Journal of Endocrinology, Diabetes and Obesity

Metabolic and Cardiovascular Determinants of Type 2 Diabetic Patent Peripheral Neuropathy

Research Article | Open Access

  • 1. Department of Internal Medicine & Diabetology College of Medicine and Health Sciences, University Hospital of Oran, Algeria
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Corresponding Authors
MS Hamdaoui, Department of Internal Medicine & Diabetology College of Medicine and Health Sciences, University Hospital of Oran, Algeria

Objective: To identify the main metabolic and cardiovascular determinants of peripheral neuropathy in type 2 diabetics.

Materials and methods: We collected 270 records of type 2 diabetic patients and compared 90 patients with peripheral neuropathy with 180 without neuropathy, and then we proceeded to a statistical analysis of the data by binary then multivariate logistic regression based on the SPSS20 software.

Results: The average age of the cases is 65.5 ± 19.4 years with a sex ratio of 0.64. The majority are sedentary and obese. Tingling is the most frequent revealing symptom (86.5%) with the abolition of DTR (51.7%), Pain affected more than 83% of cases with an average score PN4 = 4.53 ± 1.61. More than 83% of PDN+ diabetics are hypertensive and ¾ suffer from proven cardiovascular disease. The risk factors for PDN are (univariate regression): android obesity [OR = 2.43], HbA1c > 7% [OR = 4.85], cardiovascular disease [OR=5.32], 24-hour micro albuminuria [OR=6.89], dysautonomic neuropathy [OR=9.72], hypertension [OR =3.49], a as well as triglyceride level > 1.50 g/L [OR =1.89]. The multivariate model retains: Glycemic imbalance, physical inactivity, and android obesity, presence of cardiovascular disease, EUA/24 hours and dysautonomic neuropathy.

Conclusion: Our study confirms the multifactorial etiology of diabetic peripheral neuropathy involving essentially the interaction of metabolic, cardiovascular among the other clinical and dietetic factors.


Peripheral neuropathy, Hba1c, Obesity, CVD, Hypertension, UAE/24H, Hypertriglyceridemia


BMI, body mass index; CKD, chronic kidney disease; CVD, cardiovascular disease ; HbA1c, glycated hemoglobin; HBP, high blood pressure; DAN, dysautonomic neuropathy; DPN, diabetic peripheral neuropathy; DTR, deep tendon reflexes ; OR, odds ratio; UAE/24 hours, 24-hour urinary albumin excretion.


Diabetic peripheral neuropathy is the most common complication of diabetes. At least 50% of people with diabetes will develop it [1,2]; Its prevalence varies from 0 to 93% depending on the studies [3] and increases with the duration of diabetes evolution, 7% when the discovery of diabetes goes back less than 1 year, 50% after 20 years of diabetes evolution [4]. Regardless of glycemic control, about 50% of patients do not develop clinical neuropathy, even after 20 years of evolution. Furthermore, patients with good metabolic control may present with disabling neuropathy early after the diagnosis of diabetes. This suggests the existence of factors independent of the hyperglycemic state in the pathophysiology of neuropathy. These factors could be genetic, but also related to the environment, and in particular nutritional [5]. The main clinical features of DPN include symmetric, mainly sensory, deficits in the distal lower extremities and neuropathic pain [6,7]. In addition, DPN is a key risk factor for diabetic foot ulceration due to loss of protective superficial sensitivity [7-9]. Duration of diabetes and HbA1c level are major predictors of diabetic neuropathy [10]. These two predictors are commonly associated with other metabolic factors correlated with diabetic neuropathy, particularly in T2D, such as insulin resistance and high blood pressure (>130/85mmHg). Obesity is common in patients with neuropathy in population-based studies in several countries, including the United States, Denmark, China, and the Netherlands [10-15]. Independent of HbA1c levels, many components of the metabolic syndrome, such as hypertriglyceridemia, hypertension, abdominal obesity, and low high-density lipoprotein (HDL) levels, are consistently associated with diabetic neuropathy in patients with T2DM [11,12] and in some DT1 cohorts [16]. Other independent risk factors for the development of diabetic neuropathy include smoking, alcohol abuse, increased height, and advanced age [17].

Through this work, we will be able to achieve primary prevention of this complication or even secondary neurological complication by improving the management of these very highrisk patients.


This is a retrospective sex-matched case-control study, carried out at the level of the Oran Hospital and University Establishment (EHUO) between December 2019 and December 2021, which aims to identify and measure the main risk factors for Type 2 diabetic peripheral neuropathy.

Study Location

The study was conducted in the city of Oran, an urban area located in the northwest region of Algeria; it is the second largest city in Algeria and one of the most important in Northern Africa. According to the 2022 National Census, approximately 1.52 million individuals lived in Oran.

