Postprandial hyperglycemia and endothelial function in type 2 diabetes: focus on mitiglinide

ABSTRACT: The risk of cardiovascular complication in a diabetes patient is similar to that in a nondiabetic patient with a history of myocardial infarction. Although intensive control of glycemia achieved by conventional antidiabetic agents decreases microvascular complications such as retinopathy and nephropathy, no marked effect has been reported on macrovascular complications or all-cause mortality. Evidence from VADT, ACCORD, and ADVANCE would suggest that glycemic control has little effect on macrovascular outcomes. Moreover, in the case of ACCORD, intensive glycemic control may be associated with an increased risk of mortality. There is sufficient evidence that suggests that postprandial hyperglycemia may be an independent risk factor for cardiovascular disease in diabetes patients. However, there are no prospective clinical trials supporting the recommendation that lowering postprandial blood glucose leads to lower risk of cardiovascular outcomes. Mitiglinide is a short-acting insulinotropic agent used in type 2 diabetes treatment. It has a rapid stimulatory effect on insulin secretion and reduces postprandial plasma glucose level in patients with type 2 diabetes. Because of its short action time, it is unlikely to exert adverse effects related to hypoglycemia early in the morning and between meals. Mitiglinide reduces excess oxidative stress and inflammation, plays a cardioprotective role, and improves postprandial metabolic disorders. Moreover, mitiglinide add-on therapy with pioglitazone favorably affects the vascular endothelial function in type 2 diabetes patients. These data suggest that mitiglinide plays a potentially beneficial role in the improvement of postprandial hyperglycemia in type 2 diabetes patients and can be used to prevent cardiovascular diseases. Although the results of long-term, randomized, placebo-controlled trials for determining the cardiovascular effects of mitiglinide on clinical outcomes are awaited, this review is aimed at summarizing substantial insights into this topic.     

Metabolic memory - the implications for diabetic complications

Many important biochemical mechanisms are activated in the presence of high levels of glucose, which occur in diabetes. Large randomised studies have established that early intensive glycaemic control reduces the risk of diabetic complications. This phenomenon has recently been dubbed 'metabolic memory'. It has been suggested that early glycaemia normalisation can halt the hyperglycaemia-induced pathological processes associated with enhanced oxidative stress and glycation of cellular proteins and lipids. The phenomenon of metabolic memory suggests that early aggressive treatment and strict glycaemic control could prevent chronic diabetic complications.     

Research progress of coumarins and their derivatives in the treatment of diabetes

Diabetes is a group of metabolic diseases characterised by chronic hyperglycaemia caused by multiple causes, which is caused by insulin secretion and/or utilisation defects. It is characterised by increased fasting and postprandial blood glucose levels due to insulin deficiency or insulin resistance. It is reported that the harm of diabetes mainly comes from its complications, and the cardiovascular disease caused by diabetes is the primary cause of its harm. China has the largest number of diabetic patients in the world, and the prevention and control of diabetes are facing great challenges. In recent years, many kinds of literature have been published abroad, which have proved that coumarin and its derivatives are effective in the treatment of diabetic complications such as nephropathy and cardiovascular disease. In this paper, the types of antidiabetic drugs and the anti-diabetic mechanism of coumarins were reviewed.     

Macroangiopathy in adults and children with diabetes: from molecular mechanisms to vascular damage (part 1).

Type 2 diabetes mellitus (T2DM) is an increasing problem in childhood; however type 1 diabetes mellitus (T1DM) remains by far the most common type of diabetes in this age group. In this review we will focus on T1DM, because this will have the greatest implication for patients diagnosed in childhood. During the atherosclerotic process, several molecular, receptorial and cellular factors provide a continous mechanism of vascular damage. In diabetic children this state seems to be enhanced and facilitated so that accelerated atherosclerosis is associated with an increased risk of cardiovascular events in respect to the non diabetic population. Hyperglycemia PER SE and associated with diabetes is an important risk factor for atherosclerosis. At present a substantial part of children with diabetes do not reach satisfactory glycemic control. Other risk factors for the development and progression of atherosclerosis may be inherited or develop in the course of the disease: hypertension, dyslipidemia, insulin resistance, obesity, cigarette smoking, physical inactivity, disturbance of platelet function, coagulation and fibrinolysis. The development and progression of atherosclerosis should be blocked at an early age, if possible. Primary prevention to all risk factors for cardiovascular disease is important and intervention is indicated if necessary. At the moment the best therapeutic strategy is to maintain metabolic control at a physiologic level and perform screening and early intervention for vascular complications.     

