Introduction

Diabetes currently affects over 425 million people worldwide, and it is predicted to rise to be 642 million people in 2040, which represents a 50% more than the actual records; as a consequence, complications derived from diabetes will increase too¹. In Mexico, approximately 1 out of 10 adults are affected with type 2 diabetes (T2D), which represents a health burden for the country and is among the leading causes of death². Moreover, the T2D prevalence in younger age groups has increased; at present, there are more cases of children and adolescents affected (25% of diabetes cases in Mexico occur in young adults under 43 years of age)³. Hence, T2D is a complex disease to manage not only because of the lack of timely detection and the multiple complications it generates but also because addressing its causes and reducing its risk factors goes beyond the traditional limits of the health system.

It is estimated that half of patients with diabetes are unaware of their disease and they are thus more prone to developing diabetic complications⁴. An observational study of 28 countries in Asia, Africa, South America, and Europe reported that half of patients with T2D showed microvascular complications and 27% had macrovascular complications. Specifically, neuropathy was the highest microvascular complication reported in all regions, ranging from 25% in South Asia to 83% in Russia⁵. The global prevalence of diabetic neuropathy (DN) is approximately 30% in hospitalized diabetic patients and 20-30% in community-based diabetic patients⁶. Diabetic neuropathies are a heterogeneous group of disorders with diverse clinical manifestations, with the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after exclusion of other causes⁷. In Mexico, diabetes complications account for the 24.5-34.9% and DN prevalence varies from 17.1% to 81.1%; however, the studies in this field are scarce⁸,⁹. Furthermore, despite that 41.2% of the population in Mexico presented burning, pain or loss of sensitivity in the feet as reported by the ENSANUT MC 2016 (Encuesta Nacional de Salud Medio Camino 2016), only 20.9% of T2D patients reported a feet annual revision¹⁰.

The typical symptoms of DN can be found in up to 50% of T2D patients¹¹. Nevertheless, due to patients do not experimented symptoms in the course of mild neuropathy it is hard to identify subclinical DN, coupled with the fact that it starts to develop earlier than considered, as early as prediabetes¹². Results from several studies suggest that risk factors for DN include diabetes duration, levels of hemoglobin A1C (HbA1c), dyslipidemias, retinopathy, smoking, high body mass index (BMI), and hypertension, among others¹³-¹⁵. Consequently, the identification of risk factors could be helpful in the prevention and early diagnosis of DN, especially in Mexico, where there is a lack of information in this area to establish measures to avoid the progress of diabetes. At present, there is no drug that can halt or reverse the progression of the disease. In fact, most of the therapies aim at providing only symptomatic relief; therefore, the identification of new modifiable risk factors is essential¹⁶. According to some authors, it is necessary to explore treatments that consider modifiable risk factors, such as metabolic syndrome components and inflammatory process¹⁷,¹⁸. Hence, if the risk factors are modifiable, it is possible to propose lifestyle changes that could improve the condition of the affected patients, delaying the DN development. Thus, the present study aimed to evaluate the risk factors contributing to DN in Mexican patients through the comparison of T2D patients with and without DN, incorporating two new indexes triglyceride-glucose (TyG) and glycemic exposure (GE) as risk factors of DN.

Materials and methods

Results

Discussion

T2D is a leading cause of morbidity and mortality in Mexico and worldwide. Even though 87.8% of the affected population receives pharmacological treatment, only 5.3% are currently under adequate control, while 38% and 56% have poor and very poor control, respectively¹⁰,²⁷. This is consistent with the prediction that in 20 years, 65% of the population with T2D will have chronic complications of the disease²⁸.

The prevalence of DN in the present study was 28.3%, which is different from early reports in Mexico (17.1-81.1%); hence, these marked differences could be related to the different diagnosis criteria and to an under-diagnosis⁶,⁸,⁹.

