Obesity is a life-long progressive, life threatening condition marked by the excess accumulation of body fat, which can significantly reduce life expectancy.
When weight reaches extreme levels, it is called MORBID OBESITY and is a chronic condition with numerous medical, psychological and social consequences.
Obesity increases the likelihood of various diseases, particularly Hypertension, Heart Disease, Type II Diabetes, Obstructive Sleep Apnea, Certain Types of Cancer, and Osteoarthritis. Moreover, the consumption of empty-calorie foods like alcohol, aerated drinks, candies etc. Obesity is not just a physiological problem, but a physiological, psychological and social problem. Cardiovascular disease (CVD) includes coronary heart disease (CHD), stroke and peripheral vascular disease. Obese individuals are more likely to have higher blood triglycerides (blood fats) and low -density lipoprotein (LDL) cholesterol (bad cholesterol) and lower high-density lipoprotein (HDL) cholesterol (good cholesterol). The risk of hypertension in overweight adults is nearly three times higher than in non-overweight adults. Several studies found association between obesity and the incidence of certain cancers, particularly of hormone-dependent and gastrointestinal cancers. Obesity associated with male and female hormones,disrupting normal cycles and function, and leading to inability, or difficulty to conceive, or even a miscarriage. Increased intra-abdominal pressure stresses the muscles of the pelvic floor compounding the effects of childbirth, which can lead to improper function of the bladder. Morbidly obese individuals often experience menstrual disruptions, such as heavy frequent, irregular or absent periods and increased pain during the cycle.
Obesity can lead to faulty valves in the veins that promote sluggish flow in vessels causing a clot in the lower limbs. Science, Technology and Medicine open access publisher.Publish, read and share novel research. Beta-Cell Function and Failure in Type 2 DiabetesSimona Popa1 and Maria Mota1[1] Department of Diabetes, Nutrition and Metabolic Diseases; University of Medicine and Pharmacy, Craiova, Romania1. Morbid obesity drastically increases your chances of developing obesity related co-morbidities. Obesity is most commonly caused by a combination of excessive food energy intake, lack of physical activity, and genetic susceptibility, although a few cases are caused primarily by genes, endocrine disorders, medications. On the physical front, obesity can lead to several complications that could be fatal or incapacitating if left untreated. Obese women have been proved to be at greater risk of breast, endometrial, ovarian and cervical cancers. Sleep apnea is one of the leading causes of excessive daytime sleepiness, drowsiness, fatigue and headaches. Increased intrabdominal pressure weakens and overloads the valve at the top of the stomach, which then allows stomach acid to escape and irritate the esophagus.
This results in leakage of urine when coughing, sneezing or laughing or inability to hold the urine until the patient can reach a toilet.
Surgical Treatment is the only proven approach to the treatment of Morbid Obesity adjuvant to lifestyle modifications.
Perspective: emerging evidence for signaling roles of mitochondrial anaplerotic products in insulin secretion.
Glucokinase as glucose sensor and metabolic signal generator in pancreatic betacells and hepatocytes. Evidence that glucose can control insulin release independently from its action on ATP-sensitive K+ channels in mouse B cells. Beta-cell deterioration determines the onset and rate of progression of secondary dietary failure in type 2 diabetes mellitus: the 10-year followup of the Belfast Diet Study. An overview of pancreatic beta-cell defects in human type 2 diabetes: Implications for treatment.
Kir6.2 variant E23K increases ATP-sensitive K+ channel activity and is associated with impaired insulin release and enhanced insulin sensitivity in adults with normal glucose tolerance.
A candidate type 2 diabetes polymorphism near the HHEX locus affects acute glucose-stimulated insulin release in European populations: results from the EUGENE2 study.
The common SLC30A8 Arg325Trp variant is associated with reduced first-phase insulin release in 846 non-diabetic offspring of type 2 diabetes patients – the EUGENE2 study. Single-nucleotide polymorphism rs7754840 of CDKAL1 is associated with impaired insulin secretion in nondiabetic offspring of type 2 diabetic subjects and in a large sample of men with normal glucose tolerance.
Variants of CDKAL1 and IGF2BP2 affect first-phase insulin secretion during hyperglycaemic clamps. Quantitative trait analysis of type 2 diabetes susceptibility loci identified from whole genome association studies in the Insulin Resistance Atherosclerosis Family Study.
Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion.
Association of 18 confirmed susceptibility loci for type 2 diabetes with indices of insulin release, proinsulin conversion, and insulin sensitivity in 5,327 nondiabetic Finnishmen. Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIPand GLP-1 receptors and impaired beta- cell function. Impact of polymorphisms in WFS1 on prediabetic phenotypes in a population-based sample of middle-aged people with normal and abnormal glucose regulation. Association of type 2 diabetes candidate polymorphisms in KCNQ1 with incretin and insulin secretion.
A variant in the KCNQ1 gene predicts future type 2 diabetes and mediates impaired insulin secretion.
Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion.
TCF7L2 polymorphisms modulate proinsulin levels and beta-cell function in a British Europid population.
TCF7L2 controls insulin gene expression and insulin secretion in mature pancreatic beta-cells.
TCF-4 mediates cell type-specific regulation of proglucagon gene expression by beta-catenin and glycogen synthase kinase-3beta.
Hex homeobox gene-dependent tissue positioning is required for organogenesis of the ventral pancreas.
In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion.
Increased glucose sensitivity of both triggering and amplifying pathways of insulin secretion in rat islets cultured for 1 wk in high glucose.
Role of ATP production and uncoupling protein-2 in the insulin secretory defect induced by chronic exposure to high glucose or free fatty acids and effects of peroxisome proliferator-activated receptor-gamma inhibition.
Role of beta-cell dysfunction, ectopic fat accumulation and insulin resistance in the pathogenesis of type 2 diabetes mellitus. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol.
Palmitate activates AMPactivated protein kinase and regulates insulin secretion from beta cells.
Chronic activation of liver X receptor induces beta-cell apoptosis through hyperactivation of lipogenesis: liver X receptor-mediated lipotoxicity in pancreatic beta-cells.
Inhibition of PKCepsilon improves glucose-stimulated insulin secretion and reduces insulin clearance.
Palmitate inhibits insulin gene expression by altering PDX-1 nuclear localization and reducing MafA expression in isolated rat islets of Langerhans.
Palmitate inhibition of insulin gene expression is mediated at the transcriptional level via ceramide synthesis. Evidence against the involvement of oxidative stress in fatty acid inhibition of insulin secretion. Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates. Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated.
Monounsaturated fatty acids prevent the deleterious effects of palmitate and high glucose on human pancreatic beta-cell turnover and function. Free fatty acid-induced beta-cell defects are dependent on uncoupling protein 2 expression. All of this, coupled with a sedentary lifestyle, makes the ideal combination for susceptibility to obesity and diabetes. As a result, insulin resistance people blood sugar does not get into cells to be stored for energy and the blood sugar levels inevitably increase.
Fat deposits in the tongue and neck which can block the airway causing a person to temporarily stop breathing during their sleep, especially when sleeping on their back.Obesity is a leading cause of sleep apnea. Approximately 10-15% of patients with even mild heartburn can develop Barrett's esophagus, which is a pre-malignant change that can progress into esophageal cancer. Normal beta-cell functionThe main role of beta-cell is to synthesize and secrete insulin in order to maintain circulating glucose levels within physiological range. Sites of pretranslational regulation by glucose of glucose-induced insulin release in pancreatic islets.
People who are overweight are more likely to have insulin resistance, because fat interferes with the body's ability to use insulin.
The Asociación Latinoamericana de Diabetes (Latin American Diabetes Association, ALAD) brought together medical associations in 17 countries in Latin America to produce a consensus statement regarding the treatment of type 2 diabetes. Although there exist several triggers of insulin secretion like nutrients (amino acids such as leucine, glutamine in combination with leucine, nonesterified fatty acid), hormones, neurotransmitters and drugs (sulfonylurea, glinides), glucose represents the main physiological insulin secretagogue [1].According to the most widely accepted hypothesis, insulin secretion is a multistep process initiated with glucose transport into beta-cell through specific transporters (GLUT1 and GLUT2 in particular) and phosphorylation by glucokinase, which directs metabolic flux through glycolysis, producing pyruvate as the terminal product of the pathway [2]. The goal of the document is to provide practical recommendations that will guide clinicians through a simple decision-making process for managing patients. Pyruvate then enters the mitochondria and is decarboxylated to acetyl-CoA, which enters the tricarboxylic acid cycle.
