Impact of diabetes on cellular connections: Pathological insights and emerging therapeutic targets.

Pancreatic transplantation for patients with Type I diabetes

As we know diabetes mellitus is the most common metabolic endocrine disorder. According to the WHO and American Diabetes Mellitus, diabetes mellitus is the 3rd leading cause of death if we were to include all secondary complications. However without including secondary complications, it is 7th place in mortality and morbidity. The point to be considered in the case of diabetes mellitus is the secondary complications caused in this condition. Almost all organs affected by diabetes and results in a potentially worse condition. The major secondary complications are neuropathy, nephropathy, retinopathy, and diabetes foot microvascular and macrovascular complications. The long term complications grow slowly in the case of diabetes. As the time living with diabetes becomes longer, controlled glucose levels will be more difficult to achieve, meaning there there will be more long term complications. The aim of the current Research Topic on the secondary complications of diabetes and their management is to publish good quality research articles as well as reviews, which should address the management of diabetes, abnormalities of secondary complications and other disease involved in diabetes. Potential Topics includes but not restricted to: • Secondary complications of diabetes mellitus • Microvascular and macrovascular complications • The role of oxidative stress in the diabetes burden • New insights in glycemic control • New strategies/ approaches to manage secondary complications such as Stearoyl CoA dismutase, Acetyl CoA Carboxylase, Adiponectin/ Adipocyte complement-related protein 30, Hormone Sensitive Lipase (HSL) Inhibitors • Recent development in the therapeutic approaches for glucose management such as Protein tyrosine phosphatase-1B (PTP1B) inhibitors, Glycogen synthase kinase-3 (GSK3) inhibitors, β3- Adrenergic receptor agonist, Retinoid X receptor, PPARα agonist, AMP activated protein kinase • Development of new target as a target for antihyperglycemic drug designing

Diabetes mellitus is associated with secondary complications such as diabetic retinopathy (DR), nephropathy (DN), and cardiomyopathy (DCM), all of which significantly impact patient health. Intercellular adhesion molecule-1 (ICAM-1) has been implicated in inflammatory responses and endothelial dysfunction, both crucial in the pathogenesis of these complications. The goal of this review is to investigate at potential therapy methods that target ICAM-1 pathways and to better understand the multifaceted role of ICAM-1 in secondary diabetic problems. A meticulous analysis of scholarly literature published globally was conducted to examine ICAM-1involvement in inflammatory processes, endothelial dysfunction, and oxidative stress related to diabetes and its complications. Elevated ICAM-1 levels are strongly associated with augmented leukocyte adhesion, compromised microvascular function, and heightened oxidative stress in diabetes. These pathways contribute significantly to DR, DN, and DCM pathogenesis, highlighting ICAM-1 as a key player in their progression. Understanding ICAM-1 role in secondary diabetic complications offers insights into novel therapeutic strategies. Targeting ICAM-1 pathways may mitigate inflammation, improve endothelial function, and ultimately attenuate diabetic complications, thereby enhancing patient health outcomes. Continued research in this area is crucial for developing effective targeted therapies.

COVID-19 is caused by the SARS-CoV-2 virus, which has afflicted more than 245.37 million individuals worldwide and resulted in more than 4.9 million deaths as of today, with a mortality rate of 2.1%. Diabetes mellitus (DM) and its secondary complications are the major serious global health concerns today due to its growth rate, and it is the fastest-growing non-communicable disease. According to International Diabetes Federation (IDF) data, one out of 11 adults is diabetic, and the projection says that the figure will reach 642 million by 2040 globally. The occurrence of DM and its secondary complications is also associated with the severity of COVID-19 and high mortality. People with DM have a weakened immune system owing to innate immunity defects affecting phagocytosis, neutrophil chemotaxis, and cellmediated immunity; however, the high prevalence of diabetes in serious cases of COVID-19 may reflect the higher prevalence of type 2 DM (T2DM) in older people. Moreover, DM is linked to cardiovascular illness in older people, which could underlie the correlation between COVID-19 and fatal outcomes. SARS-CoV-2 infects via the angiotensin-converting enzyme 2 (ACE2), which is found in pancreatic islets, and infection with SARS-CoV-1 has been linked to hyperglycemia in individuals who do not have DM. And hence diabetic patients need to take more precautions and maintain their blood glucose levels. Many pieces of research say that COVID-19 and DM, especially its secondary complications are interlinked. But it also needs more elaborative evidence on whether the anti-diabetic drugs can manage only blood glucose or SARS-CoV-2.

