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Given its ever increasing number of patients worldwide, diabetes mellitus (DM) is a modern epidemic and a highly concerning global health care issue, with recent estimates pointing to an increase from 285 to 439 million patients from 2010 to 2030 (1). Type 2 diabetes is characterized by abnormally high blood glucose levels (hyperglycemia) due to insulin resistance that may progress toward pancreatic β-cell dysfunction and a generalized loss of insulin sensitivity in the later stages of disease (7).
Herewith, we will focus primarily on the impact of T2D in CNS, particularly in the most common form of dementia, AD, as well as on some of the currently used anti-T2D drugs. As previously mentioned, impaired insulin signaling has been critically involved in the development and progression of both T2D and AD. Under physiological conditions, glucose metabolism is critical for proper brain function (and its neuronal connections). Regarding oxidative stress, mitochondria constitute one of the major sources and targets of reactive oxygen species (ROS), and have been increasingly demonstrated to have a pivotal role in AD and diabetes pathogenesis (19). Downregulation of insulin uptake in T2D brain may deprive this organ from the hormone’s beneficial effects (24). Insulin-like growth factors-1 (IGF-1) and -2 (IGF-2) and relaxin were shown to share structural similarities with insulin, all belonging to the same protein family (39). It seems unquestionable that T2D and AD are two intrinsically related pathologies sharing several common mechanisms.
The maintenance of glycemic control within the normal range constitutes an efficient first approach to reduce the risk of T2D-associated long-term vascular and cardiovascular complications. Katie Powell, 25, had type 1 diabetes and passed away at Royal Bolton Hospital on September 18 last year.
Matthew Powell sayshis daughter injected herself with insulin when she arrived in A&E with pain in her side.
Dr Damian Bates, a consultant at the hospital who cared for Miss Powell, said: 'Katie had more painkillers than I have ever given anyone in my entire life. Mr Powell's first wife Sheridan died of uncontrolled type 1 diabetes in 1998, and he said it was like 'history repeating itself' when his daughter Katie died of the same illness this year. Miss Powell was 'screaming in pain' when she was admitted to hospital, but doctors were unable to find the source. Despite being in a wheelchair and suffering diabetes, Miss Powell was independent and lived life to the full, her father said.
Nobody took responsibility in the medical team to carry out the medication review to ensure that insulin was being prescribed and administered.
A coroner said is was clear 'nobody took responsbility' for reviewing Miss Powell's medicines, leaving her without insulin. CMR Short Reviews The Concept of CMR Historical background on global cardiometabolic risk, epidemiological aspects of obesity and type 2 diabetes, ABCs of cardiovascular disease risk factors, intra-abdominal adiposity, metabolic syndrome and contribution to cardiometabolic risk.
Obese, insulin-resistant subjects and type 2 diabetic patients often have a pro-thrombotic state.
Obesity and overweight pose a major risk for serious chronic diseases, including type 2 diabetes, cardiovascular disease, hypertension, and stroke (1, 2). Adipose tissue is much more than an organ that mobilizes energy stored in the form of triglycerides.
Leptin is mainly produced and secreted by adipose tissue and acts via the hypothalamus to suppress food intake and increase energy expenditure by modulating glucose and fat metabolism and enhancing thermogenesis (7). Oxidative stress is where the normal balance between the body?s pro-oxidant and anti-oxidant systems is disturbed in favour of oxidation (30). Endothelial dysfunction is a disturbance in the normal balance between vasoconstrictors and vasodilators, growth promoters and inhibitors, pro- and anti-atherogenic processes, and pro- and anti-coagulant factors (33). The content of this website is provided for educational and informational purposes only and is not to be used for medical advice, diagnosis or treatment.
Please, complete the form with your suscription data.If you are a member of the Spanish Society of Cardiology, you can use the same login and password that you use to access the Society's website.
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Despite the several types of diabetes existent, type 2 diabetes (T2D) constitutes an unquestionable major public health threat, accounting for more than 90% of all cases (1, 2). Chronic T2D is known to negatively affect the CNS structure and function, ultimately constituting a known risk factor for dementia [both vascular dementia and Alzheimer disease (AD)] (8). However, as disease progresses, some pharmacological approach (including combined therapy) may be required to successfully deal with T2D and its complications. However, other abnormalities common to both pathologies include glucose dysmetabolism, mitochondrial dysfunction, oxidative stress, or deposition of amyloidogenic proteins (2). As neurons are unable to store and synthesize glucose, this is transported across the blood–brain barrier (BBB) via glucose transporters (GLUTs), with GLUT-1, GLUT-3, and GLUT-4 constituting the most abundant isoforms (16). These organelles are primarily responsible for several crucial cellular processes, being also the main coordinators of energy metabolism (by generating over 90% of cellular ATP) (2). The majority of insulin in brain derives from pancreatic β-cells, being transported mostly across the BBB (26).
