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. 2024 Mar 13;33(3):260–268. doi: 10.1159/000538335

The Modulation of Euglycemic Endocrine and Exocrine Pancreatic Secretions in Iron Deficiency

Mohammad A Bani-Ahmad 1,✉, Noor E Abu Tayyem 1
PMCID: PMC11175607  PMID: 38479367

Abstract

Objectives

The contribution of pancreatic secretions in iron metabolism has been elucidated, but the clinical outcomes of iron deficiency on pancreatic function are debatable. This study aimed to investigate the modulation of euglycemic endocrine and exocrine pancreatic excretions in response to variations in iron availability.

Subjects and Methods

Serum levels of insulin, glucagon, insulin-to-glucagon ratio (IGR), and amylase were determined in 170 adult subjects with variable levels of serum iron.

Results

Control (n = 46) and iron-deficient (n = 124) subjects had significant differences (p < 0.001) in their average levels of insulin (68.7 ± 0.5 vs. 100.0 ± 2.0 pmol/dL), glucagon (17.9 ± 0.6 vs. 10.8 ± 0.8 pmol/dL), IGR (4.0 ± 0.1 vs. 19.5 ± 2.1), and amylase (29.7 ± 0.9 vs. 17.5 ± 0.2). The upregulation of serum insulin levels increases proportionally and gradually to the extent of iron deficiency as compared to an abrupt downregulation of serum levels of glucagon and amylase. A significant association was observed between serum iron and IGR (r = −0.645, p < 0.001) and amylase levels (r = 0.653, p < 0.001). The receiver operating characteristic curve analysis defines an excellent predictivity of the reduced serum iron level to discriminate subjects with upregulated IGR and amylase levels with area under curves of 0.938 and 0.905, respectively.

Conclusion

Iron deficiency is associated with an adaptive modulation of euglycemic endocrine and exocrine secretions that is consistent with a status of insulin resistance.

Keywords: Iron deficiency, Insulin, Glucagon, Amylase, Insulin resistance

Highlights of the Study

  • Iron deficiency (ID) exacerbates serum insulin levels proportional to the extent of deficiency.

  • ID decreases the serum levels of glucagon and amylase with abrupt downregulation patterns.

  • ID provides excellent predictivity for dysregulation in serum levels of insulin, glucagon, and amylase.

  • Dysregulation of insulin-to-glucagon ratio and amylase levels in ID is consistent with insulin resistance status.

Introduction

Iron is an essential trace element and a critical cellular ingredient for proper cellular metabolism and function [1]. However, it can react with oxygen to generate reactive oxygen species and induce oxidative stress [2]. Investigations on the impact of iron hemostasis on pancreatic function have focused on hemochromatosis where iron overload increases predisposition to type-2 diabetes mellitus and insulin resistance [3]. Furthermore, in patients with chronic pancreatitis and exocrine pancreatic disease, pancreatic insufficiency provokes intestinal absorption and cellular deposition of iron resulting in adverse clinical outcomes that improve upon the therapeutic administration of pancreatic extracts or iron chelators [4]. Given that anemia is the earliest and the most common clinical outcome of iron deficiency (ID), a variety of adverse systemic consequences and clinical complications are evident [5, 6]. ID results in an impairment of proinsulin generation that increases predisposition to type-1 diabetes mellitus and aggravates unfavorable clinical outcomes, including nephropathy [7, 8]. Surprisingly, it has been shown that iron-deficient rats have a metabolic hemostasis that was shifted toward hepatic glucose biosynthesis as demonstrated by glycemia and insulinemia [9]. In support of that observation, ID is associated with increased levels of glycosylated hemoglobin (HbA1c) regardless of fasting glucose levels [10].

The pancreas serves both an endocrine (hormonal) function and an exocrine (digestive) function which are determinants of the functionality of the entire body [11]. The sustainability of euglycemia is among the primary functions of the endocrine and exocrine pancreatic secretions that regulate glucose absorption and metabolism and hence, maintains normal circulatory glucose levels [12]. Insulin and glucagon are opposing balanced endocrine hormones where insulin is a glucose-depositing hormone while glucagon is a glucose-mobilizing hormone [13]. Thus, the endocrine functions of insulin and glucagon are closely synchronized to maintain euglycemia during feeding and fasting states, respectively [14].

