The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror.

Type 2 Diabetes Mellitus (T2DM) is one of the most prevalent chronic metabolic disorders, and insulin has been placed at the epicentre of its pathophysiological basis. However, the involvement of impaired alpha (α) cell function has been recognized as playing an essential role in several diseases, since hyperglucagonemia has been evidenced in both Type 1 and T2DM. This phenomenon has been attributed to intra-islet defects, like modifications in pancreatic α cell mass or dysfunction in glucagon's secretion. Emerging evidence has shown that chronic hyperglycaemia provokes changes in the Langerhans' islets cytoarchitecture, including α cell hyperplasia, pancreatic beta (ß) cell dedifferentiation into glucagon-positive producing cells, and loss of paracrine and endocrine regulation due to ß cell mass loss. Other abnormalities like α cell insulin resistance, sensor machinery dysfunction, or paradoxical ATP-sensitive potassium channels (KATP) opening have also been linked to glucagon hypersecretion. Recent clinical trials in phases 1 or 2 have shown new molecules with glucagon-antagonist properties with considerable effectiveness and acceptable safety profiles. Glucagon-like peptide-1 (GLP-1) agonists and Dipeptidyl Peptidase-4 inhibitors (DPP-4 inhibitors) have been shown to decrease glucagon secretion in T2DM, and their possible therapeutic role in T1DM means they are attractive as an insulin-adjuvant therapy.

Age-specific waist circumference cutoff-points for abdominal obesity diagnosis: a personalized strategy for a large Venezuelan population.

BACKGROUND: Evidence shows that the ageing process is a determining factor in fat distribution, composition, and functionality. The goal of this research was to determine cut-off points for waist circumference according to age in the adult population from Maracaibo city, Venezuela. METHODOLOGY: The Metabolic Syndrome Prevalence Study is a descriptive, cross-sectional study with multi-stage randomized sampling. In this post-hoc analysis 1902 individuals ≥18 years and from both sexes were evaluated. Waist circumference ROC curves were built for each age group and sex, using metabolic phenotypes for classification. RESULTS: 52.2% (n = 992) were women, and the mean age was 38.7 ± 2. Cut-off points obtained for the <30 years age group were: 91 cm for women (Sensitivity: 96,8%, Specificity: 97,7%) and 94 cm for men (Sensitivity:100%, Specificity: 99,2%); for 30-49 years: women 94 cm (Sensitivity: 93.7%, Specificity: 97.1%) and men 95 cm (Sensitivity: 97.3%, Specificity: 100%); for ≥50 years: women 94 cm (Sensitivity: 91.8%, Specificity: 86.7%) and men 101 cm (Sensitivity: 100%, Specificity: 100%). CONCLUSION: The use of specific cut-off points according to age groups is proposed to determine abdominal obesity in Maracaibo city due to the underestimation seen in young people and the overestimation observed in older people when using a unique cut-off point.

Insulin resistance indices and coronary risk in adults from Maracaibo city, Venezuela: A cross sectional study.

Background: Insulin resistance (IR) is a metabolic disorder related to atherosclerosis. Its measurement is of great importance not only as a marker of diabetes but also for cardiovascular disease. The aim of this research study was to evaluate the relationship between various IR indices and coronary risk in an adult population from Maracaibo city, Venezuela. Methods: The Maracaibo City Metabolic Syndrome Prevalence Study is a descriptive, cross-sectional study with random and multi-stage sampling. In this sub study, 1272 individuals of both genders were selected with the measurement of basal insulin and coronary risk according to the Framingham-Wilson formula calibrated for our population. The insulin resistance indices evaluated were HOMA2-IR, triglycerides and glucose index (TyG) and triglycerides/HDL ratio (TG/HDL). The predictive capacity and association between each index and the coronary risk event in 10 years were determined. Results: Of the evaluated population, 55.2% were female, 34.8% had a coronary risk ≥5% in 10 years, with the TG/HDL and TyG indices showing the highest AUC 0.712 (0.681-0.743) and 0.707 (0.675-0.739), respectively; compared to HOMA2-IR. Both were also the indices most associated with increased coronary risk, especially TG/HDL ≥3 with a higher association [OR = 2.83 (1.74-4.61); p<0.01] after multivariable adjustment. Conclusions: TyG (≥4.5) and TG/HDL (≥3) indices showed a great predictive capacity of higher coronary risk, with being TG/HDL more associated even after adjusting for abdominal obesity and hs-CRP. Therefore, these represent useful tools for determining IR.

