Treatment of type 2 diabetes mellitus by drugs modulating the incretin system

Diabetes, specifically type 2 diabetes mellitus (T2DM), one of the most common non-communicable diseases,poses a major health problem throughout the world.T2DM is characterized by insulin resistance, impaired glucose-induced insulin secretion and inappropriately regulated glucagon secretion which in combination eventually result in hyperglycemia and in the longer term microvascular and macrovascular complications of diabetes.Traditional treatment modalities, even multidrug approaches, for T2DM are often inadequate in getting patients to achieve glycemic goals as the disease progresses  due to a steady, relentless decline in pancreatic β-cell /number/function. Furthermore, current treatment modalities are often limited by inconvenient dosing regimens, safety and tolerability issues, the latter including hypoglycemia, body weight gain, edema and gastrointestinal side effects. A novel category of antihyperglycemic therapy based on modulation of the endogenous incretin system has recently evolved. The incretins, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), are gut-derived peptides secreted in response to meals, specifically the presence and absorption of nutrients in the intestinal lumen. The incretins potentiate meal-induced insulin secretion and trophic effects on the β-cell; the GLP-1 also inhibits glucagon secretion, and suppresses food intake and appetite.The activity/level of the incretins is diminished in T2DM. Both GLP-1 and GIP are rapidly degraded by the endogenous dipeptidyl-peptidase-4 (DPP-4). Hence, stable long-acting GLP-1 analogs/GLP-1 receptor agonists (incretin mimetics) have been developed. Since, the incretin mimetics have to be injected, orally active inhibitors of DPP-4, the incretin enhancers, have also been introduced for the treatment of T2DM. The GLP-1 receptor agonists and DPP-4 inhibitors are useful in the management of T2DM because they provide effective reductions in levels of fasting plasma glucose (FPG) and postprandial glucose (PPG), partly through their actions on pathogenic causes of T2DM that are not addressed by other glucoselowering agents. In addition, the GLP-1 receptor agonists promote weight loss, whereas the DPP-4 inhibitors are mostly weight neutral, and there is a low risk of symptomatichypoglycemia with both type of agents. The GLP- 1 receptor agonists and DPP-4 inhibitors are effective as monotherapy in drug-naive patients as well as in those in whom other treatments (for example with metformin, sulfonylureas, thiazolinediones, etc.) have been inadequate to achieve glycemic control. When combined with other glucose-lowering agents, the GLP-1 receptor agonists and DPP-4 inhibitors further lower FPG and PPG levels,and hemoglobin A1c. Consequently, these agents can be used for all stages of T2DM. However, the durability and long-term safety of these drugs remains to be determined.This review focuses on the therapeutic potential of the incretin mimetics and incretin enhancers in treating T2DM.In addition, the review also presents some information on the mechanism of action(s), efficacy, pharmacokinetics, pleiotropic effects, drug interactions and adverse effects of the main drugs which modulate levels and activity ofendogenous incretins

Toxoplasmosis--a global threat. Correlation of latent toxoplasmosis with specific disease burden in a set of 88 countries.

BACKGROUND: Toxoplasmosis is becoming a global health hazard as it infects 30-50% of the world human population. Clinically, the life-long presence of the parasite in tissues of a majority of infected individuals is usually considered asymptomatic. However, a number of studies show that this 'asymptomatic infection' may also lead to development of other human pathologies. AIMS OF THE STUDY: The purpose of the study was to collect available geoepidemiological data on seroprevalence of toxoplasmosis and search for its relationship with mortality and disability rates in different countries. METHODS AND FINDINGS: Prevalence data published between 1995-2008 for women in child-bearing age were collected for 88 countries (29 European). The association between prevalence of toxoplasmosis and specific disease burden estimated with age-standardized Disability Adjusted Life Year (DALY) or with mortality, was calculated using General Linear Method with Gross Domestic Product per capita (GDP), geolatitude and humidity as covariates, and also using nonparametric partial Kendall correlation test with GDP as a covariate. The prevalence of toxoplasmosis correlated with specific disease burden in particular countries explaining 23% of variability in disease burden in Europe. The analyses revealed that for example, DALY of 23 of 128 analyzed diseases and disease categories on the WHO list showed correlations (18 positive, 5 negative) with prevalence of toxoplasmosis and another 12 diseases showed positive trends (p<0.1). For several obtained significant correlations between the seroprevalence of toxoplasmosis and specific diseases/clinical entities, possible pathophysiological, biochemical and molecular explanations are presented. CONCLUSIONS: The seroprevalence of toxoplasmosis correlated with various disease burden. Statistical associations does not necessarily mean causality. The precautionary principle suggests however that possible role of toxoplasmosis as a triggering factor responsible for development of several clinical entities deserves much more attention and financial support both in everyday medical practice and future clinical research

Prevalence of latent toxoplasmosis in women of childbearing age in various countries.

<p>The second and third column show prevalence of toxoplasmosis and prevalence adjusted to a standard age of 22 years to account for variation in childbearing age in across countries (column 1) using the formula Prevalence_adj = 1−(1−Prevalence)∧(22/childbearing age) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090203#pone.0090203-Lafferty1" target="_blank">[9]</a>. Column 5 shows year(s) when the study was performed and column 6 shows number of women in the sample. For Macedonia, the 2004 WHO data were not available therefore this 30^th European country was not included in our data set.</p

Correlation of prevalence of toxoplasmosis with various disease-attributed DALY for 88 WHO-member countries.

<p>The x-axes show prevalence of toxoplasmosis (%) in women of childbearing age and y-axes the number years of ‘healthy’ life lost by virtue of being in a state of poor health or disability due to particular disease per 100,000 inhabitants in 2004.</p

Correlation of mortality and Disability Adjusted Life Year (DALY) with prevalence of toxoplasmosis for all 88 WHO member countries (29 European and 59 non-European countries).

<p>The correlations were estimated with General Linear Model with GDP per capita, latitude humidity, as covariates. Positive B (red) correspond to positive, and negative B (blue) to negative correlations. Significant results (p<0.05) are labeled with yellow and trends (p<0.10) with green colors.</p

Diseases and clinical entities associated with <i>T. gondii</i> infection.

<p>Diseases and clinical entities associated with <i>T. gondii</i> infection.</p