Correlation of C-Peptide With Complications Observed in Children and Adolescents With Type 1 Diabetes in Tanzania: A Cross-Sectional Survey

Abstract

Type 1 diabetes mellitus (T1DM) complications corelate with C-peptide levels. However, the C-Peptide role has not been explored in resource limited countries. This study explored the relationship between C-peptide and complications. A cross-sectional study involving participants aged 0 to 25 years with T1DM in Dar es salaam Tanzania, between 2021 and 2022 was done. Diabetes nephropathy and retinopathy were assessed. About 281 (92.4%) participants were screened, 144 (51.2%) were females. Mean age was 19 ± 6 years. Majority 175 (62.3%) had poor glycemic control (HbA1c) > 10%, and low C-Peptide level 201 (71.5%). Retinopathy was 11.7% and risk for nephropathy was 41.3%. About 13.4% and 41.8% with low C peptide had Retinopathy and high-risk nephropathy respectively. Age at diagnosis, poor glycemic control, low c peptide and duration of diabetes were associated with complications. Further prospective studies are needed to capture when complications set in, so to have better strategies to prevent complications.

Keywords

pancreatic reserve microvascular complications C-peptide type 1 diabetes

Background

Type 1 diabetes (T1DM) results from insulin deficiency, although some residual insulin secretion is present at diagnosis and a minority of people retain limited function even after many years of diabetes.¹ Estimation of endogenous insulin levels from β-cells can be done by measuring serum C- peptide levels as it is secreted in the ratio of 1.1 with molar insulin.² The residual Connecting peptide (C-peptide) secretion influences the clinical course of the disease, hence development of complications.^1,3-6 In the Diabetes Control and Complication Trial (DCCT) study, it was found that preserved C-peptide has beneficial clinical outcome including reduction of risk of hypoglycemia, reduction in incidence of retinopathy and micro albuminuria.⁵ In the DCCT study it was learnt that those patients who had high levels of C- peptide, had less micro vascular complications compared to the counterpart with low C- peptide level and a decrease in HbA1C⁶ reduce hypoglycemia and delay complications.⁷ The DCCT had shown that, those patients who had high levels of C-peptide, had less microvascular complications compared to the counterpart with low C-peptide level⁸ (Despite the presence of preserved C-peptide, the rate of microvascular complications is still high between 20% and 23%.⁹ As the level of C-peptide decreases during the course of the disease, the risk of microvascular complications, goes higher.⁶ Studies shows that those diagnosed with diabetes mellitus (DM) at a later age had more C-peptide reserve than those diagnoses at a young age.^9,10 The age of onset of DM may influence the risks for late complications (Retinopathy, and nephropathy). In particular, patients with onset after age 15 years have lower risk of diabetic nephropathy than onset during adolescence.^11,12 Therefore, the aim of the present study was to assess the relationship between the level of C-peptide and the micro-vascular (Retinopathy and nephropathy) complications among children and youth with type 1 diabetes mellitus (T1DM) in Tanzania.

Methods

A cross-sectional study to establish the burden of diabetes nephropathy and retinopathy as well as the association between the complications and C-peptide levels was done among children and youth (age 0-26 years) attending diabetes clinics in Dar es salaam Tanzania, between Jan 2021 and March 2022.The 4 public health pediatric diabetes clinics in Dar es Salaam under the collaboration of Life For a Child, changing diabetes in children and Ministry of Health, with one private diabetes clinic were included. A total of 281 (137 Male and 144 females) children and youth aged 0 to 25 years were included in the study. Ethical approval was obtained from the College research ethics committee (CRERC) of the Kilimanjaro Christian Medical University College (KCMUCo) with certificate No 2478 Parents/guardian gave their informed consent and children aged >12 to 18 years gave their assent to participate in additional to parental consent.

A structured questionnaire was used to collect the required study information. The questionnaire had 3 sections, including 1. demographic characteristics, 2. physical examination (Anthropometric measurements, Blood pressure and Retinal examination) and 3. laboratory investigations.