Clinical significance of cardiovascular dysmetabolic syndrome

Although diabetes mellitus is predominantly a metabolic disorder, recent data suggest that it is as much a vascular disorder. Cardiovascular complications are the leading cause of death and disability in patients with diabetes mellitus. A number of recent reports have emphasized that many patients already have atherosclerosis in progression by the time they are diagnosed with clinical evidence of diabetes mellitus. The increased risk of atherosclerosis and cardiovascular complications in diabetic patients is related to the frequently associated dyslipidemia, hypertension, hyperglycemia, hyperinsulinemia, and endothelial dysfunction. The evolving knowledge regarding the variety of metabolic, hormonal, and hemodynamic abnormalities in patients with diabetes mellitus has led to efforts designed for early identification of individuals at risk of subsequent disease. It has been suggested that insulin resistance, the key abnormality in type II diabetes, often precedes clinical features of diabetes by 5–6 years. Careful attention to the criteria described for the cardiovascular dysmetabolic syndrome should help identify those at risk at an early stage. The application of nonpharmacologic as well as newer emerging pharmacologic therapies can have beneficial effects in individuals with cardiovascular dysmetabolic syndrome and/or diabetes mellitus by improving insulin sensitivity and related abnormalities. Early identification and implementation of appropriate therapeutic strategies would be necessary to contain the emerging new epidemic of cardiovascular disease related to diabetes.     

Focus: Rare Disease: Necrotizing Fasciitis: Association with Pregnancy-related Risk Factors Early in Life

Background: Pregnancy-related risk factors for necrotizing fasciitis are poorly understood. We investigated pregnancy-related characteristics associated with the long-term risk of developing necrotizing fasciitis, a rare life-threatening infectious disease. Methods: We analyzed a longitudinal cohort of 1,344,996 parous women in Quebec, Canada between 1989 and 2020. The main exposure measures included complications of pregnancy such as gestational diabetes, preterm delivery, metabolic disorder, and other maternal characteristics. We followed the women over time to identify future hospitalizations for necrotizing fasciitis up to three decades after delivery. We estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the association of pregnancy characteristics with risk of necrotizing fasciitis in time-varying Cox proportional hazards regression models. Results: A total of 420 women were hospitalized for necrotizing fasciitis during follow-up, including 83 (19.8%) with diabetes-related necrotizing fasciitis. The incidence of necrotizing fasciitis was elevated for women with gestational diabetes (2.9 per 100,000 person-years), preterm delivery (3.2 per 100,000 person-years), and metabolic disorders (5.4 per 100,000 person-years), compared with no pregnancy complication (1.1 per 100,000 person-years). Compared with no pregnancy complication, gestational diabetes was associated with 1.87 times the risk (95% CI 1.38-2.53), preterm delivery with 2.10 times the risk (95% CI 1.65-2.66), and metabolic disorder with 3.72 times the risk (95% CI 2.92-4.74) of developing necrotizing fasciitis over time. Pregnancy complications were more strongly associated with the risk of necrotizing fasciitis 5 years or more after delivery. Conclusions: Complications of pregnancy may be associated with the long-term risk of necrotizing fasciitis in women.     

Cyclophilin-A: a potential screening marker for vascular disease in type-2 diabetes

The pathophysiology of vascular disease in diabetes involves abnormalities in endothelial cells, vascular smooth muscle cells, and monocytes. The metabolic abnormalities that characterize diabetes, such as hyperglycemia, increased free fatty acids, and insulin resistance, each provoke molecular mechanisms that contribute to vascular dysfunction. Several molecules have been identified as risk markers, and have been studied to prevent progression of disease and long-term complications. Markers such as C-reactive protein and monocyte chemoattractant protein-1 are used to assess risk for adverse cardiac events, but elevated levels are possible due to the presence of other risk factors as part of the natural physiological defense mechanism. In this review we discuss potential of cyclophilin-A, a secreted oxidative-stress-induced immunophilin with diverse functions. We present evidence for a significant role of cyclophilin-A in the pathogenesis of atherosclerosis in diabetes, and its potential as a marker for vascular disease in type-2 diabetes.     

