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Diabetes & Metabolism
Vol 27, N° 4  - septembre 2001
p. 487
Doi : DM-09-2001-27-4-1262-3636-101019-ART9
Original articles

Predictive risk factors for deterioration from normoglycemic state to type 2 diabetes mellitus or impaired glucose tolerance in a tunisian urban population
 

M. Chihaoui [1], F. Kanoun [1], B. Ben Rehaiem [1], S. Ben Brahim [1], B. Ftouhi [1], A. Mekaouar [1], M. Fekih [2], A. Mbazâd [2], B. Zouari [3], F. Ben Khalifa [1]
[1] Service d'Endocrinologie-Diabetologie, Hôpital, la Rabta, Tunis.
[2] Laboratoire de Biochimie, Hôpital la Rabta, Tunis.
[3] Département de Médecine Préventive et sociale, Faculté de Médecine de Tunis.

Abstract
Objective

To determine the predictive risk factors for the development of type 2 diabetes mellitus (DM) or impaired glucose tolerance (IGT) in a normoglycemic population.

Research design and methods

This is a ten-year prospective study in a randomly selected urban population including 1835 subjects aged >= 30 years living in Tunis, 1460 were normoglycemic according to 2 hours blood glucose WHO criteria, and 701 among them attended the follow-up assessment ten years later. Subjects with impaired glucose tolerance (IGT) were excluded. Subjects underwent a physical examination including weight/height, iliac circumference (IC) and blood pressure measurements. Fasting and 2-hour venous blood sampling, after a 75 g oral glucose load, were performed for the measurement of plasma glucose (G 0 , G 2h ), insulin (I 0 , I 2h ), total cholesterol (TC) and glycated hemoglobin (HbA 1c ) levels.

Results

Out of the 701 normoglycemic subjects in 1985, 77 developed diabetes and 130 impaired glucose tolerance after 10 years, giving a mean annual incidence rate of 1.1 % for diabetes and 1.85 % for IGT. Univariate analysis showed that risk factors for diabetes were age, BMI, IC, SBP, G 0 and total cholesterol in both sexes, I 0 and I 2h in men only and DBP G 2h and HbA 1c in women only. Risk factors for IGT were BMI, IC and G 2h in both sexes, I 2h in men only and G 0 in women only. Multivariate analysis revealed that BMI, G 0 and G 2h were independent risk factors for conversion to diabetes or IGT in both sexes, but HbA 1c and IC were risk factors only in men.

Conclusion

Early screening and prevention of diabetes must focus on obese subjects, especially those with central fat distribution, and those with moderate increase in fasting and/or two-hour blood glucose levels within the normal range.

Abstract
Facteurs de risque prédictifs du diabète de type 2 et de l'intolérance au glucose chez les sujets initialement normoglycémiques dans une population urbaine tunisienne.
Objectif

Déterminer les facteurs de risque prédictifs du développement d'un diabète de type 2 ou d'une intolérance au glucose (IGT) dans une population de sujets normoglycémiques.

Population et méthode

Etude prospective d'une cohorte de sujets adultes âgés de 30 ans ou plus, vivant à Tunis. Sur 1460 sujets initialement normoglycémiques en 1985, 701 ont pu être réexaminés 10 ans plus tard en 1994/95. Tous les sujets ont eu un interrogatoire et des examens cliniques et un test de charge glucosée orale avec 75 g de glucose pour dosage des glycémies et des insulinémies au temps 0 (G 0 et I 0 ) et au temps 2 heures (G 2h et I 2h ) de même qu'un dosage de l'hémoglobine glyquée (HbA1c) et du cholestérol total.