Pubertal assessment was done in all children and youth by using tanner staging then grouped into pre-pubertal, pubertal and post pubertal.¹³

Demographic Characteristics

Socio-demographic factors included date of birth, initial presentation before diagnosis of diabetes, number of admissions in the past 1-year, current dose and frequency of insulin used, any complications that was present at diagnosis, history of smoking and/or drinking alcohol and family history of diabetes

Physical Examination

Anthropometric measurements and blood were taken and the status of the eyes checked using fundopictures. Anthropometric measurements; body weight (was rounded to the nearest 100 g) and height (was rounded to the nearest 0.1 cm), weight was taken with subjects wearing lightweight clothes without shoes. BMI was then calculated using the Quetelet equation (weight in kilograms divided by the square of height in meters). Blood pressure; was taken by Dinamap machine using different cuffs depending on the size of children. Eye examination; A nurse trained to do eye examination in patients with diabetes took the fundal pictures which were analyzed by the ophthalmologist. At the start of the examination the child was examined for visual acuity using Snellen’s chart and standing at 6 m. This was followed by dilating the eyes of the children using one drop of tropicamide eye drop in each eye and left for 10 to 30 minutes for the pupil to dilate, after which the fundus pictures were taken by a nurse trained in fundo picture techniques, using a fundus Camera (Topcorn TRC 50 EX, Japan) were taken. An ophthalmologists read the fundus-pictures for accuracy and quality control. The results were then reported as normal, background retinopathy, non-proliferative and proliferative retinopathy.

Laboratory Investigations

We collected blood sample from the anterior cubital fossa (3mls) following standard procedures. This was after an overnight fasting. We immediately used one drop of blood on the glucostick for determination of random/fasting blood glucose, using a glucometer (Gluconavii, home health, (UK) LTD Unit A, Greatham Road, industrial estate Greatham Road, Bushey, Hertfordshire WD23 2NZ, United Kingdom), another drop was put on Hemocue^® HbA1c 501, (full automated point of care machine (Radiometer group, Angelholm-Sweden) for HbA1c determination and 1 ml, collected in the lithium heparin bottle, for C-peptide levels analysis. The C-peptide was stored in the ice box before being taken to be stored at −80°C few hours later for storage before it was transported to Exeter University, C peptide levels was measured using Mercodia C-peptide ELISA (UK). C-peptide levels was categorized as Low, if it was <200 pmol/l-, Normal −200 to 600 pmol/l- or High >600 pmol/l.

Testing for Micro Albuminuria

Two milliliters of the first morning urine of the day was collected in an empty clean bottle. The urine was then examined by multitasks URIT 14g (Accurex diagnostic, India) to determine the presence of proteins, Microalbuminuria, ketones, and sugar. The test strip was dipped into the bottle of fresh urine for 30 to 60 seconds, and the color on the test strip was then compared with the color scale on the bottle. The minimum sensitivity of the test strip was 30 mcg/dl of Albumin in urine. Then Albumin creatinine ratio were calculated from the 2 readings to get albumin creatinine ratio,

Statistical Analysis

Statistical analysis was performed using SPSS version 22 (IBM In., Chicago) SPSS was used for preliminary analysis and to examine the collinearity between variables of interest as well as the correlations. In the descriptive analysis, the results were summarized using frequency/counts and mean ± standard deviation for continuous variables while percentage/proportion was used for categorical variables. Pearson Chi-square (χ²) test was used to compare differences between the categorical variables of interest. In the inferential analysis, a bivariate logistic regression was done to find the association between complications of diabetes mellitus (Nephropathy and Retinopathy) and each of the independent factors, separately. Adjusted odds ratio (AOR) was used to present the results of the multivariate analysis.

Results

Study Participant’s Characteristics According to Age Groups

The overall mean age, systolic blood pressure (SBP) and Diastolic blood pressure (DBP) were 19.0 ± 6 years, 114.82 ± 16.12 mmHg and 73.74 ± 11.09 mmHg, respectively. Majority of the study participants 193 (68.7%) were post pubertal children and a large number of participants participants 175 (62.3%) had poor glycemic control (HbA1c) >10%, low C-Peptide level 201 (71.5%) and a high risk of Nephropathy 116 (41.3%) judged by microalbuminuria. (Table 1).

Table 1.

Baseline Characteristics of the Study Participants by Their Age Groups (N = 281).