糖尿病及其并发症与肠道菌群关系研究进展

糖尿病及其并发症作为长期的慢性代谢性疾病,对其防治应愈加重视。大量研究表明肠道菌群作为身体的一部分,直接或间接参与了疾病的发展。本研究综述了糖尿病及其并发症与肠道菌群关系及发病机制,为早期监测和预防糖尿病进展为并发症期提供新的参考依据。     

Children with type 2 diabetes: the risks of complications

Type 2 diabetes is an increasing problem in children. Two decades ago it had been described only in selected groups, e.g. the Pima Indians. Childhood type 2 diabetes appears to be similar to the metabolic syndrome in adults and is characterized by obesity, hyperglycaemia and insulin resistance. It can present a diagnostic challenge in children, as they can present with diabetic ketoacidosis; the measurement of autoantibodies and C-peptide levels may be helpful. The logarithmic association between the risk of complications with increasing glycaemia which has been established for adults with type 2 diabetes is likely to hold true for children but the conclusions of trials in adults must be extrapolated with caution. Little is known about the onset and progression of macrovascular disease in affected children but it is almost certain that they will develop an excess of premature cardiovascular disease. However, the importance of reducing glycaemia in younger adults with diabetes, in order to minimize the incidence of microvascular complications, has been unequivocally demonstrated in the Diabetes Control and Complications Trial (DCCT). Diet and exercise have a major role to play in the treatment and prevention of type 2 diabetes in children as well as adults - the escalation of type 2 diabetes throughout the developed world is a major public health problem. Extrapolating data from adults, metformin appears to be the logical first-line treatment in children with type 2 diabetes; sulphonylureas are also used but neither of these agents have been evaluated in trials in children and are not licensed for such use. With regard to other newer agents, it seems wise to use well-established drugs with a long track record and for which the long-term safety data are available.     

Mediterranean diet and metabolic diseases

PURPOSE OF REVIEW: The objective of this article is to present evidence illustrating the relationship between Mediterranean diets and metabolic diseases, including obesity, type 2 diabetes, and the metabolic syndrome, and to briefly discuss potential mechanisms by which these diets can help in disease prevention and treatment. RECENT FINDINGS: Although the Mediterranean diet has long been celebrated for its impact on cardiovascular health, mounting evidence indicates a favorable effect on obesity and type 2 diabetes, as well. While health promotion strategies aimed at preventing adult obesity are emphasizing components of Mediterranean dietary patterns, a role for Mediterranean diets in attenuating the inflammatory burden associated with type 2 diabetes is also emerging. Moreover, a lower prevalence of the metabolic syndrome is associated with dietary patterns rich in fruits, vegetables, whole grains, dairy products, and unsaturated fats. Both epidemiological and interventional studies have revealed a protective effect of the Mediterranean diet against mild chronic inflammation and its metabolic complications. SUMMARY: Mounting evidence suggests that Mediterranean diets could serve as an anti-inflammatory dietary pattern, which could help fighting diseases that are related to chronic inflammation, including visceral obesity, type 2 diabetes and the metabolic syndrome.     

Prevalence of chronic complications, metabolic control and nutritional intake in type 1 diabetes: comparison between different European regions. EURODIAB Complications Study group.

