Dr Thierry Coppola
email: coppola@ipmc.cnrs.fr

Sophie Béraud-Dufour

Dr Patricia Lebrun

Dr Nicolas Blondeau
email: blondeau@ipmc.cnrs.fr

Dr Sophie Beraud-Dufour

Bridging the gap between diabetes and stroke in search of high clinical relevance therapeutic targets

Keywords: Hyperglycemia, glucolipotoxicity, comorbidity, tolerance to brain ischemia, signaling pathways

Diabetes affects more than 425 million people worldwide, a scale approaching pandemic proportion. Diabetes represents a major risk factor for stroke, and therefore is actively addressed for stroke prevention. However, how diabetes affects stroke severity has not yet been extensively considered, which is surprising given the evident but understudied common mechanistic features of both pathologies. The increase in number of diabetic people, in the incidence of stroke in presence of this specific risk factor, and the exacerbation of ischemic brain damage in diabetic conditions (at least in animal models) warrant the need to integrate this comorbidity in pre-clinical studies of brain ischemia to develop novel therapeutic approaches. Therefore, a better understanding of the commonalties involved in the course of both diseases would offer the promise of discovering novel neuroprotective pathways that would be more appropriated to clinical situations. In this article, we will review the relevant mechanisms that have been identified as common traits of both pathologies and that could be to our knowledge, potential targets for both pathologies.

1-Introduction

Ischemic stroke is among the leading causes of mortality worldwide and of long-term cognitive disability and physical handicap. Several risk factors for ischemic stroke have been identified. They can be divided in two categories. Elderly, family history, gender, and ethnicity account for the non-modifiable risks, while high levels of blood cholesterol, triglycerides, sugar and pressure are acknowledged signs of modifiable risk factors that also include smoking and alcoholism. Given the coexistence of modifiable risk factors at up to 80% of stroke incidence [START_REF] Stoger | Epigenetics and obesity[END_REF], their control is one of the bases of current therapeutic approaches for stroke primary and secondary prevention. Biomarkers like hypercholesterolemia, hyperglycemia and hyperlipidemia are also indicators of obesity and/or diabetes. Following a continued increase in prevalence during the past decades, hypertension has been stabilized. In contrast, the prevalence of obesity and diabetes continues to expand in number in all industrialized countries. Considered as major but modifiable risk factors of stroke, obesity and diabetes have been considered almost exclusively within the domain of stroke prevention. However, how obesity and diabetes affect stroke severity has not yet been clearly clarified. While in some epidemiological studies obesity was associated with counterintuitive improved stroke outcome (so-called "obesity paradox", [START_REF] Scherbakov | Body weight after stroke: lessons from the obesity paradox[END_REF])), diabetes and hyperglycemia, its most notable feature, were associated to a higher mortality rate in stroke-patients (Kiers et al., 1992). Worth of note, the presence of Type 2 diabetes seems to vanish the paradoxical benefit of obesity on stroke survival [START_REF] Adamopoulos | Absence of obesity paradox in patients with chronic heart failure and diabetes mellitus: a propensitymatched study[END_REF]). In addition, pre-clinical investigations on diabetic animals for evaluating efficacy of protective therapy against cerebral ischemic damage (as recommended by the Stroke Therapy Academic Industry Roundtable (STAIR) guidelines) [START_REF] Fisher | Update of the stroke therapy academic industry roundtable preclinical recommendations[END_REF]) acknowledged hyperglycemia as exacerbating factor of ischemic brain damage. The confounding effects of Type 2 diabetes were recently proposed as "negative conditioning" for stroke and acute myocardial infarction, as it alters clinical outcome and also interferes with treatment by tissue plasminogen activator in stroke patients and with ischemic conditioning in the setting of acute myocardial infarction [START_REF] Jiang | Diabetes mellitus worsens outcomes in tPA thrombolytic stroke therapy[END_REF][START_REF] Wider | Cardioprotection with Ischemic Conditioning: The Diabetes Dilemma[END_REF]. Overall preclinical and clinical evidences suggest that the impact of diabetes extends beyond increasing stroke frequency, but also exacerbates ischemic brain damage [START_REF] Rehni | Diabetic aggravation of stroke and animal models[END_REF][START_REF] Rehni | Ameliorative potential of conditioning on ischemia-reperfusion injury in diabetes[END_REF].

Therefore the momentum is building in the field for scientists and physicians to gain insights in how diabetes exacerbates stroke complications and to evaluate the hypothesis that targeting diabetic aggravation of ischemic brain injury may offer more translational potential than conventional therapeutic approach.

