The potential role of dietary advanced glycation endproducts in the development of chronic non-infectious diseases: a narrative review.

Increasing clinical and experimental evidence accumulated during the past few decades supports an important role for dietary advanced glycation endproducts (AGE) in the pathogenesis of many chronic non-infectious diseases, such as type 2 diabetes, CVD and others, that are reaching epidemic proportions in the Western world. Although AGE are compounds widely recognised as generated in excess in the body in diabetic patients, the potential importance of exogenous AGE, mostly of dietary origin, has been largely ignored in the general nutrition audience. In the present review we aim to describe dietary AGE, their mechanisms of formation and absorption into the body as well as their main mechanisms of action. We will present in detail current evidence of their potential role in the development of several chronic non-infectious clinical conditions, some general suggestions on how to restrict them in the diet and evidence regarding the potential benefits of lowering their consumption.

Analysis of the interaction between transcription factor 7-like 2 genetic variants with nopal and wholegrain fibre intake: effects on anthropometric and metabolic characteristics in type 2 diabetes patients.

The transcription factor 7-like 2 (TCF7L2) genetic variants have shown differential effect on low-fat and high-fat diet in obese subjects. Nopal is a Mexican variety of cactus that is a traditional food and has been used in the treatment of diabetes. Its hypoglycaemic effect may be because of its soluble fibre (mucopolysaccharide) content. This study analysed the effects of the rs7903146 and rs12255372 TCF7L2 variants on anthropometric, metabolic and hormonal parameters in type 2 diabetes mellitus patients who consumed fibre from either nopal tortilla or wholegrain bread for 8 weeks. We followed-up seventy-four patients who consumed an individualised isoenergetic diet that included nopal tortilla (Diet 1) and sixty-three patients with a diet that included wholegrain bread (Diet 2). Anthropometric, metabolic and hormonal measures were collected at baseline and final intervention. The size effect and carry-over effect were estimated. To assess the interaction of genotype and diets, we used a general linear model repeated-measures analysis. Minor allele frequency of rs7903146T was 0·27 and for rs12255372T it was 0·13. At 8 weeks after Diet 1 intake, weight, BMI, waist and hip circumference decreased (P=0·00015) in rs7903146CC and rs12255372GG genotypes. In particular, patients carrying of the rs7903146CC and consuming Diet 1 showed a reduction in waist circumference of more than 2·5 cm compared with Diet 2 (P<0·001). No significant interaction between rs7903146 or rs12255372 and diet was seen in this study. In conclusion, in the carriers of the rs7903146CC and rs12255372GG wild types, significant changes in all anthropometric measures were observed, and had better response to both diets.

Markers of the progression of complications in patients with type 2 diabetes: a one-year longitudinal study.

Hyperglycemia induces tissue damage and complications by mechanisms that produce advanced glycation end-products (AGEs) and inflammation.To investigate the factors associated with the progression of complications in Type 2 diabetes patients.We recruited 157 patients (110 women and 47 men) with diabetes for more than 5 years who were non-smokers and did not have current infections or chronic diseases. Patients were grouped according to neuropathy, nephropathy, and retinopathy status: without (I), slight or moderate (II), and severe complications (III). We measured glucose, lipids and HbA1c, low molecular weight AGEs (LMW AGEs), high sensitivity C-reactive protein (CRP), TNF-α, IL-6, and malondialdehyde (MDA). Patients were re-evaluated 1 year later.Patients were 52.2±6.8 years old with 11.0±4.9 years since diagnosis. After 1 year, circulating AGEs increased (p<0.0001) and eGFR decreased (p<0.0007) in groups II and III. IL-6 and MDA decreased in groups I and II. CRP (p<0.029) and AGEs (p<0.0001) increased in group II. At baseline in group I, TNF-α levels were higher (p<0.002) in patients who later developed complications. In group II, TNF-α levels (p<0.015) and microalbuminuria (p<0.00004) were higher in patients whose complications progressed. Logistic regression analysis showed that complication progress was significantly associated with log(albuminuria) (p<0.004) and log(TNF-α) (p<0.008). In the total group, AGEs were associated with age (p<0.024) and HbA1c (p<0.026).Our results suggest that baseline TNF-α is an important predictor of complication progression in Type 2 diabetes patients. AGEs also increased during the deterioration of renal function after 1 year of follow-up observation.

Telomere length and type 2 diabetes in males, a premature aging syndrome.