Indeed, an acute increase in peripheral insulin levels may increase insulin in cerebrospinal fluid, whereas chronic peripheral hyperinsulinemia (as in insulin resistance or T2D) may downregulate IRs at BBB, impair brain insulin uptake (26), and culminate in learning, memory, and cognition deficits (28–30).
Similar to insulin, IGF-1 crosses the BBB, being ubiquitously distributed in rodent and human brains, and widely affecting CNS (9, 40).
Therefore, it has been hypothesized that a treatment directed against T2D may be beneficial in AD. But, as disease progresses, its successful management may also include the control of blood pressure and lipid levels (44). Among the several risk factors for T2D, obesity has been one of the closest related with the disease progression and development of late complications.


Metformin, derived from extracts of the French Lilac (55), is the best known biguanide and remains the anti-T2D drug of choice to initiate the pharmacological approach.
Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I (60–62). Weight change was a secondary endpoint, and blood pressure change was primarily assessed as a safety or exploratory efficacy endpoint in clinical trials. She always put others before herself.'She was a really happy girl and she really wanted to better herself. However, it remains to be determined whether obesity is truly an independent risk factor or whether it acts in conjunction with other well-known cardiovascular risk factors such as insulin resistance, dyslipidemia, and a pro-inflammatory and pro-thrombotic state. Most obese people have high circulating leptin concentrations, which is a signal sent by adipose tissue to limit caloric intake and restore energy balance by reducing appetite and increasing energy expenditure (19).
Fibrinogen promotes arterial and venous thrombosis by increasing fibrin formation, platelet aggregation, and plasma viscosity, and it promotes atherosclerosis by fostering the proliferation of vascular smooth muscle and endothelial cells (23) (Figure). Oxidative stress from the production of reactive oxygen species (ROS) promotes endothelial dysfunction, platelet aggregation, and thrombus formation (31) (Figure). Endothelial dysfunction is central to the development and progression of atherosclerosis and enhances the risk of future cardiovascular events (33). Heterogeneity in adipose tissue metabolism: causes, implications and management of regional adiposity.
Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease. Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity. Correlation between blood fibrinolytic activity, plasminogen activator inhibitor level, plasma insulin level, and relative body weight in normal and obese subjects. Plasminogen activator inhibitor-1, inflammation, obesity, insulin resistance and vascular risk. Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome. Effects of troglitazone on blood concentrations of plasminogen activator inhibitor 1 in patients with type 2 diabetes and in lean and obese normal subjects.
Among inflammation and coagulation markers, PAI-1 is a true component of the metabolic syndrome. Control of energy homeostasis and insulin action by adipocyte hormones: leptin, acylation stimulating protein, and adiponectin.
Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity. Impact of weight loss on plasminogen activator inhibitor (PAI-1), factor VII, and other hemostatic factors in moderately overweight adults. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Genetics of inflammation and risk of coronary artery disease: the central role of interleukin-6. Endothelial dysfunction in obesity and insulin resistance: a road to diabetes and heart disease. This is mostly due to its chronic complications that may affect brain and constitutes a risk factor for AD.
T2D-related socio-economic concern is also due to the burden constituted by its highly common, morbid, and mortal long-term complications affecting several tissues and organs, including the central nervous system (CNS) (3).
Although the precise mechanisms underlying neurodegeneration and impaired cognition in T2D remain poorly understood, it has been hypothesized that insulin resistance (impaired insulin signaling) may play a critical role, particularly in the elderly (9, 10). Therefore, besides more and more efficient (and with less secondary effects) anti-T2D drugs, it is of the outmost importance to develop efficient therapies that also minimize any further damage to the already injured organs, ultimately delaying or avoiding the development of long-term complications (as AD). However, under chronic glucose dysmetabolism (as in T2D), brain damaging effects may arise, with the formation and accumulation of advanced glycation endproducts (AGEs) constituting one of the most deleterious ones (17).
