Current Diabetes Reviews - Volume 13, Issue 4, 2017

Introduction: In order to maintain metabolic homeostasis, organisms adjust the capacity and efficiency of ATP generation to changes in energetic demand and supply. While the transcriptional control of mitochondrial biogenesis allows to adapt mitochondrial respiratory capacity with long-term requirements for differential energy demand (e.g.: exercise training), bioenergetic adaptation also needs to take place within shorter time frames in order to properly fine-tune nutrient availability, energy production and demand, either in a circadian fashion or after a meal. These quick metabolic responses can be achieved through exquisite modulation of diverse post-translational modifications, which influence a variety of mitochondrial processes, including mitochondrial dynamics, fatty acid oxidation, lipogenesis and bioenergetic efficiency. Conclusion: In this review, we will specially focus on the role of mitochondrial sirtuin enzymes as modulators of mitochondrial ac(et)ylation and the possible interactions with other posttranslational modification events.

Introduction: Obesity and type 2 diabetes are growing health problems worldwide. The three principal diabetogenic factors are adiposity, insulin resistance in skeletal muscle, and decreased insulin production by pancreatic β cells. During recent years, macroautophagy (hereafter autophagy) — sequestration and lysosomal degradation of cellular components — has emerged as an important player in these processes, playing a protective role against development of insulin resistance and diabetes. Of particular importance is the removal of dysfunctional mitochondria via mitophagy, a form of macroautophagy selective for mitochondria. Both muscle insulin resistance and β-cell dysfunction largely depend on metabolic overload of mitochondria, which results in incomplete β-oxidation, oxidative stress, accumulation of toxic lipid intermediates, and mitochondrial damage. Mitophagy eliminates this vicious cycle of oxidative stress and mitochondrial damage, and thus counteracts pathogenic processes. Autophagy also mediates exercise-induced increases in muscle glucose uptake and protects β cells against ER stress in diabetogenic conditions. On the other hand, adipose tissue autophagy promotes adipocyte differentiation, possibly through its role in mitochondrial clearance. Being involved in many aspects, autophagy appears to be an attractive target for therapeutic interventions against obesity and diabetes. Conclusion: Here we explore the connections of autophagy with mitochondria in obesity and type 2 diabetes, and discuss its roles in diabetic complications. Understanding how autophagy protects against diabetes could help design new strategies against this growing epidemic.

Introduction: Mitochondria form an interconnected and dynamic web that undergoes continuous cycles of fusion and fission events. This phenomenon, known as mitochondrial dynamics, represents a key quality control system to maintain a healthy mitochondrial population but also a mechanism to bioenergetically adapt to the cellular and tissue energetic demands. Consequently, mitochondria can be viewed not only as energy supply organelles but also as energy sensors. It is therefore not surprising that disrupted mitochondrial bioenergetics, concomitantly with alterations in mitochondrial architecture, has been associated with several diseases including metabolic disorders. Conclusion: Here, we review current evidences connecting mitochondrial dynamics and bioenergetic alterations with the development of obesity and diabetes-related phenotypes, and how current strategies to alleviate such phenotypes impact on mitochondrial network and function.

Introduction: Mitochondrial uncoupling is a physiological process that has direct and indirect consequences on glucose homeostasis. Non-shivering thermogenesis in brown adipose tissue, which is the most well-recognized biological process related to the physiological uncoupling of mitochondria, is caused by uncoupling protein-1 (UCP1), which mediates a regulated permeabilization of the mitochondrial inner membrane to protons. Conclusion: The uncoupled brown fat mitochondria are specialized to produce heat by oxidizing large amounts of substrates, making brown fat a sink that can actively drain glucose from circulation. This has been confirmed in human studies in which active brown fat was detected by glucose-derivative-based positron emission tomography scans. Thus, UCP1-mediated activation of brown fat appears to be a likely mechanism through which hyperglycemia could be ameliorated. In other tissues, mitochondria are reported to be mildly uncoupled by the UCP1-like proteins, UCP2 and UCP3. The primary role of these other UCPs does not appear to be the oxidation of a metabolic substrate (e.g., glucose) for heat production; instead, they participate in other processes, such as regulating the production of reactive oxygen species and transporting certain metabolites across the mitochondrial membrane. UCP2 activity influences glucose homeostasis by fine tuning intracellular events related to the cellular energy status, thereby controlling insulin secretion, food intake behavior and adiponectin secretion in pancreatic β- cells, brain and white adipose tissue, respectively. UCP3 appears to be more specifically involved in promoting fatty acid oxidation in muscle, and is thus likely to influence glucose metabolism indirectly. Several genetic association studies have related polymorphisms in the genes encoding UCPs with obesity and/or type 2 diabetes phenotypes. In this review, we will focus on what is known about the specific role of mitochondrial uncoupling in glucose metabolism, and its implications in diabetes.