Ethical Consideration

Ethical clearance was obtained from the Institutional Review Board of the University Hospital Institution of Oran (November 02, 2015, approval number ETAP-C.R.S 6) in accordance with the tenets of the Declaration of Helsinki (http://www.wma.net). The researcher explained the study to each person and gave them thorough information about the study and its purpose. In addition, we notified them of their right to terminate their participation in the study at any time without incurring any penalty. The concerned subjects having given a signed consent after having been duly informed. On occasion, the consent was orally given after explaining the aim of the biological assays. We collected more than 400 adult patients DT2 and retained 270 complete files.


Patients with psychiatric illness, amputees or undergoing treatment that can induce neurological pain and pregnant women. The information collected by direct questioning of patients on the one hand: Age, sex, origin and place of residence, profession, marital status, socioeconomic level and social coverage, height, weight, waist circumference, and BMI, Year of discovery, diabetes treatment, and family history of diabetes. Tobacco; Alcoholism and physical activity. On the other hand, the complete clinical examination: Measurement of blood pressure at rest in a supine or semi-seated position after 10 minutes of resting, using a sphygmomanometer or a validated electronic tensiometer. The figures to speak of a hypertension correspond to: SBP (Systolic blood pressure) > 130 mm Hg and/or a DBP (Diastoolic blood pressure) > 85 mm Hg. Eye’s fundus examination using retinal photography was performed in all patients. Coronary artery disease was defined by the presence of angina pectoris, squeal of myocardial infarction, or ischemic changes on a standard resting electrocardiogram or on stress ultrasound or coronary angiography Blood samples were collected after 12 h of fasting from a vein in the antecubital fossa without venous occlusion. All collections were made between 8:00 and 9:00 a.m. Whole blood specimens were collected in different tubes to obtain plasma. The samples were separated in aliquots and frozen immediately at −80 ?C until biochemical analyses could be performed. 2.6. Plasma Lipids and Glucose Plasma TC, HDL-C, TG, glucose and HbA1c were all measured by multiparametric automated procedure using Cobas 6000 analyzer with Roche Diagnostic’s reactives. Plasma LDL-cholesterol (LDL-C) was estimated by the Friedewald equation. None of the participants had plasma TG > 4 g/L, which can affect the calculation of LDL-C by the Friedwald equation[18]. The criteria for the diagnostic of metabolic syndrome were those defined by the NCEP-ATPIII (National Cholesterol Education Program-Adult Treatment Panel III); A subject was considered to present an abdominal obesity with an abdominal perimeter 102 cm for men and 88 cm for women.

Glomerular filtration rate (GFR) was estimated using Equation MDRD: eDFG = 175 x (Scr x 0,0113)-1,154 x year-0,203 x 0,742 (if women) x 1,212 (if black) [Scr : µmol/l] [19]. Diabetic nephropathy or CKD (Chronic kidney disease) was considered if the GFR was 30g/24hours or >20g/l).

The neurological investigations consisted of questionnaires on sensory, motor and autonomic symptoms; Peripheral neuropathy was defined by clinical symptoms (paresthesias) and/or abnormalities in sensation of touch, pinprick, pain and monofilament (Semmes Weinstein at 10g) abolition of DTR (deep tendon reflexes) at the ankle or patella and Vibration sensation was tested in the great toe, using a 128-Hz tuning fork (Rydel-Seiffer). Patent dysautonomia was defined by symptoms of gastroparesis or neurogenic bladder, diarrhea, symptomatic postural hypotension (fall in blood pressure after one minute of orthostatism of more than 20mmHg for SBP and/or 10mmHg for DBP), erectile dysfunction or sweating disorders without further explanation; Pain Neuropathy 4 survey (PN4) used to rate the degree of neuropathic pain.


Sociodemographic, clinical and biological parameters as well as complications were collected using a standardized questionnaire. Data were expressed as mean and percentages. The links between the characteristics of the patients will call upon statistical tests: The tests used are: the χ2 test of independence or homogeneity, corrected by Yates, the exact test of Fisher, the Kruskall-Wallis test for two groups, with the determination of significance levels. Student’s test for two independent samples and analysis of variance (ANOVA) were used for the comparison of continuous variables. For the bivariate analysis, the comparison of discontinuous variables between groups was carried out by non-parametric tests, the χ2 test of conformity and homogeneity for the search for statistical associations between two qualitative variables; nonparametric Fisher’s exact test for comparison of small groups. We used Pearson r correlation tests to estimate the relationship between two quantitative variables. A relationship is considered significant if the threshold was p < 0.05. Double contingency 2 × 2 cross tables were established for the calculation of Odds Ratio (OR) as an epidemiological association factor and the establishment of confidence intervals around the risk. Linear regression was used to search for a linear relationship between peripheral neuropathy and the other explanatory variables with multiple logistic regressions using maximum likelihood and 95% confidence intervals (CI). Statistical analyzes were performed using the following software: EpiData 3.0 and SPSS 20.