Low activity level, poor diet, and excess body weight (especially around the waist) significantly increase your risk for type 2 diabetes. The cornerstone elements for therapeutic decision making are: severity of hyperglycemia, clinical condition of the patient (stable or with metabolic decompensation), and body mass index. The tricarboxylic acid cycle proper begins with a condensation of acetyl-CoA and oxaloacetate, to form citrate, a reaction catalysed by citrate synthase.
NAD-linked isocitrate dehydrogenase then oxidatively decarboxylates isocitrate to form ?-ketoglutarate.
The algorithm is based on the scientific recommendations of the 2006 ALAD guidelines (a document prepared using an evidence-based approach) and data from recent randomized controlled studies. The ?-ketoglutarate is oxidised to succinyl-CoA in a reaction catalysed by ?-ketoglutarate dehydrogenase. Succinyl-CoA synthase then catalyses the conversion of succinyl-CoA to succinate, with the concomitant phosphorylation of GDP to GTP. Fumarase catalyses the conversion of fumarate to malate and after that malate dehydrogenase catalyses the ?nal step of the tricarboxylic acid cycle, oxidising malate to oxaloacetate and producing NADH.Three pathways enable the recycling of the tricarboxylic acid cycle intermediates into and out of mitochondrion, allowing a continuous production of intracellular messengers [3-5]. Malate exits the mitochondria to the cytoplasm where it is subsequently oxidised to pyruvate concomitant with the production of NADPH by cytosolic malic enzyme.
Citrate then exits the mitochondrion to the cytoplasm where it is converted back to oxaloacetate and acetyl-CoA by ATP-citrate lyase.
Oxaloacetate is converted by cytosolic malate dehydrogenase to malate before being converted to pyruvate by malic enzyme. The NADPH oxidase complex in the plasma membrane is also activated through protein kinase C, which is activated by fatty acid derived signalling molecules. Diabetes and other chronic, non-transmissible diseases are now the leading health problems.
These events result in an enhanced ratio of ATP to ADP in the cytoplasm, which determines the closure of the ATP-sensitive K+ channels, depolarization of the plasma membrane, influx of extracellular Ca2+ and activation of exocytosis which takes place in several stages including recruitment, docking, priming, and fusion of insulin granules to the beta-cell plasma membrane [1,6,7]. Despite the large and growing number of diabetes cases, this geographic area invests limited financial resources in diabetes care. Two independent studies, using diazoxide for maintaining the ATP-sensitive K+ channels in the open state or mice in which the ATP-sensitive K+ channels were disrupted, indicated that glucose –stimulated insulin secretion can also occur independently of ATP-sensitive K+ channels activity [8].Under physiological conditions, there is a hyperbolic relation between insulin secretion and insulin sensitivity.


Classically, glucose-stimulated insulin secretion is characterized by a first phase, which ends within a few minutes, and prevents or decreases glucose concentration and a more prolonged second phase in which insulin is released proportionally to the plasma glucose [9].In addition, it has been demonstrated that the release of insulin is oscillatory, with relatively stable rapid pulses occurring at every 8-10 minutes which are superimposed on low-frequency oscillations [10]. In the year 2000, the direct cost of diabetes care in Latin America and the Caribbean was approximately US$ 10 billion; minimal when compared to the indirect cost of about US$ 55 billion resulting from disease-related consequences.
Place of beta-cell dysfunction in natural history of type 2 diabetesT2DM is a progressive condition caused by genetic and environmental factors that induce tissue insulin resistance and beta-cell dysfunction. Based on the United Kingdom Prospective Diabetes Study (UKPDS) and on the Belfast Diabetes Study, it is estimated that at diagnosis of T2DM, beta-cell function is already reduced by 50-60% and that this reduction of beta-cell function seems to start with 10-12 years before the appearance of hyperglycemia [11,12]. Several lines of evidence indicated that there is no hyperglycemia without beta-cell dysfunction [13,14]. Most private health insurance plans cover medical assistance, procedures, and hospitalization, but not medication (2-5). In most subjects with obesity-induced insulin resistance developing increased insulin secretion, insulin gene expression and beta-cell mass, these compensatory mechanisms can succeed to maintain glucose homeostasis and avoidance of diabetes mellitus [13-15].