Only about 8% of all pancreas transplants for insulin-dependent diabetes mellitus are performed in the Pancreas Transplant Alone (PTA) category. PTAs are primarily performed in diabetic, non-uremic patients with unstable glucose control, hypoglycemia unawareness, and an increased risk of diabetes-related mortality, and who have failed all of the more traditional approaches to glycemic control. Tremendous, yet not widely noticed, progress in PTA outcome has been made over the past two decades. PTA is a very safe procedure with 1-and 5-year patient survival rates of 98.3% and 90.5% according to International Pancreas Transplant Registry (IPTR) data. Since the introduction of tacrolimus and mycophenolate mofetil maintenance therapy in the 1990s and the use of depleting antibody induction therapy, PTA graft survival rates at 1-and 5-years posttransplant are 87.2% and 65.0%. To avoid the need for a future kidney after pancreas (KAP) transplant due to impaired pretransplant native kidney function and the posttransplant use of calcineurin inhibitors, the estimated Glomerular Filtration Rate (eGFR) of PTA candidates should be well within the normal range and preferably > 80 mL/min/1.73m². PTAs with stable, long-term function have been shown to have a positive impact on secondary complications of diabetes mellitus. Considering the significantly improved outcome results, PTA should become the pancreas transplant option of choice before the manifestation of devastating secondary complications (kidney failure, cardio-cerebrovascular events, and blindness) that require simultaneous pancreas and kidney (SPK) transplants in qualified candidates, but with higher morbidity and mortality risks. It is important for diabetologists, endocrinologists, and other health professionals involved in the care of diabetic patients to learn about these positive PTA outcome results. Despite improvements in intensive insulin therapy, insulin-delivering devices, bioartificial pancreas, and islet transplantation, a successful PTA is the only treatment option for patients with brittle diabetes that consistently restores normal glucose homeostasis long-term without exposing recipients to the risks of severe hypoglycemia and prevents, halts, or reverses the development or progression of secondary diabetes complications.

It has been verified that serum N-acetyl-?-D-glucosaminidase (NAG) activity is elevated in diabetes, but there are no reports about changes of the sialic acid (SA) content in the carbohydrate parts of NAG A form and its influence on total NAG activity changes in type 1 diabetes mellitus patients without and with secondary complications. NAG A forms were isolated, purified and characterized from the serum of 81 IDDM patients with and without secondary complications (retinopathy, polyneuropathy and nephropathy) and 25 healthy persons. The content of ?-2,6-bound SA and isoenzyme patterns of purified A form, total NAG and A form activities were determined. In all diabetic groups, A form sialylation levels were 2-3.5 times lower compared to control, while their acidities (fractions with pI 4.25-5.1) increased, particularly with progression of secondary complications. Total serum NAG activities and percentages of A form were significantly higher (P<0.001) in all diabetic groups and negatively correlated with the ?-2,6-bound SA content of the A form. In addition, they decreased as secondary diabetic complications became more complex. Observed changes could be the consequence of structural changes in the A form due to significant increase in its acidity, i.e. negative charge which originate from groups other than SA.

Diabetes mellitus is a chronic metabolic disorder characterized by sustained hyperglycemia, tightly interlinked with a range of severe secondary complications. Diabetic retinopathy, nephropathy, and cardiomyopathy substantially contribute to the overall morbidity and mortality associated with diabetes. In light of these critical issues, it becomes imperative to unravel the intricate molecular pathways underpinning the emergence of these secondary complications. This review endeavors to furnish an all‐encompassing synopsis of ongoing research about the role of VCAM‐1 in diabetic cardiomyopathy, nephropathy, and retinopathy. It delves into the intricate molecular mechanisms that underlie VCAM‐1’s involvement, with a particular emphasis on its interactions with integrins, chemokines, and cytokines. Comprehensive literature searches were conducted across several databases, including Scopus, PubMed, and Google Scholar. To pinpoint pertinent information, specific search terms such as “Diabetes,” “diabetic retinopathy,” “diabetic nephropathy,” and “diabetic cardiomyopathy,” all‐inclusive of VCAM‐1 as a contributory factor, were employed. Epidemiological insights were gleaned from Google Scholar and the World Health Organization (WHO) website. The study topic was constructed by collating relevant data from original research publications, reviews, meta‐analyses, and cross‐referenced sources. Moreover, this review explores the therapeutic implications of targeting VCAM‐1 in the management of diabetic complications. Recent advancement in the development of VCAM‐1 inhibitors is critically evaluated. In summation, gaining a comprehensive understanding of VCAM‐1’s role in diabetic complications offers a promising avenue to mitigate their adverse impact, ultimately enhancing clinical outcomes and elevating the quality of life for individuals living with diabetes.

