Mortality and low C-peptide levels in children and young people diagnosed with type 1 diabetes in Cameroon: a case series from the Young-Onset Diabetes in sub-Saharan Africa study

¹Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, United Kingdom, ²National Obesity Centre and The Endocrinology and Metabolic Diseases Unit, Yaoundé Central Hospital, Yaoundé, Cameroon, ³Department of Non-Communicable Diseases, RSD Institute, Yaoundé, Cameroon, ⁴Faculty of Medicine and Biomedical Sciences, Department of Internal Medicine and Specialities, University of Yaoundé 1, Yaoundé, Cameroon

^&Corresponding author
Jean Claude Katte, Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, United Kingdom

Introduction    

Type 1 diabetes (T1D) is a chronic metabolic condition characterised by absolute or near-absolute insulin deficiency due to the destruction of the insulin-secreting beta cells of the pancreatic islet. It is one of the most common diseases of children and young people (CYP), although it can affect older and older people [1]. The increasing burden of T1D is a primary healthcare concern worldwide. Globally, it affects about 8.4 million individuals, with about 1.5 million CYP below 20 years of age [2,3]. The incidence of T1D varies geographically, with higher rates observed in Europe and North America compared to sub-Saharan Africa (SSA) [4]. Despite the lower incidence and prevalence of T1D in SSA compared to other regions worldwide, recent studies have suggested a continuous rise in T1D cases [5]. This rise in the number of T1D cases also coincides with a disproportionately high mortality rate compared to that seen in high-income countries [6].

Classically, T1D-associated mortality in SSA has been attributed mainly to poor insulin access, and within the last two decades, several initiatives have been set up to address this challenge. The Changing Diabetes in Children (CDiC) programme, one of such free insulin-providing initiatives, has now been implemented in 30 lower-and-middle-income countries (LMICs,) including 17 countries in SSA [7]. Many clinical and anecdotal reports have documented the benefits and impact of these initiatives in improving survival and overall quality of life of CYP with diabetes in the African continent [8-10]. However, despite these efforts, much is still to be achieved to further reduce T1D-related mortality in SSA to the level observed in high-income countries [1]. Therefore, studies examining the causes and determinants of mortality in CYP with T1D are still relevant and will be critical to inform the effective development of interventions. In this descriptive case series, we aimed to establish the number and causes of mortality within a cohort of carefully selected and phenotyped CYP diagnosed with T1D recruited into the Young-Onset Diabetes in sub-Saharan Africa (YODA) study in Cameroon.

Methods     

Study design and data collection: we conducted a descriptive review of death cases using data from the YODA study in Cameroon. The YODA study recruited CYP diagnosed with T1D at an age below 30 years, receiving insulin treatment at the time of recruitment between 2019 and 2022 (ClinicalTrials.gov identifier: NCT05013346). We reviewed all registered death cases among the YODA study participants in Cameroon and extracted relevant data into a structured data collection form. We recorded their sociodemographic (age at diabetes diagnosis, insulin regimen and dose), anthropometric (weight, BMI), and biological (HbA1c, plasma C-peptide) data collected at the time of recruitment, and data in their medical records on the circumstances of death (causes and place of death). To ensure the accurate recording of the cause-of-death information, we also verified the paper-back clinic medical records of all the death cases.

Data management and analysis: all collected data was entered into a Microsoft Excel 2013 spreadsheet and was checked item-by-item by a separate research staff for accuracy and consistency. Descriptive analysis was used to summarise participants' demographics, C-peptide levels, treatment details, and causes of death using the IBM SPSS Statistics version 23.0 (Chicago, Illinois, USA). Data were reported as median (interquartile range) for continuous variables and frequency (percentage) for categorical variables.

Ethical considerations: ethical approval was obtained from the Cameroon National Ethical Review Board for Human Health for the YODA study, and administrative authorisation was obtained from the central coordination unit of the CDiC programme in Cameroon. We anonymised all data to ensure participant confidentiality. This study adhered to the ethical principles outlined in the Helsinki Declaration [11].

Results     

General characteristics of the death cases: among the 313 individuals enrolled in the YODA study in Cameroon, we recorded 23 deaths after 53 months, consisting of 13 males (56.5%). The median (IQR) time from recruitment to the death recording was 20 (8-30) months. The median (IQR) age at diagnosis was 16 (13-18) years, ranging from 8-27 years, and the median BMI was 21.5 (18.9-24.7) kg/m². The median (IQR) HbA1c and C-peptide levels were 94 (69-104) mmol/mol and 116 (37-210) pmol/L, respectively. Table 1 shows the individual clinical characteristics of all the death cases.

Causes and circumstances of death: the causes of death were hypoglycaemia (7 cases, 30.4%), diabetic ketoacidosis (DKA, 5 cases, 21.8%), infections (4 cases, 17.4%), undefined causes (4 cases, 17.4%), chronic liver disease (2 cases, 8.7%), chronic kidney disease (1 case, 4.3%), as shown in Figure 1. The majority of the death cases (17/23, 73.9%) had significantly low C-peptide levels (<200 pmol/L, severe insulin deficiency). Notably, 85.7% (6/7) of deaths due to hypoglycaemia had significantly low C-peptide levels (<200 pmol/L). Death occurred outside of the hospital in almost half (11/23, 47.8%) of the cases and 47.8% (11/23) of deaths occurred in participants who had been rolled out of the CDiC programme.