BACKGROUND: Increased telomere shortening has been demonstrated in several diseases including type 2 diabetes. However, it is not known whether telomere length changes during the course of type 2 diabetes. OBJECTIVE: To determine telomere length at different stages of type 2 diabetes, including early and late stages. METHODS: A total of 93 males with type 2 diabetes and 10 years or more since original diagnosis; 96 males with less than one year of diagnosis; 98 age matched healthy males. Telomere length was estimated by means of real-time polymerase chain reaction. Fasting venous blood samples were obtained for measurement of lipid peroxidation and inflammation markers. RESULTS: We found a greater telomere shortening in group (A) with type 2 diabetes of 10 years or more since original diagnosis, compared with the control group (C) of healthy males (5.4 vs 9.6 Kb) (p = 0.04) and with group B (5.4 vs 8.7 kb) (p = 0.05). With regard to inflammatory markers TNF-α, malondialdehyde peroxidation and adiponectin we found significant differences. CONCLUSION: Telomere shortening increases with the duration of diabetes. The time of exhibition suggests in parallel that the progressive increase of inflammation and/or oxidative stress plays a direct role in telomere shortening.

Advanced glycosylation end products in skin, serum, saliva and urine and its association with complications of patients with type 2 diabetes mellitus.

BACKGROUND: The accumulation of advanced glycation end products (AGEs) has a key role in the pathophysiology of diabetes complications. Comparison of AGEs measurement in serum, skin, saliva and urine has not been reported. AIMS: To compare AGEs in serum, skin, saliva and urine in patients with Type 2 diabetes mellitus, with complications at different stages. MATERIALS AND METHODS: We examined 50 patients with Type 2 diabetes mellitus (40 women and 10 men) grouped according to the progression of neuropathy, nephropathy and retinopathy. The AGEs content in serum, skin, saliva and urine was measured by spectrofluorometry HPLC. RESULTS: The patients had a mean age of 56.5 +/- 7.7 yr and 12.8 +/- 6.7 yr since diagnosis. AGEs in skin correlated with years since diagnosis (p = 0.0005). AGEs in serum, skin and saliva increased with the progression of complications, nevertheless, in urine a trend to diminution was found. In the group with end-stage renal disease (ESRD), AGEs in serum increased in greater proportion. In order to account for the decreased AGEs clearance, we corrected the values for creatinine levels, and AGEs in skin gave a better association with complications. CONCLUSIONS: The AGEs measurement in skin, serum and saliva are useful to evaluate diabetes complications. AGEs in skin are associated with years since diagnosis of diabetes. Correction for renal function might discriminate AGEs in situ formation from accumulation.

Clinical and radiological improvement of periodontal disease in patients with type 2 diabetes mellitus treated with alendronate: a randomized, placebo-controlled trial.

BACKGROUND: Alendronate (ALN) is an aminobisphosphonate commonly used for osteoporosis in postmenopausal women. We studied the effect of ALN on bone loss prevention in type 2 diabetes mellitus patients with periodontal disease. METHODS: In a controlled double-blind, randomized study we evaluated prospectively diabetic patients paired by gender and years since diagnosis for 6 months. The study included 40 patients (20 men and 20 women), 50 to 60 years old, with more than 5 years since diagnosis of diabetes and established periodontitis. They were randomly allocated to alendronate (10 mg/daily) or placebo treatment for 6 months. The endpoints of treatment were: the distance between the alveolar bone border and the cemento-enamel-junction (CEJ) evaluated by means of digital radiographic imaging, a biochemical marker of bone resorption (urine N-telopeptide) (Ntx), and periodontal parameters. Metabolic control was assessed at baseline and after 6 months. RESULTS: Baseline and 6-month glycated hemoglobin levels were similar in both groups. Alendronate induced a significant decrease in NTx at 6 months (P = 0.006). Periodontal parameters improved in both groups. However, they were significantly better for the ALN treated group. Alveolar bone border-CEJ distance increased in the placebo, but decreased in the ALN group (P = 0.0003). CONCLUSIONS: In type-2 diabetic patients, alendronate induced more improvement in alveolar bone crest height than control therapy. No differences in urinary N-telopeptide or glycated hemoglobin were observed in this short-term randomized controlled pilot trial.

Perceived psychological stress in diabetes mellitus type 2.

We studied the factors associated with perceived psychosocial stress in patients with diabetes mellitus type 2. A cross-sectional study was carried out in 105 patients (27 men and 78 women) with a mean age of 51.6 (50.2-52.5, 95% CI) years and 8.6 (7.3-9.8, 95% CI) years since diagnosis. The patients were overweight with body mass index (BMI) of 27.6, and most of them had deficient metabolic control (mean glucose of 10.6 nmol/L and HbA1c of 9.2%). Glycated hemoglobin was associated with BMI (negatively, p = 0.002), with adherence to diet (negatively, p = 0.027) and with years since diagnosis (p = 0.031). The association with BMI was found only in women. It was explained by the fact that obese women had fewer years since diagnosis, and recently diagnosed patients have a better metabolic control. A stepwise multiple regression analysis showed perceived stress associated with percent body fat and blood glucose in the total group, with years since diagnosis in women (p = 0.02), and with BMI in men (p = 0.03). No association was found between perceived stress and adherence to treatment. We concluded that in our group, perceived stress was associated with obesity and metabolic control.