These evidences further support the idea that impaired insulin function and signaling may constitute another common mechanistic link between diabetes (particularly T2D) and AD (31).
Several groups worldwide have been analyzing anti-T2D drugs (either in clinical use or under clinical trials) in the context of AD.
Therefore, although the achievement of an optimal glycemic control remains the main goal of diabetes therapeutic management, lately this may not be enough to reduce cardiovascular risk (45). As such, patients’ elevated body weight should be considered when prescribing an anti-T2D treatment (48).
It is highly efficient in improving glycemic control, is not expensive (45) and has a low risk for hypoglycemia (56). It's been a really difficult time.'A A spokeswoman for Bolton NHS Foundation Trust, who run Royal Bolton Hospital, said it would not comment until the inquest was over.
This cluster of atherogenic metabolic abnormalities is now often referred to as the metabolic syndrome. Among the wide variety of bioactive substances called adipokines, several may play a role in thrombosis. It is therefore generally accepted that overweight and obese individuals are resistant to the effects of leptin (20). Fibrinogen levels are now considered to be more closely related to overall adiposity than insulin resistance (24).
In addition to its direct effects, inflammation may cause thrombosis indirectly by inducing oxidative stress and endothelial dysfunction (28). Many obesity-related metabolic abnormalities, such as hyperglycemia, dyslipidemia, and inflammation, all increase ROS production in the endothelium, which promotes oxidative stress (32).
Endothelial dysfunction is present in overweight patients, especially those with intra-abdominal obesity and insulin resistance, and weight loss can improve endothelial function (27). T2D principal hallmark is insulin resistance which also occurs in AD, rendering both pathologies more than mere unrelated diseases.


Although traditionally, T2D used to occur in people aged above 30 years, nowadays its incidence is also increasing among younger people (4), probably due to other risk factors (besides aging) associated with modern lifestyle. Brain insulin binds rapidly to the highly abundant and ubiquitously distributed IR in the CNS (26, 28). This hypothesis was further reinforced by the role of insulin in the regulation of the AD neuropathological hallmarks, Aβ and tau. This might be facilitated by the wide range of anti-T2D compounds established, accepted, and being used worldwide; however, there are probably many more under development or awaiting approval [we must remind that T2D is a highly concerning, modern epidemic (43)]. This is even more relevant as body weight gain is a frequent secondary effect of some anti-T2D therapies (48).
Being an insulin sensitizer, metformin does not stimulate insulin secretion directly; instead, it reduces insulin-mediated hepatic glucose production (57) and increases peripheral glucose disposal, most likely as an indirect consequence of reduced glucotoxicity (47, 58). This kinase is also modulated by hormones and cytokines in order to restore cellular energy homeostasis (63). This induces a pro-thrombotic state that includes endothelial activation, platelet hyperactivity, hypercoagulability, and hypofibrinolysis. The plasma levels of other clotting factors, such as tissue factor (8) and factor VII and VIII, are also elevated in obese patients (23). IL-6 may promote thrombosis indirectly by increasing platelet count and aggregation, hepatic synthesis of fibrinogen and CRP, and endothelial adhesion molecule expression, as well as by decreasing adiponectin secretion (29).
As described above, low levels of adipocyte-derived circulating adiponectin may cause endothelial damage, possibly by lowering nitric oxide (NO) production while increasing ROS (31). This hypothesis has been reinforced in the recent years, with a high number of studies highlighting the existence of several common molecular links. Besides their massive formation in diabetic patients, AGEs were also found in retinal vessels, peripheral nerves, kidneys, and CNS of aged patients (18). Moreover, insulin may protect against neuronal apoptosis via activation of mitogen-activated protein kinase (MAPK) signaling (namely p38 MAPK) and suppression of caspase-3 activity, a pathway that may also play a role in memory and learning (25).
As such, the development of several recent drugs had into account their effects on adipogenesis and fat mass regulation (49). Regarding its effects on body weight, some controversy exists, with some authors describing that metformin did not affect body weight (56), whereas others reported a metformin-induced weight loss (49).
In line with this, the roles of metformin on the reduction of insulin resistance (Figure 1), plasma fasting insulin levels, glucose, lipid and protein synthesis, and cell growth, also stimulating fatty acid oxidation (68–70), (most of them common features to T2D and AD and involving LKB1-induced AMPK activation) rendered this drug a promising therapeutic approach also against AD (Figure 1) (62, 63). Numerous studies have revealed that the amount of body fat does not necessarily determine morbidity and that body fat distribution is most closely linked to metabolic and vascular diseases (3).