	Total	Age group (%)
Variables	281 (100)	Pre –pubertal 37(13.2%)	Pubertal 51 (18.1%)	Post-pubertal 193 (68.7%)	P value
Age (mean ±SD) Years	19 (±6)	7 (±4)	13(±1)	22 (±4)	<.001
Sex
Male	137 (48.8)	11(29.7)	19 (37.3)	107 (55.4)	.003
Female	144 (51.2)	26 (70.3)	32 (62.7)	86 (44.6)	.003
Anthropometry
HT (mean ±SD) cm	154 (±16)	131 (±17)	147 (±14)	159 (±10)	<.001
HT Centile (mean ±SD) cm	22.6 (±29.2)	57.3(±34.9)	15.9(±23.7)	17.7(±24.4)	<.001
WT (mean ±SD) Kg	51 (±16)	27 (±10)	42 (±13)	51 (±16)	<.001
SBP (mean ±SD) mmHg	114.8 ± 16.1	105.3 ± 15.9	112.5 ± 16.1	114.3 ± 11.4	<.001
DBP (mean ±SD) mmHg	73.7 ± 11.1	66.0 ± 9.1	72.4 ± 10.7	73.2 ± 10.3	<.001
BMI Centiles by age and sex
Underweight	88 (31.3)	16 (43.2)	19 (37.3)	53 (27.5)	.119^a
Normal weight	147 (52.3)	13 (35.1)	22 (43.1)	112 (58.0)
Overweight	34 (12.1)	6 (16.2)	6 (11.8)	22 (11.4)
Obese	12 (4.3)	2 (5.4)	4 (7.8)	6 (3.1)
HbA1c control
< 7.5%	37 (13.2)	3 (8.1)	6 (11.8)	28 (14.5)	.331^a
7.5% to <10%	69 (24.6)	9 (24.3)	8 (15.7)	52 (26.9)
>10%	175 (62.3)	25 (67.6)	37 (72.5)	113 (58.5)
Duration of Diabetes
<1year	40 (14.2)	4 (10.8)	6(11.8)	30 (15.5)	.762^a
1-5 year	136 (48.4)	21 (56.6)	26 (51.0)	89 (46.1)
>5years	105 (37.4)	12 (32.4)	19 (37.3)	74 (38.3)
Smoking status
No	280 (99.6)	37 (100)	51 (100)	192 (99.5)	.687^a
Yes (current and past)	1 (0.4)	0 (0)	0(0)	1 (0.5)	.687^a
C-Peptide Level (pmol)
Low <200	201 (71.5)	28 (75.7)	35 (68.6)	138 (71.5)	.731^a
200-600	51 (18.1)	4 (10.8)	11 (21.6)	36 (18.7)
>600	29 (10.3)	5 (13.5)	5 (9.8)	19 (9.8)
Nephropathy
High Risk	116 (41.3)	13 (35.1)	28 (54.9)	75 (38.9)	.062
No Risk	165 (58.7)	24 (64.9)	23(45.1)	118 (61.1)
Retinopathy
No	248 (88.3)	32 (86.5)	46 (90.2)	170 (88.1)	.32
Yes	33 (11.7)	5 (13.5)	5 (9.8)	23 (11.9)

Fisher’s Exact test was used.

Furthermore, there was a large proportion of females in the pre-pubertal (70.3%), and a significantly large proportion of males in the post-pubertal 107 (55.4%) age groups, (P < .01). Slightly above 50% 147 (52.3%) had normal BMI percentile by age and sex, however, the prepubertal group had more underweights than the rest of the group, the difference that was not statistically significant (P = .119). Most of the participants 175 (62.3%) had poor glycemic control with the high percentage of poor control being in the pubertal age group 37 (72.5%). Furthermore, there was no significant difference in the proportions of C-Peptide levels, duration of T1DM, risk of nephropathy, and/or retinopathy across the age groups. For further details, see Table 1.