The burden of disease will be even greater in the coming years because the population has a large proportion of young adults living in urban areas and engaged in unhealthy lifestyles. Thus, the impact of diabetes in Latin America is growing fast and the national health systems are unprepared.
In the phase which precedes overt diabetes the decline of beta-cell function is slow but constant (2% per year) [19].
After the development of overt hyperglycemia there appears a significant acceleration (18% per year) in beta-cell failure, and the beta-cell function deteriorates regardless of the therapeutic regimen [11,19,20].
Such restructuring should be based on the best available clinical evidence, but existing international guidelines should be adapted to reflect the differences and needs of each geographic area.
Consequent deterioration in metabolic equilibrium with increasing levels of glucose and free fatty acids, enhance and accelerate beta-cell dysfunction, lead to beta-cell apoptosis that does not seems to be adequately compensated by regenerative process and subsequent decrease of beta-cell mass.4. The unique challenges regarding type 2 diabetes treatment in Latin America are a result of the interactions among the area's socioeconomic factors, its variety of cultures and traditions, and its limited health resources. Potential mechanism and modulators of beta-cell failureThe main focus of the present chapter is on potential beta-cell failure mechanisms in T2DM.The initial alterations in beta-cell function are likely to reflect intrinsic defects, whereas the accelerated beta-cell dysfunction which mainly occurs after the development of overt hyperglycemia is the consequence of glucolipotoxicity [21].
Consensus documents and practice guidelines that are specifically oriented toward the Latin American environment are needed to train and guide primary care physicians. This reflects a genetic predisposition for beta-cell defect, whereas the subsequent beta-cell failure may be a consequence of concomitant environmental conditions. Genetic factorsSeveral genes associated with increased risk of developing T2DM have been identified in genome-wide association studies [22]. In line with its commission, ALAD called upon leaders and representatives from the endocrine and diabetes associations of 17 countries in Latin America to produce a consensus statement for the treatment of type 2 diabetes mellitus. Genetic variation in this gene obviously affects the beta-cell excitability and insulin secretion [23].HHEX encodes a transcription factor necessary for the organogenesis of the ventral pancreas [49] and two SNPs (rs1111875, rs7923837) in HHEX were found to be associated with reduced insulin secretion [24-26].
The participants were divided into three groups; each group discussed and responded to three of the nine questions addressed by the present report. SLC30A8 encodes the protein zinc transporter 8, which provide zinc for maturation, storage and exocytosis of the insulin granules [50]. Variants in this gene show to be associated with reduced glucose-stimulated insulin secretion [25,27] and alterations in proinsulin to insulin conversion [42]. A writing committee prepared the summary, which was approved by all of the endorsing associations' representatives.
The final version of the document was prepared and approved by the members of the writing committee. GlucolipotoxicityGrowing evidence indicated that long-term elevated plasma levels of glucose and fatty acids contribute to beta-cell function decline, a phenomenon known as glucolipotoxicity.
Glucolipotoxicity differs from beta-cell exhaustion, which is a reversible phenomenon characterized by depletion of insulin granules due to prolonged exposure to secretagogues.
The algorithm was based on the scientific recommendations of the 2006 ALAD guidelines-a document prepared using an evidence-based approach (6)-and data from recent randomized controlled studies. Chronic exposure of beta-cells to hyperglycemia can also induce beta-cells apoptosis by increasing proapoptotic genes expression (Bad, Bid, Bik) while antiapoptotic gene expression Bcl-2 remains unaffected [54].There is a strong relationship between glucotoxicity and lipotoxicity. Thus, hyperglycemia increases malonyl-CoA levels, leading to the inhibition of carnitine palmitoyl transferase-1 and subsequently to decreased oxidation of fatty acids and lipotoxicity [52]. Increased fatty acids in the pancreas leads to intrapancreatic accumulation of triglycerides [55]. Lim E et al showed that the intrapancreatic fat is associated with beta-cell dysfunction and that sustained negative energy balance induces restoration of beta-cellular function [56].Elevated levels of glucose and saturated fatty acids in beta cells, stimulates AMP-activated protein kinase, which contributes to increased expression of sterolregulatory-element-binding-protein-1c (SREBP1c), leading to increased lipogenesis [57]. Also included in this algorithm were the possible clinical scenarios diabetes patients may present and the necessary actions to follow in each case.