This study compares the prevalence of chronic complications, the quality of metabolic control and the nutritional intake in people with type 1 diabetes in different European regions. The EURODIAB Complications Study included a sample of 3250 European patients with type 1 diabetes stratified for gender, age and diabetes duration. All examinations were performed using standardised, validated methods. HBA1c, LDL-cholesterol and fasting triglycerides were higher in the eastern European centres than in the southern or north-western European centres. Acute (severe ketoacidosis, severe hypoglycaemia) and chronic diabetes complications (retinopathy, nephropathy, neuropathy, cardiovascular disease) were all considerably more frequent in the eastern European centres. HbA1c was lower in the German centres than in the total EURODIAB cohort or in the north-western European centres, but severe hypoglycaemia and proliferative retinopathy were more common. Persons from the eastern European and the German centres consumed undesirably high amounts of cholesterol, total and saturated fat. Overall, improvements in the prevention, detection and management of diabetes complications in persons with type 1 diabetes are essential throughout Europe, particularly in eastern European regions. Since elevated LDL-cholesterol levels and hypertension were strikingly common in this relatively young cohort of European people with type 1 diabetes, generally more attention should be directed towards an adequate management of these cardiovascular risk factors.     

Oxymatrine and insulin resistance: Focusing on mechanistic intricacies involve in diabetes associated cardiomyopathy via SIRT1/AMPK and TGF-β signaling pathway

Cardiomyopathy (CDM) and related morbidity and mortality are increasing at an alarming rate, in large part because of the increase in the number of diabetes mellitus cases. The clinical consequence associated with CDM is heart failure (HF) and is considerably worse for patients with diabetes mellitus, as compared to nondiabetics. Diabetic cardiomyopathy (DCM) is characterized by structural and functional malfunctioning of the heart, which includes diastolic dysfunction followed by systolic dysfunction, myocyte hypertrophy, cardiac dysfunctional remodeling, and myocardial fibrosis. Indeed, many reports in the literature indicate that various signaling pathways, such as the AMP-activated protein kinase (AMPK), silent information regulator 1 (SIRT1), PI3K/Akt, and TGF-β/smad pathways, are involved in diabetes-related cardiomyopathy, which increases the risk of functional and structural abnormalities of the heart. Therefore, targeting these pathways augments the prevention as well as treatment of patients with DCM. Alternative pharmacotherapy, such as that using natural compounds, has been shown to have promising therapeutic effects. Thus, this article reviews the potential role of the quinazoline alkaloid, oxymatrine obtained from the Sophora flavescensin CDM associated with diabetes mellitus. Numerous studies have given a therapeutic glimpse of the role of oxymatrine in the multiple secondary complications related to diabetes, such as retinopathy, nephropathy, stroke, and cardiovascular complications via reductions in oxidative stress, inflammation, and metabolic dysregulation, which might be due to targeting signaling pathways, such as AMPK, SIRT1, PI3K/Akt, and TGF-β pathways. Thus, these pathways are considered central regulators of diabetes and its secondary complications, and targeting these pathways with oxymatrine might provide a therapeutic tool for the diagnosis and treatment of diabetes-associated cardiomyopathy.     

Glycation and biomarkers of vascular complications of diabetes

Propensity to diabetic nephropathy (DN), retinopathy (DR), and cardiovascular disease (CVD) varies between individuals. Current biomarkers such as indicators of glycemia (HbA1c), retinal examinations, and albuminuria, cannot detect early tissue damage. HbAIc also doesn’t reflect most glycative and oxidative chemical pathways that cause complications, and studies of new biomarkers to measure their end-products are needed. This review proposes the study of advanced glycation end products (AGEs) and oxidation end-products (OPs) in long-term diabetes outcome studies. AGEs integrate the activity of glycation pathways that form dicarbonyls, while OPs reflect superoxides, hydroxyl radicals, and peroxides. We discuss using these biomarkers to predict risk of development and progression of DN, DR, and CVD, and to determine if they confer risk independently of the level of HbA1c. We also discuss methods and guidelines to document sample quality in such studies. These studies have the potential to validate unique biomarkers during the early stages of diabetes in those who are at high risk of diabetic complications. Information on basic mechanisms responsible for complications could also stimulate development of therapeutic approaches to delay or arrest them. The ultimate goal is to predict those requiring aggressive therapies during the earliest stages, when prevention or reversal of complications is still possible.     

