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Hypoxia-inducible factors (HIFs) are the key regulators of oxygen homeostasis in response to hypoxia. In diabetes, multiple tissues are hypoxic but adaptive responses to hypoxia are impaired due to insufficient activation of HIF signalling, which results from inhibition of HIF-1α stability and function due to hyperglycaemia and elevated fatty acid levels. In this review, we will summarise and discuss current findings about the regulation of HIF signalling in diabetes and the pathogenic roles of hypoxia and dysregulated HIF signalling in the development of diabetes and its complications. The therapeutic potential of targeting HIF signalling for the prevention and treatment of diabetes and related complications is also discussed.

Diabetes mellitus is currently a major public health problem. A common complication of diabetes is cardiac dysfunction, which is recognized as a microvascular disease that leads to morbidity and mortality in diabetic patients. While ischemic events are commonly observed in diabetic patients, the risk for developing heart failure is also increased, independent of the severity of coronary artery disease and hypertension. This diabetes-associated clinical entity is considered a distinct disease process referred to as “diabetic cardiomyopathy”. However, it is not clear how diabetes promotes cardiac dysfunction. Vascular endothelial dysfunction is thought to be one of the key risk factors. The impact of diabetes on the endothelium involves several alterations, including hyperglycemia, fatty acid oxidation, reduced nitric oxide (NO), oxidative stress, inflammatory activation, and altered barrier function. The current review provides an update on mechanisms that specifically target endothelial dysfunction, which may lead to diabetic cardiomyopathy.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia, responsible for the onset of several long-term complications. Recent evidence suggests that cognitive dysfunction represents an emerging complication of DM, but the underlying molecular mechanisms are still obscure. Dopamine (DA), a neurotransmitter essentially known for its relevance in the regulation of behavior and movement, modulates cognitive function, too. Interestingly, alterations of the dopaminergic system have been observed in DM. This review aims to offer a comprehensive overview of the most relevant experimental results assessing DA’s role in cognitive function, highlighting the presence of dopaminergic dysfunction in DM and supporting a role for glucotoxicity in DM-associated dopaminergic dysfunction and cognitive impairment. Several studies confirm a role for DA in cognition both in animal models and in humans. Similarly, significant alterations of the dopaminergic system have been observed in animal models of experimental diabetes and in diabetic patients, too. Evidence is accumulating that advanced glycation end products (AGEs) and their precursor methylglyoxal (MGO) are associated with cognitive impairment and alterations of the dopaminergic system. Further research is needed to clarify the molecular mechanisms linking DM-associated dopaminergic dysfunction and cognitive impairment and to assess the deleterious impact of glucotoxicity.

Hypoxia can be defined as a relative deficiency in the amount of oxygen reaching the tissues. Hypoxia-inducible factors (HIFs) are critical regulators of the mammalian response to hypoxia. In normal circumstances, HIF-1α protein turnover is rapid, and hyperglycemia further destabilizes the protein. In addition to their role in diabetes pathogenesis, HIFs are implicated in development of the microvascular and macrovascular complications of diabetes. Improving glucose control in people with diabetes increases HIF-1α protein and has wide-ranging benefits, some of which are at least partially mediated by HIF-1α. Nevertheless, most strategies to improve diabetes or its complications via regulation of HIF-1α have not currently proven to be clinically useful. The intersection of HIF biology with diabetes is a complex area in which many further questions remain, especially regarding the well-conducted studies clearly describing discrepant effects of different methods of increasing HIF-1α, even within the same tissues. This Review presents a brief overview of HIFs; discusses the range of evidence implicating HIFs in β cell dysfunction, diabetes pathogenesis, and diabetes complications; and examines the differing outcomes of HIF-targeting approaches in these conditions.

