Inflammation, Obesity and Diabetes: A link
More than a century ago, it was first shown that high doses of sodium salicylate (5.0–7.5 g/d) could reduce glycosuria in patients presumably having type 2 diabetes mellitus (T2DM). As mentioned in a historical review by Shoelson et al,1 a study in 1876 revealed that the symptoms of diabetes mellitus could be completely resolved with the use of sodium salicylate. Similar findings of sodium salicylate having an impact in considerably reducing sugar excretion were found in a study published in the year 1901. In 1957, Reid and colleagues rediscovered this effect. A diabetes patient treated with insulin, given high-dose aspirin for treatment of arthritis associated with rheumatic fever, was found to no longer require daily insulin injections.2 As the joint symptoms resolved, aspirin was discontinued. A repeat glucose tolerance test gave abnormal results. The findings prompted the researchers to assess 7 additional patients. A short intensive 2-week course of high-dose aspirin (5.0–8.0 g/d) led to fall in fasting blood glucose levels from an average of >190 mg/dl before treatment to 92 mg/dl. Every patient responded to the treatment. Although, several clinical trials post this era showed equivalent efficacy with salicylates, the mechanistic studies focused on insulin secretion. As a result, insulin resistance and the role of inflammation in the pathogenesis of T2DM were not much appreciated at that time.
In the late 1950s and 1960s, several epidemiological studies linked inflammation to T2DM or obesity relating to the increase in circulating fibrinogen levels and other acute phase reactants. However, these studies could not illuminate any further on the pathogenesis and role of inflammation in these conditions. Increased levels of various markers and mediators of inflammation and acute phase reactants from the fundamental markers of inflammation i.e. white blood cell count to the more specific circulating cytokines like C-reactive protein (CRP), interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), combined elevation of interleukin-1? (IL-1? ) and IL-6, etc., have been shown to be correlated with incident T2DM.3-7
West of Scotland Coronary Prevention Study (WOSCOPS) added to the accumulating evidence implicating inflammation as a potential pathway in the pathogenesis of T2DM. It was demonstrated that CRP predicts the development of T2DM independently of established risk factors including fasting plasma triglyceride, body mass index (BMI), and glucose. In addition, it was seen that subjects in the top quintile of CRP (>4.18 mg/l) had a more than three times increased risk of developing diabetes compared with those in the lowest quintile (0.66 mg/l) after adjusting for other variables (Figure 1).8 This data strongly added to the concept of low-grade inflammation having a key role in the pathogenesis of type 2 diabetes.
Epidemiological studies, despite being highly informative, are correlative in nature and alone, cannot really determine causality. The first firm experimental evidence to support inflammation, not only as a marker but also as a mediator of T2DM, was provided almost 25 years ago by Hotamisligil et al.9 Their seminal work in rodent models of obesity and diabetes indicated a role for tumor necrosis factor-? (TNF-?), a pro-inflammatory cytokine, in obesity and particularly in insulin resistance and diabetes. They demonstrated that adipocytes constitutively expressed TNF-? and that TNF-? expression in adipocytes of obese animals was considerably increased. It was also shown that neutralization of TNF-? by soluble TNF-? receptor leads to a decrease in insulin resistance. These observations provided the first link between an increase in expression and plasma concentration of a pro-inflammatory cytokine and insulin resistance.
Several mechanisms may explain insulin resistance and islet ?-cell dysfunction in T2DM. Glucotoxicity, lipotoxicity, oxidative stress, endoplasmic reticulum (ER) stress, altered gut microbiota, endocannabinoids and the formation of amyloid deposits in the islets are among these.10 The exact relative contribution of these mechanisms is not clearly understood, yet, they all seem to be involved in the pathology of the disease. Inter-individual differences may be seen depending on genetic background, nutrition, physical activity and other environmental factors. Each of these cellular stresses may either incite an inflammatory response or may be exacerbated by, or associated with, inflammation.
Glucotoxicity, lipotoxicity and oxidative stress in pathophysiology of metabolic syndrome
There seems to be an increase in the local level of free fatty acids (FFA) in the islets, and long chain fatty acids, particularly palmitic acid, owing to glucotoxicity, and especially lipotoxicity.11,12 Prolonged exposure of pancreatic islet ?-cells to elevated concentrations of glucose and FFA tends to increase the metabolic activity of islet cells, leading to heightened formation of reactive oxygen species (ROS) eventually resulting in oxidative stress.