Comparison of Diabetes Micro-Vascular Complications by C-Peptide Levels

Table 2 shows that there is an association between low levels of c peptide and chronic complications (Risk of nephropathy and retinopathy), however, the difference was not statistically significant. Among participants with low to normal c-peptide levels, there was a high proportion of poor glycemic control 122(60.7%) and 36(70%) respectively, however, in the high c peptide there were at least 20.7% of clients with good glycemic control compared to 13.4 and 7.8% in those with low to normal C peptide levels respectively which is statistically significant (P = .004) Table 2).

Table 2.

C-peptide Levels in Relation to HbA1C and Diabetes Complications (N = 281).

Diabetes complications		Total 281 (100)	C-peptide levels n (%)
Diabetes complications		Total 281 (100)	Low 200 (71.2)	Normal 57 (20.3)	High 24 (8.5)	P-value
Nephropathy	No risk	165 (58.7)	117 (58.2)	31 (60.8)	17 (58.6)	.946
Nephropathy	High risk	116 (41.3)	84 (41.8)	20 (39.2)	12 (41.4)	.946
Retinopathy	Yes	33 (11.7)	27 (13.4)	5 (9.8)	1 (3.4)	.310^a
Retinopathy	No	248 (88.3)	174 (86.6)	46 (90.2)	28 (96.6)	.310^a
HbA1c	Well controlled	37 (13.2)	27 (13.4)	4 (7.8)	6 (20.7)	.004
	Mild-moderate controlled	69 (24.6)	52 (25.9)	11 (21.6)	6 (20.7)
	Poorly controlled	175 (62.3)	122 (60.7)	36 (70.6)	17 (58.6)

Fishers Exact test was used.

Factors Associated With Micro-Vascular Complications of T1DM Among Children and Youths

In both unadjusted and adjusted model participants who were diagnosed with DM at the age of puberty were significantly less likely to develop nephropathy [OR 0.27, 95%, 0.08-0.87] and [OR 0.24, 95%, 0.07-0.84] respectively. In the adjusted model participants who were underweight had significantly less likelihood of developing nephropathy than other groups [OR 0.51, 95% 0.28-0.94], and participants who were overweight were likely to develop nephropathy [OR 3.17 95% 1.13-8.85]. Participants who presented with high systolic blood pressure at baseline were significantly more likely to have Nephropathy compared to those who had normal SBP [OR 2.98, 95% 1.96-4.83]. Duration of DM diagnosis between 1 and 5 years was the independent risk factor predicted the developing retinopathy complication in the adjusted model [OR 2.19, 95% 1.01-4.78]. In an unadjusted and adjusted, C-peptide did not have any association with complications—[AOR 1.13, 95% CI: 0.43-2.93] (Table 3).

Table 3.

Factors Associated with Chronic Complications of T1DM Among Children and Youths.

Factors	Diabetes complications
	Nephropathy		Retinopathy
	OR [95% CI.]	AOR [95% CI.]	OR [95% CI.]	AOR [95% CI.]
C-peptide (Ref. High)	0.99 [0.46-2.17]	0.83 [0.32-2.19]	0.25 [ 0.32-1.87]	0.31 [ 0.03-2.85]
Low	0.93 [0.55-1.57]	0.85 [0.44-1.63]	1.37 [0.48-3.91]	1.27 [0.35-4.63]
(Ref. Normal)
A1c (Ref. well controlled)
Poorly controlled	0.97 [0.48-1.95]	0.87 [0.41-1.84]	1.27 [0.43-4.08]	3.07 [0.68-13.80]
Age at diagnosis (Ref. Pre-pubertal)
Pubertal	0.51 [0.28-0.94]	0.48 [0.19-1.18]	0.78 [0.29-2.14]	0.73 [0.18-2.94]
Post-pubertal	1.37 [0.83-2.28]	0.87 [0.41-1.87]	1.06 [0.48-2.32]	1.17 [0.38-3.62]
Duration of diagnosis (Ref. <1 year)
1-< 5 year	1.05 [0.50-2.24]	1.11 [0.48-2.52	2.35 [1.09-5.06]	2.19 [1.01-4.78]
5-10 year	0.79 [0.37-1.68]	0.80 [0.35-1.80]	0.41 [0.17-0.99]	0.44 [0.18-1.08]
Age at measurement (Ref. pre-pubertal)
Pubertal	0.27 [0.08-0.87] *	0.24 [0.07-0.84] *	1.30 [0.12-13.31]	0.98 [0.08-12.44]
Post-pubertal	0.43 [0.13-1.39]	0.19 [0.05-0.78] *	2.32 [0.25-21.23]	2.60 [0.19-35.50]
Sex (Ref. Female)
Male	0.87 [0.54-1.39]	0.79 [0.48-1.30]	0.87 [0.40-1.89]	0.78 [0.32-1.93]
Body Mass Index (Ref. Normal weight)
Underweight	0.59 [0.36-0.99]	0.57 [0.33-0.97]	1.33 [0.55-3.29]	0.60 [0.18-1.98]
Overweight	2.53 [1.01-6.36] *	3.17 [1.13-8.85] *	1.85 [0.51-6.68]	1.46 [0.31-6.96]
Obese	1.19 [0.44-3.18]	1.16 [0.57-2.39]	0.59 [0.07-5.02]	0.27 [0.03-2.91]
Smoking status (Ref. No)
Yes (current and past)	2.17 [0.57-8.20]	2.49 [0.59-10.55]	0.78 [0.97-6.28]	0.52 [0.04-7.07]
SBP (mmHg)	1.97 [1.15-3.21]	2.98 [1.96-4.83]	1.02 [1.03-1.04]	1.03 [0.99-1.07]
DBP (mmHg)	1.01 [0.99-1.03]	1.03 [0.01-1.07]	1.02 [0.99-1.05]	1.0 [0.95-1.05]