Persistent hyperglycemia in patients with Type 2 diabetes mellitus is driving force for developing secondary complications like neuropathy, retinopathy, nephropathy, cardiomyopathy and wound healing impairment in them. Other genetic risk factor includes variants of transcription factor 7-like 2 (TCF7L2) gene, which have been shown to be associated with these several secondary complications individually. The present study represents a systematic review and Meta analysis using electronic databases like PubMed, OMIM, ISI web of science and Embase to see the role of rs7903146 C>T variant of the TCF7L2 gene with secondary complications of T2DM. Data was collected using literature-based searching to perform a Meta analysis to pool the odds ratio (OR). This Meta analysis comprised of a total of 2060 cases with secondary complication of T2DM and 3049 age matched controls. Publication bias and study-between heterogeneity were also evaluated. The present Meta analysis of included studies showed a highly significant association of risk genotype TT with development of secondary complications in T2DM.

Women with diabetes mellitus (DM) have asymptomatic bacteriuria (ASB) more often than women without DM. It is unknown, however, what the consequences of ASB are in these women. To compare women with DM with and without ASB for the development of symptomatic urinary tract infections (UTIs), renal function, and secondary complications of DM during an 18-month follow-up period. In this multicenter study we monitored women with DM with and without ASB for the development of symptomatic UTIs, renal function, and secondary complications (ie, retinopathy, neuropathy, microvascular, or macrovascular diseases). Data on the first 18-month follow-up period are presented. At least 1 uncontaminated urine culture was available from 636 women (258 with type 1 DM and 378 with type 2 DM). The prevalence of ASB at baseline was 26% (21% for those with type 1 DM and 29% for those with type 2 DM). Follow-up results were available for 589 (93%) of the 636 women. Of these 589 women, 115 (20%) (14% with type 1 DM and 23% with type 2 DM) developed a symptomatic UTI. Women with type 2 DM and ASB at baseline had an increased risk of developing a UTI during the 18-month follow-up (19% without ASB vs 34% with ASB, P =.006). In contrast, there was no difference in the incidence of symptomatic UTI between women with type 1 DM and ASB and those without ASB (12% with ASB vs 15% without ASB). However, women with type 1 DM and ASB had a tendency to have a faster decline in renal function than those without ASB (relative increase in serum creatinine level 4.6% vs 1.5%, P = 0.2). Women with type 2 DM and ASB have an increased risk of developing a symptomatic UTI than those without ASB.

Type 2 diabetes mellitus (T2DM) is the most frequent metabolic disease and is a major risk factor for cardiovascular diseases and mortality. About 9% of the worldwide population, around 347 million people, is expected to present this condition with 50% to 80% of them having a future fatal cardiovascular complication like myocardial infarction, stroke, or heart failure.1 Even more concerning, estimations from the National Health and Nutrition Examination Survey demonstrated that ≤35.3% of the adult US population has prediabetes.2 This is 4 times the number of subjects currently having already a diagnosis of T2DM.2 However, not much is known about the preclinical cardiovascular changes, such as alterations of left ventricular (LV) structure and function, associated with dysglycemic conditions before the diagnosis of T2DM. See Article by Demmer et al The study by Demmer et al3 in this issue of Circulation: Cardiovascular Imaging investigated the associations of 3 primary exposures (glycemic status, diabetes mellitus control, and insulin resistance as assessed by homeostasis model assessment-estimated insulin resistance quintiles) with cardiac structure and function by modern echocardiographic techniques. Although the diabetes mellitus status was based on American Diabetes Association criteria, the definitions were a little mixed with the use of glycohemoglobin (HbA1c), fasting plasma glucose, and 2-hour postload plasma glucose. The agreement among fasting plasma glucose, 2-hour postload plasma glucose, and HbA1c for the definition of groups of nondiabetic, prediabetic, and diabetic is not perfect, and individuals included in each group are expected to be different depending on the test used.4 Accordingly, a more preferable approach would be the use of just one definition. The study sample consisted of 1818 individuals (57% women) aged >45 years (average age: 56 years) with Hispanic/Latino ethnicity (predominant self-identifying …