In diabetes, on account of high-glucose concentration within cells, there is an increase in the metabolism of glucose-derived pyruvate through the electron transport chain (ETC) complexes. Superoxide is thus overproduced by the mitochondria. This pathway leads to the production of more ROS on its own and also initiates other pathways, giving rise to a breakdown in the balance between pro-oxidant and endogenous antioxidant systems, such as increases in glucose flux through the aldose reductase pathway, formation of advanced glycation end products (AGEs) and protein kinase C (PKC) activation. These changes lead to oxidative stress by further activating the ROS-generating machinery inside the cells or by decreasing the activities of antioxidant enzymes.13
Along with the mitochondrial ETC, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) is also an important and early source of ROS in diabetes. Evidence indicates that the activity of NADPH oxidase is increased in diabetic patients.14,15 NOX is an enzyme complex involved in numerous proinflammatory signaling cascades including signaling of TNF-? via TNF-receptor 1 (TNFR1) and IL-1? via IL-1R. Inhibition of the endosomal NOX can immensely dwindle the downstream activation of NF?B through these pathways.16
ROS play a key role in activation of several transcription factors including NF-kB and NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome and caspase 1, leading to production of IL-1?. This islet-derived IL-1? induces various cytokines and chemokines, including IL-6, IL-8, TNF-? and chemo-attractant proteins that attract macrophages and other immune cells. The recruitment of immune cells is further enhanced by the vicious cycle of IL-1? ‘autostimulation’ ultimately leading to islet ?-cell dysfunction (figure 2).8,17
Figure 2. Regulation of IL-1? in islets
Alteration of Gut Microbiota in Pathophysiology of Metabolic Syndrome
“Father of Medicine” Hippocrates’ had once stated that “all disease begins in the gut.” This highlighted the crucial role that the gut and diet play in many of the vital homoeostatic functions of the human body. The role of the human gut microbiota is pivotal, as the gut is populated by several different microbial groups. Gut bacteria appear to be one of the crucial mediators of obesity and diabetes pathogenesis. The microbiota plays an active part in glucose and lipid metabolism.
The environmental cues involved in the pathophysiology of metabolic disease remain elusive. One emerging environmental factor is the gut microbiome which may influence metabolism as well as behavior but whether the microbiota plays a causal role in the etiology of metabolic syndrome is a matter of controversy. In 2004, Bäckhed et al demonstrated in a study that the gut microbiota is an important environmental factor that can influence energy harvest from the diet and energy storage in the host.18
In diabetic humans, there is a lack of uniformity in gut microbiota profiles. Significant correlations were exhibited with specific gut microbes, bacterial genes and metabolic pathways in T2D patients in a human metagenome-wide association study.19 A study investigated stool samples from type 2 diabetes patients and found that the amounts of probiotics is negatively correlated with the level of blood glucose, and hypoglycemic treatment can dramatically increase probiotics level to normal. Decrease in gut probiotics is believed to induce impaired glucose tolerance, reduce sugar-induced insulin secretion, increase endotoxemia, and lead to type 2 diabetes.20
There are complex interactions between gut microbiome, obesity, and human health. Research has only begun to describe and unwind these interactions. The data on therapeutic strategies aimed at altering the gut microbiome is still largely descriptive and preclinical.
Adipocytes in pathophysiology of metabolic syndrome
Adipose tissue is a pathogenic site of insulin?resistance in T2DM, underlying mechanisms of which are associated with an inflammatory response. Adipocytes have an essential role in?the?development?of?obesity-induced?inflammation and produce various bioactive?proteins?like TNF-?, leptin,?interleukins,?resistin,?monocyte?chemoattractant?protein-1?(MCP-1),?angiotensinogen, visfatin, etc., which exhibit the inflammatory state of the adipose tissue. It has also been recognized that visceral?fat is more pathogenic as compared to the subcutaneous depots.1
By storing excessive nutrients, adipocytes experience ER stress and hypertrophy — both of which have been associated with the production of cytokines and chemokines. Lipid overload itself may lead to adipocyte death and lipid accumulation leads to attraction of macrophages, further triggering an inflammatory response. An important mechanism which triggers inflammation is the local hypoxia caused by the expansion of adipose tissues faster than the vasculature that supports its oxygen and nutrient requirements.21 Hypoxia leads to recruitment of macrophages to the ischemic tissues and induces expression of numerous pro-angiogenic and pro-inflammatory genes in macrophages.
