This is difficult reading but well worth wading through to catch the broader picture of how inflammation culminates in insulin resistance which results in beta cell loss in both type 1 diabetes and type 2 diabetes. Perhaps there is a clue here for #CuringType1Diabetes naturally.
INSULIN PRODUCTION AND INSULIN RESISTANCE
Glucose homeostasis is generally achieved through a balance of input (e.g., dietary, gluconeogenesis) and tissue uptake/utilization (e.g., storage as fat/glycogen or oxidation) coordinated by the beta cells of the pancreas through the production of insulin (Saltiel and Kahn 2001; Taniguchi et al. 2006; Qatanani and Lazar 2007). Insulin itself is a polypeptide with diverse and pleiotropic effects across nearly every tissue type in the body, where, in addition to its well-appreciated metabolic effects, it also regulates fundamental cellular programs like growth, proliferation, and apoptosis (Taniguchi et al. 2006).
With regard to glycemia, however, three target tissues have primacy: fat, liver, and skeletal muscle (Saltiel and Kahn 2001). These organs represent an individual’s primary storage, production, and oxidation pathways, respectively, and together modulate glycemia.
As sites of insulin’s metabolic action, these same tissues are also the primary determinants of insulin resistance (Kahn and Flier 2000; Shulman 2000; Qatanani and Lazar 2007). However, although the base effect is shared among them, insulin resistance in each specific tissue manifests itself clinically in very different ways.
- Insulin resistance in the liver is responsible for elevated fasting serum glucose, a key clinical criterion for the diagnosis of type 2 diabetes, owing to the inability of insulin to suppress hepatic gluconeogenesis while lipid biosynthesis remains intact (Brown and Goldstein 2008).
- Insulin resistance in adipose tissue and skeletal muscle manifests as elevated lipolysis and glucose intolerance, respectively, resulting in hyperlipidemia, hyperglycemia, and compensatory hyperinsulinemia (Kahn and Flier 2000; Shulman 2000).
INSULIN RESISTANCE AND BETA CELL LOSS
The pancreas itself is another target of insulin resistance, albeit in an indirect fashion. With mounting insulin resistance, blood glucose concentrations progressively rise (hyperglycemia) because of the functional loss of insulin action in the periphery, which, in turn, leads to compensatory and progressive hyperinsulinemia. The natural history of this pathophysiology is mounting beta cell stress, eventual beta cell exhaustion, and frank diabetes (Kahn and Flier 2000; Shulman 2000). In support of this, many recent candidate genes implicated in type 2 diabetes by genome-wide association studies (e.g., INS, KCNJ11, and TCF7L2) are expressed not in insulin target tissues but in the islet itself (McCarthy and Hattersley 2008). This denouement of insulin resistance has always been seen as the end-stage pathology of type 2 diabetes; however, evidence shows that this pathway operates in parallel with, and licenses immune destruction of, beta cell mass across the diabetes spectrum [this includes type 1 diabetes].
Three mechanisms in particular couple insulin resistance to beta cell depletion and, indirectly, immune attack: glucotoxicity, lipotoxicity, and inflammation. The elevated levels of glucose and lipids, particularly saturated fatty acids, that are characteristic of insulin resistance synergize at the level of the beta cell to drive parallel increases in FAS expression, activating NK cell ligands (e.g., RAE-1, NKp46-ligand), reactive oxygen species, and endoplasmic reticulum (ER) stress, all of which culminate in IL-1β secretion and apoptosis (Lee et al. 1994; Unger 1995; Harding and Ron 2002; Ogasawara et al. 2004; Hotamisligil 2010; Mandrup-Poulsen et al. 2010).