To explore the influence of simultaneous pancreas-kidney(SPK) on secondary complications of diabetic recipients with end-stage renal disease. Methods A retrospective analysis of pre-and post-SPK data was performed in diabetic patients with end-stage renal disease. Results One case died of cerebrovascular accident, 7 cases recovered fluently. After a mean follow-up of 23.3 months, proteinuria decreased significantly, P<0.05, cardiac function and diabetic retinopathy showed no significance. Conclusions Simultaneous pancreas-kidney transplantation has a significant improvement on proteinuria in diabetic patients with end-stage renal disease. Key words: Simultaneous pancreas-kidney(SPK); Secondary complications; Postoperation

Diabetes mellitus (DM) is the third most common non-infectious disease leading to early disability and high mortality. Moreover, the number of patients is growing every year. The main symptom of DM is hyperglycemia. Increased levels of blood glucose activate polyol, hexosamine, and protein kinase metabolic pathways cause the intensification of non-enzymatic glycosylation and nitration of macromolecules. This, in turn, leads to the development of oxidative and nitrative stresses and secondary complications, such as different kinds of micro- and macroangiopathies. Metabolic disorders caused by insulin deficiency in diabetes significantly impede the functioning of a homeostasis system, which change the physical, biochemical, morphological, and functional properties of blood cells. As a result, the oxygen-transport function of red blood cells (RBCs), rheological properties of the blood, and functions of immunocompetent cells as well as the process of apoptosis are primarily affected. Modern pharmacotherapy focuses on the search for new preparations that aim to decrease blood glucose levels. Undesirable side effects and adverse reactions caused by synthetic medicines led to the search and investigation of new preparations of natural origin. Medicinal mushrooms play an important role among such new preparations. They are a source of a large number of high- and low-molecular compounds with pronounced biological effects. Our investigations show pronounced hypoglycemic and anti-anemic action of submerged cultivated mycelium powder of medicinal mushrooms Agaricus brasiliensis (A. brasiliensis) and Ganoderma lucidum (G. lucidum) on streptozotocin-induced DM in rats. Also, we showed that mycelium powders have membrane protective properties as evidenced by the redistribution of RBC populations towards the growth of full functional cell numbers. Normalization of parameters of leukocyte formula and suppression of apoptosis of white blood cells in diabetic rats treated with A. brasiliensis and G. lucidum mycelia indicates pronounced positive effects of these strains of mushrooms. Thus, the use of medicinal mushrooms for treatment of DM and in prevention development of its secondary complications might be a new effective approach of this disease’s cure. This article is aimed at summarizing and analyzing the literature data and basic achievements concerning DM type 1 treatment using medicinal mushrooms and showing the results obtained in our research.

Diabetes mellitus is a metabolic disorder with pathophysiology leading to various secondary complications such as nephropathy, neuropathy and retinopathy. The primary objective of the current study was to understand whether diabetic condition predisposes to exogenous neurotoxin insult. The neurotoxin chosen was acrylamide (ACR) because of its formation/ presence seen among various foods such as French fries, cookies and all deep fried or high heat processed carbohydrate-rich foods. Male adult Wistar rats were rendered diabetic using a single dose of streptozotocin (55mg/ kg bw, ip). After 1 week, the control and diabetic rats were sub-divided as follows: Group I: Control (received equal-volume of saline); Group II: ACR control (25 mg/ kg bw, ip, 3x/ wk); Group III – Diabetic control (received equal-volume of saline); Group IV – Diabetic administered with ACR (Diabetic + ACR; 25 mg/ kg bw, ip, 3x/ wk). Behavioural studies were carried out to check for sensory and motor functions on a weekly basis. At the end of 5 weeks, the rats were sacrificed and brain and sciatic nerve (SN) were collected for assessment of biochemical markers of oxidative mechanism and neurotransmission. Results suggest that diabetic rats were indeed predisposed to the neurotoxic effects of ACR (low dose). The development of neuropathic signs was advanced among the diabetic rats administered with ACR. The degree of oxidative impairments among diabetic rats administered with ACR was evident in SN and brain regions; the effects being more pronounced in SN. Further, an alteration in the cholinergic and dopaminergic function was also evident. Thus results obtained in this experimental design are suggestive of the vulnerability of diabetes to the neurotoxin.

