, A.; Merad, M.; Goodridge, H.S.; Mazmanian, S.K. Gut microbiota promote hematopoiesis to control bacterial infection. Cell Host Microbe 2014, 15, 374–381.
  88. Fei, N.; Zhao, L. An opportunistic pathogen isolated from the gut of an obese human causes obesity in germfree mice. ISME J. 2012, 7, 880.
  89. Rabot, S.; Membrez, M.; Bruneau, A.; Gérard, P.; Harach, T.; Moser, M.; Raymond, F.; Mansourian, R.; Chou, C.J. Germ-free C57BL/6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism. FASEB J. 2010, 24, 4948–4959.
  90. Ridaura, V.K.; Faith, J.J.; Rey, F.E.; Cheng, J.; Duncan, A.E.; Kau, A.L.; Griffin, N.W.; Lombard, V.; Henrissat, B.; Bain, J.R.; et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 2013, 341, 1241214.
  91. Levy, M.; Kolodziejczyk, A.A.; Thaiss, C.A.; Elinav, E. Dysbiosis and the immune system. Nat. Rev. Immunol. 2017, 17, 219–232.
  92. Larsen, N.; Vogensen, F.K.; Van Den Berg, F.W.J.; Nielsen, D.S.; Andreasen, A.S.; Pedersen, B.K.; Al-Soud, W.A.; Sørensen, S.J.; Hansen, L.H.; Jakobsen, M. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS ONE 2010, 5, e9085.
  93. Sonnenburg, E.D.; Smits, S.A.; Tikhonov, M.; Higginbottom, S.K.; Wingreen, N.S.; Sonnenburg, J.L. Diet-induced extinctions in the gut microbiota compound over generations. Nature 2016, 529, 212.
  94. Azad, M.B.; Konya, T.; Persaud, R.R.; Guttman, D.S.; Chari, R.S.; Field, C.J.; Sears, M.R.; Mandhane, P.; Turvey, S.; Subbarao, P.; et al. Impact of maternal intrapartum antibiotics, method of birth and breastfeeding on gut microbiota during the first year of life: A prospective cohort study. BJOG 2016, 123, 983–993.
  95. Serino, M.; Luche, E.; Gres, S.; Baylac, A.; Bergé, M.; Cenac, C.; Waget, A.; Klopp, P.; Iacovoni, J.; Klopp, C.; et al. Metabolic adaptation to a high-fat diet is associated with a change in the gut microbiota. Gut 2012, 61, 543–553.
  96. Segain, J.-P.; De La Blétière, D.R.; Bourreille, A.; Leray, V.; Gervois, N.; Rosales, C.; Ferrier, L.; Bonnet, C.; Blottière, H.M.; Galmiche, J.-P. Butyrate inhibits inflammatory responses through NF-κB inhibition: Implications for Crohn’s disease. Gut 2000, 47, 397–403.
  97. Sanna, S.; Van Zuydam, N.R.; Mahajan, A.; Kurilshikov, A.; Vila, A.V.; Võsa, U.; Mujagic, Z.; Masclee, A.A.M.; Jonkers, D.M.A.E.; Oosting, M.; et al. Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases. Nat. Genet. 2019, 51, 600–605.
Subjects: Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to : , , , , ,
View Times: 142
Revisions: 2 times (View History)
Update Date: 12 Jul 2023