Pancreatic Beta Cell Death: Novel Potential Mechanisms in Diabetes Therapy.

PURPOSE OF REVIEW: Describing the diverse molecular mechanisms (particularly immunological) involved in the death of the pancreatic beta cell in type 1 and type 2 diabetes mellitus. RECENT FINDINGS: Beta cell death is the final event in a series of mechanisms that, up to date, have not been entirely clarified; it represents the pathophysiological mechanism in the natural history of diabetes mellitus. These mechanisms are not limited to an apoptotic process only, which is characteristic of the immune-mediated insulitis in type 1 diabetes mellitus. They also include the action of proinflammatory cytokines, the production of reactive oxygen species, DNA fragmentation (typical of necroptosis in type 1 diabetic patients), excessive production of islet amyloid polypeptide with the consequent endoplasmic reticulum stress, disruption in autophagy mechanisms, and protein complex formation, such as the inflammasome, capable of increasing oxidative stress produced by mitochondrial damage. SUMMARY: Necroptosis, autophagy, and pyroptosis are molecular mechanisms that modulate the survival of the pancreatic beta cell, demonstrating the importance of the immune system in glucolipotoxicity processes and the potential role for immunometabolism as another component of what once known as the "ominous octet."

Biochemical and clinical characterization of metabolic phenotypes: a cross-sectional study from Maracaibo city, Venezuela.

Background: In 1980, Reuben Andresen observed that in certain individuals, obesity did not increase mortality, introducing an atypical phenotype called "healthy obese". Other studies reported that 10-15 % of lean individuals presented insulin resistance, hyperglycemia and dyslipidemia. The objective of this study was to evaluate biochemical and clinical characteristics of metabolic phenotypes in Maracaibo city. Methods: A descriptive, cross-sectional study with a randomized multistage sampling was performed including 1226 non diabetic individuals from both sexes. For phenotype definition, the subjects were first classified according to their BMI into Normal-Weight, Overweight and Obese; then divided in metabolically healthy and unhealthy using a two-step analysis cluster. To evaluate the relationship with coronary risk, a multiple logistic regression model was performed. Results: In the studied population, 5.2% (n=64) corresponded to unhealthy lean subjects, and 17.4% (n=217) to healthy obese subjects. Metabolically unhealthy normal-weight (MUNW) phenotype was found in males in 53.3% in contrast to 51.3% of metabolically unhealthy obese (MUO) phenotype found in females. An association between metabolically unhealthy phenotypes and a higher risk of a coronary event was found, especially for obese individuals (MHO: OR=1.85 CI95%: 1.11-3.09; p=0.02 and MUO: OR=2.09 CI95%: 1.34-3.28; p<0.01). Conclusion: Individuals with atypical metabolic phenotypes exist in Maracaibo city. Related factors may include insulin resistance, basal glucose levels, and triglycerides levels. Lastly, cardiovascular risk exhibited by healthy obese individuals should be classified in categories of major coronary risk related to lean subjects.

Cigarette smoking and metabolic syndrome components: a cross-sectional study from Maracaibo City, Venezuela.