Type 2 diabetes is a metabolic, chronic disorder characterized by insulin resistance and elevated blood glucose levels. Although a large drug portfolio exists to keep the blood glucose levels under control, these medications are not without side effects. More importantly, once diagnosed diabetes is rarely reversible. Dysfunctions in the kidney, retina, cardiovascular system, neurons, and liver represent the common complications of diabetes, which again lack effective therapies that can reverse organ injury. Overall, the molecular mechanisms of how type 2 diabetes develops and leads to irreparable organ damage remain elusive. This review particularly focuses on novel targets that may play role in pathogenesis of type 2 diabetes. Further research on these targets may eventually pave the way to novel therapies for the treatment—or even the prevention—of type 2 diabetes along with its complications. Type 2 diabetes is a complex metabolic disorder associated with a plethora of complications in peripheral organs. This review article highlights the novel targets that might play role in pathogenesis of type 2 diabetes. Further research on these targets might eventually pave the way to novel therapies for the treatment–or even the prevention–of type 2 diabetes.

Ferroptosis is a novel form of nonapoptotic regulated cell death (RCD). It features iron-dependent lipid peroxide accumulation accompanied by inadequate redox enzymes, especially glutathione peroxidase 4 (GPX4). RAS-selective lethal 3 (RSL3), erastin, and ferroptosis inducing 56 (FIN56) induce ferroptosis via different manners targeting GPX4 function. Acyl-CoA synthetase long-chain family 4 (ACSL4), lysophosphatidylcholine acyltransferase 3 (LPCAT3), and lipoxygenases (LOXs) participate in the production of lipid peroxides. Heat shock protein family B member 1 (HSPB1) and nuclear receptor coactivator 4 (NCOA4) regulate iron homeostasis preventing ferroptosis caused by the high concentration of intracellular iron. Ferroptosis is ubiquitous in our body as it exists in both physiologic and pathogenic processes. It is involved in glucose-stimulated insulin secretion (GSIS) impairment and arsenic-induced pancreatic damage in the pathogenesis of diabetes. Moreover, iron and the iron-sulfur (Fe-S) cluster influence each other, causing mitochondrial iron accumulation, more reactive oxygen species (ROS) production, endoplasmic reticulum (ER) stress, failure in biosynthesis of insulin, and ferroptosis in β-cells. In addition, ferroptosis also engages in the pathogenesis of diabetic complications such as myocardial ischemia and diabetic cardiomyopathy (DCM). In this review, we summarize the mechanism of ferroptosis and especially its association with type 2 diabetes mellitus (T2DM).

Asymptomatic hypoglycemia is a major problem in diabetes. Mechanisms involved in a patient's inability to sense low glucose levels are reviewed. Autonomic dysfunction is a key contributor. Mechanistic studies suggest interventions that may restore the normal autonomic response. Iatrogenic hypoglycemia is the limiting factor in the glycemic management of diabetes. 1 It causes recurrent illness in most people with type 1 diabetes mellitus and in many with advanced type 2 diabetes mellitus and is sometimes fatal. It generally precludes maintenance of euglycemia over a lifetime of diabetes and thus full realization of the benefits of glycemic control. Various mechanisms, discussed in this review, cause a vicious cycle of recurrent hypoglycemia. Compromised Defenses against Hypoglycemia As plasma glucose levels fall, the physiologic defenses against hypoglycemia 1 , 2 are a decrease in the secretion of the glucose-lowering pancreatic beta-cell hormone insulin, an . . .