2-Stroke fact

Apart from reperfusion therapies, for which most patients are still ineligible and only a limited number of those that do receive treatment experience a full recovery, stroke patients are currently left with an extremely limited repertoire of therapeutic options. New stroke incidence, deaths and disablement (50% of stroke survivors experience residual motor or cognitive/amnesic deficits severe enough to require assistance in daily living) are still growing. Historically, stroke research aimed to specifically target one deleterious mechanism of the ischemic cascade triggered by the occlusion of brain circulation. The specificity of neuronal death related to the pathophysiology of stroke rests in a massive and uncontrolled release of glutamate from neurons, the major physiological excitatory neurotransmitter in the mammalian brain. It leads to an overactivation of ionotropic glutamate receptors, predominantly the N-methyl-D-aspartate (NMDA) glutamate receptor subtype, that accounts for a lethal influx of calcium in the cell. However, employment of a mono-therapeutic approach targeting these specific features of ischemic stroke has utterly failed in Human clinical trials examining acute administration of a neuroprotective therapeutic after onset of stroke [START_REF] Labiche | Clinical trials for cytoprotection in stroke[END_REF][START_REF] O'collins | 1,026 experimental treatments in acute stroke[END_REF]). These failures led to diminished commitments in preclinical and clinical stroke research taking away the prompt perspective of finding a cure. Therefore, stroke is undoubtedly one of the most devastating diseases worldwide, exerting an enormous societal and economic burden [START_REF] Moskowitz | The science of stroke: mechanisms in search of treatments[END_REF].

3-Diabetes fact

Type 2 diabetes accounts for 90% of diabetes cases nationwide and has been increasing at an alarming rate in association to the rise of obesity in the world. Diabetes affects more than 425 million people worldwide [START_REF] Guariguata | Global estimates of diabetes prevalence for 2013 and projections for 2035[END_REF]) and pharmaceutical companies are actively working to develop drugs for the broad market. Diabetes is a disorder of the assimilation, use and storage of sugars from food resulting in high blood glucose levels called hyperglycemia. Food is composed of lipids (fats), proteins (animal or vegetable proteins) and carbohydrates (sugars, starches). By passing through the intestine and then entering the bloodstream, nutrients provide energy to the body for its proper functioning. Eating leads to an increase in circulating level of sugar, and the corresponding carbohydrates will for the high majority be converted into glucose. As soon as the increase in blood sugar level is detected by pancreas, the pancreatic cells, grouped into clusters called islets of Langerhans, start to secrete insulin. Insulin works like a switch, allowing glucose to penetrate the cells into the muscles and fat tissues for being processed and stored, and preventing glucose synthesis and release by the liver. Overall, it leads to a decrease of glucose amount in the blood. When energy or blood sugar levels drop, mainly between meals, another hormone called glucagon, releases glucose stored by the liver. To summarize, the balance of insulin and glucagon maintains stable blood sugar levels. While the alteration of this regulatory system of glucose homeostasis appears as a signature of diabetes, being sneaky and painless, the development of type 2 diabetes can go unnoticed for a long time. Indeed, it takes an average of 5 to 10 years from the appearance of the first hyperglycemia to diagnosis.

Repeated and prolonged hyperglycemia induces long-term damage to nerves and blood vessels throughout the body leading to blindness, foot disorders (that can lead to amputations), erectile dysfunction, kidney failure, heart attack and stroke. Therefore, treatments in type 2 diabetes aim to normalizing blood sugar levels. The first oral antidiabetic agents, sulfonylureas, which induce cell depolarization by inhibition of ATP-sensitive potassium (KATP) channels, were developed in the 1950s [START_REF] Charbonnel | Pharmacological management of type 2 diabetes: the potential of incretin-based therapies[END_REF].

Their use still continues worldwide for triggering release of insulin from the pancreas.

Belonging to the same class of insulin secretion potentiators, two other therapeutic molecules have been released on the market since 2008: dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon like peptide-1 (GLP-1) analogues used to promote insulin secretion without the risk of hypoglycemia observed with the sulfonylureas [START_REF] Charbonnel | Pharmacological management of type 2 diabetes: the potential of incretin-based therapies[END_REF]. These two drug therapies take advantage of the stimulation of the "incretin effect" that is reduced or absent in type 2 diabetic patients, while in physiological conditions the insulinotropic actions of the incretin hormones account for two-thirds of the insulin normally secreted after food ingestion. Therefore drug-driven improved incretin-mediated augmentation of insulin secretion by the islets of Langerhans after a meal succeed in decreasing blood glucose levels in type 2 diabetic patients. Several long-lasting analogs of GLP-1 have been developed, for example exenatide and liraglutide. The other approach is to inhibit the enzyme that inactivates GLP-1.Thus several DPP-4 inhibitors that can be orally taken as tablets have been developed [START_REF] Charbonnel | Pharmacological management of type 2 diabetes: the potential of incretin-based therapies[END_REF]. Nevertheless the number of people with diabetes is expected to pick above 650 million in the next 20 years.