Background: A growing body of evidence suggests that cigarette smoking can cause the onset of metabolic syndrome prior to cardiovascular diseases. Therefore, the objective of this study was to evaluate the relationship between smoking habit and metabolic syndrome components in an adult population from Maracaibo city, Venezuela. Methods: The Maracaibo City Metabolic Syndrome Prevalence Study is a descriptive, cross-sectional study with random and multi-stage sampling. In this sub-study, 2212 adults from both genders were selected. On the basis of their medical background, they were classified as smokers, non-smokers and former smokers. Metabolic syndrome was defined according to Harmonizing 2009 criteria, using population-specific abdominal circumference cut-off points. The association between risk factors was evaluated using a logistic regression model. Results: In the studied population, 14.8% were smokers, 15.4% were former smokers. In the multivariate analysis, the presence of metabolic syndrome (smokers: OR, 1.54; 95% CI, 1.11-2.14; p=0.010) and its components were related to cigarette smoking, with the exception of hyperglycemia. High blood pressure was inversely associated with current smoking status (smokers: OR, 0.70 (0.51-0.95); p=0.025). Conclusion: Cigarette smoking represents a related factor with metabolic syndrome, being associated with low high-density lipoprotein-cholesterol, increased abdominal circumference and elevated triacylglyceride levels. Former smokers did not present a greater risk for developing this metabolic disease when compared to non-smokers. The effect of avoiding this habit should be evaluated in future studies in our population.

Optimal cutoff for the evaluation of insulin resistance through triglyceride-glucose index: A cross-sectional study in a Venezuelan population.

Background: Insulin resistance (IR) evaluation is a fundamental goal in clinical and epidemiological research. However, the most widely used methods are difficult to apply to populations with low incomes. The triglyceride-glucose index (TGI) emerges as an alternative to use in daily clinical practice. Therefore the objective of this study was to determine an optimal cutoff point for the TGI in an adult population from Maracaibo, Venezuela. Methods: This is a sub-study of Maracaibo City Metabolic Syndrome Prevalence Study, a descriptive, cross-sectional study with random and multi-stage sampling. For this analysis, 2004 individuals of both genders ≥18 years old with basal insulin determination and triglycerides < 500 mg/dl were evaluated.. A reference population was selected according to clinical and metabolic criteria to plot ROC Curves specific for gender and age groups to determine the optimal cutoff point according to sensitivity and specificity.The TGI was calculated according to the equation: ln [Fasting triglyceride (mg / dl) x Fasting glucose (mg / dl)] / 2. Results: The TGI in the general population was 4.6±0.3 (male: 4.66±0.34 vs. female: 4.56±0.33, p=8.93x10 -10). The optimal cutoff point was 4.49, with a sensitivity of 82.6% and specificity of 82.1% (AUC=0.889, 95% CI: 0.854-0.924). There were no significant differences in the predictive capacity of the index when evaluated according to gender and age groups. Those individuals with TGI≥4.5 had higher HOMA2-IR averages than those with TGI <4.5 (2.48 vs 1.74, respectively, p<0.001). Conclusions: The TGI is a measure of interest to identify IR in the general population. We propose a single cutoff point of 4.5 to classify individuals with IR. Future studies should evaluate the predictive capacity of this index to determine atypical metabolic phenotypes, type 2 diabetes mellitus and even cardiovascular risk in our population.

Prevalence and Associated Factors of Insulin Resistance in Adults from Maracaibo City, Venezuela.

Background and Aim. Insulin resistance (IR) is a prominent pathophysiologic component in a myriad of metabolic disorders, including obesity, prediabetes, and type 2 diabetes mellitus, which are common in our locality. The objective of this study was to determine the prevalence of IR and factors associated with this condition in an adult population from Maracaibo city, Venezuela. Methodology. A cross-sectional, descriptive study with multistaged randomized sampling was carried out in 2026 adults. IR was defined as HOMA2-IR ≥ 2. A multiple logistic regression model was constructed in order to evaluate factors associated with IR. Results. The prevalence of IR was 46.5% (n = 943), with 46.7% (n = 450) in the general population, 46.4% (n = 493) in females, and 47.90% (n = 970) in males (p = 0.895). IR prevalence tended to increase with age and was significantly greater in subjects aged ≥30 years (χ (2) = 16.726; p = 2.33 × 10(-4)). Employment, alcohol consumption, obesity, high triacylglycerides, low HDL-C, and dysglycemia were associated with greater odds of IR, whereas a high level of physical activity appeared to be weak protective factor against IR. Conclusions. The prevalence of IR is elevated in our locality. The main determinants of this condition appear to be the presence of obesity, high triacylglycerides, low HDL-C, dysglycemia, and alcohol intake.