We observed differences between patients with ND and without ND in the evolution of the disease, GE index, urea concentration, and transaminase activity (p < 0.05) (Table 1). Several reports have demonstrated that duration of diabetes is a risk factor for DN independent of patient´s age²⁹. In the present study, patients with DN have longer disease evolution than patients without DN, as reported previously¹². On the other hand, GE index is an algorithm that combines Hb1Ac, duration of diabetes, and age at onset of diabetes, which correlates significantly with complications and predicts late complications better than single components³⁰. Patients with DN presented higher GE index values than patients without DN; therefore, patients with DN have a higher GE compared with patients without DN; this is important to note, because higher GE index values correlates and predicts microvessel complications³⁰. A recent study in Indian population has suggested that high urea levels correlates with poor glycemic control, indicated by GE index³¹. Ata et al. have suggested moderate elevations of serum ALT with poor glycemic control, suggesting that patients with DN might have more time exposed to chronic hyperglycemia as implied by GE index, which impacts in levels of urea, AST, and ALT³².

The frequency of complications associated with T2D was not different between patients without DN or with DN, as we would have expected. However, the phenomenon that calls our attention (Table 1) is the high prevalence of hyperuricemia (5.3% in the total studied population) in T2D patients. In Mexico, the epidemiological data in this matter are scarce; the most recent report informed a prevalence of 2.4-4.7% in general population³³, which is inferior compared with the frequency in T2D patients in this study. It is known that patients with gout have a high frequency of cardiovascular and renal type comorbidities; moreover, hyperuricemia in patients with metabolic disorders affect patient prognosis and treatment³⁴. Interestingly, the frequency of hypothyroidism in T2D patients was similar to the prevalence reported in the general Mexican population, which suggest a underestimation in our country, though further studies are needed (9.0% vs. 5.7%, respectively)³⁵.

Several studies have proposed the TyG index as a surrogate for estimating insulin resistance²⁵,³⁶. TyG index results from the product of fasting triglycerides and fasting glucose levels and has been recently recommended as a simple and inexpensive index to evaluate insulin resistance, with a good correlation with gold standard hyperglycemic clamp according to studies in Brazilian population²⁵,³⁶. To evaluate the effect of insulin resistance as TyG index, we classified patients with DN in three quartiles (Table 2). The groups in second and third quartile showed higher values of HbA1c and GE index compared with group in first quartile. The accumulation of glycated hemoglobin in tissues may adversely affect vessel walls and induce endothelial cell dysfunction, which contributes to atherosclerosis³⁷. Furthermore, the TyG index has been considered as a good indicator of overall glycemic control and possible risk for long-term complications³⁸. Recent studies have proposed the TyG index as a predictor of cardiovascular disease (CVD) events in clinical practice, subclinical atherosclerosis, progression of coronary artery calcification, and cardiac autonomic neuropathy, suggesting that patients in second and third quartile have a greater risk of CVD events and cardiac autonomic neuropathy compared with patients in Q1³⁹.

It should be pointed out that patients in third quartile when grouping by GE index, presented the highest TyG index compared with the first and second quartiles, which suggest that this group is mostly exposed no only to chronic hyperglycemia but to insulin resistance, both risk important factors to the development of DN, although further studies in this matter are needed in our population (Table 3)⁴⁰.

The factors associated with DN in Mexican population were diabetes duration, GE index, and metformin treatment after adjustment by BMI, sex, and age as confounder's variables (Table 4). As mentioned above, it is well established that duration of diabetes is a risk factor for development of DN²⁹. Although there was a trend (p = 0.069) in the increase of the risk in patients with early onset T2D vs. late onset, the significance was not achieved; however, the association of DN with duration of diabetes remained significant independently of the diagnostic methodology. It is important to mention that a stringent metabolic control can reduce the risk of DN⁴¹. In a 24-year follow-up of patients with type 1 diabetes, 64% of participants with poor glycemic control and none in good glycemic control developed DN⁴². Some studies have associated plasmatic levels of HbA1c with DN; however, in this study, we failed to find an association. Nevertheless, GE index (as determinant of chronic hyperglycemia exposure) was associated with DN after adjustment of sex, age, and BMI¹³,⁴³.