4-Association between prevalence of Diabetes Mellitus, and Cardiovascular Disease and Stroke

Cardiovascular complications, such as coronary artery disease and stroke, account for the majority of the death of patients with type 2 diabetes. Indeed, nearly 80% of them die of a cardiovascular disease (CVD). In relation to a non-diabetic control population, the relative risk is multiplied by 2 to 6 [START_REF] Beckman | Diabetes and atherosclerosis: epidemiology, pathophysiology, and management[END_REF]. In addition, patients with type 2 diabetes free from any coronary pathology have a similar risk to have a heart attack than a non-diabetic population who have previously had a coronary event [START_REF] Haffner | Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction[END_REF]. All these elements indicate that the accelerated atherosclerosis found in type 2 diabetic subjects (that leads to considerable morbidity and mortality) needs an aggressive care strategy [START_REF] Chiquette | Cardiovascular disease: much more aggressive in patients with type 2 diabetes[END_REF][START_REF] Solomon | Reducing cardiovascular risk in type 2 diabetes[END_REF]. With regard to stroke, it is known since a long time that diabetes increases the risk of stroke independently of its effect on blood pressure [START_REF] Barrett-Connor | Diabetes mellitus: an independent risk factor for stroke?[END_REF][START_REF] Burchfiel | Glucose intolerance and 22-year stroke incidence. The Honolulu Heart Program[END_REF]. In type 2 diabetic patients, the risk of suffering from stroke, as well as the risk of dying from stroke, is at least two times greater than in the normal population, independently of other known risk factors for CVD [START_REF] Almdal | The independent effect of type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a population-based study of 13,000 men and women with 20 years of follow-up[END_REF]). Among stroke survivors, diabetic patients also display a higher risk of long-term disability [START_REF] Hankey | Rate, degree, and predictors of recovery from disability following ischemic stroke[END_REF]). Interestingly, insulin resistance and impaired glucose tolerance, which are crucial steps in the course of diabetes development (known as prediabetic conditions), are also associated with the development of stroke incidence (Figure 1) [START_REF] Kernan | Metabolic rehabilitation: science gathers to support a new intervention to prevent stroke[END_REF][START_REF] Thacker | Fasting and post-glucose load measures of insulin resistance and risk of ischemic stroke in older adults[END_REF]. The interconnections between diabetes and stroke are so intense that both the Food and Drug Administration and the European Medicines Agency issued guidance on the necessity to evaluate the potential cross-actions of new drugs on diabetes and stroke [START_REF] Castilla-Guerra | Antidiabetic drugs and stroke risk. Current evidence[END_REF]. While anti-diabetics aimed at lowering circulating glucose have not been shown so far to reduce stroke incidence, it should be noted that recent randomized controlled trials have identified new anti-diabetics that may improve stroke outcomes [START_REF] Chawla | Interpreting Cardiovascular Endpoints in Trials of Antihyperglycemic Drugs[END_REF]. There is therefore an emerging hope to discover new anti-diabetic drugs that will interfere with the course of stroke, reducing its incidence and/or its consequences. However, how diabetes increases the risk and/or the consequences of stroke is still weakly understood, and the interconnections between diabetes and stroke have not been fully investigated, which may be surprising given the common risk factors and mechanistic features between both pathologies.

5-Common risk factors a. Behavioral risk factors: unbalanced nutrition and sedentarity

The role of the environment (Figure 1) in the development of diabetes, obesity and in the increase in their current prevalence has been extensively documented. Over the last few decades, in westernized populations, an increase of the caloric intake was monitored concurrently with a reduction of physical activity, explaining the development of obesity.

Technological innovations and socio-demographic factors have also contributed to this fact.

Factors such as lower prices and increased accessibility of nutritionally poor, but energydense foods have played their part, as well as the unrelenting marketing of this product. Fat intake has also increased significantly (saturated and trans fats) in recent years, promoting increased caloric intake (energy rich and flavourful content). Regarding carbohydrates, the last century witnessed an overall decrease in their consumption: previously accounting for more than 50% of the daily caloric intake, it nowadays represents less than 40%. Within carbohydrates, the consumption of complex forms has decreased, while the consumption of refined-sugars (mono and disaccharides) has considerably increased [START_REF] Bleich | Why is the developed world obese?[END_REF].

In addition, a significant reduction in physical activity partly linked to a more sedentary urban lifestyle and an increase in time spent in front of television or other screens, also contributes significantly to the increase in obesity. This is particularly accurate for children and adolescents [START_REF] Rennie | Association of physical activity with body-composition indexes in children aged 6-8 y at varied risk of obesity[END_REF]. Such sedentary lifestyle increases all causes of death, doubles the CVD risk, diabetes and obesity, and increases the risk of high blood pressure, osteoporosis, lipid disorders, depression and anxiety. According to WHO, 60-85% of the world's population in both developed and developing countries has a sedentary lifestyle, making it one of the biggest public health problems of our time, although it is still not receiving enough attention [START_REF] Charansonney | Disease prevention--should we target obesity or sedentary lifestyle?[END_REF]. It is also estimated that two thirds of children are not physically active enough, which will have serious consequences for their future health. Finally, overweight/obesity and physical inactivity have been closely linked to metabolic syndrome, an umbrella term used to describe a cluster of health conditions, including hypertension, hyperglycemia, hypertriglyceridemia, hypercholesterolemia and excessive waist fat, that occurrences are risk factors for stroke and diabetes.

b. Metabolic and cellular risk factors

Hypertension is very common in 30% of people with type 1 diabetes and 60% of people with type 2 diabetes. The concomitant manifestation of hypertension and diabetes synergistically increases the risk of stroke and cardiovascular accident (Figure 1). According to the ADA, the blood pressure target for diabetic patients is 130/80 mmHg (American Diabetes 2017; Chobanian 2017; [START_REF] Chobanian | Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure[END_REF]. Targeting this blood pressure level, that could be achieved with different antihypertensive agents, has largely contributed to the decreased of morbidity and mortality in people with diabetes since 1990 [START_REF] Ford | Explaining the decrease in U.S. deaths from coronary disease, 1980-2000[END_REF]).