Also, long-term?elevated glucose concentrations?and?the?production of increased numbers?of?AGEs associated with it, can activate NF-?B, which in turn promotes insulin resistance.1 Additionally, the association of obesity with increased gut leakiness for bacterial products (endotoxins) induces changes in the gut flora and further triggers tissue inflammation.
Molecular pathways in metabolic syndrome
The metabolic and hypoxic stresses trigger several intracellular inflammatory pathways. Glucose, free fatty acids and other lipids, and the endotoxins recruit fetuin-A, which, together with the recruiting agent, activate TLR2 and TLR4. This, together with other inflammatory cytokines and/or bacterial lipopolysaccharides, stimulates I-kappa-B (IkB) kinase-b (IKK?), and possibly IKK?, to induce activation of NF-kB. Following activation, NF-kB translocates to the nucleus, resulting in the subsequent transcription of genes leading to release of a host of cytokines and chemokines including TNF, IL-1?, IL-8 and MCP-1 (Box 1).1 These cytokines then promote the accumulation of various immune cells including macrophages leading to insulin resistance. In macrophages, hyperglycemia, lipids and endotoxins promote the formation of inflammasomes that lead to the splicing of pro-IL-1?. The product, active IL-1?, is a potent cytokine which activates multiple immune cells and thereby promotes insulin resistance (Fig. 3).
Similarly, RAGE activates c-Jun-N-terminal kinase (JNK), which promotes insulin resistance owing to phosphorylation of serine residues in insulin receptor substrate-1 (IRS-1).1 Phosphorylation of IRS-1 as a direct effect or a downstream effect of the inflammatory mediators inhibits the insulin receptor signaling cascade thus leading to insulin resistance. Similar mechanisms have been noted in other insulin-sensitive tissues, especially the liver and muscle, to underlie insulin resistance as those described in the adipose tissue.
Box 1. NF-?B target gene products with potential involvement in the pathogenesis of insulin resistance in T2DM
Cytokines and chemokines Transcription factors Receptors and surface proteins Others
TNF-? TNFR p55 p65 RelA PAI-1
IFN-? TNFR p75 NF-?B p50 SAA
Resistin IFNR subunits IKK? Angiotensinogen
IL-1? IL-1R IKK? CRP
IL-6 IL-6R I?B? COX2
IL-8 CD40 A20 iNOS
IL-10 CD40 ligand VEGF
IL-12 E-selectin IGFBPs
IL-18 P-selectin MnSOD
Lymphotoxins ICAM-1 TGF-? VCAM-1 MCP-1 CCR2 MIP-1? TLR2 MIP-1? TLR4 MIP-2 Lox-1 MIP-3? RAGE RANTES IFNR: IFN receptor; IGFBP: IGF-binding protein; IL-1R: IL-1 receptor; MnSOD: Manganese superoxide dismutase; SAA: Serum amyloid; TNFR: TNF receptor.
Glucose, FFAs, endotoxins
Glucose, FFAs, endotoxins
Hypoxia, ER stress
Figure 3. Storage of excessive nutrients in adipose tissues leads to an inflammatory response and insulin resistance
Besides the?adipose?tissue,?the?liver?is?also affected?by?obesity and non-alcoholic fatty liver disease (NAFLD) is often associated with abdominal adiposity and T2DM. There is enhanced inflammatory?gene?expression in?the liver?as?adiposity increases, underlining the fact that inflammation?has a key?role to play?in?the?progression?of?this?disease?process. Different mechanisms may explain initiation of inflammation in the liver. Similar?to?the?adipose?tissue?inflammation?that?follows?adipocyte?lipid?accumulation, hepatocyte?lipid?accumulation, or steatosis,?induces?a?subacute?inflammatory?response?in liver.?An alternate trigger that can initiate hepatic inflammation may be the proinflammatory?substances?in the?portal?circulation,?potentially?produced?in?abdominal?fat. Regardless of the trigger mechanism,?NF-?B?is?activated?in hepatocytes, leading to over-production of cytokines?including?IL-6,?TNF-??and?IL-1? in?the?liver.?The?proinflammatory?cytokines?activate?Kupffer?cells,? resident?hepatic?macrophages, and other immune cells including T?and?B?lymphocytes,?natural killer?cells,?dendritic cells?as?well?as?hepatic?stellate?cells giving rise to a state of chronic inflammation and insulin resistance in the liver.1 Although inflammation has been noted even in the skeletal muscles, another important site of insulin resistance, the trigger is thought to be intralipid infusion and not the increased adiposity as in the adipose tissues or liver. Thus, just like the role of portal delivery of abdominal fat-derived cytokines and lipids in hepatic inflammation and insulin resistance, the proinflammatory and proatherogenic mediators in the adipose tissue and liver seem to give rise to a systemic inflammatory diathesis and stimulate insulin resistance in skeletal muscle and other tissues and atherogenesis in the vasculature (fig. 4).1
Skeletal muscle, kidney, etc.
