Insulin resistance (IR) is commonly observed during aging and is at the root of many of the chronic nontransmissible diseases experienced as people grow older. Many factors may play a role in causing IR, but diet is undoubtedly an important one. Whether it is total caloric intake or specific components of the diet, the factors responsible remain to be confirmed. Of the many dietary influences that may play a role in aging-related decreased insulin sensitivity, advanced glycation end products (AGEs) appear particularly important.
1. Introduction
Insulin resistance (IR) is a pathophysiological condition in which organs—mostly skeletal muscle, adipose tissue, and liver—do not respond at an adequate rate to insulin, and it is considered to be a consequence of the disruption of different molecular pathways affected by insulin in these tissues
[1]. In the general population, sensitivity to insulin-mediated glucose disposal in several tissues varies greatly
[2]. The major consequence of IR, type 2 diabetes, arises when people who are insulin-resistant are unable to maintain the level of hyperinsulinemia required to correct the insulin action deficiency. Clinically, it appears as a defect in insulin-mediated glucose control in tissues, prominently in the above named muscle, fat and liver. Primary characteristics of IR are inhibited lipolysis in adipose tissue, impaired glucose uptake by muscle and inhibited gluconeogenesis in liver
[3]. Therefore, IR also encompasses defects in lipid metabolism, in line with the multifaceted roles of insulin in metabolism regulation
[4]. IR is one of the earliest manifestations of a constellation of human pathologic conditions that include metabolic syndrome, type 2 diabetes, cardiovascular diseases and aging
[5]. Lifestyle modifications, including reduced intake of ultraprocessed foods containing advanced glycation (AGEs) and lipo-oxidation end products (ALEs), body weight loss and increased physical activity, have been shown to increase insulin sensitivity, thereby preventing IR
[6][7].
Whether total caloric intake with body fat accretion or the presence of specific nutrients or diet-derived insulin-signaling disruptors is mostly responsible for the IR of aging is unclear
[8]. Of the many dietary factors that may play a role in the aging-related lack of or decreased insulin sensitivity, AGEs appear potentially important. Recent clinical data suggest that food-derived AGEs may contribute to IR
[9].
2. Evidence of an Association between Dietary AGEs and IR
2.1. Animal Data
A role of dietary AGEs as a causative agent in IR has been well documented in several studies in different mouse strains by independent teams. Researchers review some of these studies here and in
Table 1. Reduced AGE intake leads to lower levels of circulating AGEs and to improved insulin sensitivity in the db/db mouse IR model
[10]. To demonstrate this, db/db mice were randomly placed for 20 weeks (more than 50% of their usual life span) on a diet with either low AGE content (LAGE) or a 3.4-fold higher content of AGEs (HAGE). LAGE mice showed lower fasting plasma insulin levels and body weight compared with HAGE mice, despite equal caloric intake. LAGE mice had improved responses to both glucose (at 40 min,
p = 0.003) and insulin (at 60 min,
p = 0.007) tolerance tests, which correlated with a doubling of glucose uptake by adipose tissue. LAGE mice had twofold lower serum carboxymethyllysine (CML) and methylglyoxal (MG) concentrations and a better-preserved structure of pancreatic islets compared with HAGE mice
[10]. Thus, the effect of dietary AGEs affects multiple tissues (liver, adipose tissue, pancreas), leading overall to impaired metabolism.
Table 1. Selected animal studies showing an association between dietary AGEs and IR.
Author, Reference |
Animal Model |
Study Design |
Intervention |
Findings |
Hofmann [10] |
Db/Db mice (5 week old) |
Dietary intervention with random assignment into two parallel groups for 20 weeks (n = 20) |
High versus low AGE diets |
Lower body weight, lower serum AGEs, better response to both glucose and insulin tolerance tests and better preservation of pancreatic islets than with the high AGE diet |
Sandu [11] |
C57/BL6 female mice (6 week old) |
Dietary intervention with random assignment into two parallel groups for 6 months |
High fat (35% fat) high AGE diet (HAGE-HF) versus High fat low AGE diet (LAGE-HF) |
None of the LAGE-HF mice became diabetic, while 75% of HAGE-HF did. |
Cai [12] |
C57/BL6 |
Dietary intervention with random assignment into three parallel groups for 18 months |
Pair-fed three diets throughout life: (1) low AGE (MG−) *, (2) MG supplemented low AGE chow (MG+) and regular chow (Reg) |
Older MG+ and Reg fed mice developed IR (higher fasting insulin levels and abnormal intraperitoneally glucose tolerance test) and dementia, which did not happen in MG− mice. |
32]. Since circulating AGE levels appear to be useful surrogates of dietary AGE exposure, their lack of change during the study raises the possibility that the dietary intervention might not have been effective.
