Inhibition of dipeptidyl peptidase-4: The mechanisms of action and clinical use of vildagliptin for the management of type 2 diabetes

Postprandial hyperglycemia in type 2 diabetes is characterized by impaired insulin secretion and action, decreased glucose effectiveness and defective suppression of glucagon secretion. Newly available therapies for type 2 diabetes target the pathway of the incretin hormone glucagon-like peptide-1 (GLP-1). Oral inhibitors of dipeptidyl peptidase-4 (DPP-4) raise the level of endogenous GLP-1 by inhibiting its clearance thereby lowering fasting and postprandial glucose concentrations. Unlike compounds which act as agonists of the GLP-1 receptor, DPP-4 inhibitors are not associated with significant effects on gastrointestinal motility, which led to a controversy around the mechanisms responsible for their glucose-lowering effects. Here we review the evidence in regards to the mechanisms whereby DPP-4 inhibitors lower glucose concentrations. Their effects are most likely mediated by an increase in endogenous GLP-1, although additional mechanisms may be involved. The pharmacology, efficacy and safety of vildagliptin, a novel DPP-4 inhibitor, are also discussed

Qualification and investigation of crimes motivated by jealousy, hatred, and enmity

The article is devoted to a comprehensive study of the criminal law, criminological and criminalistic aspects of combating crimes motivated by hatred, jealousy, or enmity. The background of the study is high statistical indicators that reflect the wide prevalence of the considered motives for committing crimes. At the same time, the article, for the first time, conducts a comprehensive study that examines these crimes and countering them from various sides. The objective of the study is to analyze the current state and develop current recommendations for considering factors of jealousy, hatred, or enmity in the qualification of acts, the development of criminological and criminalistic measures to counteract these crimes, as well as criminalistic programs and algorithms for the investigation of a group of crimes committed on the grounds of hatred, jealousy, or enmity. The methodology is based on the universal dialectical cognitive method. Besides, the authors used specific scientific methods: comparative-legal, hermeneutical, and logical methods, which ensure compliance with the general principles of scientific knowledge. The study is based on a systematic approach. The research novelty is due to the authors’ non-trivial approach, which combines the achievements of criminal law, criminology, and criminalistics and develops a single set of issues based on this symbiosis of knowledge. As a conclusion, it is noted that the specifics of the qualification of crimes motivated by jealousy, hatred, and enmity depend not only on the internal emotional state of the person committing them but also on the external conditions in which the subjective attitude of the perpetrator towards the committed act is formed. It is necessary to develop recommendations for practitioners containing rules for the qualification of crimes in the competition of criminal law norms, in which to provide answers to questions related to typical errors in the qualification of crimes and to offer an interpretation of the evaluation categories, the application of which causes the most significant difficulty in practice. The paper presents the algorithms of the two main investigation programs developed based on the selected investigative situations

Qualification and investigation of crimes motivated by jealousy, hatred, and enmity

The article is devoted to a comprehensive study of the criminal law, criminological and criminalistic aspects of combating crimes motivated by hatred, jealousy, or enmity. The background of the study is high statistical indicators that reflect the wide prevalence of the considered motives for committing crimes. At the same time, the article, for the first time, conducts a comprehensive study that examines these crimes and countering them from various sides. The objective of the study is to analyze the current state and develop current recommendations for considering factors of jealousy, hatred, or enmity in the qualification of acts, the development of criminological and criminalistic measures to counteract these crimes, as well as criminalistic programs and algorithms for the investigation of a group of crimes committed on the grounds of hatred, jealousy, or enmity. The methodology is based on the universal dialectical cognitive method. Besides, the authors used specific scientific methods: comparative-legal, hermeneutical, and logical methods, which ensure compliance with the general principles of scientific knowledge. The study is based on a systematic approach. The research novelty is due to the authors’ non-trivial approach, which combines the achievements of criminal law, criminology, and criminalistics and develops a single set of issues based on this symbiosis of knowledge. As a conclusion, it is noted that the specifics of the qualification of crimes motivated by jealousy, hatred, and enmity depend not only on the internal emotional state of the person committing them but also on the external conditions in which the subjective attitude of the perpetrator towards the committed act is formed. It is necessary to develop recommendations for practitioners containing rules for the qualification of crimes in the competition of criminal law norms, in which to provide answers to questions related to typical errors in the qualification of crimes and to offer an interpretation of the evaluation categories, the application of which causes the most significant difficulty in practice. The paper presents the algorithms of the two main investigation programs developed based on the selected investigative situations

Defects in GLP-1 response to an oral challenge do not play a significant role in the pathogenesis of prediabetes.

CONTEXT: There has been much speculation as to whether defects in glucagon-like peptide-1 (GLP-1) secretion play a role in the pathogenesis of type 2 diabetes and the progression from normal glucose tolerance to prediabetes and diabetes. OBJECTIVE: Our objective was to determine whether fasting and postchallenge concentrations of active and total GLP-1 decrease as glucose tolerance and insulin secretion worsen across the spectrum of prediabetes. DESIGN: This was a cross-sectional study. SETTING: The study was performed in the clinical research unit of an academic medical center. PARTICIPANTS: Participants included 165 subjects with a fasting glucose below 7.0 mmol/liter and not taking medications known to affect gastrointestinal motility or glucose metabolism. INTERVENTION: Intervention included a 2-h, 75-g oral glucose tolerance test with insulin, C-peptide, glucagon, and GLP-1 measurements at seven time points. MAIN OUTCOME MEASURE: We evaluated the association of integrated, incremental active, and total GLP-1 concentrations with integrated, incremental glucose response to 75 g oral glucose. RESULTS: After accounting for covariates, there was no evidence of a relationship of incremental glucose concentrations after oral glucose tolerance test with active and total GLP-1 (r(s) = -0.16 and P = 0.14, and r(s) = 0.00 and P > 0.9, respectively). There also was no association of GLP-1 concentrations with insulin secretion and action. CONCLUSIONS: The lack of association of GLP-1 concentrations with glucose tolerance status and with insulin secretion and action in a cohort encompassing the full spectrum of prediabetes strongly argues against a significant contribution of defects in GLP-1 secretion to the pathogenesis of prediabetes