madman
Super Moderator
Metabolic effects of L-citrulline in type 2 diabetes (2023)
Fatemeh Bagheripour, Sajad Jeddi, Khosrow Kashfi, Asghar Ghasemi
Abstract
The prevalence of type 2 diabetes (T2D) is increasing worldwide. Decreased nitric oxide (NO) bioavailability is involved in the pathophysiology of T2D and its complications. L-citrulline (Cit), a precursor of NO production, has been suggested as a novel therapeutic agent for T2D. Available data from human and animal studies indicate that Cit supplementation in T2D increases circulating levels of Cit and L-arginine while decreasing circulating glucose and free fatty acids and improving dyslipidemia. The underlying mechanisms for these beneficial effects of Cit include increased insulin secretion from the pancreatic β-cells, increased glucose uptake by the skeletal muscle, as well as increased lipolysis and β-oxidation, and decreased glyceroneogenesis in the adipose tissue. Thus, Cit has antihyperglycemic, antidyslipidemic, and antioxidant effects and has the potential to be used as a new therapeutic agent in the management of T2D. This review summarizes available literature from human and animal studies to explore the effects of Cit on metabolic parameters in T2D. It also discusses the possible mechanisms underlying Cit-induced improved metabolic parameters in T2D.
1. Introduction
The prevalence of diabetes mellitus in the adult population has increased from 151 to 537 million during the first two decades of the 21st century and is estimated to reach 783 million by the year 2045. 1 About 90–95% of all people with diabetes have type 2 diabetes (T2D), characterized by insulin resistance and β-cell dysfunction. 2 Currently, various treatments are available for T2D, but unfortunately, most have insufficient efficacy. 3 For example, the effectiveness of antidiabetic drugs for achieving glycemic control is only 41%, emphasizing the need for further investigations to provide more efficient treatments. 4 In addition, it has been suggested that the treatment approach to T2D needs to be changed from only a glycemic control to a pathophysiological-based approach, which also includes managing lipids, blood pressure, and obesity. 5
Endothelial dysfunction, mainly characterized by decreased nitric oxide (NO) bioavailability, is involved in the pathophysiology of T2D. 6 NO is produced from the L-arginine (Arg)-NO synthase (NOS) and the nitrate-nitrite-NO pathways. 7 Decreased endothelial NOS (eNOS)-derived NO, increased inducible NOS (iNOS)-derived NO, 8,9 and impaired nitrate-nitrite-NO pathway10 have been reported in T2D. Results from human studies on polymorphisms in NOS genes, genetically altered animals, and pharmacological studies support the involvement of disturbed NO homeostasis in developing T2D. 10 Obtained data indicate that NO produced by constitutive isoforms of NOS (cNOS), i.e., eNOS and neural NOS (nNOS), increases insulin secretion and sensitivity10, increases skeletal muscle glucose uptake, 11 and decreases hepatic glucose output. 12 In contrast, iNOS-derived NO increases insulin resistance and leads to the development of T2D. 9 In addition, NO-releasing drugs can improve carbohydrate metabolism in T2D, and the NO system partially mediates favorable metabolic effects of some antidiabetic medications (e.g., metformin). 13,14 Therefore, boosting the NO system may have therapeutic effects on T2D. 15-17 One strategy for NO boosting is enhancing endogenous NO synthesis, 18 which can be achieved by administration of Arg, 19,20 nitrate/nitrite, 21,22, and L-citrulline (Cit). 23
Results of clinical and experimental studies indicate that Arg, an NO precursor, has beneficial effects on T2D19,24-28 and improves endothelial20,24 and β-cell29,30 function and glucose tolerance. 3 1 However, Arg does not affect fasting glucose and hemoglobin A1c (HbA1c) levels in patients with T2D. 32,33 In addition, it has undesirable side effects, including induction of arginase activity,3 4 enhancing inflammatory and immunologic responses, 35-37 and increased mortality in patients with myocardial infarction. 38
Inorganic nitrate and nitrite supplementation to boost the nitrate-nitrite-NO pathway have shown promising metabolic effects in animal models of T2D. 10,39-41 These anions increase insulin secretion from the β-cells15,42,43 and improve glucose utilization at the periphery. 44-48 However, this has not been the case in human studies where nitrate or nitrite was ineffective in improving metabolic disorders; 49,50 for details, see a recent review. 51 In addition, a high intake of nitrate and nitrite may increase the risk of β-cell autoimmunity and type 1 diabetes. 52
Cit, a precursor of Arg de novo synthesis and NO production, 53 has a highly efficient intestinal absorption rate, low first-pass metabolism, and high renal reabsorption. These characteristics make Cit a good candidate for NO boosting in NO-disrupted conditions, including diabetes. 54 In addition, it is needed to manage other comorbidities, including obesity, dyslipidemia, and hypertension in patients with T2D. 55 This increases the prevalence of polypharmacy, using greater than 5 drugs/day, as reported to be 57% to 84% in patients with T2D. 56,57 Polypharmacy is associated with increased drug side effects 58 (e.g., higher risk of bone fracture and depression59), lower quality of life, and higher healthcare costs. 60 The therapeutic effects of Cit against oxidative stress, hyperglycemia, hypertension, hypertriglyceridemia, hypercholesterolemia, and insulin resistance have been reported in experimental61-64 and clinical studies65-71 in both male61-64,66-71 and females. 67-71 Therefore, Cit can potentially act as a one-drug-multi-target agent in patients with T2D. In this review, we first summarize the effects of Cit on metabolic parameters in T2D and then discuss the possible mechanisms that underlie such improved outcomes.