Discussion

The relationship between C-peptide and diabetic micro-vascular complications among children and adolescents with T1DM attracted the attention of many researchers worldwide.

The current results show a relatively high prevalence of low C-peptide levels among study participants confirming that the majority are type 1 diabetes patients. With this finding many of our patients have a risk of further decline in C- peptide hence poor glycemic control leading to complications (eg, retinopathy, and nephropathy), and poorer metabolic control.^14-16 After disintegrating the levels of low C-peptide by age groups, participants in the post-pubertal group had a significantly higher proportion of low C-peptide compared to pre-pubertal and pubertal age groups. These findings are consistent with those from previous studies which showed that C-peptide commonly tends to decrease over time after the onset of disease^15,17 and this confirms that even in our setting the commonest form of diabetes in children and youth is still T1DM. Diabetes has been reported to cause microvascular complications such as retinopathy and nephropathy.^3,12 Occurrences of these complications have been connected to hyperglycemia a hallmark of patients with diabetes. The findings from our study have shown that a high proportion of study participants are at higher risk of having diabetic nephropathy due to a high rate of poor glycemic control. Similar findings have been reported by other studies in Northern Tanzania,⁵ in Botswana,⁶ and Zimbabwe.⁴ The reported high prevalence of diabetic Retinopathy and nephropathy in these countries are incongruent with findings highlighted in the previous systematic review and meta-analysis which included the studies conducted in Sub Sahara 11.7% which is higher compared to the study conducted in Ethiopia⁷ and Brazzaville—Congo¹⁸ but lower compared to the study conducted in Sudan.¹¹ The retinopathy was not associated with levels of C-peptide similar to a study that showed high levels of microvascular complications despite the high level of C peptide.¹⁰ However the DCCT findings showed high levels of C- peptide meant less microvascular complications.¹⁹ The differences between the findings in the 2 studies might have been contributed by other factors in an African setting, including, poor glycemic control, limited economic resources, reduced parental support, lack of regular SMBG, poor insulin storage, and poverty as shown in the previous studies in Africa.⁹ Furthermore a correlation between Retinopathy and the duration of diabetes from 1 to 5 years, the finding has been shown by other studies that says the duration of diabetes is a risk to the development of retinopathy.²⁰