Dysfunctional High-Density Lipoprotein: An Innovative Target for Proteomics and Lipidomics.

High-Density Lipoprotein-Cholesterol (HDL-C) is regarded as an important protective factor against cardiovascular disease, with abundant evidence of an inverse relationship between its serum levels and risk of cardiovascular disease, as well as various antiatherogenic, antioxidant, and anti-inflammatory properties. Nevertheless, observations of hereditary syndromes featuring scant HDL-C concentration in absence of premature atherosclerotic disease suggest HDL-C levels may not be the best predictor of cardiovascular disease. Indeed, the beneficial effects of HDL may not depend solely on their concentration, but also on their quality. Distinct subfractions of this lipoprotein appear to be constituted by specific protein-lipid conglomerates necessary for different physiologic and pathophysiologic functions. However, in a chronic inflammatory microenvironment, diverse components of the HDL proteome and lipid core suffer alterations, which propel a shift towards a dysfunctional state, where HDL-C becomes proatherogenic, prooxidant, and proinflammatory. This heterogeneity highlights the need for further specialized molecular studies in this aspect, in order to achieve a better understanding of this dysfunctional state; with an emphasis on the potential role for proteomics and lipidomics as valuable methods in the search of novel therapeutic approaches for cardiovascular disease.

Physiologic Course of Female Reproductive Function: A Molecular Look into the Prologue of Life.

The genetic, endocrine, and metabolic mechanisms underlying female reproduction are numerous and sophisticated, displaying complex functional evolution throughout a woman's lifetime. This vital course may be systematized in three subsequent stages: prenatal development of ovaries and germ cells up until in utero arrest of follicular growth and the ensuing interim suspension of gonadal function; onset of reproductive maturity through puberty, with reinitiation of both gonadal and adrenal activity; and adult functionality of the ovarian cycle which permits ovulation, a key event in female fertility, and dictates concurrent modifications in the endometrium and other ovarian hormone-sensitive tissues. Indeed, the ultimate goal of this physiologic progression is to achieve ovulation and offer an adequate environment for the installation of gestation, the consummation of female fertility. Strict regulation of these processes is important, as disruptions at any point in this evolution may equate a myriad of endocrine-metabolic disturbances for women and adverse consequences on offspring both during pregnancy and postpartum. This review offers a summary of pivotal aspects concerning the physiologic course of female reproductive function.

Relationship between Alcohol Consumption and Components of the Metabolic Syndrome in Adult Population from Maracaibo City, Venezuela.

Introduction. Although the relationships between alcohol and disorders such as cancer and liver disease have been thoroughly researched, its effects on cardiometabolic health remain controversial. Therefore, the objective of this study was to assess the association between alcohol consumption, the Metabolic Syndrome (MS), and its components in our locality. Materials and Methods. Descriptive, cross-sectional study with randomized, multistaged sampling, which included 2,230 subjects of both genders. Two previously determined population-specific alcohol consumption pattern classifications were utilized in each gender: daily intake quartiles and conglomerates yielded by cluster analysis. MS was defined according to the 2009 consensus criteria. Association was evaluated through various multiple logistic regression models. Results. In univariate analysis (daily intake quartiles), only hypertriacylglyceridemia was associated with alcohol consumption in both genders. In multivariate analysis, daily alcohol intake ≤3.8 g/day was associated with lower risk of hypertriacylglyceridemia in females (OR = 0.29, CI 95%: 0.09-0.86; p = 0.03). Among men, subjects consuming 28.41-47.33 g/day had significantly increased risk of MS, hyperglycemia, high blood pressure, hypertriacylglyceridemia, and elevated waist circumference. Conclusions. The relationship between drinking, MS, and its components is complex and not directly proportional. Categorization by daily alcohol intake quartiles appears to be the most efficient method for quantitative assessment of alcohol consumption in our region.