The general comparison of cases and controls finds a statistically significant difference for age, BMI and waist circumference; the cases were older with an average age of 65.5 ± 19.4 years (p < 10-6). The sex ratio (M/F) in DPN cases is 0.63, while in controls it is 0.91, indicating a female predominance. Tingling is the most frequent revealing symptom (86.5%) with the following clinical signs: abolition of DTR (deep tendon reflexes) (51.7%), abnormalities of the tuning fork test (48.3%), and non-sensitivity monofilament (27%). Pain affects more than 83% of cases with an average score PN4 = 4.53 ± 1.61. There is no significant difference for height (p = 0.49), the average height of men is 1.72 ± 0.07 m against an average height of 1.58 ± 0.06 m in women. The cases are more obese (p=0.002), with a waist circumference of 108 ±10.20 cm for men and 107.51 ± 12.83 cm for women, with a significant difference between cases and controls (p = 0.004). The group of cases with DPN is more sedentary than that of controls (p < 10-8). On the other hand, no significant difference is reported for lifestyle, level of education, smoking and family history of diabetes between the two groups. The duration of diabetes is longer in patients with DPN (13.83 ± 9.57 years vs. 7.36 ± 6.54 years in controls; p<10-3). 83.33% of patients with peripheral neuropathy are hypertensive, and 76.67% have at least one cardiovascular complication, while 90% suffer from a microvascular complication (other than peripheral neuropathy) Patients with DPN have renal function lower than the controls (p < 10-7) with a 24-hour microalbuminuria rate much higher than that found in the controls (p < 10-8).

There is a significant difference between diabetics with DPN and controls concerning the glycemic profile: FPG and Hba1c (p < 0.0001), on the other hand this difference is not reported concerning the levels of total cholesterol, LDL and HDL. Nevertheless, there is a significant difference in the level of triglycerides (p=0.029). More than 75% of cases were taking a statin vs 45.55% of controls (p = 0.46). We note that 90% of

cases are in glycemic imbalance: Hba1c > 7% (p < 0.0001), and this despite the fact that 71% of them benefit from insulin therapy (p < 10-6) (Table 1). The risk factors statistically linked to DPN according to the univariate analysis are: Age [OR = 2.94] (p 7% [OR = 4.85](p 1.50g/L [OR =1.89] (p<0.029) as well as insulin therapy [OR=3.96](p <0.00001) (Table 2). There is no statistically significant relationship between gender, height and dyslipidemia in the occurrence of DPN in our population.

The multivariate model retains the following factors: Glycemic imbalance (HBA1c>7%) [OR = 2.8], physical inactivity [OR = 8.2], android obesity [OR = 3.6], macroangiopathy [OR = 2.4], 24-hour micro albuminuria [OR = 5.9] and dysautonomic neuropathy [OR = 8.5] (Figure 1).


The results of our study have identified a number of risk factors related to the occurrence of peripheral neuropathy. Hyperglycemia is undeniably a major risk factor for distal and symmetrical peripheral neuropathy (DSPN). It has been calculated that every 1% increase in HbA1c is associated with an

Table 1: Comparison of the general characteristics of the case-control sample.

Explanatory Factors NPD + (n=90) NPD – (n=180) p
Age (years) 65,5 ± 19,4 58,02 ±10,5 < 10^{-4}
Sexe M/F 35/55 86/94 0,166
Height (m) 1,64±0,1 1,65±0,1 0,49
Normal 9 31  
BMI Overweight 26 75 0,002
Obesity 55 73  
Weist sise(cm) M/F 108,00±10,20 107,51±12,83 100,59±13,42 100,71±10,49 0,004
Sedentary 32 10
Familly history of T2D 71 140 0,934
Smoking 17 25 0,285
Duration of T2D (years) 13,81±9,57 7,36±6,54 <10-3
High blood pressure 75 106 < 10-3
Microalbuminuria (mg/24h) 105,66±188,7 19,98±25,50
Clearance of creatinine (ml/min) 62,20±22,50 85,25±20,13 < 10^{-7}
Macroangiopathy 69 62
Microangiopathy (except NDP) 86 113
FPG (g/l)* 1,71±0,58 1,41±0,40 < 10^{-4}
HBA1c (%) 8,75±1,70 7,60±1,42 < 10^{-4}
HBA1c>7% 81 117 < 10^{-4}
Chol T (g/l) 1,68±0,50 1,60±0,37 0,15
LDL (g/l) 0,97±0,42 0,95±0,30 0,65
HDL (g/l) M/F 0,38±0,11 0,39±0,11 0,91
  0,46±0,15 0,44±0,12 0,52
TG (g/l) 1,47±0,70 1,23±0,56 0,029
Insulin 64 69
*FPG : Fasting plasmatic glucose

Table 2: DPN Risk Factors after univariate regression.