While insulin secretion by β-cells is glucose-sensitive, glucagon production is insulin-dependent [15]. Therefore, as opposed to their absolute levels, the insulin-to-glucagon ratio (IGR) is a more reliable predictor of the cellular demand for anabolism and catabolism, specifically in the pathological context of disease [16]. Alternately, pancreatic amylase is a digestive enzyme that enhances intestinal digestion and subsequent absorption of polysaccharides [17]. In contrast to iron overload, the association of ID to the imbalance of endocrine pancreatic function is less investigated and requires elucidation. To the best of our knowledge, exocrine pancreatic function in ID has not been investigated. This study aimed to investigate the adaptive modulation of euglycemic endocrine and exocrine pancreatic function in the context of ID. To achieve this, serum levels of insulin, glucagon, and amylase were compared and correlated among subjects with variable extents of serum iron availability.

Materials and Methods

Study Subjects

This study included randomly selected patients who were recently diagnosed with ID anemia and remained untreated till the time of their inclusion. Subjects with chronic inflammatory disease, diabetes mellitus, pancreatitis, and personal or family history of hematological disorders, were excluded. For comparative purposes, we included a control group of healthy subjects with no clinical presentations of ID and any excluding medical conditions. Control subjects were those who visited periodically for routine health check and were recruited to participate following their clinical assessment.

5 mL of plain blood samples were withdrawn aseptically by venipuncture from subjects who confirmed fasting for 12 h before blood withdrawal. Blood samples were allowed to clot after which serum samples were obtained by centrifugation at 4,500 rpm for 5 min. Serum samples were stored frozen at −80°C until analyzed. Prior to their inclusion.

Measurement of Serum Iron

In the context of ID, serum levels of soluble transferrin receptors and transferrin saturation are debatable while serum ferritin level is inconclusive, being an acute phase reactant and may vary irrespective of body iron contents [18]. Accordingly, we have chosen serum iron level as a biomarker to define the status of iron availability among our subjects. Serum levels of iron were measured using an automated instrument (Beckman Coulter Access 2, Europe). Results are presented in micrograms per deciliter (μg/dL).

Serum Levels of Insulin, Glucagon, and Pancreatic Amylase

Serum levels of insulin (ab200011, Abcam, USA), glucagon (MK156, Takara, Japan), and pancreatic amylase (ab137969, Abcam, USA) were determined by enzyme-linked immunosorbent assay using commercially available kits. According to the manufacturer’s instructions, standards and samples were added into corresponding wells of the capture antibody-coated plate and incubated at room temperature (25°C) for 2 h (insulin and amylase assays) and for 1 h (glucagon assay). After washing the wells, a specified volume of biotinylated antibody was added into each well and incubated at room temperature for 1.5 h (insulin assay) and 1 h (amylase and glucagon assays). After a second washing step, horse-reddish peroxidase-streptavidin was added for 30 min at room temperature. Following a third washing step, a 3,3′,5,5′-tetramethylbenzidine substrate solution was added and incubated in the dark at room temperature. Finally, the stop solution was added, and the absorbance measured at a wavelength (λ) of 450 nm.

Statistical Analysis

Data were analyzed using version 23 of the Statistical Package for the Social Sciences (SPSS). Descriptive analysis was conducted, and results were presented as mean ± standard error of mean. Analysis of variance (ANOVA) was used for comparative purposes and results were considered significant when the p value was less than (0.05). Correlation analyses were conducted using parametric Pearson’s (r) and nonparametric Spearman’s (Rho) correlation analysis. The receiver operating characteristic (ROC) curve was plotted to evaluate the diagnostic value of serum iron against study parameters. Graphs were prepared using GraphPad Prism 6 software.

Results

170 adult subjects with an average age of 39.7 ± 14.6 years old (17–68 years old), were included in this study. 124 subjects had ID, and 46 were control subjects with adequate iron levels. Most of the subjects were females with females-to-males ratio of 10:1. The normal reference range of serum iron levels in healthy adults is established to be 50.0–180.0 μg/dL [19]. Still, a minimum concentration of 60 μg/dL is associated with no adverse impacts while clinical outcomes are evident at a concentration lower than 40.0 μg/dL [20]. Comparative analysis revealed that iron-deficient subjects (with serum iron <60 μg/dL) had significantly higher average levels of serum insulin and lower average levels of serum glucagon as compared to their corresponding average levels among normal subjects (p < 0.001). The average IGR among deficient subjects is significantly higher than the corresponding ratio among control subjects (p < 001). Regarding serum amylase, iron-deficient subjects had a significantly lower average level as compared to the corresponding average level among control subjects (p < 0.001). The results of the comparative analysis are illustrated in Table 1.