Advanced glycosylation end products (AGEs), insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) in patients with type 2 diabetes mellitus.

BACKGROUND: Advanced glycosylation end product (AGE) formation is a major mechanism for the development of complications in diabetes, and the possible roles of insulin-like growth factor 1 (IGF-1) and IGF binding protein 3 (IGFBP-3) are not clearly established. METHODS: We examined the associations of AGEs, free IGF-I and IGFBP-3 in Type 2 diabetes mellitus (DM) patients under diverse conditions. In a cross-sectional design we studied 110 subjects (67 women and 43 men): non-diabetic controls in group 1, (n = 15) and diabetes patients as follows: group 2, without complications (n = 25); group 3, with chronic complications (n = 25); group 4, with acute or chronic infections (n = 24); group 5, hospitalized for reasons unrelated to diabetes (n = 9); group 6, with end-stage renal disease (ESRD) (n = 12). AGEs were determined by a spectrofluorometric method (HPLC). Insulin and IGFBP-3 were measured by RIA and free IGF-1 with an IRMA method. RESULTS: AGEs were 13-fold higher in patients with ESRD (p<0.001), and lower in healthy individuals. Free IGF-1 was lower in the patients with complications (p = 0.017), with infections (p = 0.006) and hospitalized (p = 0.04). IGFBP-3 was higher in hospitalized patients (p=0.017). AGEs were associated with free IGF-1 (r = 0.41, p = 0.04) in the group with complications, and with HbA(1c) (r = -0.90, p = 0.002) in hospitalized patients. In the total group, free IGF-1 (r = -0.25, p = 0.008), and IGFBP-3 (r = -0.22, p = 0.021) were associated with HbA(1c). CONCLUSION: We concluded that AGEs were markedly increased in diabetic patients with ESRD, IGF-1 was decreased in patients with infections and hospitalized, and was negatively associated with HbA(1c). IGFBP-3 was increased in hospitalized patients, with higher levels in patients with long bone fractures. A complex interaction of humoral factors may participate in the acceleration of complications of diabetes.

Plasma epinephrine and norepinephrine response to stimuli in autonomic neuropathy of type 2 diabetes mellitus.

The objective of this study was to examine epinephrine and norepinephrine plasma levels in patients with clinical type 2 diabetes mellitus, at different stages of autonomic neuropathy. Eighteen patients were classified in groups without (n = 6) and with early (n = 6), definite (n = 3) and severe (n = 3) neuropathy. Blood catecholamine levels were measured after the Valsalva maneuver, cold exposure and orthostatic tests. The norepinephrine basal levels were lower in patients with severe neuropathy (0.4 +/- 0.2 nmol/l), compared with the group with no neuropathy (1.3 +/- 0.5 nm/l, p = 0.034), or with early neuropathy (1.3 +/- 0.7 nm/l, p = 0.035). After the Valsalva maneuver, no increase was found in the group with severe alteration. In patients without neuropathy, cold exposure induced a peak of norepinephrine at 5 min (delta = 1.9 +/- 1.6 nmol/l). The increase was lower in groups with definite and severe damage. In patients with definite or moderate neuropathy, the orthostatic test induced minimal or no response. The epinephrine response to the maneuvers was not significant, and no differences were found among the groups. Norepinephrine basal levels and cold responses are diminished in patients with definite and severe autonomic neuropathy. This provides further evidence on their impaired response to stress. The comparable epinephrine levels in patients with or without autonomic neuropathy indicates that adrenal medullar function is not significantly altered.

Denial of disease in Type 2 diabetes mellitus: its influence on metabolic control and associated factors.

AIMS: We have investigated denial of disease in patients with Type 2 diabetes mellitus (DM) and its possible association with metabolic control, and with psychosocial variables: satisfaction with medical care, perceived stress, social support, knowledge of diabetes and belief in conventional medicine. METHODS: We studied 160 patients in a cross-sectional design, in two groups: with (70) and without social security coverage (90). The mean age for the total group was 53.6 years, with a known diabetes duration of 8.1 years. RESULTS: Denial of disease was similar in those with < or = 5 years since diagnosis (73 patients) and with > 5 years (87). The group without social security had higher scores of perceived stress, and lower scores of social support, knowledge about diabetes and belief in conventional medicine; denial, however, was similar in the two groups with or without social security. Multiple regression analysis showed that denial of disease was positively associated with HbA1c in the total group (P < 0.001), in the groups with < or = 5 and > 5 years since diagnosis, as well as in the groups with or without social security. Denial was also associated with years since diagnosis (P = 0.009) for the group with < or = 5 years since diagnosis. CONCLUSIONS: We concluded that, in patients with Type 2DM denial of disease increases with time during the first 5 years of evolution of diabetes; is associated with poor metabolic control; but is not associated with knowledge of diabetes, belief in conventional medicine, social support or perceived stress.