Additionally, two groups of patients-divided according to the level of glycemic control and clinical condition-are included: Group 1. Activation of the isoform of protein kinase C (PKC?) by free fatty acids which has been suggested as a possible candidate signaling molecule underlying the decrease in insulin secretion [60].Impaired insulin gene exepression by down-regulation of PDX-1 and MafA insulin gene promoter activity [61]. PDX-1 is affected in its ability to translocate to the nucleus, whereas MafA is affected at the level of its expression [61]. Free fatty acid impairs insulin gene expression only in the presence of hyperglycemia [62]. Palmitate affects both insulin gene expression and insulin secretion, unlike oleate which affects only insulin secretion [63]. Endoplasmic reticulum stressThe endoplasmic reticulum is responsible for the protein synthesis, being involved in protein translation, folding and assessing quality before protein secretion. Accumulation of unfolded and misfolded protein in the endoplasmic reticulum lumen may impose endoplasmic reticulum stress [79,80]. Inflammatory cytokines such as IL-1? and IFN-?, can also cause endoplasmic reticulum stress [72].Endoplasmic reticulum stress induced beta-cell activation of an adaptive system named unfolded protein response by which it attenuates protein translation, increases protein folding and promotes misfolded protein degradation [81,82]. These patients constitute a therapeutic challenge; primary care units do not have the resources to manage such cases.
Thus, it prevents additional protein misfolding and further accumulation of unfolded protein; increase the folding capacity of the endoplasmic reticulum to deal with misfolded proteins via the induction of endoplasmic reticulum chaperones.
Without a multidisciplinary approach and adequately informed medical personnel, patients, and relatives, obese patients with diabetes frequently continue gaining weight and do not achieve treatment goals.
Mitochondrial dysfunction and ROS productionBeta cell mitochondria play a key role in the insulin secretion process, not only by providing energy in the form of ATP to support insulin secretion, but also by synthesising metabolites that can act as factors that couple glucose sensing to insulin granule exocytosis [3].Mitochondrial dysfunction and abnormal morphology occur before the onset of hyperglycemia and play an important role in beta-cell failure [89].
The section on obesity emphasizes the importance of helping patients follow a healthy lifestyle before and during the escalation of pharmacological treatment. In diabetic state, the proteins from the mitochondrial inner membrane are decreased, and also may exist transcriptional changes of the mitochondrial proteins [89]. Mitochondrial dysfunction, induced by glucolipotoxicity, plays a pivotal role in beta-cell failure and leads to increased ROS production as a result of metabolic stress. Levels of antioxidant enzymes in beta cells are very low (catalase and glutathione peroxide levels were much lower than those of superoxide dismutase), making beta cells be vulnerable to oxidative stress [92].Low concentrations of ROS contribute to increased glucose-stimulated insulin secretion, but only in the presence of glucose-induced elevations in ATP [93]. All these effects are reversible in time after transient increase ROS.Chronic and significant elevation of ROS, resulted from an imbalance between ROS production and scavenging by endogenous antioxidants, may lead to beta-cell failure [95,96]. Persistent oxidative stress mediates beta-cell failure through several different mechanisms, including:Decreased insulin secretion. In type 2 diabetes, the Kumamoto study (7) and the United Kingdom Prospective Diabetes Study (UKPDS) (8, 9) demonstrated significant reductions in microvascular and neuropathic complications with intensive therapy.
Similar to the Diabetes Control and Complications Trial-Epidemiology of Diabetes Interventions and Complications (DCCTEDIC) studies' findings (10), long-term follow-up of the UKPDS cohort has recently demonstrated a "legacy effect" of early, intensive glycemic control on long-term rates of microvascular complications.
Beta-cells lipid accumulation via SREBP1c [108].The antioxidant effect varies depending on the type of exposure of beta cells to ROS.
This benefit continues, even if the differences in glycemic control between the intensive and standard cohorts are lost after the end of the study (10, 11).
Thus, under beta-cells exposure to low concentrations of ROS, antioxidants lower the insulin secretion [109,110]. In Latin America, fasting blood glucose (venous or capillary) values are the key elements used by physicians to evaluate their patients and guide decisions.