Table 1.

Comparison analysis of demographic characteristics and serum levels of pancreatic secretions among study control subjects with normal serum iron (≥50 µg/dL) and iron-deficient patients

Control Iron-deficient p value
Female:male ratio 8.2:1 7.1:1 >0.05
Age, years 38.8±1.4 38.6±1.6 >0.05
Iron, µg/dL 84.0±2.5 52.5±0.8 <0.001
Insulin, pmol/L 68.7±0.5 100.0±2.0 <0.001
Glucagon, pmol/L 17.9±0.6 10.8±0.8 <0.001
IGR 4.0±0.1 19.5±2.1 <0.001
Amylase, IU/L 29.7±0.9 17.5±0.2 <0.001
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IGR, insulin-to-glucagon ratio.

To further investigate the modulation of pancreatic secretion with the extent of availability of iron, iron-deficient subjects were subcategorized as follows: 38 subjects were iron insufficient (II), 44 were iron deficient (ID), and 42 were extremely iron deficient (EID) with serum iron concentration of 40–59 μg/dL, 20–39 μg/dL, and <19 μg/dL, respectively. Figure 1 illustrates the results of comparative ANOVA analysis of serum insulin levels among study subcategories. The average concentration of serum insulin among IS subjects was 68.7 ± 0.5 pmol/L, which is not significantly different from the corresponding concentration among II subjects with an average of 71.2 ± 1.1 pmol/L (p > 0.05). Subjects with ID and EID had average levels of 89.9 ± 1.7 pmol/L and 109.3 ± 3.5 pmol/L, respectively, which are significantly higher than the corresponding average levels among IS and II subjects (p < 0.001). Additionally, the average level among EID is significantly higher than the corresponding average level among ID subjects (p < 0.001).

Fig. 1.

Fig. 1.

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Comparative analysis of serum insulin concentration in picomole per liter (pmol/L) between the study groups. Results demonstrate an insignificant difference between iron-sufficient and insufficient subjects (p = 1.00). A significant increase was evident among iron-deficient subjects (p < 0.001) which in turn is significantly lower than the corresponding average level among subjects with extreme ID (p < 0.001).

A comparative analysis of serum glucagon levels is illustrated in Figure 2. There were no significant differences in the average serum glucagon levels between neither IS (17.9 ± 0.6 pmol/L) and II subjects (16.9 ± 0.4 pmol/L) nor between ID (11.2 ± 1.3 pmol/L) and EID (10.2 ± 0.9 pmol/L) subjects (p > 0.05). However, the lower average levels among both EID and ID were significantly different from the corresponding average levels among IS and II subjects (p < 0.001).

Fig. 2.

Fig. 2.

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Comparative analysis of serum glucagon concentration in picomole per liter (pmol/L) between the study groups. Results demonstrate an insignificant difference between iron-sufficient and insufficient subjects (p = 1.00) as well as between iron-deficient and extremely deficient subjects (p = 1.00). Glucagon levels among deficient and extremely deficient subjects are significantly lower in comparison to the corresponding levels among both of subjects with iron sufficiency and insufficiency (p < 0.001).

We performed a comparative analysis of the molar IGR among study groups. Results illustrated in Figure 3 revealed that the IS and II subjects had an insignificant difference in their average IGR with 4.0 ± 0.1 and 4.9 ± 0.7, respectively (p > 0.05). Similarly, subjects with ID and EID were insignificantly different in their average IGR with 18.3 ± 3.1 and 19.6 ± 3.3, respectively (p > 0.05). However, the averages of IGR among ID and EID subjects are significantly higher as compared to corresponding ratios among IS and II subjects (p < 0.001).

Fig. 3.

Fig. 3.

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Comparative analysis of serum molar insulin-to-glucagon concentration between the study groups. Results demonstrate insignificant differences between iron-sufficient and insufficient subjects (p = 1.00) as well as between iron-deficient and extremely deficient subjects (p = 1.00). While the ratios among deficient and extremely deficient subjects are significantly higher than the corresponding ratios among subjects with iron sufficiency and insufficiency (p < 0.001).