It inhibits plasminogen activator (tPA), which cleaves plasmin from plasminogen and is therefore the primary physiological inhibitor of fibrinolysis in vivo (7) (Figure). Leptin promotes human platelet aggregation by increasing normal platelet response to the agonists adenosine diphosphate and thrombin (Figure). Several studies have shown that weight loss can reverse numerous disturbances in the plasma coagulation cascade (25). TNF-α stimulates leptin production and reduces adiponectin secretion by adipose tissue, induces PAI-1 expression in adipose tissue, and promotes endothelial adhesion molecule expression (7) (Figure). Not only does NO reduce inflammation, platelet aggregation, vascular smooth muscle cell migration and growth, and monocyte and macrophage adhesion, it also encourages vasodilatation (33).
Cano-Pereza, Juan Pedro-Botetca Servicio de Endocrinologia y Nutricion, Hospital del Mar, Barcelona, Spain. And when this occurs, catabolic pathways (as fatty acid oxidation or glucose transport) that generate ATP are induced, whereas ATP-consuming, anabolic processes (namely fatty acid and protein synthesis) are switched off (49). This hypothesis is further supported by the recent observations that metformin prevented the accumulation of AD-like molecular and pathological features in a differentiated neuronal cell line submitted to chronic hyperinsulinemia, including Aβ generation and tau protein hyperphosphorylation (71, 72). Several reports have demonstrated that intra-abdominal or visceral fat is associated with significant, and largely preventable, morbidity and mortality, including an increased incidence and prevalence of arterial and venous thrombotic events (4). This has recently been suggested as one mechanism responsible for acute thrombotic events in obesity (22).
Low NO production may therefore help increase platelet activation, arterial thrombosis (Figure), and atherogenesis.
Departamento de Medicina, Universidad Autonoma de Barcelona, Barcelona, Spain b Servicio de Endocrinologia y Nutricion, Hospital del Mar, Barcelona, Spain c Departamento de Medicina, Universidad Autonoma de Barcelona, Barcelona, Spain.
Strikingly, AGEs may also react with free radicals, promoting oxidative damage and further exacerbating cellular injury (11).
Additionally, AMPK activation has been suggested to indirectly improve hepatic insulin sensitivity (47, 49), to promote GLUT-4 protein expression and glucose uptake in human adipocytes (64) and to regulate adipogenic differentiation via inhibition of peroxisome proliferator-activated receptor gamma (PPAR-γ) (49). Moreover, atherothrombotic complications in the metabolic syndrome are partly due to a dysregulation of hemostasis, inducing a pro-thrombotic state that encompasses endothelial activation, platelet hyperactivity, hypercoagulability, and hypofibrinolysis (Figure).
Elevated PAI-1 concentrations hinder normal clearance of fibrin and promote thrombosis (9), which increases the risk of myocardial infarction and stroke (10).
Therefore, as T2D exacerbates the production of such deleterious molecules, it is not surprising that AGEs production (and eventually the vicious cycle of oxidative stress) may constitute another putative biochemical link between T2D and increased risk of AD. In parallel, metformin was also described to inhibit adenylate cyclase (AC) via accumulation of AMP and related nucleotides, thus reducing cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) activity in mouse hepatocytes, culminating in ablation of glucagon-dependent glucose production and output (49).
However, increased plasminogen activator inhibitor-1 (PAI-1) expression with attendant hypofibrinolysis is the main hemostasis disorder linked to insulin resistance and is now considered part of the cluster of abnormalities of the metabolic syndrome (5).
These results suggested that rosiglitazone-mediated stimulation of insulin signaling could lead to a decrease of the hormone available to compete with IDE, therefore promoting Aβ degradation (34). This was accompanied by a protection against neuronal lipid and protein oxidation, particularly the increase in the formation of 4-hydroxynonenal (4-HNE, a byproduct of oxidation) adducts on neuronal GLUT-3 transporters upon oxidative stress (35). Soedamah-Muthu SS, Chaturvedi N, Toeller M, Ferriss B, Reboldi P, Michel G, et al, for the EURODIAB Prospective Complications Study Group.



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