Introduction: The mitochondrion plays a critical role in cellular energy metabolism. For this reason it is considered as a plausible target for the treatment of metabolic diseases such as obesity and type-2 diabetes. Although several mitochondrial molecular targets have been suggested and investigated, currently there are no marketed drugs that target the mitochondrion to treat metabolic diseases. Through an investigation of current drugs and investigational compounds, two hypotheses have emerged: 1) inhibition of mitochondrial substrate utilization is associated with increased insulinstimulated glucose uptake; 2) stimulation of mitochondrial biogenesis is related to increased energy expenditure and potentially weight loss. The mode-of-action of both mechanistic hypotheses is currently unknown and potentially controversial since they contradict other experimental findings. However, the fact that both processes are stimulated by different types of compounds with different sites of action supports their potential existence. Conclusion: This review summarizes the data that support these two hypotheses; with the hope that this will stimulate further research and intensify the development of future drugs for the treatment of obesity and type-2 diabetes.

Introduction: Sodium glucose cotransporter 2 (SGLT2) inhibitors have a unique mechanism of action leading to excretion of glucose in the urine and subsequent lowering of plasma glucose. This mechanism is independent of β-cell function; thus, these agents are effective treatment for type 2 diabetes mellitus (T2DM) at theoretically any disease stage. This class should not confer an additional risk of hypoglycemia (unless combined with insulin or an insulin secretagogue) and has the potential to be combined with other classes of glucose-lowering agents. Empagliflozin is one of three currently approved SGLT2 inhibitors in the United States, and has shown a favorable benefit-risk ratio in phase 3 clinical trials as monotherapy and as add-on to other glucose-lowering therapy in broad patient populations. In addition to its glucose-lowering effects, empagliflozin has been shown to reduce body weight and blood pressure without a compensatory increase in heart rate. Moreover, on top of standard of care, empagliflozin is the first glucoselowering agent to demonstrate cardiovascular risk reduction in patients at high risk of cardiovascular disease in a prospective outcomes trial: a 14% reduction in risk of the 3-point composite endpoint of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Like other SGLT2 inhibitors, empagliflozin is associated with a higher rate of genital mycotic infections than placebo and has the potential for volume depletion–associated events. Conclusion: This review summarizes the empagliflozin phase 3 clinical trials program and its potential significance in the treatment of patients with T2DM. Evidence from these clinical trials show reductions in glycated hemoglobin (–0.59 to –0.82%) with a low risk of hypoglycemia except when used with insulin or insulin secretagogues, and moderate reductions in body weight (–2.1 to – 2.5 kg) and systolic blood pressure (–2.9 to –5.2 mm Hg), thus supporting the use of empagliflozin as monotherapy or in addition to other glucose-lowering agents. In addition, evidence from the recent EMPA-REG OUTCOME study, which demonstrated relative risk reductions in major adverse cardiac events (14%), cardiovascular mortality (38%) and all-cause mortality (32%), as well as hospitalization for heart failure (36%), supports use of empagliflozin in patients with T2DM and increased cardiovascular risk.

Introduction: Diabetes mellitus is one of the most common metabolic problems and is characterized by persistent hyperglycaemia. Exposure to chronic hyperglycaemia can affect many tissues including the Achilles Tendon, which is one of the largest tendons in the body. The current literature on the effects of hyperglycaemia on tendons is sparse, though evidence on rat models does suggest a process of chronic degeneration, which is increased in the presence of neuropathy and deformity. There is no epidemiological data on rupture of Achilles tendon in diabetes. Similarly, the knowledge of the best treatments for this condition in people with diabetes is also lacking. Conclusion: In this review we have systematically analysed current literature in this area and suggested future studies

Introduction: Type 2 diabetes (T2D) and cardiovascular disease (CVD) risk associate with ferritin and percent transferrin saturation (%TS) levels. However, increased risk has been observed at levels considered within the “normal range” for these markers. Objective: To define normative ferritin and %TS levels associated with T2D and CVD risk. Methods: Six-monthly ferritin, %TS and hemoglobin levels from 1,277 iron reduction clinical trial participants with CVD (peripheral arterial disease, 37% diabetic) permitted pair-wise analysis using Loess Locally Weighted Smoothing plots. Curves showed continuous quantitative ferritin, hemoglobin (reflecting physiologic iron requirements), and %TS (reflecting iron transport and sequestration) levels over a wide range of values. Inflection points in the curves were compared to ferritin and %TS levels indicating increased T2D and CVD risk in epidemiologic and intervention studies. Results: Increasing ferritin up to about 80 ng/mL and %TS up to about 25% TS corresponded to increasing hemoglobin levels, and minimal T2D and CVD risk. Displaced Loess trajectories reflected lower hemoglobin levels in diabetics compared to non-diabetics. Ferritin levels up to about 100 ng/mL paralleled proportionately increasing %TS levels up to about 55%TS corresponding to further limitation of T2D and CVD risk. Ferritin levels over 100 ng/mL did not associate with hemoglobin levels and coincided with increased T2D and CVD risk. Conclusions: Recognition of modified normal ranges for ferritin from about 15 ng/mL up to about 80- 100 ng/mL and %TS from about 15% up to about 25-55% may improve the value of iron biomarkers to assess and possibly lower T2D and CVD risk.