The belief in conventional medicine and adherence to treatment in non-insulin-dependent diabetes mellitus patients.

We investigated the role of belief in conventional medicine, the type of medical care, and familiar and socioeconomic factors on the adherence to treatment in non-insulin-dependent diabetes mellitus (NIDDM) patients. In a cross-sectional design, we selected 156 patients from two institutions, who agreed to fill out a questionnaire, which included general data, socioeconomic level, somatometric data, type of medical care, complications, if they had friends and relatives with diabetes, the family function, and a score on the belief in conventional medicine. Factors associated with adherence to diet and medication were analyzed. Patients had a mean age of 55.6 years and 8.9 years since diagnosis. A total of 51.3% of them were not covered by social security, and 62.8% received attention by a general physician. Patients under the care of a specialist had better adherence to diet and medication, and better belief in conventional medicine. The principal factor associated with adherence to medication and diet was the belief in conventional medicine (p < 0.001 in both). Adherence to diet was also associated with the socioeconomic level (p=0.001) and years since diagnosis (p=0.004). Adherence to medication was also associated with schooling (p=0.001). We concluded that belief in conventional medicine is strongly associated with adherence to treatment and other factors such as schooling, socioeconomic level, and medical care under a specialist; adherence to diet was better in patients with more years since diagnosis.

Novel analytical approach to monitoring advanced glycosylation end products in human serum with on-line spectrophotometric and spectrofluorometric detection in a flow system.

We proposed a simple analytical procedure for measurement of serum advanced glycosylation end products (AGEs) based on simultaneous detection of low-molecular-mass peptides and AGEs with a flow system and two detectors connected on-line: spectrophotometric for peptides (lambda = 280 nm) and spectrofluorometric for AGEs (lambda ex = 247 nm, lambda em = 440 nm). Sample pretreatment was carried out in microcentrifuge tubes: Serum (20 microL) was deproteinized with trichloroacetic acid (480 microL, 0.15 mol/L) and lipids were extracted with chloroform (100 microL). Twenty microliters of the filtered aqueous layer was injected to the flow system and the relation between fluorescence and absorption signals was measured. A peptide-derived AGE calibrator was used for calibration. Within-day and between-day CVs were 6.7% and 9.1%, respectively, at an AGE concentration corresponding approximately to that in healthy individuals. Mean results (+/-SD) in 10 healthy individuals were 10.1% +/- 1.0%, in 21 patients with diabetes without complications 18.0% +/- 6.2%, in 25 patients with complications 24.1% +/- 15.4%, and in 12 diabetic patients in end-stage renal disease 92% +/- 30%. Comparison with an ELISA procedure (x, in arbitrary units/L) yields a regression equation y = 0.713x + 1.24 (Sy [symbol: see text] x = 6777, r = 0.8477, n = 41).

Adherence to treatment and social support in patients with non-insulin dependent diabetes mellitus.

We carried out a cross-sectional study to investigate factors associated with adherence to diet and medication in non-insulin-dependent diabetes mellitus (NIDDM) patients. A total of 200 patients not seeking treatment from clubs for diabetics from two hospitals in León, Mexico, accepted inclusion. Patients interviewed had a mean age of 58.8 (53.3-56.4, 95% C.I.) years. We evaluated adherence to diet and medication, knowledge on diabetes, social support, family's structure and functioning (with a modified McMaster model), metabolic control, and complications. Stepwise multiple regression procedure showed that adherence to diet was associated with years since diagnosis (p = 0.003) and with social support (p = 0.007). Adherence to medication was associated with social support (p = 0.002), and the age of the spouse (p = 0.016). Adherence to medication was lower in patients from families with rigid control than in the group with Laissez-faire type of control (p = 0.010) or the group with flexible control (p = 0.002). Social support was lower in the group with chaotic control than that in the group with flexible control (p < 0.001). Compliance to diet was associated with peripheral neuropathy and plasma creatinine, and adherence to medication with plasma glucose and peripheral neuropathy. We concluded that (1) adherence to treatment in NIDDM patients is associated with social support; (2) some aspects related to the family, such as the age of the spouse and the control of behavior, were also associated with compliance to treatment; and (3) it is important for the practicing physicians, and for institutional programs, to consider factors associated with adherence to treatment.