Risk Factors DPN+ DPN – Brut OR CI 95% P value
Age ≥ 61 years 61 75 2,94 [1,66 –5,23] < 10-4
Obesity (Kg/m²) 55 74 2,25 [1,29 –3,93] 0,002
waist size (cm) 74 118 2,43 [1,25 –4,78] 0,004
T2D Duration ≥ 8 ans 60 77 2,68 [1,52 – 4,73] < 10-3
Hba1c > 7% 81 117 4,85 [2,16 – 11,19] < 10-4
Insulin therapy 64 69 3,96 [2,21 – 7,14] < 10-6
Sedentarity 32 10 9,38 [4,08 – 22,03] < 10-8
BP > 130/85mmHg 75 106 3,49 [1,78 – 6,93] < 10-3
Triglyceridaemia > 1,5g/L 37 50 1,89 [1,02–3,19] 0,029
Albuminuria / 24h >30 mg 49 27 6,89 [3,66 – 13,04] < 10-8
Dysautonomic Neuropathy 71 50 9,72 [5,09 – 18,73] < 10-8
Heart failure 60 53 4,8 [2,78– 8,25] < 10-5
Coronaropathy 34 18 5,46 [2,72 – 11,07] < 10-7
Peripheral arteriopathy 26 12 5,69 [2,55 – 12,88] < 10-4
Cervical arteritis 22 10 5,50 [2,31 –13,32] < 10-5
Rétinopathy 62 51 5,60 [3,10 – 10,2] < 10-8
CKD* 80 87 7,89 [3,45 – 18,55] < 10-7
*CKD:Chronic Kidney Disease

Figure 1 Forrest Plot of Independent DPN Risk Factors (Multivariate Analysis).

Figure 1: Forrest Plot of Independent DPN Risk Factors (Multivariate Analysis).

approximately 10-15% higher frequency of DSPN [6]. Therefore, the effectiveness of tight glycemic control in reducing the incidence and progression of DSPN has been the subject of several ambitious studies in both types of diabetes [20-27]. Weight and waist circumference are independent risk factors for both DSPN and painful DSPN in diabetic patients from the population-based MONICA cohort study/KORA surveys from southern Germany [28-30]. Low physical activity has been associated with the presence of DSPN in the southern German population [28,29] with an OR= 6.36 CI [2.94 –13.78] (p < 0.001) which confirms the results of our series where physical inactivity was identified as being a factor strongly correlated with the development of DPN. Bilateral and symmetrical neuropathy is frequently associated with cardiovascular disease [31-33], which makes cardiovascular involvement an independent factor in the development of neuropathy after 10 years of diabetes progression (OR = 2.32, 95% CI: 1.03–5.22) [34]. Compared to hyperglycemia which is a major risk factor in the development of diabetic polyneuropathy, evidence has emerged suggesting that vascular factors also appear to play a primary role in its pathogenesis and clinical phenotype. [35,36]. The results of the prospective EURODIAB study (Tesfaye et al. 2005) proved that systolic hypertension was an independent predictor of neuropathy after adjusting for age, duration of diabetes and metabolic control [35]. In the Tunisian series of Sebai et al. the presence of DPN was correlated with urinary albumin excretion > 30mg/24 hours (r = 0.325, p = 0.005). Zigler et al. demonstrated a significant association in diabetics with the rate of albumin excretion with an OR = 1.24 [1.09 –1.42] (p = 0.001)[28]. Overall, our results agree with those of the Algerian study by Ayad et al. conducted on a population of diabetics from Oran, and which demonstrated a statistically strong relationship between DPN and CAN (Cardiac autonomic neuropathy)(p <0.0001), also they suggest the important role played by sympathetic hyperactivity in the development of microvascular complications via hemodynamic disorders that she leads [37]. The coexistence of DSPN and DAN increases crescendo with the duration of diabetes and poor metabolic control. Also, the concomitant presence of autonomic neuropathy is important for the prognosis, since it is a risk factor for mortality from cardiovascular disease [31]. Other factors described in the literature, such as height and smoking, show no statistical relationship with DPN according to our results (p = 0.49: NS; OR = 1.44 [0.69–3.00], p = 0.285: NS) respectively; Data from systematic meta-analyses are controversial if not contradictory: height is more likely a risk factor in T1Diabeties, while there is a rather protective effect of smoking in certain populations in the United States [6,38,39]. High total cholesterol [40] and hypertriglyceridemia [41] have been reported as independent risk factors for DSPN (after adjusting for HbA1c, age, and other potential confounders).In addition, there are several genes linked to diabetic neuropathy could explain some ethnic specificities ; Much more research is needed to better understand the role of genetics in the development of diabetic neuropathy, and several existing cohort studies are currently underway [40,41].