Importantly, IL-1β has been a known mediator of beta cell dysfunction and death for more than 25 years (Mandrup-Poulsen et al. 1985) and is potentiated by TNFα and IFNγ (Eizirik 1988; Pukel et al. 1988), both of which are present at high levels under conditions of insulin resistance. Indeed, beta cells are uniquely susceptible to IL-1β’s effects as they express higher levels of IL-1R1 than any other cell type in the body (Boni-Schnetzler et al. 2009). Engagement of the IL-1R1 results in activation of NF-κB, MAPK, PKCδ, and JNK signaling pathways (Maedler et al. 2011), resulting in direct promotion of apoptosis and FAS up-regulation (Elouil et al. 2005), as well as the inhibition of insulin signaling, which is critical for optimal beta cell function (Maedler et al. 2011). In addition, IL-1β signaling results in the production of pro-inflammatory mediators that act in a feed-forward autocrine/paracrine manner in beta cells and local innate immune cells to amplify these effects.
The net result of these processes is an islet microenvironment replete with a damaged and vulnerable beta cell mass, copious antigenic beta cell debris, and a phlogistically [of or relating to inflammations] primed local innate immune response. The culmination of this inflammatory milieu is the licensing of a lymphocyte-driven autoimmune assault on the remaining beta cell pool.
Whether this licensing occurs early in the disease course, when much of the beta cell mass remains (typical in type 1 diabetes), or late, after much of the beta cell mass has been degraded by long-standing insulin resistance (typical in type 2 diabetes), it is clear that the terminal mechanisms of beta cell failure are identical. As such, the coupling of insulin resistance to exhaustion, direct toxicity, and autoimmune destruction of the beta cell provides a mechanism by which the obesity epidemic is driving the incidence of both type 1 and type 2 diabetes to historic levels.
INFLAMMATION AND INSULIN RESISTANCE
These data advance insulin resistance to the fore as one of the primary pathophysiological determinants of diabetes, and considerable effort has been expended to define the mechanisms and origins of this process (Kahn and Flier 2000; Shulman 2000; Hotamisligil 2003; Odegaard and Chawla 2008; Olefsky and Glass 2010). These determinants can be classified into cell intrinsic and extrinsic effects. Broadly speaking, cell-intrinsic effects comprise endoplasmic reticulum (ER) stress, intracellular lipid deposition/imbalance, mitochondrial dysfunction, oxidative stress, and anabolic demand, whereas circulating cytokines and adipokines, serum fatty acid composition, and hypoxia are the dominant extrinsic pathways that modulate peripheral insulin signaling (Qatanani and Lazar 2007).
Despite their biological diversity, a striking majority of these determinants converge on the common pathway of inflammation.
Both cell-intrinsic and cell-extrinsic pathways drive intracellular signaling cascades that converge on one or more of a handful of key inflammatory mediators, which, in turn, directly impinge on the insulin signaling pathway (Hotamisligil 2006). Inflammatory cytokines, saturated fatty acids, hypoxia, and ER stress converge on inhibitor of nuclear factor-κB (NF-κB), kinase-β (IKKβ), and Jun kinase (JNK) to directly inhibit insulin action via serine phosphorylation of insulin receptor substrate 1 and 2 (IRS-1 and IRS-2) (Yuan et al. 2001; Hirosumi et al. 2002; Arkan et al. 2005; Cai et al. 2005). In addition, activation of NF-κB and AP-1 transcription factors by these kinases activates transcription of inflammatory cytokines and establishes an autocrine/paracrine feed-forward loop of inflammation (Wellen and Hotamisligil 2005). Similarly, cytokines and adipokines activate multiple suppressor of cytokine signaling (SOCS) proteins (notably SOCS3), which interfere with activating tyrosine phosphorylation of IRS-1 and IRS-2 and target them for proteasomal degradation (Qatanani and Lazar 2007). Irrespective of the precise signaling mechanism, the net effect is a broad and potent inhibition of intracellular insulin signal transduction. Because a full mechanistic discussion of these determinants is beyond the scope of this article (Qatanani and Lazar 2007; Hotamisligil 2010; Lumeng and Saltiel 2011), we focus on metabolic inflammation as a common pathway by which these protean effects drive insulin resistance.
