Abstract:
Background: Type 2 Diabetes Mellitus (T2DM), characterized by hyperglycemia (≥126 mg glucose/100 ml blood after overnight fasting) and insulin resistance, presents an escalating global health and economic crisis. According to the 11th edition of the International Diabetes Federation (IDF) diabetes atlas, approximately 589 million adults live with diabetes worldwide as of 2024, a figure projected to surge to 853 million by 2050. The global financial strain is unprecedented: global diabetes-related healthcare expenditures reached $1.015 trillion in 2024. In the United States, the annual economic burden has reached $412.9 billion, comprising $306.6 billion in direct medical expenses and $106.3 billion in indirect costs due to lost productivity and disability, amounting to 25% of the national healthcare cost. In the context of etiology of diabetes, in 2007, Cani et al. demonstrated that mice develop obesity and insulin resistance when infused with Lipopolysaccharides (LPS), the endotoxin component of the Gram-negative bacterial cell wall. Endotoxin in blood, defined as endotoxemia, leads to low-grade systemic inflammation. Previously, we have shown that LPS is detoxified by Intestinal Alkaline Phosphatase (IAP), a gut enzyme secreted by villus-associated enterocytes and excreted with stool. IAP acts as an anti-inflammatory agent by dephosphorylating and detoxifying LPS alongside other bacterial toxins. In IAP-knockout mice (Akp−/−) lacking this baseline defense, the animals spontaneously develop metabolic syndrome characteristics, including hyperglycemia, dyslipidemia, and fatty liver. However, exogenous oral delivery of calf IAP effectively shields the mice from these metabolic disruptions. Based on animal data we hypothesized that IAP Deficiency (IAPD) might be associated with diabetes in humans. In 2015, we conducted a case-control study, and observed that, indeed, IAPD is associated with type 2 diabetes, revealing that the IAP level is half in the stool of diabetes patients compared to healthy persons (35 U/g stool vs 65 U/g stool, respectively). We then decided to conduct a prospective cohort study to determine if IAPD plays any role in the pathogenesis of diabetes.
Methods: We conducted a 5-year prospective cohort study targeting healthy, non-diabetic adults aged 30 to 60. Our sample included 188 subjects without IAPD (defined as IAP level ≥65 U/g stool) and 386 subjects suffering from IAPD (defined as IAP level <65 U/g stool). By recording longitudinal changes in Stool IAP (STAP) and fasting plasma glucose, we successfully extracted Risk Ratios (RR) through log-binomial regression analyses to quantify the exact likelihood of diabetes development.
Results: The longitudinal human cohort study confirmed a direct causal link, revealing that T2DM incidence rates scaled dramatically with the severity of IAP Deficiency (IAPD), resulting in a 14-fold higher risk of developing T2DM over 5 years in individuals with severe IAPD (IAP level: <15 U/g stool) compared to those with higher IAP levels (>115 U/g stool). Also, the rate of increase of glycemia was double in the people with severe IAPD. Furthermore, remission of IAPD prevented the development of diabetes. The study established IAP as a predictor biomarker of diabetes.
Conclusion: IAPD is a foundational pathology driving metabolic endotoxemia and systemic insulin resistance. Measuring fecal IAP using the STAP assay offers a highly sensitive framework to diagnose "incipient (latent) diabetes" before blood glucose levels rise. Intervening via targeted oral IAP supplementation represents a powerful preventative opportunity to mitigate the catastrophic global and domestic economic toll of the diabetes pandemic.