Despite levels of LDL-C, total cholesterol and triglycerides were not associated with DN, low levels of HDL-C were associated (Table 4). After adjustment by sex, age, and BMI, the significance was lost; however, factors like lowering lipid drugs use was not considered in the analysis. A 6-year follow-up study of 48 Korean patients revealed that reduced HDL-C (odds ratio [OR]: 5.292, p = 0.05) and high triglycerides (OR: 6.129, p = 0.043) significantly increased the risk of diabetic distal symmetrical polyneuropathy, after adjusting for age and sex⁴⁰. Tesfaye et al. showed in a 7-year follow-up study in the European population that there is no association of DN with dyslipidemia⁴³. Hence, more studies that consider covariates such as lowering lipid drugs therapy, diabetes duration, smoking, and chronic hyperglycemia exposure are needed.

Several studies have suggested a clinical association between metformin use and Vitamin B12 deficiency, and as a consequence DN development⁴⁴,⁴⁵. Nevertheless, other studies have shown a negative correlation between metformin treatment and Vitamin B12 levels and the association with DN, while others have shown that despite metformin therapy is associated with lower Vitamin B12 status, there does not appear to be any significant effect on peripheral neuropathy in European patients receiving metformin⁴⁴-⁴⁶. In Mexico, there are no studies related with metformin therapy and DN. Indeed, this is the first study in our country that showed a significant association between the metformin treatment and DN. It is important to note that the association remained after adjustment by sex, age, and BMI, and by HbA1c and diabetes duration (OR: 2.513, p = 0.003 and OR: 2.209, p = 0.001, respectively). Furthermore, the 70% of the participants in the present study have metformin as glucose lowering treatment, which suggests double risk to develop DN as suggested by the OR obtained (Table 4). The ADA guidelines recommend periodic testing of Vitamin B12 in metformin-treated patients (especially in those with peripheral neuropathy); however, only 4.5% of Mexican T2D patients in this study have been prescribed with Vitamin B12⁴⁷. Therefore, to prevent or delay the appearance of DN in diabetic patients, it is important to implement follow-up programs that include prescription and monitoring of Vitamin B12.

Furthermore, an association between diabetic retinopathy and DN was found (OR: 1.646, p = 0.025), nonetheless, when adjusted by sex, age, and BMI, the significance was lost. A study in T2D patients from Asia identified an association between diabetic retinopathy and cardiovascular autonomic neuropathy; in this study, the authors suggested that diabetic retinopathy is the most significant risk factor predictive of the presence of cardiovascular autonomic neuropathy in patients with T2D⁴⁸. Further studies with a bigger sample are needed, to elucidate the relationship between DN and diabetic retinopathy development.

Smoking was associated with DN; however, when was adjusted by different covariates, the effect was lost. A robust meta-analysis including 10 prospective and 28 cross-sectional studies has found that smoking had an unadjusted OR of 1.26 for developing DN⁴⁹. The mechanism involved is not clear, but it is well established that smoking could contribute to insulin resistance occurrence, which could impact in DN development.

Finally, in the present study, the TyG index was not a risk factor associated with DN, perhaps because the TyG index is only an estimator of insulin resistance. It will be necessary to carry out studies to evaluate the agreement of this index with HOMA-IR in the Mexican population and to test its usefulness as a risk factor of DN. In contrast, GE index could be an important risk factor for DN development.

Conclusions

In general, the risk factors that mostly contribute to the development of DN in the Mexican population are diabetes duration, metformin therapy, GE index, and diabetic retinopathy (Figure 1). Diabetic retinopathy is associated with DN, but further studies are needed to elucidate the mechanisms involved. For 1^st time, an association between metformin treatment and DN development is identified in Mexican population. Finally, it is important to recognize risk factors that contribute to the development of DN to prevent or delay diabetic complications in Mexican diabetes patients that allow us to implement personalized strategies to improve the overall T2D patients' quality of life and reduce healthcare costs in our country.

Figure 1 Risk factors for diabetic neuropathy (DN). Risk factors associated with DN were glycemic exposure index, diabetes duration, low levels of HDL-C, metformin treatment, and smoking p < 0.05.