Retrospective analyzes of primary care databases are generally limited by the validity and completeness of the data. In particular, the exact daily doses of insulin prescribed, as well as the exact diagnosis of the onset of diabetes, but rather we used the data of the first diagnosis of diabetes recorded in the database. In conclusion, using real-world data, the prevalence of diabetic neuropathy affected at the time of diagnosis of type 2 diabetes was low in western Algeria. , it is not devoid of certain biases which can compromise the exact interpretation of the results; however, multivariate analysis makes it possible to control for these biases: Some factors no longer become significantly correlated with the development of DPN.


Diabetic neuropathy is common in patients in western Algeria, mainly in Oran. This complication is shown here to be associated with android obesity, lack of physical activity, poor glycemic control, cardiovascular disease, and other microvacular complications. The results underscore the need for intensified programs aimed at early detection and rapid implementation of health education. We were able to draw a profile of type 2 diabetic patients at high risk of developing DPN, which suggests the role of clinical recommendations for the management of diabetes in preventing the development of associated foot complications which should be further reduced in care primaries.


1. Feldman EL, Callaghan BC, Pop-Busui R, Douglas WZ, Douglas EW, David LB, et al. Diabetic neuropathy. Nat Rev Dis Primers. 2019; 5: 41.

2. Feldman EL, Callaghan BC, Pop-Busui R, Douglas WZ, Douglas EW, David LB, et al. Diabetic neuropathy. Nat Rev Dis Primers. 2019; 5: 42.

3. Vinik AI, Holland MT, Beau JML, Liuzzi FJ, Stansberry KB, Colen LB. Diabetic neuropathies. Diabetes care 1992; 15: 1926-75.

4. Young MJ, Boulton AJ, MacLeod AF, Williams DR, Sonksen PH. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia. 1993; 36: 150-4.

5. Raccah D. Epidemiology and physiopathology of degenerative complications of diabetes mellitusEpidemiology and physiopathology of degenerative complications of diabetes. EMC – Endocrinology. 2004; 1: 29-42.

6. Ziegler D, Papanas N, Vinik AI, Shaw JE. Epidemiology of polyneuropathy in diabetes and prediabetes. Handb Clin Neurol. 2014; 126: 3-22.

7. Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes care. 2010; 33: 2285-93.

8. Boulton AJ. The diabetic foot: grand overview, epidemiology and pathogenesis. Diabetes Metab Res Rev. 2008; 24: S3-S6.

9. Papanas N, Maltezos E. The diabetic foot: established and emerging treatments. Acta Clin Belg. 2007; 62: 230-8.

10. Andersen ST, Witte DR, Dalsgaard E-M, Andersen H, Nawroth P, Fleming T, et al. Risk factors for incident diabetic polyneuropathy in a cohort with screendetected type 2 diabetes followed for 13 years: ADDITION-Denmark. Diabetes care. 2018; 41: 1068-75.

11. Callaghan BC, Gao L, Li Y, Zhou X, Reynolds E, Banerjee M, et al. Diabetes and obesity are the main metabolic drivers of peripheral neuropathy. Ann Clin Transl Neurol. 2018; 5: 397-405.

12. Callaghan BC, Xia R, Banerjee M, Rekeneire ND, Harris TB, Newman AB. et al. Metabolic syndrome components are associated with symptomatic polyneuropathy independent of glycemic status. Diabetes care. 2016; 39: 801-7.

13. Callaghan BC, Xia R, Reynolds E, Banerjee M, Rothberg, Burant CF, et al. Association Between Metabolic Syndrome Components and Polyneuropathy in an Obese Population. JAMA Neurol. 2016; 73: 1468-76.

14. Hanewinckel R, Drenthen J, Ligthart S, Dehghan A, Franco OH, Hofman A, et al. Metabolic syndrome is related to polyneuropathy and impaired peripheral nerve function: a prospective population-based cohort study. J Neurol Neurosurg Psychiatry. 2016; 87: 1336-42.

15. Lu B, Hu J, Wen J, Zhang Z, Zhou L, Li Y, et al. Determination of peripheral neuropathy prevalence and associated factors in Chinese subjects with diabetes and pre-diabetes–ShangHai Diabetic neuRopathy Epidemiology and Molecular Genetics Study (SH-DREAMS). PLoS One. 2013; 8: e61053.

16. Tesfaye S, Selvarajah D. The Eurodiab study: what has this taught us about diabetic peripheral neuropathy?. Curr Diab Rep. 2009; 9: 432-4.

