Of cardiometabolic risk factors, high BMI, i.e., overweight/obesity, is most likely to be associated with low serum amylase independently of age, as shown in Figure 1, with an almost linear correlation between serum amylase and BMI (overall correlation, r = -0.22, P < 0.0001, Pearson's correlation). Partial correlation analysis controlling for age showed similar significant correlation (r = -0.21, P < 0.0001, data not shown). Thus, our subsequent analysis takes into account BMI. Noteworthy, serum amylase levels were significantly higher in older subjects aged 55 years old or more (n = 1,114) than in younger subjects aged 54 years old or less (P < 0.0001, ANOVA), probably due to lower kidney function in older subjects (serum creatinine based estimated glomerular filtration rate for older group and younger group, 71.1 ± 13.0 and 80.5 ± 12.9 ml/min/1.73 m2, respectively, P < 0.0001, t-test).
Considering these inverse associations between serum amylase and unfavorable factors such as obesity and smoking, it is likely that serum amylase may act similarly to other cardiometabolic protective factors such as HDL and adiponectin, both of which reflect better insulin sensitivity, anti-atherogenic and anti-inflammatory properties. Studies have shown that HDL-C and adiponectin levels are often elevated in mild to moderate drinkers [11]. Actually, in our study, HDL-C levels were significantly higher in drinkers (Figure 2, P = 0.006, ANOVA). Of note, however, is that serum amylase levels were significantly lower in drinkers, particularly daily drinkers (n = 746, Figure 3, P < 0.0001, ANOVA). This may be the most remarkable difference regarding alcohol consumption between serum amylase and HDL-C and adiponectin. Indeed, chronic mild to moderate alcohol consumption often injures and attenuates pancreatic functions [12, 13], eventually resulting in chronic pancreatitis and reduced amylase secretion. In contrast, it has been reported that high alcohol consumption increases the risk of developing type 2 diabetes [14], which may be related to low serum amylase. However, the mechanism underlying this link between alcohol consumption and low serum amylase is unclear.
Our previous study also showed a significant association between low serum amylase and diabetes, presumably type 2 diabetes [7]. Nevertheless, the relationship between serum amylase and HbA1c, which reflects overall glucose metabolism, may be rather complicated. As shown in Figure 4A, we observed a significant but weak correlation between serum amylase and fasting glucose levels (r = -0.14, P < 0.0001, Pearson's correlation), but not with HbA1c (r = -0.03, P = 0.12) that is estimated as NGSP equivalent value calculated by the formula HbA1c (%) = HbA1c (JDS)(%) + 0.4%, considering the relational expression of HbA1c (JDS)(%) measured by the previous Japanese standard substance and measurement methods and HbA1c [15] (Figure 4B), suggesting that overall glucose homeostasis is unlikely to be associated with serum amylase, particularly in individuals with normal or mildly impaired glucose metabolism (up to HbA1c 6.0% (NGSP)). A plausible explanation is that mild insulin resistance was almost compensated with hyperinsulinemia, resulting in euglycemia (normal HbA1c) and relatively lower serum amylase levels than expected based on BMI. Moreover, glomerular hyperfiltration, which is often observed in obese people [16, 17] or at early stage of diabetic nephropathy [18], might interfere with the observed associations by excess elimination of circulating amylase from the kidney. In contrast, moderate to severe insulin resistance was not compensated with hyperinsulinemia (or the hypoinsulinemia was already apparent), resulting in substantially impaired insulin action, overall hyperglycemia (high HbA1c), and very low serum amylase levels.
Other reason for the discrepancy between serum amylase and HbA1c may be that HbA1c reflects glucose metabolism over the preceding 1-2 months, whereas serum amylase may change rapidly in response to changes in plasma glucose concentration [19]. Zini et al. [10] reported that low circulating amylase normalized within 1 week of insulin therapy in cats with diabetes. Furthermore, histological examination in their study revealed that low amylase activities in diabetic cats may reflect an imbalance in glucose metabolism rather than pancreatitis. Nevertheless, further studies are needed to elucidate the mechanisms involved in the association.
In terms of the inverse association between serum amylase and obesity, some explanations are possible. Reduced insulin action including insulin resistance is a critical physiological feature accompanied with excess fat accumulation, primarily in adipose tissues. In this context, reduced pancreatic amylase secretion might represent a physiological mechanism designed to reduce the absorption of carbohydrates by suppressing their digestion, leading to reduced energy intake. Thus, it is possible that the pancreas might contribute to the overall control of energy balance and glucose homeostasis not only via its established endocrine effects, but also via the exocrine system by controlling energy intake through the small intestine.
There is a growing body of research focusing on products that slow carbohydrate absorption by inhibition of α-amylase, which is responsible for their digestion [20, 21]. Many clinical studies have shown that α-amylase inhibitors (although not clinically available), most of which are extracted from plants, can reduce the post-prandial glucose excursions, thus correcting abnormal glucose metabolism and prevention of type 2 diabetes [20, 21].
Meanwhile, several studies have reported the possibility that alpha-amylase is produced by some nonpancreatic gastrointestinal organs such as stomach [22, 23], although controversy still remains. Therefore, low serum amylase might reflect the endocrine-gastrointestinal system, rather than the endocrine-exocrine system in the pancreas. Nevertheless, to our knowledge, no studies have examined the expression of α-amylase in the intestine or the secretion of α-amylase from the intestine in patients with type 2 diabetes. If expression or secretion of α-amylase in the gut is actually reduced in patients with type 2 diabetes, it is likely that α-amylase inhibitors, once approved, and acarbose, which inhibits both α-glucosidases and pancreatic α-amylase, should be given to people before the reductions in pancreatic amylase occur.
Regarding the possible role of serum amylase in clinical practice, collectively, low serum amylase may reflect the pathophysiological condition of obesity, a fundamental cause of MetS, which is mostly caused by energy imbalance between food intake and physical activities. On the other hand, high serum amylase may reflect thinness, i.e., possible energy shortage, and kidney dysfunction.
In conclusion, revisiting the cardiometabolic relevance of serum amylase may yield novel insight not only into glucose homeostasis and metabolic abnormalities related to obesity, but also carbohydrate absorption in the gut. Nevertheless, this hypothesis remains to be tested in future clinical and animal studies considering insulin resistance and energy imbalance.