Therefore, a large proportion of type 2 diabetes patients are on anti-hyperglycemic treatment plus antihypertensive drugs (often both aspirin and lipid-lowering agents that are mandated by the current standards of medical care). Although several antihypertensive treatment may be available, the interest in ACE inhibitors (angiotensin converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) is growing since they seem also to reduce the development of kidney injury and improve insulin action in diabetic patients [START_REF] Kirpichnikov | Role of ACE inhibitors in treating hypertensive diabetic patients[END_REF].

Hyperglycemia is closely related to increased morbidity and mortality in stroke and is recognized both as risk and aggravating factor in both diabetic and non-diabetic patients (Figure 1). Increment of glycated hemoglobin A1c blood level (HbA1c test evaluates the average level of blood sugar over the past months) is associated to an increased risk of firstever ischemic stroke in both diabetic and non-diabetic patients [START_REF] Mitsios | Relationship Between Glycated Hemoglobin and Stroke Risk: A Systematic Review and Meta-Analysis[END_REF]). For several years, various studies have shown beneficial effects of treatments aimed at lowering blood sugar levels on ischemic risks and current guidelines strongly recommend reducing HbA1c levels to < 7% to reduce the risk of cardiovascular complications. Nevertheless in the ADVANCE study, intensive treatments aimed at reducing HbA1c levels (<6.5%; witnesses a suitable control of glycemia) did not necessarily show a decrease in cardiovascular risk [START_REF] Group | Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes[END_REF][START_REF] Zoungas | Follow-up of bloodpressure lowering and glucose control in type 2 diabetes[END_REF]. Stricter therapeutic approaches with the objective of lowering HbA1c levels (<6%) (ACCORD study) have even indicated an increase in patient mortality. The same type of conclusion that glucose-lowering therapy did not significantly reduce cardiovascular events was first drawn in the Veterans Affairs Diabetes Trial (VADT) [START_REF] Murata | Blood glucose monitoring is associated with better glycemic control in type 2 diabetes: a database study[END_REF]). Nevertheless ulterior evidence showed that this strategy had led to reduced CVD events in VADT participants with lower calcified coronary atherosclerosis [START_REF] Reaven | Intensive glucose-lowering therapy reduces cardiovascular disease events in veterans affairs diabetes trial participants with lower calcified coronary atherosclerosis[END_REF]) and several limitations were noted in these randomized controlled trials [START_REF] Mitsios | Relationship Between Glycated Hemoglobin and Stroke Risk: A Systematic Review and Meta-Analysis[END_REF]. Overall, lessons from several studies indicate that intensive treatments for decreasing high blood sugar when initiated early lead to a reduction in cardiovascular risk.

Diabetes-related increase in intracellular glucose concentrations leads to the activation of deleterious metabolic pathways such as hexosamines and aldose reductase inducing the increased amount of reactive oxygen species, ROS and the depletion of antioxidant enzyme substrates. ROS are reactive molecules produced by aerobic metabolism. There is a link between the increase in ROS, under the control of NF-B, and the production of inflammatory cytokines. In addition, there is an increase in production of glycated products and activation of protein kinase Cdelta (deltaPKC), which plays a role in apoptosis after cerebral ischemia [START_REF] Perez-Pinzon | Role of reactive oxygen species and protein kinase C in ischemic tolerance in the brain[END_REF]. Altogether this suggests that diabetes manifestations including increased ROS and inflammation may silently weaken the brain before stroke and/or predispose the brain to exaggerated inflammatory and injury responses after stroke. Therefore it is not surprising that increased proinflammatory response due to diabetes is further exacerbated in response to stroke and probably is a major leader of the observed increased ischemic damage [START_REF] Shukla | Cerebral ischemic damage in diabetes: an inflammatory perspective[END_REF].

Hypertriglyceridemia, hypercholesterolemia and excess in waist fat: With the increasing number of obese people worldwide [START_REF] Poirier | Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism[END_REF] concentration. These changes are often associated with a predisposition to rapid and aggressive atherosclerosis [START_REF] Watts | Dyslipoproteinaemia and hyperoxidative stress in the pathogenesis of endothelial dysfunction in non-insulin dependent diabetes mellitus: an hypothesis[END_REF]. LDL-lowering therapies -primarily statins-are commonly prescribed to reduce the risk of stroke. More interestingly, reduction in LDL-cholesterol and triglycerides and increase in HDL-cholesterol are known to be protective for stroke risk in patients with type 2 diabetes [START_REF] Colhoun | Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebocontrolled trial[END_REF]. A recent work showed that antihyperglycemic drugs like sodium-glucose co-transporter-2 (SGLT-2) inhibitor, dapagliflozin, might also suppress potent atherogenic LDL-cholesterol and increased HDL2cholesterol, a favorable cardiometabolic marker [START_REF] Hayashi | Dapagliflozin decreases small dense low-density lipoprotein-cholesterol and increases highdensity lipoprotein 2-cholesterol in patients with type 2 diabetes: comparison with sitagliptin[END_REF]). However, the approach for efficacious lipid modification in these high-risk individuals is somewhat complicated and deserves more attention.