Proinflammatory and proatherogenic mediators
Hepatocytes, ECs, immune cells
Figure 4. Local, portal, and systemic effects of inflammation in T2DM
In summary, multiple mechanisms contribute to inflammation in T2DM, some of which are general and others are tissue-specific. Thus in the pancreatic islet cells, inflammation may be initiated by direct sensing of excess nutrients, leading to activation of the IL-1 system, whereas in adipose tissue, excess storage of fat causes hypoxia and inflammation. Common downstream mechanisms include the activation of NF-?B and JNK pathways and cytokine and chemokine release, leading to the recruitment of immune cells causing ?-cell dysfunction and development of insulin resistance.
CNS inflammation and diabetes
Endogenous glucose production (EGP) is essential for homeostatic mechanisms that maintain blood glucose at appropriate levels. The dysregulation in EGP in type 2 diabetes contributes to hyperglycemia. The discovery of insulin in 1921 diverted the focus of glucose metabolism research to peripheral organs (liver, skeletal muscle and fat) where insulin was thought to exert its primary effect. This led to the hypothesis that abnormal regulation of glucose metabolism in obesity and type 2 diabetes could be attributed to a failure of insulin action in liver, skeletal muscle and fat, thus guiding drug discovery efforts focused on improving insulin sensitivity in these tissues.22
Over the years, new experimental tools have shown that the central nervous system (CNS) is central to the regulation of glucose metabolism (fig. 5).22
Gut hormone secretion
Figure 5. CNS regulation of glucose homeostasis
CNS could be a target for the treatment of diabetes mellitus. However, there are several obstacles that render it as a challenging task. There is a possibility that the available compounds mediate antagonistic effects in the CNS and in the periphery. There may be instances where the role of a drug target in the CNS is opposite to its role in the periphery. Insulin is one such example. Both in the CNS and the periphery, insulin actions yield glucose reduction. However, in the periphery, insulin’s action is that of an anabolic hormone and stimulates nutrient storage as glycogen and adipose tissue, giving way to weight gain. In the CNS; however, it acts as a catabolic hormone and inhibits food intake and stimulates energy expenditure. Therefore, while through its peripheral actions, it causes weight gain in diabetes patients, lipid soluble insulin mimetics that presumably cross the blood-brain barrier (BBB) to a greater extent have been found to reduce food intake and body weight in experimental models.22
Sulphonyurea compounds are another such example. They bind to KATP channel. The subunit isoforms of KATP channels in pancreatic ? cells and the hypothalamus are similar. These channels seem to have an important role in overall CNS glucose sensing, yet evidence suggest that their closure may lead to different effects in the CNS and the periphery. Closure of KATP channels in response to sulphonylurea receptor agonists in ? cells leads to insulin secretion, and mediates beneficial effects on glucose control in diabetes patients. On the contrary, CNS administration of diazoxide, a compound that opens the KATP channel, seems to improve glucose homeostasis.22
Components of the signaling pathways that differ between major CNS systems and their omnipresent peripheral counterparts need research in order to yield novel molecular targets. This may gain significance as the onset of type 2 diabetes occurs at younger ages owing to the rising prevalence of childhood obesity. Therefore, simply managing increased glucose levels mediated by the periphery without targeting the underlying cause could pose a problem in the long run.
Inflammation has often been linked to T2DM and obesity. Increased levels of various markers and mediators of inflammation and acute phase reactants have been correlated with incident T2DM.
Insulin resistance and islet ??cell failure are the hallmarks of T2DM. Failure of the functional expansion of islet ?-cells to compensate for the degree of insulin resistance leads to insulin deficiency, and ultimately T2DM. The gut microbiota plays an active role in glucose and lipid metabolism and seems to be one of the crucial mediators of obesity and diabetes pathogenesis. Adipocytes have also been shown to have an essential role in?the?development?of?obesity-induced?inflammation.
Therefore, there are multiple mechanisms that contribute to inflammation in T2DM, some being general while others being tissue-specific.
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