Relationship between inflammation, insulin resistance and type 2 diabetes: 'cause or effect'?
WebMD describes the connection between type 2 diabetes and inflammation. and the resulting insulin resistance also leads to inflammation. Inflammation has been implicated as an important aetiological factor in the development of both insulin resistance and type 2 diabetes mellitus. This conclusion. Inflammation, Insulin Resistance, and Type 2 Diabetes: Back to the Future? has established that the link between inflammation and insulin resistance resides .
To find out, researchers bred mice that lacked the ability to make certain immune cells. Such mice wouldn't survive long outside a sterile lab, but when they were fed a special diet designed to make them obese, they had no signs of inflammation—and no insulin resistance or diabetes. Now it seems pretty clear that inflammation plays a major role in the development of insulin resistance.
That's why Kratz is working to test the connection between inflammation and insulin resistance in people. In a series of pilot studies, he took fat samples from just underneath the skin of volunteers. Using a sophisticated machine called a flow cytometer that can separate and identify individual cells, he did a sort of cell census, counting how many of each cell type were in the samples.
The results were promising. He discovered that the presence of a certain macrophage was a red flag. Now, Kratz is taking his study a step further. People with fat deep inside the body tend to have more serious problems with insulin resistance than people whose fat is concentrated closer to their skin.
The association of insulin resistance with lipid intermediates is not a novel idea; however, the novelty of the work by Haus et al. The results demonstrate that plasma levels are elevated in type 2 diabetes and that the lipid species appear not only to be associated with the severity of insulin resistance but also to be a marker of inflammation, i.
Inflammation, Insulin Resistance, and Type 2 Diabetes: Back to the Future?
So, what is the next step for this research? Are plasma ceramides now considered a surrogate marker for tissue lipid stores? Would they be valuable markers to assess the effectiveness of strategies to reduce inflammation at the myocellular level?
If so, would they be viable markers that give us insight into muscle metabolism and eliminate the need to obtain muscle tissue by biopsy? Do plasma ceramides really serve to identify individuals at high risk to develop type 2 diabetes as suggested? Given the observations in this study, these are important questions that now need to be answered.
The most relevant question, however, is whether therapies that specifically target inflammation will evolve into future diabetes medications. With the focus now clearly on modulating the inflammatory pathway as a potential target for future diabetes therapies, it is truly an exciting time for human investigation.
However, let us not forget that the interesting reports from the s appear to be the first to suggest modulation of inflammation as a therapy for diabetes. Given the lack of understanding of insulin action during the s, it is understood why research into inflammation was not given more attention.
Mechanisms Linking Inflammation to Insulin Resistance
In this regard, the present-day approach of modulating inflammation as a potential diabetes therapy reminds me of the movie from the s, in which Michael J. Fox goes back in time and then returns to the present. Notes See accompanying original articles, p.Fatty Acids and Disease in Type 2 Diabetes
The costs of publication of this article were defrayed in part by the payment of page charges. Section solely to indicate this fact. Macrophage content in subcutaneous adipose tissue: Plasma ceramides are elevated in obese subjects with type 2 diabetes and correlate with the severity of insulin resistance. Are we ready to move beyond Celsus? Br J Sports Med. Inflammation and insulin resistance. J Clin Invest Influence of the inflammatory cytokines on the status of insulin resistance. Besides, IL-6 is also found to induce IR by impairing the synthesis of glycogen through downregulating the expression of miRs and upregulating that of FOG IL-6 IL-6 is secreted by multiple tissues, particularly adipose tissue, and is recognized as an inflammatory mediator that causes IR by reducing the expression of glucose transporter-4 GLUT-4 and insulin receptor substrate-1 IRS Therefore, hybrid training can ameliorate insulin resistance by suppressing serum IL-6 in skeletal muscle [ 34 ].
Leptin Leptin is a protein that is derived primarily from white adipose tissue WAT [ 38 ].
It suppresses appetite and increases energy expenditure by repressing anabolic neuronal circuits and activating catabolic neuronal circuits. In addition, leptin levels are affected by nutriture [ 39 ].
Leptin-mediated appetite and energy homeostasis are associated with the progression of IR [ 40 ]. Furthermore, a state called leptin resistance, which was disputed lately by the concept of hypothalamic leptin insufficiency, is often observed in the obese individuals, and weight loss simultaneously reduces serum leptin levels. This suggests that leptin might have a role in regulating IR.
It is likely that an increased concentration of leptin, an anti-inflammatory cytokine, during inflammation in AT is associated with leptin resistance in obese individuals. Interestingly, leptin was recommended as a biomarker for in utero insulin resistance based on the link between maternal and fetal leptin and IR [ 4344 ].
Leptin is a potential treatment for IR because it improves glycometabolism, insulin sensitivity, and lipometabolism [ 4546 ].
Adiponectin Adiponectin is produced mainly by WAT. Its levels reduce in obesity, IR, or T2DM, where it acts as an anti-inflammatory cytokine, but increase in osteoarthritis OA and type 1 diabetes mellitus T1DMwhere it acts as a proinflammatory cytokine [ 3947 ].
Two receptors are involved in the glucose metabolism that links adiponectin to the amelioration of IR. Adiponectin receptor 1 AdipoR1 is likely to reduce the expression of the genes that encode hepatic gluconeogenic enzymes and molecules involved in lipogenesis by activating AMPK. AdipoR1 and AdipoR2 are expressed at high levels in skeletal muscle and the liver, respectively [ 2850 ].
There was a problem providing the content you requested
In brief, adiponectin ameliorates hepatic insulin resistance by reducing glycogenesis and lipogenesis, as well as increasing glucose consumption. Resistin The production of resistin is complex. In rodents, it is generated from adipocytes, whereas it is produced mostly by macrophages in humans. Its concentrations increase concurrently with the levels of inflammatory mediators [ 51 ]. It was suggested that resistin participates in the pathogenesis of IR and that its levels might be elevated due to obesity and IR [ 52 ].
MCP-1 Monocyte chemoattractant protein-1 MCP-1 is a proinflammatory chemokine produced by adipocytes, macrophages, and endothelial cells, which might lead to the recruitment of macrophages, DCs, and memory T cells [ 1154 ]. Adipocytes and macrophages are the main source of proinflammatory cytokines.
However, the expression of MCP-1 increases during adiposity, which might stimulate the recruitment of macrophages and DCs, which further increases the expression of cytokines to exacerbate inflammation-induced IR [ 22 ]. The expression of MCP-1 increases during obesity, particularly in visceral fat areas, which might contribute to the pathogenesis of IR, particularly in the liver [ 5455 ].
In adipose tissue of CCR2 knockout mice, macrophage content and inflammatory profile were reduced. CCR2 deficiency also ameliorated hepatic steatosis and improved insulin sensitivity [ 57 ]. It is involved in a series of pathological processes such as inflammation and innate and adaptive immune responses [ 5859 ]. Inflammatory pathways linking inflammation to insulin resistance. JNK contributes to inflammation and metabolic syndrome MSobesity, and IR by regulating the production of proinflammatory cytokines, karyomitosis, and cellular apoptosis [ 63 — 65 ].
JNK plays a role in the phosphorylation of the c-Jun component of activator protein AP-1 transcription factor, but there is no evidence of a direct relationship between this transcriptional pathway and JNK-reduced IR. Moreover, the excessive activation of JNK in peripheral insulin-sensitive tissues promotes IR [ 67 ].