Diabetes, obesity and the associated insulin resistance are related to low noise inflammation. This is characterized by the over-expression of cytokines produced by adipose tissue and activated macrophages [START_REF] Hotamisligil | Inflammation and metabolic disorders[END_REF]. Insulin resistance causes, partially by increasing Free Fatty Acid (FFA) in the blood, reduced glucose uptake in the liver, adipose tissues and muscles and increased hepatic neoglucogenesis. These sequential deregulation mechanisms lead to hyperinsulinemia as a compensation process of insulin resistance. The relationships between FFA, ROS, TNF and other cytokines generate the expression of many genes associated with insulin resistance [START_REF] Shoelson | Inflammation and insulin resistance[END_REF][START_REF] Wellen | Inflammation, stress, and diabetes[END_REF].

The expression of a number of cytokines (IL1-, CRP, Adiponectin) indicates a cellular response to stress. Thus, it is likely that this low noise inflammation may be a common causal factor in diabetes, insulin resistance, obesity and cardiovascular disorders. However, how the priming of these mechanisms affects stroke risk and severity has not yet fully considered despite evident mechanistic overlap and commonalty in signal transduction between both pathologies.

6-Mechanistic overlap / commonalty in signal transduction

The common features observed in different organs and cellular systems are often viewed as bases of the correlations existing between pathologies. This concept of conservation of cellular signaling and mechanisms between organs and cell types may also apply for diabetes and stroke. Many signaling pathways involved in the loss of function, in the regression of key organs or even in cell death are found both at the periphery and the central system. It is also interesting to note that the expression of the same genes is necessary for certain endocrine and neural functions. In addition, the cell dysfunctions are often driven by alteration of shared mechanisms such as the loss of expression of transcription factors such as CREB, NF-B and kinases activated by second messengers, such as JNK, protein kinase A (PKA) and Ca2+/calmodulin kinase (CamK). Phosphorylation is a crucial post-translational modification of proteins, which is involved in a very large number of cellular processes (differentiation, division, proliferation, apoptosis, etc.) and particularly in signaling mechanisms.

a. Cyclic adenosine monophosphate (cAMP)

cAMP, the second most common and versatile messenger, controls a range of physiological processes such as regulated secretion (of neurotransmitters and peptide hormones), ion channel conductance, learning and memory, apoptosis and inflammation [START_REF] Beavo | Cyclic nucleotide research --still expanding after half a century[END_REF]. G protein-coupled receptors closely control the cellular content of cAMP through adenylyl cyclase and cyclic nucleotide phosphodiesterase [START_REF] Hanoune | Regulation and role of adenylyl cyclase isoforms[END_REF][START_REF] Lugnier | Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents[END_REF]. Protein kinase A (PKA) and the two EPAC proteins (cAMP-activated guanine nucleotide exchange factor for Ras-like GTPases) are the cAMP mediators. This signal transduction cascade can ultimately lead to the phosphorylation of CREB (Figure 2).

The activation of the PKA phosphorylates the CREB Ser133 located in its inducible kinase domain. PKA pathway modulating CREB activity is implicated in survival and preservation of function of endocrine cells [START_REF] Jhala | cAMP promotes pancreatic beta-cell survival via CREB-mediated induction of IRS2[END_REF] and neurons [START_REF] Riccio | Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons[END_REF]. Preclinical studies indicate that new anti-diabetic therapies based on GLP1 receptor agonists may be capable, in addition to promote insulin secretion regulation, of facilitating the maintenance of endocrine function, boosting cell proliferation while preventing their apoptosis through the activation of cAMP/PKA/CREB pathway [START_REF] Lee | Anti-diabetic actions of glucagon-like peptide-1 on pancreatic betacells[END_REF]. Similarly in neurons, ligands capable of stimulating cAMP production increase the amount of P-CREB that is acknowledged as a multifaceted regulator of neuronal plasticity and protection (Figure 2) [START_REF] Sakamoto | CREB: a multifaceted regulator of neuronal plasticity and protection[END_REF].

b. Ca 2+ /calmodulin-dependent protein kinase (CaMK)

An increase in cytosolic calcium concentration generates signaling pathways that involve the multifunctional calcium-binding messenger protein calmodulin (CaM, Figure 2). The Ca 2+ /CaM dependent kinase cascade (CaMKinase) consists of three kinases: CaM kinase kinase (CaMKK) and CaMK I and IV, which are phosphorylated by the activated CaMKK.

These kinases are involved in survival and function maintenance processes [START_REF] Soderling | The Ca-calmodulin-dependent protein kinase cascade[END_REF].