Instead, under the glucolipotoxicity, antioxidants increase the insulin secretion and reduce beta cell apoptosis [108].9. However, in line with other scientific organizations (12-14), glycosylated hemoglobin (HbA1c) is recommended as the optimal method to assess glycemic control. As shown in Table 1, A1c levels can be translated to mean plasma glucose concentrations, making it easier for patients to understand the information.
Additionally, beta-cells dysfunction and apoptosis may also be triggered by pro-inflammatory signals from other organs, such as adipose tissue [111,112]. In several large, randomized, prospective clinical trials, treatment regimens that reduced A1C < 7% were associated with fewer long-term microvascular complications. Whereas many studies and meta-analyses (15-17) have shown a direct relationship between A1C and the incidence of cardiovascular events, the potential of intensive glycemic control to reduce cardiovascular mortality has been less clearly defined. Chronic exposure of beta-cell to inflammatory cytokines, like Il-1?, IFN-? or TNF-?, can cause endoplasmic reticulum stress and the unfolded protein response activation in beta-cells, and also beta-cells apoptosis [72,115].
Based on current clinical evidence (18-21), an HbA1c < 7% is recommended as the most appropriate level for the majority of patients. Because, as indicated by Donath et al, the apoptotic beta-cells can provoke, in turn, an immune response, a vicious cycle may develop [115].
Another cytokine involved in beta-cells dysfunction is the PANcreatic DERived factor (PANDER). In addition, this Consensus highlights plasma lipid and blood pressure goals as prominent objectives of diabetes management (Table 2).
Several controlled studies and meta-analyses have shown the benefits of lipid lowering therapies in patients with diabetes. There have not been revealed significant effects of adiponectin on basal or glucose-stimulated insulin secretion [112].Leptin is another adipocytokine that may interfere with beta-cell function and survival. In studies on animal model, leptin has been shown to inhibit insulin secretion via activation of ATP-regulated potassium channels and reduction in cellular cAMP level [116], inhibit insulin biosynthesis by activating suppressor of cytokine signalling 3 (SOCS3) [119], suppress acetylcholine-induced insulin secretion [116] and induce the expression of inflammatory genes [120]. Studies performed on human islets indicated that chronic exposure to leptin stimulates the release of IL-1? and inhibits UCP2 expression, leading to beta-cell dysfunction and apoptosis [111]. Other adipocytokines including TNF-?, IL-6, resistin, visfatin may also modulate beta-cell function and survival, although it is unclear whether the amount released into the circulation is sufficient to affect beta-cells [111].10.
The concentration of microalbuminuria should be measured annually in all type 2 diabetes patients and in type 1 diabetes patients with disease duration > 5 years. Islet amyloid polypeptideHuman islet amyloid polypeptide (amylin) is expressed almost exclusively in beta-cells and is costored and coreleased with insulin in response to beta-cells secretagogues. Microalbuminuria should be treated by achieving blood pressure targets; the use of angiotensinconverting enzyme (ACE) inhibitors inhibitors and angiotensin II receptor blockers have been shown to delay the progression to macroalbuminuria. Glucolipotoxicity causes increased insulin requirement and those lead to increased production of both insulin and amylin.
High concentrations of amyloid are toxic to beta-cells and have been implicated in beta-cell dysfunction and apoptosis [121,122].The effect of Islet amyloid polypeptide on beta-cell function is not fully elucidated. Studies in vivo have shown that the islet amyloid polypeptide inhibits the first and second phase of glucose-stimulated insulin secretion, but this occurs only at concentrations of islet amyloid polypeptide above physiological range [77]. Beta-cell failure — Implication for treatmentUnderstanding the causes for beta-cell failure is of capital importance to develop new and more effective therapeutic strategies.Taking into consideration the existence of early beta-cell dysfunction and the significant reduction of beta-cell mass in the natural history of T2DM as well as the progressive character of these pathophysiological modifications, insulin therapy could be an important option for obtaining and maintaining an optimal glycemic control. Drugs currently used in diabetic care, including mean and maximum doses are described in Table 4. The pharmacological characteristics of insulin preparation and insulin analogues are included in Table 5. Several lines of evidence indicated that metformin could improve beta-cell function and survival.