2. L-citrulline metabolism
2.1. Cit-Arg cycle
3. Circulating concentrations of L-citrulline in T2D
4. Metabolic effects of L-citrulline in T2D
4.1. Dose and safety of Cit
5. Mechanisms underlying beneficial effects of L-citrulline in T2D
5.1. Increased insulin secretion
5.2.Improved peripheral glucose metabolism
5.2.1. Skeletal muscle
5.2.2. Adipose tissue
6. Conclusions and perspectives
Cit improves insulin sensitivity and has antihyperglycemic, antidyslipidemic, and antioxidant effects. The mechanisms underlying these effects include: (1) increased GSIS in pancreatic β-cells by activating VDCCs, stimulation of insulin gene promoter, and promotion of mitochondrial ATP production, (2) increased glucose uptake in the skeletal muscle by promoting the expression and translocation of the GLUT4 and increasing mitochondrial biogenesis, (3) increased lipolysis, βoxidation, and thermogenesis as well as decreased glyceroneogenesis in adipocytes. These effects are mainly NO-dependent and occur through the Cit-Arg cycle and NO production.
Some points should be considered about the beneficial metabolic effects of Cit in T2D. First, a large body of evidence has been provided from in vitro or animal studies. Because Cit metabolism shows species differences, extrapolation of these findings to humans needs caution. Second, Cit metabolism is different between males and females; for example, the blood pressure-lowering effects of Cit are more significant in women than men; 92,93 these findings highlight the importance of considering sex differences on the impact of Cit when carbohydrate metabolism is evaluated. Third, most reported animal and human studies on the metabolic effects of Cit are from short-term studies, with concerns remaining about their long-term potential adverse effects. 112 Finally, most of the beneficial metabolic effects of Cit are attributed to NO, and further studies are needed to explore the NO-independent metabolic effects of Cit.
All in all, Cit administration can be considered a promising treatment for T2D, but it needs to be investigated in randomized clinical trials.
Fatemeh Bagheripour, Sajad Jeddi, Khosrow Kashfi, Asghar Ghasemi
Abstract
The prevalence of type 2 diabetes (T2D) is increasing worldwide. Decreased nitric oxide (NO) bioavailability is involved in the pathophysiology of T2D and its complications. L-citrulline (Cit), a precursor of NO production, has been suggested as a novel therapeutic agent for T2D. Available data from human and animal studies indicate that Cit supplementation in T2D increases circulating levels of Cit and L-arginine while decreasing circulating glucose and free fatty acids and improving dyslipidemia. The underlying mechanisms for these beneficial effects of Cit include increased insulin secretion from the pancreatic β-cells, increased glucose uptake by the skeletal muscle, as well as increased lipolysis and β-oxidation, and decreased glyceroneogenesis in the adipose tissue. Thus, Cit has antihyperglycemic, antidyslipidemic, and antioxidant effects and has the potential to be used as a new therapeutic agent in the management of T2D. This review summarizes available literature from human and animal studies to explore the effects of Cit on metabolic parameters in T2D. It also discusses the possible mechanisms underlying Cit-induced improved metabolic parameters in T2D.