While expressed in all eukaryotic cells, these proteins are particularly abundant in the brain and immune cells. CaMKK and CaMK IV are located in both nucleus and cytosol, while CaMK I is only cytosolic. CaMK IV regulates transcription through the phosphorylation of transcription factors such as CREB. There is a crosstalk between CaMK and other signaling pathways like PKA and serine-threonine kinase Akt (also known as protein kinase B (PKB).

The CaM Kinases cascade modulates apoptosis. For example, CaMKK is required for neuroprotection induced by the Akt pathway. Inversely, CaMKK can phosphorylate and activate the Akt pathway in vitro [START_REF] Yano | Calcium promotes cell survival through CaM-K kinase activation of the protein-kinase-B pathway[END_REF]), that will inhibit apoptosis modulating the pro-apoptotic Bcl2 pathway [START_REF] Soderling | The Ca-calmodulin-dependent protein kinase cascade[END_REF]. Interestingly, these protective effects have also been observed in the peripheral organs. The GLP1 receptor agonist, exendin 4, by activating CaMKK/CaMK IV increases glucokinase expression. This protein that prepares glucose for entering its metabolic pathways has a central role in the metabolic coupling between glucose concentration and insulin secretion [START_REF] Murao | Exendin-4 regulates glucokinase expression by CaMKK/CaMKIV pathway in pancreatic beta-cell line[END_REF]). In addition, exendin 4, an efficient GLP-1 analogue, controls the expression of the glucose transporter in  cells [START_REF] Chen | Exendin-4 regulates GLUT2 expression via the CaMKK/CaMKIV pathway in a pancreatic beta-cell line[END_REF]) via the CaMKK/CaMKIV pathway. In cytotoxic contexts, transcriptome analysis has shown that expression of genes encoding CaMKIIa and CaMKIV were suppressed under glucotoxic conditions [START_REF] Sugiyama | Calcium/calmodulin-dependent protein kinase IV involvement in the pathophysiology of glucotoxicity in rat pancreatic beta-cells[END_REF]) and also under ischemic stroke in apoptotic neurons [START_REF] Demyanenko | Profiling of Signaling Proteins in Penumbra After Focal Photothrombotic Infarct in the Rat Brain Cortex[END_REF].

c. c-Jun N-terminal kinases (Jun Kinase)

While the members of c-Jun N-terminal kinases (JNKs, Figure 2) family represent promising therapeutic targets for protection against ischemic processes and diabetes, their number and variety of physiological implications render their therapeutic targeting extremely complex. Numerous studies have carefully addressed the role of these stress-activated kinases in both stroke and diabetes. JNKs are involved in DNA proliferation, apoptosis, motility, metabolism and repair. JNKs phosphorylate cJun Ser63 and 75 in response to stress signals [START_REF] Behrens | Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation[END_REF]). JNKs are central in ischemia-induced apoptosis in brain [START_REF] Borsello | A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia[END_REF]. Increased JNK activity has deleterious effects leading to ischemic cell death. Transient focal ischemia induces nuclear localization of p-JNK and increase in cJun phosphorylation shortly after reperfusion [START_REF] Ferrer | Early modifications in the expression of mitogen-activated protein kinase (MAPK/ERK), stress-activated kinases SAPK/JNK and p38, and their phosphorylated substrates following focal cerebral ischemia[END_REF]. JNK is also activated in cardiac ischemia and reperfusion (Fryer 2001). Inhibitory approaches have demonstrated the involvement of JNKs in ischemic-induced cell death [START_REF] Waetzig | Context-specific inhibition of JNKs: overcoming the dilemma of protection and damage[END_REF], and preclinical evaluation of specific targeting of the JNK signaling pathway for preventing increase in c-Jun activation has demonstrated protective effect against pancreatic  [START_REF] Bonny | IB1 reduces cytokine-induced apoptosis of insulin-secreting cells[END_REF] and neuronal [START_REF] Borsello | A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia[END_REF] cell death. In addition, experimental evidence suggests that pharmacological inhibition of JNK activity by new antidiabetics, including exendin-4, metformin and rosiglitazonenonetheless acting through different pathways -may themselves be protective against brain ischemia in diabetic conditions [START_REF] Shvedova | c-Jun N-Terminal Kinases (JNKs) in Myocardial and Cerebral Ischemia/Reperfusion Injury[END_REF]).

The JNK pathway, that increased activity was found in tissues from diabetics is linked to insulin resistance and type 2 diabetes [START_REF] Wellen | Inflammation, stress, and diabetes[END_REF]. In the context of obesity and insulin resistance, JNK1 action seems predominant. JNK pathways are associated to transcription factor activity and abnormally elevated concentration of TNF observed in obesity condition leads to JNK mediated phosphorylation at Ser 307 of IRS-1 [START_REF] Hirosumi | A central role for JNK in obesity and insulin resistance[END_REF]. While future search for selective JNKs inhibitors remains crucial, the concept that specific inhibitors for JNK would ameliorate insulin resistance and diabetes hold promises [START_REF] Solinas | JNK at the crossroad of obesity, insulin resistance, and cell stress response[END_REF].

d. Transcription factor CREB

Among the transcription factors described for maintaining the neuronal phenotype, the cAMP response element binding protein (CREB, Figure 2) has been extensively studied.