Discussion     

This study aimed to establish the number and causes of death amongst a group of CYP with diabetes recruited into the YODA study in Cameroon. We found that 53 months after the end of the YODA study recruitment, 23 death cases were recorded out of 313 participants enrolled in the cohort. The leading cause of death was hypoglycaemia, and the overall proportion with significantly low C-peptide levels (plasma C-peptide <200 pmol/L), a level where insulin treatment is absolutely needed for survival (severe insulin deficiency) [12], within this group was extremely high at 73.9%. Also, most of the hypoglycaemia-related death cases had extremely low C-peptide levels (plasma C-peptide <200 pmol/L). These results raise the question of whether, beyond the provision of free insulin treatment in resource-low settings, inherent biological factors such as endogenous insulin secretion, which can easily be estimated by measuring C-peptide levels, may be an important determinant of survival.

Mortality due to T1D in SSA has traditionally been associated with acute complications such as diabetic ketoacidosis (DKA) and hypoglycaemia, consistent with what we observed in this series. Several reasons have been advocated for high rates of DKA and hypoglycaemic-related deaths in T1D in SSA. Overall lack of awareness, late presentation at diagnosis, insufficient diabetes education, social deprivation, misuse of insulin treatment, and the absence of monitoring accessories are thought to contribute to the excess mortality seen in T1D in SSA [6,13]. Conversely, the causes of T1D-related mortality in high-income countries are predominantly chronic complications of cardiovascular and renal origins [14]. This disparity highlights the urgent need for improved healthcare infrastructure, access to medications, and education in low-resource settings, which will be important to prevent both acute and chronic complications of diabetes in CYP. Death occurred out of the hospital setting in almost half of the cases, which meant that the true cause of death may have been missed in some cases. This may explain why, in four cases, the cause of death was unknown. These further underscores the importance of awareness and that targeted diabetes-orientated education on sick-day attitudes, hypoglycaemia management and general health-seeking behaviours should be emphasised in this setting. We previously had shown that education and place of residence are independent contributors to T1D-related mortality in Cameroon [6]. The fact that almost half of the death cases had been rolled out of the insulin-provision initiative also provides an additional layer of complexity on the long-term sustainability of such initiatives within health systems in resource-limited settings and should be studied independently.

C-peptide, a peptide secreted in equimolar concentrations as insulin from the pancreas, has been demonstrated to be a reliable marker for endogenous insulin secretion in many clinical studies of people with diabetes [12]. Significantly low plasma C-peptide levels of <200 pmol/L, indicative of insulin deficiency, is one of the hallmark features of T1D and is recognised as a risk factor for hypoglycaemia [15]. We found that over three-quarters of all the death cases in this series and over 80% of hypoglycaemia-related deaths had significantly low C-peptide levels. This could be due to their reliance on exogenous insulin for survival, making them vulnerable to potential overdose, changes in insulin sensitivity, and other factors that can lead to low glycaemic levels [16]. These findings suggest that, beyond the provision and use of insulin in this SSA setting, endogenous insulin secretion may be a decisive factor in explaining mortality amongst CYP patients with T1D diabetes. This also highlights the importance of exploring the potential use of the C-peptide level as a prognostic marker for mortality risk in future research.

Limitations: this study has some limitations. The study's design is descriptive only, and therefore, we cannot ascertain causality between low plasma C-peptide and mortality within this cohort of children and young people living with type 1 diabetes. Also, death occurred outside of the hospital setting in almost half of all the reported death cases which could explain why the cause of death was unidentified in some cases. However, the findings from this study should drive further research on the association between endogenous insulin secretion and mortality or survival amongst children and young people living with T1D in Cameroon and in other sub-Saharan African countries.

Conclusion     

The majority of the reported death cases in this descriptive case series had significantly low plasma C-peptide levels, indicating severe insulin deficiency. This finding suggests that endogenous insulin secretion may be an independent contributor to mortality in children and young people living with type 1 diabetes in sub-Saharan Africa and must be considered and thoroughly investigated in future studies.

Competing interests     

The authors declare no competing interests.

Funding     

No external funding was received for this research. JCK is supported by a National Institute for Health and Care Research (NIHR) Exeter Biomedical Research Centre (BRC) Translational Fellowship. The views expressed are those of the authors and not necessarily those of the CDiC programme, the UK National Health Service (NHS), the NIHR, or the Department of Health and Social Care.

Authors' contributions     

Conception and study design: Jean Claude Katte and Mesmin Yefou Dehayem. Data collection: Christiale Kenne Feuatsap and Liliane Kamdem. Data analysis and interpretation: Emmanuel Gwan, Adele Chetcha, and Jean Claude Katte. Manuscript drafting: Emmanuel Gwan and Jean Claude Katte. Manuscript revision: Emmanuel Gwan, Jean Claude Katte, Adele Chetcha and Mesmin Yefou Dehayem. Guarantor of the study: Jean Claude Katte. All authors read and approved the final version of the manuscript.

Acknowledgments     

We acknowledge the Changing Diabetes in Children (CDiC) programme in Cameroon for providing access to the medical records of the children and young people with diabetes enrolled. We thank the family members and clinic nurses who contributed by providing relevant clinical information.

Table and figure     

Table 1: clinical characteristics of the 23 death cases

Figure 1: description of the causes of death

References