Résultats

Parmi les 701 normoglycémiques au départ, 77 ont développé un diabète de type 2 et 130 une IGT soit une incidence moyenne de 1,1 % et 1,85 % par an respectivement. En analyse univariée, les facteurs de risque de diabète étaient l'âge, l'indice de masse corporelle (BMI), la circonférence iliaque (IC), la tension artérielle systolique (TAS), G o et le cholestérol total dans les 2 sexes, I 0 et I 2h chez les hommes et TA diastolique (TAD) chez les femmes. Les facteurs de risque de l'IGT étaient le BMI, la circonférence iliaque et G 2h dans les 2 sexes, I 2h chez les hommes et G 0 chez les femmes uniquement. En analyse multivariée, BMI, G 0 et G 2h étaient les facteurs de risque indépendants prédictifs de la conversion vers le diabète ou l'IGT dans les 2 sexes et l'HbA 1C et l'IC chez les hommes uniquement.

Conclusion

Le dépistage précoce et la prévention du diabète doivent être ciblés sur les sujets obèses et ceux ayant une augmentation modérée de leur niveaux glycémiques et ceci même en dessous des limites considerées comme pathologiques.


Mots clés : facteurs de risque. , diabète de type 2. , intolérance au glucose.

Keywords: risk factors. , type 2 diabetes. , impaired glucose tolerance.


POPULATION AND METHODS

The prevalence of type 2 diabetes is increasing word-wide. It reaches epidemic rates (> 50 %) in some communities such as the Naureans and Pima Indians [ [1]]. This is also true in the Tunisian urban population where it was 5.1 % in 1976 [ [2]] and reached 9.8 % in 1985 [ [3]] which means a twofold increase in prevalence within ten years.

Diabetes is a chronic disease that deteriorates quality of life and leads to a heavy morbidity and mortality [ [4], [5]]. Moreover, diabetes has an economic impact in terms of management of the disease and its complications [ [6]]. This represents a serious public health concern, especially in developing countries [ [3]]. It is well known that type 2 diabetes is a very heterogeneous disease with a genetic component [ [7]] associated with environmental factors which play an important role in the expression of the disease. The determination of the factors implicated in the pathogenesis of diabetes will help us to prevent it and to screen it earlier in high risk population. Only a few prospective studies in the world have aimed at determining predictive factors for diabetes: this was done in the Pima Indians [ [8]], Mexican-Americans [ [9]], British [ [10]], Swedish [ [11]], Norwegians [ [12]], Koreans [ [13]], Parisians [ [14]]. The aim of our study was to determine the specific risk factors for type 2 diabetes in a Tunisian urban population.

Population

The initial population included 1 835 subjects aged 30 years old or more living in Tunis. They were selected in 1985 using a two stage random sampling: 1/10 of the districts, then in each district 1/10 of the households from the data base of the population and lodging census carried out in 1984. This cohort was used for the epidemiological study of diabetes and associated risk factors in the urban population in 1985.

According to 2 hours blood glucose WHO criteria, 182 subjects were classified as type 2 diabetes mellitus (DM), 193 subjects as impaired glucose tolerance (IGT) and 1460 as normoglycemic subjects. Ten years later, in 1994 we tried to find again the subjects by going to their home. Among the 1460 normoglycemic subjects, we found 890 subjects of whom 75 were deceased, 114 refused to participate again in the study, and 701 (271 men and 430 women) accepted to be reexamined. These subjects represented the studied population for the determination of the predictive risk factors for type 2 DM. The missing 570 subjects had moved out Tunis and we failed to contact them. The total number of subjects lost for follow up was 759 (368 men and 391 women) Fig. 1

. Subjects with IGT were excluded and will be analyzed elsewhere separately.

The comparison of baseline characteristics recorded in 1985 between the 701 normoglycemic subjects that we could reexamine and the 759 normoglycemic subjects lost for follow up showed that the latter were significantly older (mean age was 46.8 ± 13.5 vs 45.3 ± 11.1 years, p < 0.05) and included more men (48.5 % vs 38.7 %, p < 0.05). In reexamined subjects, both men and women as compared with missing subjects had higher BMI (24.6 ± 3.9 vs 23.9 ± 3.9 kg/m

2

, p < 0.02, in men and 27.6 ± 5.4 vs 26.7 ± 5.6 kg/m

2

, p < 0.02, in women).