The average serum amylase levels have significantly decreased between subjects with IS, II, and ID subjects with averages of 29.7 ± 0.9 IU/L, 23.4 ± 1.6 IU/L, and 17.7 ± 0.4 IU/L, respectively (p < 0.001) (Fig. 4). Subjects with EID had an average concentration of 17.3 ± 0.3 IU/L which is not different from ID subjects (p > 0.05) though is significantly lower than the corresponding concentration among II and IS subjects (p < 0.001).

Fig. 4.

Fig. 4.

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Comparative analysis of serum amylase concentration in units per liter (U/L) between the study groups. A gradual significant decrease in serum amylase among subjects with iron sufficiency, insufficiency, and deficiency (p < 0.001). No significant difference was seen among extremely deficient subjects as compared to deficient subjects (p = 1.00).

Pearson’s correlation analysis was conducted to define the association of serum iron concentration with the circulatory levels of insulin, glucagon, IGR, and amylase. We have reported significantly inverse relationships between serum iron concentration and the serum levels of insulin and IGR with correlation coefficients (r) of −0.700 and −0.645 (p < 0.001), respectively. On the other hand, there were significantly direct associations between serum iron concentration and the serum levels of glucagon and amylase with correlation coefficients of 0.551 and 0.653 (p < 0.001), respectively.

Figure 5 is a scatterplot histogram that represents the association of serum levels of insulin, glucagon, and amylase with levels of serum iron. According to the best-fit curve for each, we observed a dramatic and gradual increase in serum insulin levels in response to the incessant ID that commenced at an approximate serum iron concentration of 50 μg/L. This is compared to abrupt drops in serum levels of glucagon and amylase at that approximate serum iron concentration that was followed by steady or insignificant changes at lower concentrations. To further evaluate the predictive value of serum iron concentration in discriminating subjects with elevated serum IGR and amylase levels, a ROC analysis was created. Results revealed an area under curve of 0.938 ± 0.016 (p < 0.001) and 0.905 ± 0.029 (p < 0.001), respectively. Area under curve values are suggestive that serum iron is an excellent predictor of IGR and amylase levels. We have reported that the sensitivity of the predictive ability of serum iron level influences significant upregulation of IGR where cut-off values of ≤60 μg/dL, ≤50 μg/dL, ≤40 μg/dL, and ≤20 μg/dL are associated with an approximate sensitivity of 52.9%, 77.7%, 80.2%, and 95.5%, respectively. On the other hand, cut-off values of serum iron levels of ≤60 μg/dL and ≤50 μg/dL defined a predictive sensitivity of 85.4% and 100%, respectively.

Fig. 5.

Fig. 5.

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A scatterplot histogram for the association of serum levels of insulin, glucagon, and amylase with serum iron concentration. Lines demonstrate the best-fit curve for the association study parameters and serum iron concentration. The graph demonstrates a gradual increase in serum insulin levels that commenced at an approximate serum iron concentration of 50 μg/dL. This is compared to abrupt drops in serum levels of glucagon and amylase at that approximate serum iron concentration that was followed by insignificant reduction at lower iron concentrations.

Discussion

Iron is integral for cellular energy production and thus ID defines a stressful condition that enhances the metabolic dependence and utilization of glucose in response to restricted iron availability [21, 22]. This is a result of the inhibition of the iron-dependent Krebs cycle that alters cellular energy requirements by diverting into a glucose-dependent mechanism [23, 24]. In support of that, the upregulation of circulatory concentrations of glucose and lactic acid was evident in rats with ID [25, 26]. This may explain the gradual upregulation of fasting serum insulin levels in accordance with the extent of reduction in serum iron concentration. The significant correlation between serum iron and insulin levels is supportive of this nexus.

The adaptive secretion of insulin by β-cells is glucose-sensitive [15]. Therefore, a high level of serum insulin is a consequence of elevated levels of blood glucose among subjects with ID. Study subjects were fasting at the time of their inclusion and blood sampling, indicating that glycemia is not postprandial and might be a result of de novo gluconeogenesis. During fasting, glucagon promotes hepatic gluconeogenesis and glycogenolysis to enhance the output of glucose in response to hypoglycemia or continuous systemic demands for glucose [16]. Surprisingly, we observed a gradual reduction in serum levels of glucagon which indicates that de novo gluconeogenesis may not be promoted. This contradicts previous findings on iron-deficient rats that reported a shifted metabolic hemostasis toward hepatic glucose biosynthesis [9].

