Low serum amylase in association with metabolic syndrome and diabetes: A community-based study

Elevated serum amylase levels often accompany acute pancreatitis [1‐3] and are occasionally caused by other conditions such as pancreatic tumors, diabetic ketoacidosis and kidney dysfunction [1‐6]. In contrast, low serum amylase is thought to be due to diffuse pancreas destruction secondary to advanced chronic pancreatitis or alcoholic disease [7‐9]. Low serum amylase is also associated with insulin deficiency in patients with type 1 diabetes and, less commonly, with type 2 diabetes [10‐13], as well as the pathogenesis of insulin resistance in obese animal models [14, 15]. Because serum amylase can be classified as pancreatic-type and salivary-type amylase [2, 3], it is often necessary to distinguish between the two types for precise clinical diagnosis. Nevertheless, the measurement of serum amylase is useful to determine the pathogenesis of many diseases.

To date, the clinical relevance of low serum amylase levels remains poorly understood. Animal and cellular studies regarding the relationship between the endocrine and the exocrine pancreas have consistently showed that insulin affects basal and stimulatory amylase secretion via the islet-acinar axis [16‐19]. Briefly, insulin binds to its receptor on acinar cells and stimulates amylase secretion through various pathways [17‐19]. However, the nature of this relationship between low serum amylase and clinical conditions has been addressed by relatively few, small-scale human studies that yielded some conflicting results [10‐13, 19, 20].

To date, no large-scale epidemiological studies have been conducted to explore the relationship between low serum amylase levels and cardiometabolic diseases associated with insulin resistance and/or inadequate insulin secretion, such as metabolic syndrome (MetS) and diabetes. Therefore, the aim of this epidemiological study was to determine whether low serum amylase levels are associated with cardiometabolic risk factors, MetS, and diabetes, which could yield insight into a possible exocrine-endocrine relationship in clinical conditions. In this context, we examined these associations in a cross-sectional community study of asymptomatic adults. In addition, because some proportion of the participants underwent checkups 5 years ago, we retrospectively evaluated whether the previous low serum amylase was associated with MetS, diabetes, and changes in metabolic abnormalities over time. Fluctuations in serum amylase levels were also examined according to kidney function assessed by estimated glomerular filtration rate (eGFR), which often deteriorates following the development of MetS and diabetes, and is a key factor that increases serum amylase [2‐6].

The clinical characteristics of subjects according to serum amylase quartile are shown in Table 1. Across increasing amylase quartiles, the prevalence of men, smokers, daily alcohol consumption, infrequent exercise, MetS, and diabetes decreased significantly. Most clinical variables were decreased (HDL-C was increased) across increasing amylase quartiles, except for age and eGFR which showed unfavorable changes. Intriguingly, the prevalence of history of stroke and medications for hypercholesterolemia were higher in the highest quartile. Unexpectedly, the statistical significance for the relationship between HbA1c and serum amylase was weaker (P = 0.02) than that of other variables. Of clinical parameters listed in Table 1, stepwise regression analysis revealed that serum amylase level was significantly explained by BMI, eGFR, smoking, age, daily alcohol consumption, FPG, diastolic blood pressure, and triglyceride (ß coefficient = -0.17, -0.17, -0.11, 0.11, -0.07, -0.05, -0.05, and -0.04, respectively, data not shown). Figure 1 shows serum amylase levels according to NAMC categories. In both non-smokers and in smokers, serum amylase levels decreased significantly with increasing NAMC almost in parallel, with an approximately 10 IU/l decline in smokers. Figure 2 shows the changes in plasma glucose levels during OGTTs according to serum amylase quartiles. Because subjects with definite diabetes did not undergo OGTT, overall responses to OGTT showed a near-normal pattern. Nevertheless, the plasma glucose levels at 1- and 2-hrs increased significantly with decreasing amylase quartiles.

Multiple logistic analyses (Table 2) showed that, compared with the highest amylase quartile, lowest quartile was significantly associated with increased risk for MetS and diabetes even after adjustment for clinical confounders including eGFR.