Reexamined men had also a higher iliac circumference (90.4 ± 9.4 vs 88.5 ± 10.3 cm, p < 0.02). There was no significant difference in both sexes according to other clinical and biological parameters between the two groups (Table I)

. The distribution of reexamined subjects by G

0

and G

2h

classes at baseline showed that the whole subjects had initial fasting blood glucose levels below 1.26 g/l and 2 hours post load blood glucose below 1.40 g/l (Table II)

.

Methods

At baseline in 1985, all subjects were interviewed about their age, family history of diabetes and physical activity. A physical activity score was determined based on the frequency and the intensity of the reported activities; subjects with no or low activity were considered as inactive, those with moderate or intensive activity were considered as active. All subjects underwent a physical examination consisting in the determination of weight, height, iliac circumference (IC) and systolic (SBP) and diastolic blood pressure (DBP). Venous blood sampling were performed in the morning after an overnight fast for the determination of plasma glucose, total cholesterol glycated hemoglobin (HbA

1c

) and insulin (I

o

) and two hours after 75 g oral glucose load for the determination of plasma glucose and insulin (I

2h

). The 701 initially normoglycemic subjects were reexamined in 1994-95 according to the same protocol described above, including a second oral glucose tolerance test to assess the conversion from a normal glucose tolerance state to diabetes or IGT. Body mass index (BMI) was calculated as weight (kg)/height (m)

2

. Iliac circumference was measured at the iliac crests. Blood pressure was recorded with the same mercury manometer in a sitting position after 10-15 minutes rest. Each subject had two measurements of blood pressure at 5 minutes interval. Hypertension was considered if subject was treated for hypertension or if the mean of systolic blood pressure SBP >= 140 mmHg and/or diastolic blood pressure DBP >= 90 mmHg. Laboratory techniques for biological analysis were glucose oxidase for plasma glucose, chromatography on micro column for HbA

1c

, radio-immuno assay for insulin and enzymatic method for total cholesterol.

Statistical analysis: Analysis of variance (ANOVA) was used to compare the means of quantitative variables in different groups.

c

2

test was used to test the association of the various risk factors with the development of type 2 DM or IGT. Multiple logistic regression analysis was used to test the importance of variables that were associated with development of IGT or DM in univariate analysis. For the calculation of the Odds ratios, continuous variables were divided into two classes using (mean + 1SD) as cut-off point. A p < 0.05 value was taken as the limit level for significance.

RESULTS

According to the 2 hours plasma glucose WHO criteria, among the 701 initially normoglycemic subjects in 1985, 77 (32 men/45 women) developed type 2 diabetes mellitus in the subsequent ten years giving a mean annual incidence rate equal to 1.1 %. This incidence rate was slightly but not significantly lower in women than men: 1.05 % vs 1.18 %. Among the 77 type 2 DM, 21 (28 %) were already known and treated for type 2 diabetes mellitus and 56 (72 %) were screened during the 1994/95 survey. A total of 130 subjects developed IGT with a mean annual incidence rate equal to 1.85 % and a moderately but not significantly higher incidence rate in women than in men: 1.95 % vs 1.70 %, respectively, while 494 remained normoglycemic (NGT group).

Univariate comparison of baseline clinical and biological characteristics recorded in 1985 between the three groups (Table III)

showed that diabetic subjects were significantly older than normoglycemic subjects in both sexes, 48.5 ± 8.9 vs 47.3 ± 11.8 years (p < 0.05) in men and 48.1 ± 10.1 vs 43.1 ± 10.4 years (p < 0.01) in women, respectively. BMI and IC increased significantly and linearly with the degree of glucose tolerance abnormality: type 2 DM subjects exhibited the highest mean in BMI (p < 0.001) and the largest IC (p < 0.001) as compared with normoglycemic subjects in both sexes. SBP was significantly higher only in subjects converted to diabetes in both sexes (p < 0.05 in men and p < 0.01 in women). DBP was significantly higher only in women converted to DM (p < 0.01). In women, fasting blood glucose as well as 2 hour- blood glucose were significantly higher in diabetic and IGT groups than in NGT. In men, G

0

was significantly higher only in DM group and G

2h

was significantly higher only in IGT group as compared with NGT group. Fasting and 2 hour-post load plasma insulin levels were significantly higher only in men who developed diabetes. No relationship was found between plasma insulin levels and glucose tolerance abnormalities in women. Glycated hemoglobin was associated with conversion to DM only in women. Total plasma cholesterol levels were significantly higher only in diabetes group in both sexes as compared with normoglycemic subjects. Diabetic subjects were less active than those who became IGT or who remained normal. There was no significant difference regarding family history of diabetes between the three groups in both sexes.