Some of the previous studies linked micro-vascular complications (diabetes nephropathy and retinopathy) directly to low level of C-peptide,²¹ yet our study has linked the low C-peptide with poor glycemic control—indicating the possibility of early microvascular complications down the line indirectly linking low C-peptide to complications. The study found that the odds of developing retinopathy were 5 times higher for those with more than 10 years of diabetes diagnosis compared to those with less than one year after being diagnosed. The similar findings have been reported by previous studies conducted in Brazil²² and Kuwait.²³ These findings indicates that duration of diabetes from the time of diagnosis is one of the crucial determinant of diabetic retinopathy.²⁰ Nevertheless, there is a possibility that those who develop retinopathy early, had delayed diagnosis, hence they had been hyperglycemic way before diagnosis. Retinopathy would have been more in children and youth with diabetes duration of more than 10 years as shown from others studies,^24,25 however our study has shown a different result, probably because survival of children and youth with diabetes in the country have lower survival rate (69% ) with the mean age of death at 17 years.²⁶

Global evidence from several previous studies showed no association between BMI and diabetic retinopathy.^22,27-29 Our findings have also shown that there was no significant association between BMI centiles and diabetic retinopathy. However, our findings indicate a significant association between BMI centiles and diabetic nephropathy in which the odds of developing diabetic nephropathy were about 3 times higher for participants with overweight compared to those with underweight which was protective. Similar findings have reported in previous studies.^30,31 On the centrally Obesity did not have any association with the BMI percentile—most likely because of smaller number of participants generally and those who are obese

Strength of the Study

This study was able to screen the largest and longest cohorts of children and youth with T1DM in Dar es salaam region and in Tanzania generally. These children have been followed up from the initial study in 2005 when we had started a very first pediatric diabetes clinic in Tanzania. The analysis has included children and youth since the beginning of separate pediatric clinics, which allows for the different cohorts’ times, and duration. This cohort has faced unawareness in both public and health care providers, about diabetes in children and youth to care policies in Africa, hence a better perspective of the cohorts.

Limitations

A large proportion of our subjects have very poor glycemic control, so that it is difficult to get the real difference between those with good glycemic control and poor glycemic control as well as the relationship with C-peptide.

It is a cross section study- hence lack the benefit of long-term effect of poor glycemic control, probably those who had poor glycemic control at that point, had good glycemic control throughout their diabetes duration.

ISPAD guideline advocates for screening after 10 years of age or 2 years after diagnosis for those in puberty unfortunately, in our setting this is difficult hence we never know when the complications set in -generally

Also, BMI may not be accurate due to stunted growth of many participants.

Conclusion

The overall prevalence of microvascular complications (diabetic nephropathy and diabetic retinopathy) is relatively high. The majority of the participants had a low level of C-peptide confirming the severe insulin deficiency in T1DM. The was a slight association between low levels of C-peptide and complications. Duration of DM, age at a clinic visit, BMI centiles, and glycemic control were potential predictors of diabetic microvascular complications. We also need prospective studies to capture the exact time when complications set in so that we can have better strategies to prevent complications.

Supplemental Material

sj-docx-1-gph-10.1177_2333794X231159790 – Supplemental material for Correlation of C-Peptide With Complications Observed in Children and Adolescents With Type 1 Diabetes in Tanzania: A Cross-Sectional Survey

Supplemental material, sj-docx-1-gph-10.1177_2333794X231159790 for Correlation of C-Peptide With Complications Observed in Children and Adolescents With Type 1 Diabetes in Tanzania: A Cross-Sectional Survey by Edna Siima Majaliwa, Kandi Catherine Muze, Joel Ndayongeje, Sayoki Geofrey Mfinanga, Blandina Theophil Mmbaga and Kaushik Ramaiya in Global Pediatric Health

Footnotes

Author’s Note

Edna Siima Majaliwa is also affiliated to Muhimbili National Hospital, Dar es Salaam, United Republic of Tanzania.Sayoki Geofrey Mfinanga is now affiliated to National institute for Medical Research-Muhimbili, Dar es salaam, United Republic of Tanzania.

Author Contributions

Edna Siima Majaliwa: Conceptualization, design, data collection, analysis, writing, and review

Blandina Theophil Mmbaga: conceptualization, analysis, writing, and review

Sayoki Geofrey Mfinanga: conceptualization, study design, and review

Kaushik Ramaiya: Conceptualization, Design, Writing and Review

Kandi Catherine Muze: Designs, data analysis, and review reviewing

Joel Ndayongeje: design, data analysis, writing, and review

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Edna Siima Majaliwa

Supplemental Material

Supplemental material for this article is available online.

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