Innate Immunity Connects Type 1 and Type 2 Diabetes
The escalating epidemic of obesity has driven the prevalence of both type 1 and 2 diabetes mellitus to historically high levels. Chronic low-grade inflammation, which is present in both type 1 and type 2 diabetics, contributes to the pathogenesis of insulin resistance. The accumulation of activated innate immunity cells in metabolic tissues results in release of inflammatory mediators, in particular, IL-1β and TNFα, which promote systemic insulin resistance and beta-cell damage. In this article, we discuss the central role of innate immunity and, in particular, the macrophage in insulin sensitivity and resistance, beta-cell damage, and autoimmune insulitis. We conclude with a discussion of the therapeutic implications of this integrated understanding of diabetic pathology.
The past 30 years have borne witness to one of the most dramatic phenotypic shifts in humankind’s history. We have, in an evolutionary eyeblink, become fat. Within a single generation, the obesity epidemic has swept from Western cultures into the developing world, leaving behind an estimated 1.5 billion overweight individuals, of which 500 million are clinically obese (Flegal et al. 2010). The public health burden associated with our waxing waistlines is staggering. In 2000 alone, an estimated 400,000 people died from obesity-related diseases in the United States alone, putting obesity on par with smoking in terms of lives lost (Mokdad et al. 2004, 2005).
These grim trends have been more quietly paralleled by a similarly dramatic increase in type 1 diabetes incidence. Type 1 diabetes incidence has more than doubled in the past 20 years and is set to double again before 2020 (Patterson et al. 2009). Unexpectedly, however, the surplus incidence is not uniformly distributed.
The incidence of type 1 diabetes in high-risk HLA types over the past 20 years has remained stable, whereas the contemporaneous incidence in medium-, low-, and very-low-risk genotypes has increased by twofold, threefold, and sevenfold, respectively (Fourlanos et al. 2008b).
Importantly, these “surplus” type 1 diabetics show a remarkable tendency toward obesity and insulin resistance, often meeting full criteria for type 2 diabetes and mimicking the trends seen in obesity-related type 2 diabetes (Fourlanos et al. 2008b). Indeed, prospective cohort studies have shown that children who go on to develop type 1 diabetes are heavier than their peers who remain free of disease (Baum et al. 1975; Johansson et al. 1994; Hypponen et al. 1999, 2000; Bruining 2000) and that within type 1 diabetics, increasing BMI strongly correlates with earlier presentation (Kibirige et al. 2003; Betts et al. 2005; Knerr et al. 2005; Kordonouri and Hartmann 2005; Dabelea et al. 2006). Moreover, obesity-related insulin resistance not only precedes clinical disease but is also the strongest predictor of type 1 diabetes aside from HLA genotype (Baum et al. 1975; Johansson et al. 1994; Hypponen et al. 1999, 2000; Bruining 2000; Xu et al. 2007; Fourlanos et al. 2008a). Finally, insulin-sensitizing drugs and interventions (e.g., weight loss, exercise) are effective in preventing, delaying, and even partially reversing type 1 disease (Kjems et al. 2003; Miller and Silverstein 2006; Kilpatrick et al. 2007; Moon et al. 2007; Neovius et al. 2008).
These data exemplify fundamental shifts in diabetes demographics in which expanding Western waistlines have blurred the once crisp distinction between type 1 and type 2 diabetes mellitus. Indeed, Himsworth’s world in which type 1 diabetes was epitomized by the spindly child and type 2 diabetes limited to the corpulent middle-aged gourmand no longer exists (Himsworth 1939). Some recent series, for example, record more than half of all newly diagnosed type 1 diabetics as adults, many of whom meet criteria for metabolic syndrome (Molbak et al. 1994; Thorn et al. 2005), whereas type 2 diabetes is now a common disease of children, many of whom are positive for anti-beta-cell antibodies.
The startling prevalence of patients, children in particular, meeting criteria for both type 1 and type 2 diabetes has left a confused flurry of vague terminology in its wake: “double diabetes,” “type 1.5 diabetes,” “hybrid diabetes,” “latent autoimmune diabetes of the young (LADY) and of the adult (LADA),” and so on (Pozzilli and Guglielmi 2009; Wilkin 2009). Irrespective of classification schema, the advent of near-ubiquitous obesity has expanded the once tight circles of type 1 and type 2 diabetes to a degree that obesity-related insulin resistance has become a driving etiologic force across the diabetes spectrum.