Multivariate analysis by sex was performed to assess the relative independence of these risk factors. We used a model including: age, BMI, IC, SBP, DBP, G

o

, G

2h

, HbA

1c

, I

0

, I

2h

and TC (Table III)

. In women G

0

, G

2h

and TC were independent risk factors for diabetes, with respective ORs and 95 % confidence intervals 2.37 [1.00-5.63], 3.33 [1.37-8.00], 3.06 [1.26-7.46] and age, IC, and G

0

were risk factors for IGT with respective ORs and 95 % CI 2.17 [1.03-2.76], 2.45 [1.02-5.89] and 2.99 [1.45-6.15]. In men only iliac circumference and glycated hemoglobin were significantly associated with conversion to diabetes mellitus with respective ORs and 95 % confidence interval 4.62 [1.7-12.7] and 2.79 [1.03 -7.57], no factor was associated independently with conversion to IGT. BMI, G

0

and G

2h

could independently predict the risk for development of either type 2 DM or IGT, in both sexes, ORs and 95 % CI were 2.52 [1.09-5.82] and 2.08 [1.00-4.34] for BMI in men and women respectively; 2.49 [1.18-5.24] and 1.77 [1.00-3.14] for G

0

and 2.28 [1.05-4.93] and 2.41 [1.35-4.30] for G

2h

.

DISCUSSION

Our results showed that the incidence rate of conversion to type 2 DM or IGT in initially normoglycemic subjects aged 30 years old or more were 1.10 % and 1.85 %, respectively. The most predictive risk factors for conversion to IGT or Type 2DM were, in both sexes, obesity, iliac circumference, fasting blood glucose and 2 hour-post load blood glucose. HbA

1C

level was a predictive risk factor only in men.

Participating rate in our study was relatively weak, 52 % lost for follow-up for different reasons. This might be a source of bias. The comparison of baseline characteristics between the reexamined and those lost for follow-up showed that the responders were significantly younger and included more women than the non responders. The consequence of this selection bias may be an underestimation of incidence rate of type 2 DM and IGT. There was no significant difference regarding the other baseline anthropometric (BMI, IC, SBP, DBP) and metabolic parameters (G

0

, G

2h

, HbA

1c

, I

0

, I

2h

and TC). The analysis of predictive risk factors has been done separately by gender and after adjustment of variables on age. So our results might not be seriously affected by the low participating rate.

In our study, among the 77 subjects converted to diabetes after 10 years, only 26 (28 %) were known to be affected by DM and the 56 remainders (72 %) were screened during the survey. In the population selected in 1985, 181 cases of diabetes were detected of whom 36 % were not aware of their metabolic diseases. In 1976, the rate of unknown diabetics was higher (51 %). This rate varies from one population to another, 80 % in Tanzania [ [15]], 70.3 % in China [ [16]], 60 % in Uppsala [ [11]] and Cameroon [ [17]], 48 % in USA and 46 % in Alaskan Eskimoes [ [18]]. This excess in undiagnosed diabetic condition could be explained by the high frequency of asymptomatic forms which are much better screened by 2 hour-blood glucose concentration than with fasting blood glucose used in our first survey in 1976. Moreover, initially IGT subjects who may developed symptomatic diabetes has been excluded for this analysis. Harris estimated to 4-7 years the mean course of diabetes before its diagnosis [ [19]]. Thus, owing to the benefit of early diagnosis of diabetes on the setting of microvascular complications and worsening of macrocascular ones, it is suitable to limit the number of unknown cases of diabetes by early screening of the diseases. But such an action can be profitable only if it concerns a high risk population. Therefore the identification of risk factors for diabetes is necessary for screening and also for the prevention of the disease. For the identification of risk factors for type 2 DM in Tunisia, we have chosen the urban population of Tunis that gather subjects of different origins and of different socio-economic levels living a fast lifestyle changes. Another problem related to the possibility that some of our patients may belong to the so called "slowly progressive type 1 diabetes". It is possible that some of our patients might be slowly progressive type I diabetes, unfortunately we did not perform immunogenetic tests to identify them. However, diabetic patients were mostly screened according to G