A second study also failed to show a relationship between dietary AGE restriction and changes in insulin sensitivity
[30]. However, several key facts, mainly related to differences in the composition and methods to measure AGEs of the experimental diets, could help clarify the inconclusive outcome of the study in comparison with other studies. For example, mass-spectrometry-based AGE measurement may differ profoundly in the content of several bio-accessible AGE products assessed by immunological measurements such as ELISA. Moreover, in those studies showing a clear effect of dietary AGEs in IR, dietary AGEs were delivered mostly by ingestion of meats and animal products, highly processed and cooked at high temperatures, while in this negative study
[30], most dietary AGEs came predominantly from cereals and were based on dietary frequency in a specific Dutch population
[33]. Processing of samples before AGE measurement, particularly the inclusion or not of delipidation, may also be relevant, as AGE content in dietary lipids is important
[34]. All these points emphasize that standardization is a key factor in designing dietary interventions. Of interest, individual factors, such as ethnicity and age, may also be relevant in interpreting insulin sensitivity tests
[35][36]. Genotypic characteristics have been shown to influence interaction with dietary AGEs (for example, FADS2 (definer) polymorphisms)
[37]. Lastly, intervention length is key in interpretating data employing methods with a high interindividual variation, such as the hyperglycemic–euglycemic clamp, which in the case of the cited negative study showed a 50% standard deviation over the mean values
[30]. In fact, a prior randomized controlled trial employing isotope-based euglycemic clamps showed that insulin sensitivity changed only after a six-month intensive weight-loss and exercise program
[6].
2.4. Clinical Trials with Mediterranean and Vegan Dietary Patterns Support the Association between Dietary AGEs and IR in Humans
The above studies (
Table 2) show that—generally, although not universally—reducing dietary AGE intake can diminish IR markers. One of the limitations of these studies is that they are of short duration. A longer study, CORDIOPREV, indirectly evaluated the potential impact of dietary AGEs in IR
[38]. Reduction in serum AGE levels in subjects following a Mediterranean diet as part of the CORDIOPREV study, lasting for 5 years, was shown to increase significantly the probability of type 2 diabetes remission, a hard measure of IR. All participants had previous cardiovascular events and type 2 diabetes when recruited
[38].
In a cohort of overweight subjects (
n = 244) randomly assigned to an intervention with a low-fat plant-based diet (
n = 122) or a control diet (
n = 122) for 16 weeks, dietary AGE consumption decreased on a low-fat plant-based diet, and this was associated with changes in body weight, body composition, and insulin sensitivity, independently of energy intake
[39].
Therefore, the epidemiological data and most of the interventional studies in humans support a long-term reduction in dietary AGEs being associated with an improvement in clinically relevant outcomes (insulin sensitivity, weight loss, probability of type 2 diabetes remission) requiring minimal time for revealing its beneficial effects.
Table 2. Summary of selected clinical trials evaluating the effect of an AGE-restricted diet on insulin resistance.
Author, Year, Reference |
Study Design |
Intervention |
Number of Participants |
Randomized |
Participant Characteristics |
Duration and Allocation |
Specified Outcomes |
Findings |
Birlouez, 2010 [64] |
Crossover |
High- and low-AGE diets |
62 |
Yes |
Healthy individuals |
1 month, France |
Changes in serum AGEs and HOMA |
Decreased serum AGEs and HOMA |
Uribarri, 2011 [70] |
Parallel |
High- and low-AGE diets |
18 |
Yes |
Patients with diabetes |
3 months, USA |
Changes in serum AGEs, markers of OS and inflammation and HOMA |
Decreased levels of serum AGEs, markers of OS *, inflammation and HOMA |
Luevano-Contreras 2013 [71] |
Parallel |
High- and low-AGE diets |
26 |
Yes |
Patients with diabetes |
1.5 months, Mexico |
Changes in serum AGEs, markers of OS and inflammation and HOMA |
Decreased markers of OS and inflammation, but no changes in serum AGEs or HOMA |
Wang [13] |
C57/BL6 male mice (12 week old) |
Dietary intervention with random assignment into three parallel groups for 24 weeks |
Three parallel diets: (1) regular chow (n = 10), (2) regular chow + MG (n = 15) or (3) heat-treated chow (n = 15) |
IR (high fasting insulin, HOMA and abnormal intraperitoneal glucose tolerance test) developed in groups 2 and 3, but not 1. Microbiota was also altered in groups 2 and 3 (not in group 1) leading to loss of butyrate-producing bacteria |
Mastrocola [14] |
Db/Db and C57/BL6 mice |
Dietary intervention followed by pharmacological intervention in the C57/BL6 mice |
C57/BL6 mice were randomly assigned to 4 groups for 12 weeks: (1) standard diet, (2) high fat diet (60%trans-fat), (3) standard diet + pyridoxamine for last 8 weeks, (4) high fat diet + pyridoxamine for last 8 weeks |
High levels of AGEs and RAGE and abnormal enzymes of sphingolipid metabolism were found in the liver of Db/Db and group 2 C57/BL6, but not in groups 1, 3 and C57/BL6 |