Looking beyond overnutrition for causes of epidemic metabolic disease.

I n 1500 B.C., when the author of the Egyptian papyrus Ebers first described an obscure illness that later became known as diabetes mellitus (from Greek diabetes meaning siphon and Latin or Greek mel meaning honey) (1), he could hardly have envisioned the pandemic of metabolic disease that would take place at the end of the 20th century through the beginning of the 21st century. According to the International Diabetes Federation, diabetes affects ∼366 million people worldwide (2). This number is projected to rise to 552 million by 2030 (2). Additionally, there were 280 million people with impaired glucose tolerance in 2011 (2); this number is projected to increase to 398 million in 2030 (2). Thus, by 2030, close to 1 billion people are expected to have abnormal glucose tolerance. The epidemic of diabetes is accompanied by epidemics of obesity and atherosclerotic heart disease and may have at its roots an insulin-resistant state called the metabolic syndrome (3). Why is this epidemic of metabolic disease taking place now? In PNAS, Cai et al. (4) propose one possible explanation. The contribution of genetics to diabetes is important (5). However, aside from epigenetic effects and the microbiome, it is unlikely that the genetic makeup of humankind has changed significantly in the past 3–4 decades. Therefore, it is generally accepted that the “unholy triumvirate” of obesity, diabetes, and atherosclerosis is probably due to overnutrition, which is spreading in both the developed and developing worlds (6, 7). When they consume more calories than are expended, humans deposit the excess of energy as adipose tissue. This tissue is an active endocrine organ (8), which, if present in excess, contributes to the development of insulin resistance (9). In susceptible individuals with a genetic deficiency of insulin secretion in pancreatic β-cells, this process ultimately leads to diabetes (Fig. 1). The mechanisms by which excessive adipose tissue accumulation, particularly in the intraabdominal space, leads to insulin resistance are still poorly understood but may involve increased production of inflammatory markers [e.g., TNF-α (9–11)] and inadequate production of certain insulin-sensitizing adipokines (e.g., adiponectin) (12). Inflammation is thought to be a key underlying component of these processes (9–11). What triggers inflammation? In a series of elegant and convincing experiments in mice, Cai et al. (4) now may have found a possible “missing link.” They demonstrate that advanced glycation end products (AGEs) are responsible for inducing an inflammatory state, which, in turn, leads to the development of insulin resistance and hyperglycemia. AGEs are formed in tissues and circulation through nonenzymatic glycation of proteins and lipids, and they are also present in abundance in the modern diet (13). The most familiar pre-AGE is glycosylated hemoglobin, a marker widely used for diagnosing and assessing progress in the treatment of diabetes (14). Glycosylated hemoglobin is a predictor of devastating microand macrovascular complications of diabetes (retinopathy, leading to blindness; nephropathy, leading to the loss of renal function; and vasculopathy and neuropathy, contributing to the amputation of extremities) (15, 16). New tests measuring AGEs in circulation, including those absorbed from the diet, have been developed and are poised to enter clinical practice (13). These may offer greater advantages than glycosylated hemoglobin toward early detection and treatment of diabetes as well as prediabetes. Cai et al. (4) fed a diet enriched in methyl-glyoxal (MG) derivatives (highly reactive glycating agents) to mice that were maintained on isocaloric diets with the control animals by pair-feeding, such that confounding by overnutrition was avoided. After several generations, MGfed mice developed increased adiposity and insulin resistance, manifested by increased glucose and insulin levels on intravenous glucose tolerance tests and abnormalities in the insulin-receptor signaling cascade (tyrosine-phosphorylated insulin receptor, IRS-1, IRS-2, and Akt). Insulin-stimulated 2-deoxyglucose uptake by adipose tissue and skeletal muscle was reduced in MG-fed mice. Macrophages and adipocytes shifted to a proinflammatory phenotype, manifested by elevated levels of TNF-α, CD11c, and MCP-1 in adipocytes, stromal vascular cells, and peritoneal macrophages. These changes developed in the third generation of MG-fed Fig. 1. Traditional view (green) of the pathogenesis of diabetes mellitus describes a combination of genetic and environmental factors leading to obesity, insulin resistance, reduced insulin secretion, and hyperglycemia. A more recent approach includes a proinflammatory state contributing to insulin resistance (yellow). The current hypothesis also includes the effects of AGEs (red), which induce a proinflammatory state, increase adiposity, induce insulin resistance, and inhibit insulin secretion (details and references are provided in main text).