2h

criteria and where aged 40 years or more at examination 10 years later. Moreover they exhibited high levels of BMI and IC, such characteristics are more likely associated with type 2 DM.

As reported in many other studies [ [9], [13]], we have noted an increase in the risk of diabetes with age but only in univariate analysis. Positive relationship between family history of diabetes and the development of the disease is noted in Swedish [ [20]], Chinese [ [16]] and Eskimoes [ [18]], but not in the Koreans [ [13]]. In our study, the absence of this relation could be explained by the fact that we only considered the presence of diabetes in the parent and not in the other members of the family and by a probable misreading of the family history of diabetes because almost of subjects were born outside of Tunis and have lost contact with their family. Physical activity had a strong protective effect against the development of diabetes as reported by Lynch [ [20]] and Sherman [ [21]] who noted that moderate physical activity decrease by more than 60 % the risk of diabetes in a high risk population after adjustment to other risk factors. Physical activity acts by lowering insulin levels and thereby improves insulin sensitivity [ [22]]. The skeletal muscle is the main site of insulin resistance and exercise can reduce it. Moreover, physical exercise have a favorable effect on fat distribution. Univariate analysis showed that BMI was strongly associated with conversion to IGT or type 2 DM in both sexes. In multivariate analysis this association disappeared for IGT and type 2 DM when analyzed separately but BMI remained as an independent risk factor when the two types of glucose tolerance abnormalities were regrouped. BMI was strongly associated with type 2 DM in several studies all over the world: Mexican-Americans [ [9]], British [ [10]], Swedish [ [11]], Pima Indians [ [8]], Norwegian [ [12]], Chinese [ [16]] and Parisians [ [14]], but not in Koreans [ [15]] where this could be explained by the small number of obese subjects in this population. Colditz estimated that the risk for diabetes was 4-fold higher when BMI in adults exceeded 22 to 25 kg/m

2

as compared with the risk if BMI is lower and the risk for diabetes attributable to obesity was equal to 92 % [ [23]]. He also noted that a gain in weight leads to in increase in the risk of diabetes and conversely a loss of weight can be protective against diabetes. Association between obesity and diabetes is generally attenuated in multivariate analysis [ [8]]. This may be related to fat distribution which plays a major role in the pathogenesis of type 2 DM. Abdominal obesity was associated with metabolic abnormalities in both sexes [ [23], [24]]. In Finnmarks study [ [8]], the association between BMI and diabetes was greatly attenuated after multivariate analysis in women and was less influenced in men. Abdominal fat distribution evaluated by waist to hip ratio (WHR) has been demonstrated to be a predictive risk factor for diabetes in Mexican-Americans [ [9]], Pima Indians [ [8]] and Chinese [ [16]]. Fat distribution was evaluated in our study by iliac circumference or waist circumference. Waist circumference has been demonstrated to be better correlated than WHR to visceral abdominal fat [ [25], [26]] and that it is the stongest and the most important factor compared with BMI and WHR, indicating that visceral abdominal fat is more important than total body fat or subcutaneous fat in the risk leading to diabetes. Okosun [ [27]] has noted that lifestyle can change the relationship between BMI and waist circumference, with an increase of waist circumference with westernization independently of BMI. Abdominal visceral fat acts by higher rate of lipolysis in the adipocytes leading to an increase of free fatty acid concentration in the portal vein that reduces the hepatic insulin sensitivity, stimulates hepatic glucose production and inhibits hepatic insulin extraction [ [28]]. In our study, iliac circumference was associated with conversion to IGT or type 2 DM in both sexes but in multivariate analysis, this association persisted only with IGT in women and with diabetes in men. This may be due to the fact that iliac circumference was also increased in general obesity and did not discriminate in these cases between abdominal and peripheral fat distribution. M. Daniel [ [29]] found that WHR discriminates risk for type 2 DM in overweighted (BMI from 25 to 29 kg/m