Early- and advanced non-enzymatic glycation in diabetic vascular complications: the search for therapeutics

Cardiovascular disease is a common complication of diabetes and the leading cause of death among people with diabetes. Because of the huge premature morbidity and mortality associated with diabetes, prevention of vascular complications is a key issue. Although the exact mechanism by which vascular damage occurs in diabetes in not fully understood, numerous studies support the hypothesis of a causal relationship of non-enzymatic glycation with vascular complications. In this review, data which point to an important role of Amadori-modified glycated proteins and advanced glycation endproducts in vascular disease are surveyed. Because of the potential role of early- and advanced non-enzymatic glycation in vascular complications, we also described recent developments of pharmacological inhibitors that inhibit the formation of these glycated products or the biological consequences of glycation and thereby retard the development of vascular complications in diabetes.     

Small for gestational age and the metabolic syndrome: which mechanism is suggested by epidemiological and clinical studies?

The metabolic and cardiovascular complications associated with in-utero undernutrition have been identified during the past 10 years. Reduced fetal growth is independently associated with an increased risk of development of cardiovascular diseases, the insulin-resistance syndrome or one of its components (i.e., hypertension, dyslipidaemia, impaired glucose tolerance and type 2 diabetes). Insulin resistance appears to be a key component underlying these metabolic complications. Although the mechanism remains unclear, several pieces of evidence support an active role of adipose tissue in the emergence of insulin resistance (an abnormal growth pattern and repartition, hypersensitivity to catecholamines, regulation of leptin and adiponectin secretion and modulation of peroxisome proliferator-activated receptor gamma). Among individuals born SGA, those who are more at risk of gaining excess adiposity are those who are thin at birth following a period of fetal growth restriction. This period of undernutrition is followed by a neonatal period of catch-up growth and renutrition. This pattern induces important modifications in adipose tissue, with long-term consequences, among which is a high risk of early development of insulin resistance. Not all individuals born SGA will show such modifications in adipose tissue, meaning that not all of those born SGA are at risk of insulin resistance and diabetes. From a broader point of view, several hypotheses have been proposed over the past 10 years to explain this unexpected association between being born SGA and the later development of disease. Each of them points to a detrimental fetal environment, to a genetic susceptibility or to interactions between these two components playing a critical role in this context. Although not confirmed, the hypothesis suggesting that this association could be the consequence of genetic/environmental interactions remains the most attractive.     

Application of dietary supplements in the prevention of type 2 diabetes-related cardiovascular complications

Type 2 diabetes, which accounts for the vast majority of diabetes worldwide is the result of a lowered sensitivity of the insulin receptors, resulting in impaired sugar metabolism is and chronic hyperglycaemia. There is no cure for type 2 diabetes, though some people with pre-diabetes and diabetes manage to reach and hold normal blood sugar levels, thus avoiding most of the complications that come with chronic hyperglycaemia; this is sometimes referred to as ‘reversing diabetes’. A healthy diet, with sufficient amounts of fruits, nuts, and vegetables is positively correlated with maintaining glycaemic control and prevention of diabetes-related complications. Whereas many different dietary phytochemicals have been considered to play a role in the glycaemic control and in prevention of degenerative diseases, there is currently no consensus on a particular mode of action. In this review, a range of pre-clinical studies and intervention studies, including randomised double-blind, placebo controlled clinical studies, are considered that investigate the role of dietary compounds in the prevention of type 2 diabetes-related complications. Three generic mechanisms of action can be discerned: compounds that reduce sugar uptake, compounds that restore insulin function, and compounds that attenuate the effects of oxidative stress and chronic inflammation. Particularly the latter has received wide attention in the form of activation of the Nrf2-antioxidant response element signalling pathway by various polyphenolic or triterpenoid compounds. Although individual reports may present models with clear looking signalling cascades, an overall review shows that many biologically active compounds in the human diet are pan assay interference substances that alter several cell functions simultaneously, which makes them less attractive for drug development.