Although the connection between inflammation and insulin resistance has been postulated for decades, the first direct evidence emerged in the early 1990s with the demonstration that TNFα, a known inflammatory mediator, was (1) present in fat in levels proportional to insulin resistance in obese animals and individuals, (2) necessary for obesity-related insulin resistance, and (3) sufficient to recapitulate insulin resistance in lean, otherwise insulin-sensitive animals (Hotamisligil et al. 1993, 1996).
These seminal findings firmly established the relationship between insulin resistance and inflammation within the fat and unleashed a torrent of association studies indicting insulin resistance as a bona fide inflammatory disorder. Insulin resistance has been associated with elevated serum levels of pro-inflammatory cytokines (e.g., IL-1β, IL-6, IL-8, IL-12, and TNFα), chemokines (e.g., MCP-1, RANTES, and MIP-1), acute phase reactants (e.g., C-reactive protein, serum amyloid A, and ferritin), and insulin resistance–associated adipokines (e.g., retinol binding protein-4 and resistin), as well as with decreased serum levels of the so-called negative acute-phase reactants (e.g., transcortin, and transferrin), insulin sensitivity–associated adipokines (e.g., adiponectin, visfatin, omentin, and vaspin), and Th2-type cytokines (IL-4, IL-10) (Shoelson et al. 2006; Qatanani and Lazar 2007; Olefsky and Glass 2010).
ISLET INFLAMMATION AND MACROPHAGES
Macrophages are white blood cells within tissues, acting in both non-specific defense (innate immunity) as well as to help initiate specific defense mechanisms (adaptive immunity). Their role is to phagocytose (engulf and then digest) cellular debris and pathogens either as stationary or as mobile cells, and to stimulate lymphocytes and other immune cells to respond to the pathogen.
Emerging data suggest that the macrophage’s diabetogenic role extends into the islet itself in a manner strikingly similar to that observed in the adipose tissue. For instance, both adipose tissue and islets isolated from both type 1 and type 2 diabetics are characterized by abnormally high macrophage representation in human subjects and animal models (Hutchings et al. 1990; Ehses et al. 2007; Ferrante 2007; Uno et al. 2007; Richardson et al. 2009).
In both instances, this macrophage infiltration parallels the development of peripheral insulin resistance and precedes the emergence of islet-specific immune responses (Dahlen et al. 1998).
Furthermore, increasing macrophage representation within these tissues is correlated with the expression of classical activation markers including IL-1β and TNFα, which abrogate insulin secretion and signaling in the islet and peripheral tissues, respectively (Arnush et al. 1998; Dahlen et al. 1998; Weisberg et al. 2003; Lumeng et al. 2007b). Accordingly, inhibition of macrophage recruitment effectively blunts development and progression of type 1 and type 2 diabetes (Hutchings et al. 1990; Weisberg et al. 2006).
Health-e-Solutions comment: We think the fact that the Health-e-Solutions lifestyle emphasizes foods that are anti-inflammatory is very important. Other research suggests that a very low-glycemic diet, coupled with insulin therapy if necessary, is also fundamental to success in achieving glucose homeostasis and avoiding beta cell stress leading to beta cell depletion. It is helpful to understand that insulin resistance is an inflammatory disorder. We believe dietary choices are a means within our control to help minimize the risk of inflammatory disorders.
There are many different inflammatory diseases, including diabetes, yet all of them share the same underlying driver: an inappropriate inflammatory response. Inflammation impacts the lives of millions of people around the world. It is an epidemic that has been accelerated by the modern western diet. We were not designed to eat primarily the foods that are found most commonly in today’s society. The rising cost of health care is due, in part, to the drastic rise of chronic inflammatory disease.
It is important that we empower ourselves with the knowledge and tools to fight back. One of the Primary Food Filters we employ to help us select only the best foods for thriving health and better #BloodSugarControl is to determine whether or not a food is inflammatory. Our Primary Food Filters downloadable, printable special report will fully equip you to make the best food and ingredient choices following the Health-e-Solutions lifestyle to help you #MasterDiabetesNaturally.