Recognition of insulin resistance’s catastrophic health sequelae has engendered intense interest in its pathophysiology and led to the identification of literally hundreds of dietary, behavioral, and environmental disease modifiers (Kahn and Flier 2000; Shulman 2000; Wellen and Hotamisligil 2005, 2006; Qatanani and Lazar 2007; Olefsky and Glass 2010). Despite the daunting complexity of inputs and modifiers, the vast majority converge on a single sentinel pathophysiology: chronic, low-level inflammation (Hotamisligil 2006; Shoelson et al. 2006; Odegaard and Chawla 2008; Olefsky and Glass 2010; Lumeng and Saltiel 2011). In this context, innate immunity has emerged as a primary determinant of obesity-related pathology including the full spectrum of diabetic disease.
The diabetogenic environment has changed dramatically in recent decades such that our traditional dualistic concept of type 1 and type 2 diabetes is no longer operable. Rather, obesity, inactivity, dietary indiscretion, and other environmental trappings of the modern world have positioned inflammatory insulin resistance as the driving factor across the diabetic spectrum.
Indeed, perhaps the most common presentation of type 1 diabetes is now in a young type 2 diabetic.
Recognition of inflammation-induced insulin resistance as a primary etiologic determinant across the modern diabetes landscape has important therapeutic implications.
Indeed, therapeutic approaches originally limited to type 2 diabetes—for example, weight loss, exercise, and insulin-sensitizing agents – have shown remarkable efficacy in preventing/slowing type 1 disease as well (Kjems et al. 2003; Miller and Silverstein 2006; Kilpatrick et al. 2007; Moon et al. 2007; Neovius et al. 2008; Pozzilli and Guglielmi 2009), confirming the validity of integrated diabetes therapy.
With these approaches, therapies have begun not only to stave off relentless beta-cell destruction but, for the first time, to actually rebuild beta-cell mass by tapping the inherent regenerative capacity of beta-cells (Meier et al. 2005).
One salient example of such a resurrection therapy is the IL-1β-targeted therapeutics. This class of agents—typified by anakinra, a competitive IL-1R antagonist—has shown remarkable promise in both type 1 and type 2 disease. As mentioned above, IL-1β—a pro-inflammatory mediator produced in spades in inflammatory insulin resistance—potently inhibits insulin secretion and induces beta-cell apoptosis (Poitout and Robertson 2008) in addition to directly inhibiting insulin activity in the periphery (Yuan et al. 2001; Hirosumi et al. 2002; Arkan et al. 2005; Cai et al. 2005). Congruent with these observations, overexpression or exogenous administration of the naturally occurring inhibitor of IL-1β signaling, IL-1R antagonist (IL-1Ra), has shown potent therapeutic effect in animal models and pilot studies (Osborn et al. 2008; Sauter et al. 2008; Owyang et al. 2010) where, remarkably, these interventions not only halted disease progression but actually reversed beta-cell loss (Tellez et al. 2005), showing that even a battered reserve of beta-cells is sufficient to repopulate the islet. Indeed, a recent clinical trial confirmed the therapeutic efficacy of IL-1R antagonism in established type 2 diabetics (Larsen et al. 2007) and provided practical justification for similar efforts in progress in type 1 disease (Mandrup-Poulsen et al. 2010).
The efficacy of these integrated, innate immunity-targeted therapeutic approaches—in addition to providing desperately needed therapeutic options—underscores the importance of inflammatory insulin resistance across the diabetic spectrum and reiterates the continued role of innate immunity in human health and disease.
Health-e-Solutions comment: We believe, along with these researchers, that obesity, inactivity, dietary indiscretion, and other environmental trappings of the modern world have positioned inflammatory insulin resistance as the driving factor across the diabetic spectrum. Recognition of inflammation-induced insulin resistance as a primary etiologic determinant across the modern diabetes landscape has important therapeutic implications. We think an anti-inflammatory diet and lifestyle can have great impact on disease development and progression, regardless of the classification of diabetes type.
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.