     

Nouveaux marqueurs dans l’homéostasie glucidique : physiologie et physiopathologie

The term diabetes mellitus describes a metabolic disorder resulting from defects in insulin secretion, insulin action, or both. People with diabetes are at increased risk of cardiovascular, peripheral and cerebrovascular disease. In consequence, it is important to better understand early step in this disease in order to prevent complications. Incretine hormones are defined as intestinal hormones released in response to nutrient ingestion, which potentiate the glucose-induced insulin response. The incretine effect is mainly caused by two peptide hormones, glucose-dependent insulin releasing polypeptide (GIP) and glucagons-like peptide-1 (GLP-1). Analogs of GLP-1 and dipeptidyl-peptidase IV (DPP-IV) inhibitors are actually used as antidiabetic drugs. Adiponectin is an adipokine, which is expressed in adipose tissue and is thought to play an important role in glucose metabolism. Hypoadiponectinemia was related to obesity, insulin-resistance and as a risk factor of diabetes, cardiovascular events and death. Plasmatic quantification of GLP-1 and adiponectin should improve insulin-resistance diagnosis and diabetes prevention.     

The use of fibrates and of statins in preventing atherosclerosis in diabetes.

Atherosclerotic cardiovascular disease is the most common complication of diabetes. Recent guidelines in the USA have underlined the importance of treating lipid abnormalities in people with diabetes in order to reduce the risk of this complication. Should lifestyle approaches not be sufficient drugs will need to be added. The two most common classes of drugs to correct lipoprotein abnormalities are the statins and the fibrates. Each has a role to play and their use depends on the nature of the lipid abnormality that is present. Thus, rather than considering their use as an 'either/or' situation, this review will consider the uses of each class. In addition, as correcting the lipoprotein abnormalities may not account for all of the benefit produced by these agents, their non-lipid, pleotropic effects that may be antiatherogenic will also be reviewed.     

Macroangiopathy in adults and children with diabetes: risk factors (part 2).

Autoimmune or type 1 diabetes mellitus (T1DM), accounts for 90-95% of all cases of diabetes, while type 2 diabetes mellitus (T2DM), characterized by impaired insulin sensitivity and production, accounts for the other 5-10%. Atherosclerotic process starts during childhood and recognize several mechanisms that are activated in response to NOXIUS STIMULI and participate in a complex state which is accepted to be a chronic inflammatory state. T1DM patients, especially those with a non-optimal metabolic control, have a higher risk of developing all macrovascular complications such as myocardial infarction, stroke and silent ischemia. Macrovascular disease is mainly associated with hyperglycemia, dyslipidemia, obesity, hypertension, hypercoagulable state, cigarette smoking, lack of exercise, endothelial dysfunction, hyperhomocysteinemia and vascular wall abnormalities. In this paper we review the importance of traditional and non-traditional risk factors for macrovascular complications in children with T1DM and discuss their role in the pathogenesis of the excess cardiovascular mortality in these patients.     

Lipid metabolism in children and adolescents with insulin dependent diabetes. II. Evaluation of changes in lipoprotein A-I in children and adolescents with insulin dependent diabetes]

The levels of lipoprotein A-I (LP A-I) containing apolipoprotein A-I (apo A-I) and devoid of apolipoprotein A-II (apo A-II) have been determined in a group of 86 children and adolescents with insulin-dependent diabetes of age between 1.3 and 22 years. The duration of diabetes in the studied group ranged between 0.25 and 15 years. The patients studied were further divided into subgroups taking into account the duration of diabetes as well as the occurrence of complications of diabetes, obesity and predisposition to early development of atherosclerosis in family history. The analysis of the results took into account the relations between the levels of LP A-I and other parameters of lipid metabolism like cholesterol, triglycerides, HDL-cholesterol, apo A-I and apo A-II concentrations as well as the effectiveness of metabolic control of diabetes. LP A-I concentration was the lowest in group of children with diabetes lasting up to one year. This parameter was correlated positively with the levels of HDL-cholesterol and apo A-I, and negatively with HbA1c. It was not related to the coexisting complications, obesity or predisposition to atherosclerosis in family history. The above results indicate that the state of metabolic control of diabetes significantly influences the level of LP A-I. Considering the importance of LP A-I in preventing atherosclerosis it should be stressed that a decrease in its level during the period of prolonged hypoglycemia constitutes still another risk factor for development of atherosclerosis in diabetic children and adolescents.