t Diabetes mellitus, a significant cause of mortality around the globe, can result in several secondary complications, including diabetic foot syndrome, which is brought on by diabetic neuropathy and ischemia. Approximately 15% of diabetic patients suffer from diabetic foot complications, which results in high rates of morbidity and mortality of people with Diabetes mellitus. The study's objective is to measure serum levels of IL-37, IL-38 &amp; IL-17A in diabetic mellitus (type 1 &amp; 2) patients with and without diabetic foot ulcer complications and in the control group as well as the possibility of using them as early biomarkers for diagnosis of diabetic mellitus complications &amp; future prevention. Overall, of 193 participants included in this case-control study, they were divided into three groups: the first one contains patients with type 1 diabetes mellitus (29 with diabetic foot ulcer DFU+ 35 non-diabetic foot), the second group includes type 2 diabetes mellitus patients (41 with DFU + 38 Non). The third group includes (50) as apparently healthy controls. Serological techniques of sandwich ELISA did laboratory tests for specific serum human IL-37, IL-38, and IL- 17A. The study revealed that IL-37 and IL-17A levels were significantly high (P&lt;0.01) in all diabetic groups compared to the control healthy group. The results of IL-38 show substantially higher levels of T1DM and T2DM (P&lt;0.05) compared to the control group. In addition, the DFU group of T2DM illustrated higher levels of IL-37, IL-38, and IL-17A compared with other diabetic groups. In conclusion, Iraqi DM subjects with and without complications had higher values of interleukins, IL-37, IL-38, and IL-17A, than healthy controls, which suggests an inflammatory state in these patients. In addition, the DFU of T2DM patients expressed higher levels of interleukins than other diabetic groups. This can be focused on using them as novel therapeutic targets for preventing and treating DM complications. As well as the possibility of using them as markers of inflammation and progression for complications in DM patients.

Microvascular and macrovascular complications are common in type 2 diabetes mellitus. The presence of a trace amount of albumin in the urine was originally considered a marker of renal microangiopathy but recently this concept has been challenged in several respects and microalbuminuria has been found to be associated with epithelial cell damage associated microvascular and macrovascular complications. Hence, the need to look at alternative predictive parameters. Type 2 diabetic patients with and without microvascular (retinopathy) and macrovascular (cardiovascular) complications as a class representative were selected for this study and screened for urinary excretion of microalbumin (mg/g creatinine, UACR) and IgG (mg/g creatinine, UIgGCR). The eGFR was calculated by MDRD equation and patients were sub-classified according to eGFR 60–74 ml/min/1.73 m2 and eGFR ≥75 ml/min/1.73 m2. The adjusted odds ratio for UACR increases significantly with secondary complications which further increases with declined eGFR up to 1.39 (95 % CI 1.26–1.53, P < 0.001) and 1.41 (95 % CI 1.27–1.57) when adjusted for total antioxidant capacity of plasma (TAC), the adjusted odds ratio for UACR shows a higher influence on adjustment with other traditional confounders. Whereas the odds for UIgGCR was associated with secondary complications in a selective manner, and significant only in patients shown declined renal function (eGFR 60–74 ml/min/1.73 m2) with and without secondary complications. The adjusted odds for UIgGCR in diabetic patients with microvascular and macrovascular complications was insignificant for normal renal function moreover it was 1.22 (95 % CI 1.12–1.33, P < 0.001) and 1.21 (95 % CI 1.11–1.31, P < 0.001) for declined renal function, which further increases if adjusted for TAC as 1.25 (95 % CI 1.13–1.37, P < 0.001) and 1.24 (95 % CI 1.12–1.36 P < 0.001) respectively. These results suggest that IgG could serve as stronger predictor of protenuria over microalbumin in type 2 diabetic patients and might help to identify individuals at higher risk of diabetic nephropathy.