17. Callaghan BC, Price RS, Feldman EL. Distal symmetric polyneuropathy: a review. JAMA. 2015; 314: 2172-81.

18. Wilson PW, Abbott RD, Garrison RJ, Castelli WP. Estimation of very-low-density lipoprotein cholesterol from data on triglyceride concentration in plasma. Clin chem. 1981; 27: 2008-10.

19. Livio F, Biollaz J, Burnier M. Estimation de la fonction rénale par l’équation MDRD: intérêt et limites pour l’adaptation des doses de médicaments. Rev Med Suisse. 2008; 4: 2596-600.

20. Albers JW, Herman WH, Pop-Busui R, Feldman EL, Martin CL, Cleary PA, et al. Effect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. Diabetes care. 2010; 33: 1090-6.

21. Martin CL, Albers JW, Pop-Busui R, Group DEr. Neuropathy and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes care. 2014; 37: 31-8.

22. Ziegler D, Behler M, Schroers-Teuber M, Roden M. Near-normoglycaemia and development of neuropathy: a 24-year prospective study from diagnosis of type 1 diabetes. BMJ open. 2015; 5: e006559.

23. Control D, Group CTR, Nathan DM, Genuth S, Lachin J, Cleary P. The effect of intensive treatment of diabetes on the development and progression of longterm complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329: 977-86.

24. Group UPDS. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998; 352: 837-53.

25. Patel A, MacMahon S, Chalmers J. Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release and Controlled Evaluation (ADVANCE) Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008; 358: 2560-72.

26. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009; 360: 129-39. 27.

27. Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J, C o h e n RM, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet. 2010; 376: 419-30.

28. Ziegler D, Rathmann W, Dickhaus T, Meisinger C, Mielck A, KORA Study Group. Prevalence of polyneuropathy in pre-diabetes and diabetes is associated with abdominal obesity and macroangiopathy: the MONICA/KORA Augsburg Surveys S2 and S3 . Diabetes care. 2008; 31: 464-9.

29. Ziegler D, Rathmann W, Meisinger C, Dickhaus T, Mielck A, KORA Stuy Group. Prevalence and risk factors of neuropathic pain in survivors of myocardial infarction with pre-diabetes and diabetes. The KORA Myocardial Infarction Registry. Eur J Pain. 2009; 13: 582-7.

30. Ziegler D, Rathmann W, Dickhaus T, Meisinger C, Mielck A, KORA Study Group. Neuropathic pain in diabetes, prediabetes and normal glucose tolerance: the MONICA/KORA Augsburg Surveys S2 and S3. Pain med. 2009; 10: 393-400.

31. Vinik AI, Maser RE, Ziegler D. Neuropathy: the crystal ball for cardiovascular disease?. Diabetes Care. 2010:1688-90.

32. Brownrigg JR, de Lusignan S, McGovern A, Hughes C, Thompson MM, Ray KK, et al. Peripheral neuropathy and the risk of cardiovascular events in type 2 diabetes mellitus. Heart. 2014; 100: 1837-43.

33. Charles M, Ejskjaer N, Witte DR, Borch-Johnsen K, Lauritzen T, Sandbaek. Prevalence of neuropathy and peripheral arterial disease and the impact of treatment in people with screen-detected type 2 diabetes: the ADDITIONDenmark study. Diabetes care. 2011; 34: 2244-9.

34. Ybarra-Muñoz J, Jurado-Campos J, Garcia-Gil M, Zabaleta-Del-Olmo E, MirColl T, Zabalegui A, et al. Cardiovascular disease predicts diabetic peripheral polyneuropathy in subjects with type 2 diabetes: A 10-year prospective study. Eur J Cardiovasc Nurs. 2016; 15: 248-54.

35. Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Witte DR, et al. Vascular risk factors and diabetic neuropathy. N Engl J Med. 2005; 352: 341-50.

36. Cameron NE, Eaton S, Cotter MA, Tesfaye S. Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. Diabetologia. 2001; 44: 1973-88.

37. Ayad F, Belhadj M, Pariés J, Attali JR, Valensi P. Association between cardiac autonomic neuropathy and hypertension and its potential influence on diabetic complications. Diabet Med. 2010; 27: 804-11.

38. Adler AI, Boyko EJ, Ahroni JH, Stensel V, Forsberg RC, Smith DG. Risk factors for diabetic peripheral sensory neuropathy: results of the Seattle Prospective Diabetic Foot Study. Diabetes care. 1997; 20: 1162-7.

39. Franklin GM, Shetterly SM, Cohen JA, Baxter J, Hammam RF. Risk factors for distal symmetric neuropathy in NIDDM: the San Luis Valley Diabetes Study. Diabetes care. 1994; 17: 1172-7.