Incubation of T2DM islets with metformin was associated with increased insulin content, insulin mRNA expression and glucose responsiveness, and also with reduced cell apoptosis by normalization of caspase 3 and caspase 8 activities [103]. It has been shown that metformin, and also the PPAR gamma agonists can protect beta-cell from deleterious effects of glucolipotoxicity [126,127].Other therapeutic options for beta-cell protection, such as incretins are actually under debate. Besides its therapeutic effects, Metformin has been shown to decrease cardiovascular complications in retrospective (22, 23) and prospective analyses (8, 9) and has the advantage of being easily accessible for virtually all populations.
The eGFR can be estimated by using the Cockcroft-Gault formula (24) or the MRDS equation used in the Diet in Renal Disease Study-recommended by the National Kidney Disease Education Program (United States, 25).


However, the risk of hypoglycemia (especially with first generation, long-acting sulfonylureas) and weight gain should be considered (28). The efficacy of sulfonylureas over the longterm is less than that of Metformin and glitazones. Due to their short half-life, meglitinides can be used in patients with renal failure (29).
Patients should be carefully selected for this therapeutic option in order to reduce the risk of heart failure, coronary events, or fractures (particularly in postmenopausal women) (30). Gliptins are orally active, safe, and highly tolerable, with a minimal risk for hypoglycemic events. These drugs have been used in combination with Metformin, sulfonylureas, and thiazolidinediones.
However, additional evidence is required to assess the long-term effects of the DPP-IV inhibitors, in particular issues such as safety and their effectiveness in the prevention of the diabetes-related chronic complications (32).
The decision should be based on cost-effectiveness analysis and individualized patient care. Other options based on Metformin may also be considered at this stage: Metformin + Meglitinides, Metformin + Glitazones, Metformin + DPP-4 inhibitors, and Metformin + Incretin Analogues (6, 28, 35, 36). Options include the use of DPP-IV inhibitors, GLP-1 analogue, or glitazones, in addition to Metformin and a sulfonylurea. The intervention of a diabetes specialist could be considered in patients who are not reaching the treatment targets despite the use of three agents. What should be done to manage overweight patients not controlled by monotherapy and who continue to gain weight? These patients require closer monitoring and the support of a multidisciplinary team, if available, for the implementation of an adequate dietary plan, an exercise program, and psychological support.
The use of combination therapy that may provoke weight gain should be limited to cases that remain hyperglycemic despite lifestyle modifications.
The timeframe for considering combination therapy will depend on the patient's circumstances (39). This is due to the progressive decline in insulin secretory capacity that occurs in type 2 diabetes. Initially, control can be achieved with a bedtime dose of Neutral Protamine Hagedorn (NPH) insulin or a long-acting insulin analogue (Glargine or Detemir) in combination with oral agents.
The frequency of the adjustments depends on the patient characteristics and the experience of the practitioner.
Changes in the dosage on a daily basis may be necessary in severely hyperglycemic patients.
When the treatment goals are close to being achieved, it is better to adjust the amount of insulin every 3-4 days. A time period of at least 1-3 months is recommended to assess whether treatment goals are achieved before considering a change in treatment regime. Of note, the combination of insulin with glitazones is not recommended due to the increased risk of edema and heart failure. The choice depends on insulin availability, patient requirements, metabolic behavior, and risk of hypoglycemia.
One option is a mixture of 2 types of insulin, such as regular insulin and NPH insulin, or a combination of a short acting insulin analogue (Lispro, Aspart, or Glulisine) with NPH insulin.
Another option is 1-2 doses of a long-acting analogue (Glargine or Detemir) with a dose of regular human insulin or a rapid-acting insulin analogue before each meal. Time of action, peak activity, and duration of different insulins and insulin analogues are shown in Table 5 (40, 41). At this stage of intensive insulin therapy, referral of the patient to a specialist is recommended. If there is a lack of response after a 1-3 month period, patients should be started on an insulin regimen (42). Any of the insulin regimens described above is useful for the prompt correction of hyperglycemia and nutritional status (43). Later, once these patients are stable and have regained weight, the treatment should be reassessed; the possibility of switching to oral drugs can be considered.