CREB is a mediator of response to neurotrophins such as the Nerve Growth Factor (NGF).

Gene expression under the control of CREB is necessary for NGF-induced survival [START_REF] Riccio | Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons[END_REF]. The activation of the cellular transcription factor CREB requires the activation of different upstream signaling pathways and kinases. But taken as a whole the increase in phosphorylated CREB is an acknowledged marker of cell survival. CREB plays a central role in survival processes, but also in many other physiological processes. Thus, it is not surprising that a decrease in its expression has considerable effects. CREB is not only activated by the stimuli necessary for growth and survival but also by cellular stresses, such as hypoxia and oxidative stress representing a form of cellular defense. Specifically, recovery from stroke is associated with increased plasticity around the infarct zone [START_REF] Rivera-Urbina | Parietal transcranial direct current stimulation modulates primary motor cortex excitability[END_REF]. This study indicates that there is a transcription under CREB control that is crucial for the modulation of neuronal excitability and in the structuring of cortical plasticity and memory.

Recently, Caracciolo and colleagues [START_REF] Caracciolo | CREB controls cortical circuit plasticity and functional recovery after stroke[END_REF]) have shown that the overexpression of CREB accelerates the recovery of motor deficits after stroke. In parallel, it has been shown that the CREB extinction in the insulin secreting endocrine  cell is associated with glucose intolerance in type 2 diabetes [START_REF] Abderrahmani | ICER induced by hyperglycemia represses the expression of genes essential for insulin exocytosis[END_REF]Favre et al. 2011b). This decline in CREB activity is correlated with the emergence of a related gene transcript, ICER (inducible cAMP early repressor), that is the natural inducible CREB antagonist. The inappropriate expression of ICER explains the dysfunction of  cells and ultimately  cell death due to chronic hyperglycemia, hyperlipidemia and oxidized LDL [START_REF] Salvi | Decompensation of beta-cells in diabetes: when pancreatic beta-cells are on ICE(R)[END_REF]. Chronic exposure of  cells to high glucose concentrations causes a decrease in CREB protein due to hyper ubiquitination and its subsequent degradation [START_REF] Costes | Degradation of cAMP-responsive element-binding protein by the ubiquitin-proteasome pathway contributes to glucotoxicity in beta-cells and human pancreatic islets[END_REF]). Nevertheless, a fine regulation of the equilibrium in the expression level of CREB and ICER is required, as an uncontrolled CREB expression and activity will also lead to insulin-resistance. Indeed, in the insulin-resistant adipocytes of obese patients, reduction of ICER level elevates CREB activity, which activates the expression of the CREBtargeted gene activating transcription factor 3 (ATF3). ATF3 that is described as an adaptive response gene to stressful stimuli belongs to the ATF/cyclic AMP responsive element binding family of transcription factors. The ATF3 raise downregulates the expression of Glut4 in white adipose tissue (WAT), thereby contributing to systemic insulin resistance [START_REF] Brajkovic | Evidence for tuning adipocytes ICER levels for obesity care[END_REF]Favre et al. 2011a). Adding a level of complexity, it is worth of note that in obese condition the regulation of ICER differs among cell types, possibly leading to different modulation of CREB activity in cells other than adipocytes. With regard to stroke, at the central level, ATF3 is weakly expressed in normal condition but rapidly upregulated in response to ischemic injury. ATF3 expression in neurons is accepted as a neuroprotective step against stroke, while its role in heart failure is still controversial [START_REF] Hunt | Activating transcription factor 3 and the nervous system[END_REF][START_REF] Zhang | A signaling cascade of nuclear calcium-CREB-ATF3 activated by synaptic NMDA receptors defines a gene repression module that protects against extrasynaptic NMDA receptor-induced neuronal cell death and ischemic brain damage[END_REF][START_REF] Brooks | Induction of activating transcription factor 3 limits survival following infarct-induced heart failure in mice[END_REF].

e. Transcription factor NF-B

The family of NF-B transcription factors includes a collection of dimeric proteins formed from the subunits p50, p52, RalA/p65, RelB and c Rel. In most resting cells, NF-B is located in the cytoplasm, associated with its inhibitor IB. In response to a wide range of stimuli, such as IL1, TNF, LPS or various forms of stress, IB is phosphorylated by IKK kinase.

After ubiquitination, IB becomes a substrate for the proteasome, which releases a NF-B dimer that can then enter the nucleus and regulate its target genes. This is part of the inflammatory response. The IKK/NF-B signaling pathway is essential to connect inflammation with altered metabolism and decreased insulin action [START_REF] Hotamisligil | Nutrient sensing and inflammation in metabolic diseases[END_REF][START_REF] Solinas | JNK1 and IKKbeta: molecular links between obesity and metabolic dysfunction[END_REF][START_REF] Medzhitov | Origin and physiological roles of inflammation[END_REF]. Metabolic stress signals generate insulin resistance and/or a dysfunction of pancreatic  cells. In liver cells and adipocytes of obese people, NF-B activation is induced in response to nutritional overload or cytotoxic factor production, allowing macrophage recruitment and subsequent inactivation of insulin receptor signaling.