While insulin secretion is glucose-sensitive, glucagon production is insulin-dependent [15]. Therefore, the endocrine functions of insulin and glucagon are closely synchronized to maintain euglycemia during fed and fasting states, respectively [14]. As opposed to their absolute levels, the IGR is a more reliable predictor of the cellular demand for anabolism and catabolism, specifically in the pathological context of disease [16]. The value of IGR has been reported to be inversely proportional to the need for endogenous glucose production [16, 27]. A low IGR enhances glycogenolysis, gluconeogenesis, and lipolysis to promote glucose and fatty acids mobilization to their storage sites [16]. On the other hand, high IGR reduces hepatic glycogenesis, systemic glycolysis, and fatty acid release [16]. Our findings are in agreement with the suggested metabolic changes of insulin resistance, hyperinsulinemia, and gluconeogenic activity in iron-deficient rats [8, 28]. Accordingly, elevated serum insulin levels and decreased glucagon levels, among our fasting iron-deficient subjects, is suggestive of an impaired cellular uptake of glucose and suggestive of an insulin resistance status in the context of ID.

Serum amylase has been shown to contribute to intestinal absorption and utilization of glucose along with a positive correlation with higher insulin sensitivity and an inverse association with endocrine insulin levels [29, 30]. In patients with type II diabetes mellitus, reduced serum amylase was evident as a consequence of either defective insulin secretions and/or insulin resistance as indicated by elevated serum glucose levels [31]. The reduction in intestinal absorption and passage of glucose is a regulatory mechanism in response to circulatory glycemic status [32]. Thus, based on its physiological function, we may define that the reduction in serum amylase level among deficient subjects may correspond to impaired digestion and absorption of glucose.

As revealed by the scatterplot histogram, we noted a gradual increase in serum insulin level that commenced at an approximate cut-off of 50 μg/dL at which abrupt drops in serum levels of glucagon, IGR, and amylase. Earlier studies have suggested that a threshold ID is associated with a negative potential on metabolic activities, while others have stated that even moderate ID can disrupt glucose hemostasis [8, 33, 34]. The ROC analysis defines a predictive significance of the proposed cut-off in discriminating subjects with upregulated IGR and downregulated amylase levels, hence the impaired glycemic status. In that regard, it has been proposed that reduced iron availability beyond the deficiency level, enhances insulin release and sensitivity and so provides prolonged but reversible protection against diabetes [35]. It is worth mentioning that the link between iron homeostasis and glucose metabolism is complicated and includes a variety of systemic and cellular compartments [36]. The clinical impact of iron dysregulation on the development of insulin resistance is debatable [37]. We understand that the lack of the homeostatic model assessment index is a limitation as it has been identified as a potential risk factor for the development of metabolic syndrome [38].

Conclusions

ID is associated with adaptive modulation of the serum levels of euglycemic endocrine and exocrine pancreatic secretions that is compatible with a status of insulin resistance. The modulation of pancreatic excretion commences beyond ID level. Insulin level exacerbates proportionally to the extent of ID as compared to steadily reduced serum levels of glucagon and amylase regardless of the extent of ID. Better understanding of long-term clinical glycemic consequences of ID requires further study.

Statement of Ethics

This study protocol was reviewed and approved by a Local Institutional Review Board (Reference number GM7601-12-119-246). All participants in the study were informed about the study and requested to participate voluntarily. They were requested to sign an informed consent form.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

Funding for this study was provided by the Deanship of Research at our affiliated institute.

Author Contributions

Mohammad A. Bani-Ahmad contributed to the conception and design of the study and supervised the study, performed statistical analysis, and drafted the manuscript; Noor E. Abu Tayyem was involved in recruiting study subjects, conducting experimental analysis, and read and approved the final manuscript; Mohammad A. Bani-Ahmad and Noor E. Abu Tayyem interpreted the obtained results of the study.

Funding Statement

Funding for this study was provided by the Deanship of Research at our affiliated institute.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author.

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