40. Herman WH, Aubert R, Engelgau M, Thompson TJ, Ali MA, Sous ES, et al. Diabetes mellitus in Egypt: glycaemic control and microvascular and neuropathic complications. Diabet Med. 1998; 15: 1045-51.

41. Tesfaye S, Stevens L, Stephenson J, Fuller JH, Plater M, Nuber A, et al. Prevalence of diabetic peripheral neuropathy and its relation to glycaemic control and potential risk factors: the EURODIAB IDDM Complications Study. Diabetologia. 1996; 39: 1377-84.

Received : 25 Jan 2023
Accepted : 06 Feb 2023
Published : 07 Feb 2023
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Journal of Preventive Medicine and Health Care
ISSN : 2576-0084
Launched : 2018
Journal of Chronic Diseases and Management
ISSN : 2573-1300
Launched : 2016
Annals of Vaccines and Immunization
ISSN : 2378-9379
Launched : 2014
JSM Heart Surgery Cases and Images
ISSN : 2578-3157
Launched : 2016
Annals of Reproductive Medicine and Treatment
ISSN : 2573-1092
Launched : 2016
JSM Brain Science
ISSN : 2573-1289
Launched : 2016
JSM Biomarkers
ISSN : 2578-3815
Launched : 2014
JSM Biology
ISSN : 2475-9392
Launched : 2016
Archives of Stem Cell and Research
ISSN : 2578-3580
Launched : 2014
Annals of Clinical and Medical Microbiology
ISSN : 2578-3629
Launched : 2014
JSM Pediatric Surgery
ISSN : 2578-3149
Launched : 2017
Journal of Memory Disorder and Rehabilitation
ISSN : 2578-319X
Launched : 2016
JSM Tropical Medicine and Research
ISSN : 2578-3165
Launched : 2016
JSM Head and Face Medicine
ISSN : 2578-3793
Launched : 2016
JSM Cardiothoracic Surgery
ISSN : 2573-1297
Launched : 2016
JSM Bone and Joint Diseases
ISSN : 2578-3351
Launched : 2017
JSM Bioavailability and Bioequivalence
ISSN : 2641-7812
Launched : 2017
JSM Atherosclerosis
ISSN : 2573-1270
Launched : 2016
Journal of Genitourinary Disorders
ISSN : 2641-7790
Launched : 2017
Journal of Fractures and Sprains
ISSN : 2578-3831
Launched : 2016
Journal of Autism and Epilepsy
ISSN : 2641-7774
Launched : 2016
Annals of Marine Biology and Research
ISSN : 2573-105X
Launched : 2014
JSM Health Education & Primary Health Care
ISSN : 2578-3777
Launched : 2016
JSM Communication Disorders
ISSN : 2578-3807
Launched : 2016
Annals of Musculoskeletal Disorders
ISSN : 2578-3599
Launched : 2016
Annals of Virology and Research
ISSN : 2573-1122
Launched : 2014
JSM Renal Medicine
ISSN : 2573-1637
Launched : 2016
Journal of Muscle Health
ISSN : 2578-3823
Launched : 2016
JSM Genetics and Genomics
ISSN : 2334-1823
Launched : 2013
JSM Anxiety and Depression
ISSN : 2475-9139
Launched : 2016
Clinical Journal of Heart Diseases
ISSN : 2641-7766
Launched : 2016
Annals of Medicinal Chemistry and Research
ISSN : 2378-9336
Launched : 2014
JSM Pain and Management
ISSN : 2578-3378
Launched : 2016
JSM Women's Health
ISSN : 2578-3696
Launched : 2016
Clinical Research in HIV or AIDS
ISSN : 2374-0094
Launched : 2013
Journal of Substance Abuse and Alcoholism
ISSN : 2373-9363
Launched : 2013
JSM Neurosurgery and Spine
ISSN : 2373-9479
Launched : 2013
Journal of Liver and Clinical Research
ISSN : 2379-0830
Launched : 2014
Journal of Drug Design and Research
ISSN : 2379-089X
Launched : 2014
JSM Clinical Oncology and Research
ISSN : 2373-938X
Launched : 2013
JSM Bioinformatics, Genomics and Proteomics
ISSN : 2576-1102
Launched : 2014
JSM Chemistry
ISSN : 2334-1831
Launched : 2013
Journal of Trauma and Care
ISSN : 2573-1246
Launched : 2014
JSM Surgical Oncology and Research
ISSN : 2578-3688
Launched : 2016
Annals of Food Processing and Preservation
ISSN : 2573-1033
Launched : 2016
Journal of Radiology and Radiation Therapy
ISSN : 2333-7095
Launched : 2013
JSM Physical Medicine and Rehabilitation
ISSN : 2578-3572
Launched : 2016
Annals of Clinical Pathology
ISSN : 2373-9282
Launched : 2013