Some cases may be eligible for a more intensive therapeutic regimen with multiple insulin doses or an insulin pump. It is assumed that measures for adopting a healthy lifestyle are in place and reinforced regularly. All therapeutic alternatives should be given a reasonable amount of time to evaluate their maximal efficacy. This is especially relevant if there is clinical improvement, weight stabilization, and gradual improvement of fasting and post-prandial glucose and HbA1c values. Primary care physicians are discouraged from delaying the addition of an oral glucose-lowering agent or insulin. Clinical inertia is a contributing factor for not achieving treatment targets in all health systems.
In most countries, the primary care physician is responsible for the treatment of a large proportion of the diabetic population. Self-monitoring is a fundamental tool for all patients with diabetes; in particular, those on insulin treatment who require intensive glucose monitoring. It helps determine whether patients are on the right track for achieving treatment objectives (44).
Capillary glucose measurement has become more accessible in Latin America; however, the high cost of glucometers and test strips is still a significant problem for many patients. It must be taken into account, however, that this index is not readily available throughout Latin America, and where it is available, cost is often a deterrent. General practitioners are often responsible for making treatment decisions during the early stages of the disease. However, it is essential that practitioners aim to achieve the standards of diabetes care in their patients. Continuing medical education for primary care physicians must be a priority for national and international medical institutes. Patients who do not achieve treatment goals within a 6-12 month period should be referred to a specialist.
Training of medical students and primary care physicians should be updated to provide the necessary skills for successfully implementing diabetes care and promoting long-term adherence to therapy (45). In addition, diabetes education programs are needed for both patients and the general public. If these actions are not implemented, a large percentage of the diabetic population will remain outside of the treatment target levels (45, 46). They can prepare position documents that guide doctors in achieving better therapeutic results.
Latin American countries share many ethnic, social, cultural, and lifestyle characteristics. As such, ALAD has produced specific recommendations for Latin America for the last 40 years.
This document was approved and recommended by the Pan American Health Organization (PAHO) as guidelines for Latin America (49). The aim was to integrate the ALAD guidelines with important information from each organization to produce a common standard for diabetes in Latin America. The recommendations are applicable to practically every patient, with some possible exceptions.
Acknowledges the importance of reaching treatment targets early, especially in the initial years of the disease. Includes special notes regarding obese patients who are unable to reach glucose treatment goals and continue to gain weight.
Recommends the early use of combination therapy and the timely addition of insulin in patients who do not achieve adequate glucose control.
Primary care physicians are discouraged from delaying the addition of an oral glucose lowering agent or insulin because this practice results in prolonged exposure to the adverse effects of hyperglycemia. Describes clinical traits of the available glucose-lowering agents to aid in selecting from among the treatment options. Recognizes that, in Latin America, logistics can limit the use HbA1c determination-the gold standard for glycemic control-and offers regular determination of venous and capillary glycemia as an acceptable alternative. The position statement recommends treatment targets for both HbA1c and fasting glucose levels.
In addition, the importance of individual practitioners as providers of diabetes care in Latin America is highlighted. Provides clinical indications and possible contraindications for all of the existing glucose lowering agents. It is the responsibility of each medical institute and ALAD to educate physicians to ensure correct medication usage. Because this consensus takes into account the unique challenges faced by patients and physicians in Latin America, its strategies are more feasible and it is hoped that its impact will go farther than that of past efforts to improve diabetes management. Special emphasis is given to the management of the obese patient with type 2 diabetes not reaching the treatment targets.
With the help of all participating institutions, we expect that this consensus document will be helpful to improving the quality of diabetes care in Latin America.
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Effects of exenatide on glycemic control and weight over 30 weeks in Metformin-treated patients with type 2 diabetes. PRESERVE-B: two year efficacy and safety of initial combination therapy with nateglinide or glyburide plus Metformin. Effect of Metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus. Weight loss reverses secondary failure of oral hypoglycaemic agents in obese non-insulin-dependent diabetic patients independently of the duration of the disease. Approaches to treatment of pre-diabetes and obesity and promising new approaches to type 2 diabetes.
Self monitoring of blood glucose in patients with type 2 diabetes who are not using insulin: a systematic review.
A Multi-Center, Epidemiologic Survey of the Current Medical Practice of General Practitioners Treating Subjets with type 2 Diabetes Mellitus In Latin America. Nathan DM, Buse JB, Davidson MB, American Diabetes Association, European Association for the Study of Diabetes.



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Comments

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    07.01.2015

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