Although the pathogenic features of reduced amylase secretion and the underlying mechanisms linking islets and acinar cells have been extensively examined in animal and cellular studies [14‐19], clinical evidence supporting such exocrine-endocrine relationships has not been established in large human studies. Our results in this epidemiological study indicate that serum amylase levels are inversely associated with most cardiometabolic risk factors, especially those associated to obesity. Furthermore, the serum amylase level decreased with worsening of metabolic abnormalities and these declines were independent of smoking, a strong factor for increasing insulin resistance [25, 26]. Meanwhile, the pattern of changes in plasma glucose levels during the OGTTs suggest that subjects with low serum amylase have lower glucose tolerance. Significant associations of current and previous low serum amylase with current MetS and diabetes (current low serum amylase only) were observed and remained after adjustment for confounding factors. Additionally, the severity of metabolic abnormalities worsened over 5 years in subjects with low serum amylase at the previous checkup. Accordingly, our results suggest that low serum amylase levels may reflect metabolic abnormalities and abnormal glucose metabolism, both of which are associated with impaired insulin action due to insulin resistance and/or inadequate insulin secretion.

In terms of cardiometabolic risk factors, only kidney dysfunction contributes to elevations in serum amylase levels because the kidney plays the main role in eliminating circulating amylase [2‐6]. Nevertheless, the fluctuation in serum amylase levels in subjects in the lowest quartile 5 years ago was not affected by kidney dysfunction (Figure 4), suggesting that low serum amylase may be a stable marker for cardiometabolic disorders related to impaired insulin action. One reason for the decrease over 5 years in the highest quartile 5 years ago is that insulin sensitivity decreased or kidney function improved before the current checkup. The most plausible explanation for the significant increase in proportions of elevated blood pressure is that resultant hyperinsulinemia may affect Na+ reabsorption by the kidney and circulating volume retention, leading to increased blood pressures. In contrast, dyslipidemia and abnormal FPG in subjects in the lowest quartile were already evident and did not deteriorate thereafter, as compared with those in other quartiles. Furthermore, the small sample size in cohort data may interfere with the outcomes. Noteworthy, the finding that prevalence of history of stroke was increased in subjects with higher amylase (Table 1) may be contradicting. However, this might be consistent with the recent report that reduced eGFR, which was observed with increasing serum amylase in this study, was associated with increased intima-media thickness of the carotid artery in patients with type 2 diabetes [27]. Furthermore, it is unclear why the prevalence of treatment for hypercholesterolemia mostly with statins was higher in subjects with higher amylase levels (Table 1). Therefore, large cross-sectional and prospective studies will be needed for the exploration of relationship between low serum amylase and metabolic abnormalities as well as the treatment with medications.

Regarding the cause-effect relationship, low serum amylase levels were believed to be due to deficient insulin activity [10‐13], which is consistent with early findings that insulin and ciglitazone (this drug was never approved for clinical use), a peroxisome proliferator-activated receptor-γ agonist respectively increased and restored the secretion of amylase from pancreases isolated from rats [15, 16]. In contrast, the results of our retrospective longitudinal analysis suggest that low serum amylase levels preceded the overt metabolic abnormalities. Alternatively, as proposed by Dandona et al. [11], a common pathological process exists in the pancreas that simultaneously affects the endocrine and exocrine components of the pancreas. Consistent with this notion, Hayden et al. [28] suggested that a continuous interstitial matrix connection between endocrine and exocrine is lost in animal models and humans with type 2 diabetes, resulting in a dysfunctional insulino-acinar-ductal-incretin gut hormone axis. Besides these putative mechanisms, there are multiple defects in insulin secretion and signaling in type 2 diabetes [24, 28], which might be associated with the low amylase secretion from the pancreas.

Several limitations of this study should be mentioned. First, the blood insulin levels were not measured. However, previous studies have shown positive correlations between amylase secretion and circulating C-peptide or 24-hr urinary C-peptide excretion in diabetic patients, principally in type 1 diabetes [10‐12], suggesting that low circulating amylase may reflect low insulin secretion. Nevertheless, obese people with MetS and type 2 diabetes tend to show hyperinsulinemia to compensate for insulin resistance. Therefore, whether low serum amylase levels are truly associated with hypoinsulinemia or hyperinsulinemia is unclear. Measurement of insulin levels would help confirm the associations observed in this study, including the weak association between HbA1c and serum amylase. Second, although it has been reported that pancreatic serum amylase secretion was decreased in the presence of hyperglycemia [2], the actual level of pancreatic amylase relative to salivary amylase in subjects with low 'total serum amylase' is unknown and should be determined.

In conclusion, our study demonstrated that serum amylase levels may be inversely related with many cardiometabolic risk factors. Furthermore, low serum amylase levels may be unchangeable even in the presence of kidney dysfunction and are independently associated with MetS and diabetes, suggesting a possible exocrine-endocrine relationship in various clinical conditions. The causality, underlying mechanisms, and whether low serum amylase is a valuable marker for these states remain to be elucidated.