Type 2 diabetes mellitus (T2DM) is associated with cognitive impairment and may progress to dementia. However, the brain functional mechanism of T2DM‐related dementia is still less understood. Recent resting‐state functional magnetic resonance imaging functional connectivity (FC) studies have proved its potential value in the study of T2DM with cognitive impairment (T2DM‐CI). However, they mainly used a mass‐univariate statistical analysis that was not suitable to reveal the altered FC “pattern” in T2DM‐CI, due to lower sensitivity. In this study, we proposed to use high‐order FC to reveal the abnormal connectomics pattern in T2DM‐CI with a multivariate, machine learning‐based strategy. We also investigated whether such patterns were different between T2DM‐CI and T2DM without cognitive impairment (T2DM‐noCI) to better understand T2DM‐induced cognitive impairment, on 23 T2DM‐CI and 27 T2DM‐noCI patients, as well as 50 healthy controls (HCs). We first built the large‐scale high‐order brain networks based on temporal synchronization of the dynamic FC time series among multiple brain region pairs and then used this information to classify the T2DM‐CI (as well as T2DM‐noCI) from the matched HC based on support vector machine. Our model achieved an accuracy of 79.17% in T2DM‐CI versus HC differentiation, but only 59.62% in T2DM‐noCI versus HC classification. We found abnormal high‐order FC patterns in T2DM‐CI compared to HC, which was different from that in T2DM‐noCI. Our study indicates that there could be widespread connectivity alterations underlying the T2DM‐induced cognitive impairment. The results help to better understand the changes in the central neural system due to T2DM. We used high‐order functional connectivity to reveal the abnormal connectomics pattern in T2DM with cognitive impairment with a multivariate, machine learning‐based strategy. We also investigated whether such patterns were different between T2DM with cognitive impairment and T2DM without cognitive impairment to better understand T2DM‐induced cognitive impairment. Our study is well suited for publication in Human Brain Mapping as we used this method is highly advanced and desirable for extensive applications in the future. Meanwhile, it is of great help for standardizing the methodology and boosting clinical applications of the functional imaging‐based machine learning with improved reproducibility, generalizability, and interpretability.

Elevated blood pressure is closely related to increased circulatory fluid volume and peripheral vascular resistance. Patients with diabetes mellitus experience increased peripheral artery resistance caused by vascular remodeling and increased body fluid volume associated with insulin resistance-induced hyperinsulinemia and hyperglycemia. Both of these mechanisms elevate systemic blood pressure. Thus, fully understanding the pathophysiology of hypertension in diabetes mellitus requires knowing the natural history of type 2 diabetes. Patients exhibit hyperinsulinemia with insulin resistance due to impaired glucose tolerance and early-stage diabetes. Hypertension occurs because of increased body fluid volume. After reaching mid-stage diabetes the vascular remodeling has progressed and peripheral vascular resistance also contributes to hypertension. Moreover, vascular remodeling strongly influences diabetic complications. Specifically, afferent arteriolar remodeling during diabetic nephropathy leads to increased glomerular pressure. Thus, treatment with a renin-angiotensin system inhibitor that promotes renal damage regression is critical to lowering the systemic blood pressure and dilating efferent arterioles to reduce glomerular pressure.

Early microvascular damage in diabetes (e.g. capillary nonperfusion and ischemia) can now be assessed and quantified with optical coherence tomography-angiography (OCT-A). The morphology of vascular tissue is indeed affected by different factors; however, there is a paucity of data examining whether OCT-A metrics are influenced by ocular, systemic and demographic variables in subjects with diabetes. We conducted an observational cross-sectional study and included 434 eyes from 286 patients with diabetes. Foveal avascular zone (FAZ) area, FAZ circularity, total and parafoveal vessel density (VD), fractal dimension (FD), and vessel diameter index (VDI) from the superficial capillary plexus OCT-angiogram were measured by a customized automated image analysis program. We found that diabetic retinopathy (DR) severity was associated with increased FAZ area, decreased FAZ circularity, lower VD, lower FD, and increased VDI. Enlarged FAZ area was correlated with shorter axial length and thinner central subfield macular thickness. Decreased FAZ circularity was correlated with a reduction in visual function. Decreased VD was correlated with thinner macular ganglion-cell inner plexiform layer. Increased VDI was correlated with higher fasting glucose level. We concluded that the effects of ocular and systemic factors in diabetics should be taken into consideration when assessing microvascular alterations via OCT-A.