Annals of Cardiovascular Diseases
ISSN : 2641-7731
Launched : 2016
Journal of Behavior
ISSN : 2576-0076
Launched : 2016
Annals of Clinical and Experimental Metabolism
ISSN : 2572-2492
Launched : 2016
Clinical Research in Infectious Diseases
ISSN : 2379-0636
Launched : 2013
JSM Microbiology
ISSN : 2333-6455
Launched : 2013
Journal of Urology and Research
ISSN : 2379-951X
Launched : 2014
Journal of Family Medicine and Community Health
ISSN : 2379-0547
Launched : 2013
Annals of Pregnancy and Care
ISSN : 2578-336X
Launched : 2017
JSM Cell and Developmental Biology
ISSN : 2379-061X
Launched : 2013
Annals of Aquaculture and Research
ISSN : 2379-0881
Launched : 2014
Clinical Research in Pulmonology
ISSN : 2333-6625
Launched : 2013
Journal of Immunology and Clinical Research
ISSN : 2333-6714
Launched : 2013
Annals of Forensic Research and Analysis
ISSN : 2378-9476
Launched : 2014
JSM Biochemistry and Molecular Biology
ISSN : 2333-7109
Launched : 2013
Annals of Breast Cancer Research
ISSN : 2641-7685
Launched : 2016
Annals of Gerontology and Geriatric Research
ISSN : 2378-9409
Launched : 2014
Journal of Sleep Medicine and Disorders
ISSN : 2379-0822
Launched : 2014
JSM Burns and Trauma
ISSN : 2475-9406
Launched : 2016
Chemical Engineering and Process Techniques
ISSN : 2333-6633
Launched : 2013
Annals of Clinical Cytology and Pathology
ISSN : 2475-9430
Launched : 2014
JSM Allergy and Asthma
ISSN : 2573-1254
Launched : 2016
Journal of Neurological Disorders and Stroke
ISSN : 2334-2307
Launched : 2013
Annals of Sports Medicine and Research
ISSN : 2379-0571
Launched : 2014
JSM Sexual Medicine
ISSN : 2578-3718
Launched : 2016
Annals of Vascular Medicine and Research
ISSN : 2378-9344
Launched : 2014
JSM Biotechnology and Biomedical Engineering
ISSN : 2333-7117
Launched : 2013
Journal of Hematology and Transfusion
ISSN : 2333-6684
Launched : 2013
JSM Environmental Science and Ecology
ISSN : 2333-7141
Launched : 2013
Journal of Cardiology and Clinical Research
ISSN : 2333-6676
Launched : 2013
JSM Nanotechnology and Nanomedicine
ISSN : 2334-1815
Launched : 2013
Journal of Ear, Nose and Throat Disorders
ISSN : 2475-9473
Launched : 2016
JSM Ophthalmology
ISSN : 2333-6447
Launched : 2013
Journal of Pharmacology and Clinical Toxicology
ISSN : 2333-7079
Launched : 2013
Annals of Psychiatry and Mental Health
ISSN : 2374-0124
Launched : 2013
Medical Journal of Obstetrics and Gynecology
ISSN : 2333-6439
Launched : 2013
Annals of Pediatrics and Child Health
ISSN : 2373-9312
Launched : 2013
JSM Clinical Pharmaceutics
ISSN : 2379-9498
Launched : 2014
JSM Foot and Ankle
ISSN : 2475-9112
Launched : 2016
JSM Alzheimer's Disease and Related Dementia
ISSN : 2378-9565
Launched : 2014
Journal of Addiction Medicine and Therapy
ISSN : 2333-665X
Launched : 2013
Journal of Veterinary Medicine and Research
ISSN : 2378-931X
Launched : 2013
Annals of Public Health and Research
ISSN : 2378-9328
Launched : 2014
Annals of Orthopedics and Rheumatology
ISSN : 2373-9290
Launched : 2013
Journal of Clinical Nephrology and Research
ISSN : 2379-0652
Launched : 2014
Annals of Community Medicine and Practice
ISSN : 2475-9465
Launched : 2014
Annals of Biometrics and Biostatistics
ISSN : 2374-0116
Launched : 2013
JSM Clinical Case Reports
ISSN : 2373-9819
Launched : 2013
Journal of Cancer Biology and Research
ISSN : 2373-9436
Launched : 2013
Journal of Surgery and Transplantation Science
ISSN : 2379-0911
Launched : 2013
Journal of Dermatology and Clinical Research
ISSN : 2373-9371
Launched : 2013
JSM Gastroenterology and Hepatology
ISSN : 2373-9487
Launched : 2013
Annals of Nursing and Practice
ISSN : 2379-9501
Launched : 2014
JSM Dentistry
ISSN : 2333-7133
Launched : 2013
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