BMJ Open Diabetes Research & Care: BMJ Journal
Bangladeshi researchers identify new pathological cause of diabetes.
The team of researchers from multiple local and foreign universities, through a five-year (2015-2020) study on 574 non-diabetic people aged between 30 and 60, have discovered that deficiency of the Intestinal Alkaline Phosphatase (IAP) enzyme is a leading cause for developing diabetes.
People with Intestinal Alkaline Phosphatase enzyme deficiency have a 13.8 times higher risk of developing diabetes, finds the study.
Introduction
Type 2 diabetes mellitus (T2DM), a chronic metabolic disease manifested with hyperglycemia and insulin resistance, is a major global health problem with devastating consequences in terms of morbidity, mortality, and healthcare costs.
The pathogenesis of T2DM is poorly understood. Various factors have been postulated to be involved in the development of T2DM, notably genetic polymorphism, ethnicity, metabolic syndrome, obesity, diets, infection, dysbiosis, autoimmunity, drugs, stress, and pregnancy.
Low-grade systemic inflammation has been implicated to play a pivotal role in the pathogenesis of T2DM.
Death of Gram-negative bacteria results in fragmentation of the cell wall, releasing its lipopolysaccharide (LPS), an endotoxin that causes inflammation. Intestinal luminal LPS is usually excreted with stool; however, under certain circumstances, such as increased gut permeability and increased intake of a high-fat diet, alcohol, and fructose, LPS may translocate to blood circulation, causing endotoxemia.
Recently, ‘metabolic endotoxemia’, defined as persistently increased levels of LPS in blood, has been shown to induce low-grade systemic inflammation, leading to insulin resistance, hyperglycemia (T2DM), dyslipidemia, and fatty liver in mice.
Authors have previously demonstrated that mice deficient in Intestinal Alkaline Phosphatase (IAP) develop metabolic syndrome (hyperglycemia, dyslipidemia, and fatty liver) that can be prevented by oral IAP supplementation.
Significance of this study
What is already known about this subject?
The deficiency of intestinal alkaline phosphatase (IAP), an anti-inflammatory gut enzyme secreted by intestinal enterocytes and excreted with stool, is directly associated with type 2 diabetes mellitus (T2DM), and a high level of IAP plays a protective role against T2DM irrespective of obesity.
IAP deficiency (IAPD) is also directly associated with type 1 diabetes mellitus.
What are the new findings?
This 5-year prospective cohort study shows that IAPD increases the rate of fasting plasma glucose.
IAPD increases the risk of developing T2DM.
Remission of IAPD prevents the development of T2DM.
How might these results change the focus of research or clinical practice?
Regular stool IAP tests would diagnose vulnerability to T2DM, and prevention of IAPD would prevent T2DM.
Intervention of IAPD by oral IAP supplementation might prevent T2DM.
Eradication of the worldwide pandemic of T2DM is possible by early diagnosis of IAPD-associated vulnerability to T2DM followed by pre-emptive preventive measures.
Introduction Previous case–control study demonstrated that a high level of intestinal alkaline phosphatase (IAP), an endotoxin-detoxifying anti-inflammatory enzyme secreted by villus-associated enterocytes and excreted with stool, plays a protective role against type 2 diabetes mellitus (T2DM) irrespective of obesity. In the current study, authors investigated the long-term effect of IAP deficiency (IAPD) on the pathogenesis of T2DM.
Research design and methods A healthy cohort of participants without diabetes (30–60 years old), comprising 188 without IAPD (IAP level: ≥65 U/g stool) and 386 with IAPD (IAP level: <65 U/g stool), were followed up for 5 years. We measured stool IAP (STAP) and fasting plasma glucose, and calculated the risk ratio (RR) using log-binomial regression model.
Results T2DM incidence rates were 8.0%, 11.7%, 25.6%, and 33.3% in participants with ‘persistent no IAPD’ (IAP level: always ≥65 U/g stool), ‘remittent IAPD’ (IAP level: increased from <65 U/g stool to ≥65 U/g stool), ‘persistent IAPD’ (IAP level: always <65 U/g stool), and ‘incident IAPD’ (IAP level: decreased from ≥65 U/g stool to <65 U/g stool), respectively. Compared with ‘persistent no IAPD’ the risk of developing T2DM with ‘incident IAPD’ was 270% higher. With ‘persistent IAPD’ the risk was 230% higher. ‘Remittent IAPD’ showed insignificant risk. Sensitivity analyses of persistent IAP levels revealed that, compared with participants of the highest persistent IAP pentile (always >115 U/g stool), the rate of increase of fasting glycemia was double and the risk of developing T2DM was 1280% higher in participants of the lowest persistent IAP pentile (always <15 U/g stool). A diabetes pathogenesis model is presented.
Conclusions IAPD increases the risk of developing T2DM, and regular STAP tests would predict individual vulnerability to T2DM. Oral IAP supplementation might prevent T2DM.
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