1. Introduction
The prevalence of diabetes mellitus in the adult population has increased from 151 to 537 million during the first two decades of the 21st century and is estimated to reach 783 million by the year 2045. 1 About 90–95% of all people with diabetes have type 2 diabetes (T2D), characterized by insulin resistance and β-cell dysfunction. 2 Currently, various treatments are available for T2D, but unfortunately, most have insufficient efficacy. 3 For example, the effectiveness of antidiabetic drugs for achieving glycemic control is only 41%, emphasizing the need for further investigations to provide more efficient treatments. 4 In addition, it has been suggested that the treatment approach to T2D needs to be changed from only a glycemic control to a pathophysiological-based approach, which also includes managing lipids, blood pressure, and obesity. 5
Endothelial dysfunction, mainly characterized by decreased nitric oxide (NO) bioavailability, is involved in the pathophysiology of T2D. 6 NO is produced from the L-arginine (Arg)-NO synthase (NOS) and the nitrate-nitrite-NO pathways. 7 Decreased endothelial NOS (eNOS)-derived NO, increased inducible NOS (iNOS)-derived NO, 8,9 and impaired nitrate-nitrite-NO pathway10 have been reported in T2D. Results from human studies on polymorphisms in NOS genes, genetically altered animals, and pharmacological studies support the involvement of disturbed NO homeostasis in developing T2D. 10 Obtained data indicate that NO produced by constitutive isoforms of NOS (cNOS), i.e., eNOS and neural NOS (nNOS), increases insulin secretion and sensitivity10, increases skeletal muscle glucose uptake, 11 and decreases hepatic glucose output. 12 In contrast, iNOS-derived NO increases insulin resistance and leads to the development of T2D. 9 In addition, NO-releasing drugs can improve carbohydrate metabolism in T2D, and the NO system partially mediates favorable metabolic effects of some antidiabetic medications (e.g., metformin). 13,14 Therefore, boosting the NO system may have therapeutic effects on T2D. 15-17 One strategy for NO boosting is enhancing endogenous NO synthesis, 18 which can be achieved by administration of Arg, 19,20 nitrate/nitrite, 21,22, and L-citrulline (Cit). 23
Results of clinical and experimental studies indicate that Arg, an NO precursor, has beneficial effects on T2D19,24-28 and improves endothelial20,24 and β-cell29,30 function and glucose tolerance. 3 1 However, Arg does not affect fasting glucose and hemoglobin A1c (HbA1c) levels in patients with T2D. 32,33 In addition, it has undesirable side effects, including induction of arginase activity,3 4 enhancing inflammatory and immunologic responses, 35-37 and increased mortality in patients with myocardial infarction. 38
Inorganic nitrate and nitrite supplementation to boost the nitrate-nitrite-NO pathway have shown promising metabolic effects in animal models of T2D. 10,39-41 These anions increase insulin secretion from the β-cells15,42,43 and improve glucose utilization at the periphery. 44-48 However, this has not been the case in human studies where nitrate or nitrite was ineffective in improving metabolic disorders; 49,50 for details, see a recent review. 51 In addition, a high intake of nitrate and nitrite may increase the risk of β-cell autoimmunity and type 1 diabetes. 52
Cit, a precursor of Arg de novo synthesis and NO production, 53 has a highly efficient intestinal absorption rate, low first-pass metabolism, and high renal reabsorption. These characteristics make Cit a good candidate for NO boosting in NO-disrupted conditions, including diabetes. 54 In addition, it is needed to manage other comorbidities, including obesity, dyslipidemia, and hypertension in patients with T2D. 55 This increases the prevalence of polypharmacy, using greater than 5 drugs/day, as reported to be 57% to 84% in patients with T2D. 56,57 Polypharmacy is associated with increased drug side effects 58 (e.g., higher risk of bone fracture and depression59), lower quality of life, and higher healthcare costs. 60 The therapeutic effects of Cit against oxidative stress, hyperglycemia, hypertension, hypertriglyceridemia, hypercholesterolemia, and insulin resistance have been reported in experimental61-64 and clinical studies65-71 in both male61-64,66-71 and females. 67-71 Therefore, Cit can potentially act as a one-drug-multi-target agent in patients with T2D. In this review, we first summarize the effects of Cit on metabolic parameters in T2D and then discuss the possible mechanisms that underlie such improved outcomes.
2. L-citrulline metabolism
2.1. Cit-Arg cycle
3. Circulating concentrations of L-citrulline in T2D
4. Metabolic effects of L-citrulline in T2D
4.1. Dose and safety of Cit
5. Mechanisms underlying beneficial effects of L-citrulline in T2D
5.1. Increased insulin secretion
5.2.Improved peripheral glucose metabolism
5.2.1. Skeletal muscle
5.2.2. Adipose tissue
6. Conclusions and perspectives
Cit improves insulin sensitivity and has antihyperglycemic, antidyslipidemic, and antioxidant effects. The mechanisms underlying these effects include: (1) increased GSIS in pancreatic β-cells by activating VDCCs, stimulation of insulin gene promoter, and promotion of mitochondrial ATP production, (2) increased glucose uptake in the skeletal muscle by promoting the expression and translocation of the GLUT4 and increasing mitochondrial biogenesis, (3) increased lipolysis, βoxidation, and thermogenesis as well as decreased glyceroneogenesis in adipocytes. These effects are mainly NO-dependent and occur through the Cit-Arg cycle and NO production.
Some points should be considered about the beneficial metabolic effects of Cit in T2D. First, a large body of evidence has been provided from in vitro or animal studies. Because Cit metabolism shows species differences, extrapolation of these findings to humans needs caution. Second, Cit metabolism is different between males and females; for example, the blood pressure-lowering effects of Cit are more significant in women than men; 92,93 these findings highlight the importance of considering sex differences on the impact of Cit when carbohydrate metabolism is evaluated. Third, most reported animal and human studies on the metabolic effects of Cit are from short-term studies, with concerns remaining about their long-term potential adverse effects. 112 Finally, most of the beneficial metabolic effects of Cit are attributed to NO, and further studies are needed to explore the NO-independent metabolic effects of Cit.
All in all, Cit administration can be considered a promising treatment for T2D, but it needs to be investigated in randomized clinical trials.