Inflammatory reactions can be both beneficial and harmful to the brain, depending on the strength of their activation. The same can be said for NF-B, which activation is required for getting the protective effect of several models of brain preconditioning [START_REF] Blondeau | Activation of the nuclear factor-kappaB is a key event in brain tolerance[END_REF], and is conversely crucial to mediate neuroinflammatory harmful effects following stroke. NF-B is activated in neurons and glial cells under acute neurogenerative conditions such as stroke and trauma. NF-B activation in neurons can promote their survival by inducing the expression of anti-apoptotic proteins such as Bcl2 and the enzyme Mn-superoxide dismutase [START_REF] Chu | Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-kappaB control[END_REF][START_REF] Tamatani | Tumor necrosis factor induces Bcl-2 and Bcl-x expression through NFkappaB activation in primary hippocampal neurons[END_REF]). On the other hand, by inducing the production and release of inflammatory cytokines and reactive oxygen molecules, NF-B activation in microglia and astrocytes can contribute to neuronal degeneration [START_REF] Bruce | Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors[END_REF][START_REF] John | Cytokines: powerful regulators of glial cell activation[END_REF]. Therefore while the contribution of NF-κB pathways is complex, the idea of its therapeutic targeting in both diabetes and stroke is still the focus of intense investigations.

7-Concluding remarks

While consequences of diabetes are not anymore underestimated in stroke and as supported by the present review, it seems now intuitive that mechanistic overlaps are key issues in the genesis and consequences of stroke and diabetes. However, there is still a paucity of scientific and clinical data to direct the public and clinicians in this important area.

Whereas, it is clear that more work should be devoted to understand how diabetes leads to an increased risk of stroke and an exacerbation of stroke damage, another area of interest has also emerged. This is the novel concept that therapeutic drugs aimed at targeting the overlapping pathways may benefit to both pathologies. We are now witnessing the beginning of a mindset switch from the FDA requesting cardiovascular outcome trials for testing putative side effects of glucose-lowering agents on cardiovascular risks, to the integration of cardiovascular outcome as readout for all new diabetes treatments to evaluate their capacity of significantly reducing cardiovascular risks in diabetic patients. This switch in mindset that these drugs may have benefits beyond lowering blood glucose could be of great value to discover new anti-diabetic treatments associated to the opportunity to reduce stroke risks and/or consequences. Such clinical fact echoes the Stroke Therapy Academic Industry Roundtable (STAIR) guidelines that have identified since long time the necessity of evaluating therapeutic candidates against stroke in animals presenting co-morbidities to closely reproduce stroke clinical scenario (Stroke Therapy Academic Industry 1999). As recently detailed in a nice review by Ashish K. Rehni, several animal models to study ischemic brain injury during diabetes may be available and their use should be spread to ensure generation of more clinically relevant data in the field [START_REF] Rehni | Diabetic aggravation of stroke and animal models[END_REF]. Given the high incidence of stroke and exacerbation of ischemic brain damage in diabetic patients, the momentum is built to increase the development of animal studies to 1/ evaluate the importance of targeting the effect of diabetes on stroke outcomes, 2/ identify key pathophysiological mechanisms of diabetic enhancement of brain injury during stroke.

Research in this area would probably emerge of overlapping pathways and common drug targets against both pathologies.

FIGURE LEGEND

Figure 1: The hypnotic spiral linking diabetes, obesity, behavioral risk and ischemic stroke.

A common view is that environmental risks (like nutrition and sedentarity) and metabolic pathologies (including obesity and diabetes) are interconnected and share common pathological features, including hyperglycemia and hypertension at the systemic level and increased inflammation and ROS at the molecular level. Overall each of these parameters individually or in association contribute to an hypnotic spiral toward increased risk of having a stroke and displaying exacerbated ischemic damage.

  , we are witnessing a parallel progression in the other risks of chronic diseases. Obesity, mainly characterized by the accumulation of visceral fat, is often associated with an increase in low noise inflammation and elevation of serum factors such as cytokines and chemokines that can generate multiple deleterious effects, including CNS tissue damage induced by stroke (Allan and Rothwell 2003; Le Thuc et al. 2015). Excess ROS generated by hyperglycemia induces histone 3 methylation, which increases NF-B expression (El-Osta et al. 2008). Obesity is often accompanied by dyslipidemia, increased very low density lipoprotein (VLDL) cholesterol, triglycerides, low-density lipoprotein (LDL) and decreased high-density lipoprotein (HDL)

Figure 2 :Figure2

 2 Figure 2: Signaling pathways overlapping in diabetes and stroke and occurring in both  and neuronal cell.

Funding

This work was funded by the Centre National de la Recherche Scientifique -CNRS.

Conflict of Interest

The authors declare that they have no conflict of interest.