2

) but not in obese (BMI>=30 kg/m

2

) individuals.

Blood glucose levels G

0

and G

2h

were associated with conversion to IGT or type 2 DM in both sexes. The increased plasma glucose concentration within the normal range is a strong and independent risk factor for abnormal glucose tolerance. The risk increased linearly with the increase of plasma glucose levels in both sexes. Most studies are consistent with the fact that G

0

and G

2h

levels were strong risk factors for diabetes [ [30], [31]]. Thus a mild increase within normal ranges could be an intermediate state in the evolution of the disease. We have to stress on the fact that even a moderate increase of fasting blood glucose could lead to an increase in microvascular complications and this justified the recent changes in fasting blood glucose criteria for diagnosis of diabetes by the ADA and WHO expert committee [ [32]].

No association were found between insulin levels (at fast and 2 hours post glucose load) and conversion to IGT or to type 2 DM in our study. I

0

as indirect indicator of insulin resistance did not predict IGT and diabetes in our population although it was higher in subjects converted to IGT and type 2 DM. Given the fact that central obesity acts by insulin resistance, it is surprising that Io did not have a significant positive relation with the development of the disease. High fasting insulin level was a known predictive factor for diabetes in other populations such as Mexican-Americans [ [9]], Pima Indians [ [8]] and Swedish [ [11]] but not in Koreans [ [13]] where obesity does not predict diabetes. Low 2 hour-post load insulin levels commonly reflect a quantitative defect of the B cells which are unable to react correctly to hyperglycemia and has been found to be a risk factor for diabetes in Pima-Indians in whom the role of insulin deficiency has been well demonstrated with low insulin response to intravenous dextrose injection [ [8]]. In Mexican-Americans, high I

2h

predicted diabetes as does a low

D

I

30

/

D

G

30

ratio during OGTT that reflects a B cell dysfunction [ [9]]. So, high I

2h

did not exclude an abnormal insulin secretion, but on the contrary it could be insufficient regarding to blood glucose levels. Actually, the assay used at that time to measure insulin level cross-reacts with pro-insulin by 70 to 100 %, so high levels of I

2h

probably results from excessive release of pro-insulin caused by an abnormal cleavage of pro-insulin to insulin after the stress caused by hyperglycemia [ [33], [34]]. In that context, the B cell dysfunction is probably qualitative rather than quantitative, essentially at the early stages of the disease. B-cell quantitative or qualitative dysfunction has been noted in different population studies. Haffner [ [35]] have demonstrated that both insulin-resistance and B-cell dysfunction were important in the etiology of type 2 diabetes in high and low risk populations and concluded that the risk factors for diabetes are the same in different populations with the same patho-physiological mechanism despite genetic differences.

CONCLUSION

Our study showed that obesity especially with central fat distribution and moderate increase, within normal range, of fasting or 2 hour-post load blood glucose, were the most important risk factors for conversion to IGT or type 2 DM in initially normotolerant subjects followed up during 10 years. Preventive action for diabetes must focus on reducing the prevalence of obesity by promoting physical activity and nutritional education. This preventive action have been integrated in the National Program for Prevention of Cardio-vascular Diseases undertaken since 1996 in Tunisia.Acknowledgements

This work was supported financially by the Tunisian Ministry of high education and scientific research (grant no 87DGRST 93) and the Ministry of Public Health.

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The owners of this website hereby guarantee to respect the legal confidentiality conditions, applicable in France, and not to disclose this data to third parties.
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