The possible mechanism of increased urinary C-peptide due to neprilysin inhibitors is investigated. Neprilysin inhibition blocks degradation of natriuretic peptides, and elicits a natriuretic and antihypertensive effect. Neprilysin inhibition might similarly block degradation of C-peptides in the kidney and thus increase the urinary C-peptide level.
Subjects with diabetes develop marked disturbances in amino acid metabolism and the concentration in plasma and tissues. Most consistently, the levels of branched-chain amino acids (BCAAs) and aromatic amino acids are increased, and the levels of l-serine and glycine are decreased1. Aberrant nonessential amino acid metabolism is involved in the pathogenesis of diabetes. Elevated levels of plasma BCAAs have been associated with insulin resistance and type 2 diabetes since the 1960s2. A cluster of obesity-associated changes in the specific amino acid, acylcarnitine, and organic acid metabolites in obese compared with lean subjects was also associated with insulin resistance. Although it is also speculated that disturbances in aminoacidemia play a role in the development of diabetic complications, their pathogenesis has not been sufficiently elucidated in detail.
Diabetic peripheral neuropathy (DPN) is the most frequent complication among diabetic patients. Its symptoms are pain, hyperalgesia, hypoalgesia, and paralysis, which can decrease the quality of life of patients. In diabetic peripheral neuropathy, peripheral nerve fibers are affected from the prediabetic stage. Because diabetic peripheral neuropathy is a retrograde-type neuropathy, small nerve fibers located in the epidermis or cornea are first degraded. Small nerve fibers consist of myelinated Aδ fibers and unmyelinated C fibers. Small fiber neuropathy is a disorder of these nerve fibers, manifesting as spontaneous pain or loss of pain sensation with reduction of their density. As diabetic peripheral neuropathy progresses, large myelinated fibers are also decreased with segmental demyelination and microvascular changes, such as thickening of the vascular wall and stenosis of intraneuronal vessels. Without proper treatment, these patients develop paralysis or ulcer formation on the foot. To date, diabetic peripheral neuropathy is thought to be caused by aberrant glucose metabolism in neuronal cells, Schwann cells and endothelial cells in the peripheral nervous system. Abnormal glycemic metabolism elicits nerve dysfunction with activation of the polyol pathway, protein kinase C, advanced glycation end products and its receptor, the receptor for advanced glycation end product (RAGE) pathway, oxidative stress, and inflammation. Clinically, in addition to hyperglycemia, metabolic syndrome, including dyslipidemia, obesity and hypertension, is well known to be a contributor to the pathogenesis of diabetic peripheral neuropathy. In addition to glucose and fatty acid metabolism, recent metabolomics studies have revealed the involvement of another metabolite, glucosamine, in the pathogenesis of diabetic peripheral neuropathy. Lower baseline amino acid levels such as asparagine and glutamine were correlated with cardiovascular autonomic neuropathy in a small sample of subjects with type 1 diabetes3. Thus, to
The main aim of diabetes management is to prevent atherosclerotic cardiovascular diseases (ASCVD) and microvascular complications. ASCVD, the major cause of diabetes-related mobility and mortality, greatly increases healthcare costs in patients with type 2 diabetes1. Dyslipidemia often coexists with diabetes mellitus and is a significant risk factor for ASCVD, along with smoking, hypertension and chronic kidney disease. Dyslipidemia is involved in the progression of diabetic kidney disease2 and diabetic retinopathy3. Patients with diabetes mellitus show atherogenic lipid profiles exhibiting elevated low-density lipoprotein cholesterol (LDL-C) levels with small dense LDL particles; decreased high-density lipoprotein cholesterol (HDL-C) levels; and hypertriglyceridemia (TG) due to insufficient insulin action. Furthermore, a retrospective cohort study identified an elevated LDL-C/HDL-C ratio as a potential independent risk factor for new-onset diabetes4. Therefore, abnormal lipid profiles must be managed to reduce the risk of cardiovascular (CV) events and microvascular complications.
A high LDL-C level is a strong risk factor for ASCVD in patients with and without diabetes mellitus. Numerous outcome trials have shown that cholesterol-lowering therapy using 3-hydroxy 3-methylglutaryl-coenzyme A reductase inhibitors (statins) reduces the relative risk of primary and secondary ASCVD events5. Furthermore, a recent randomized controlled trial showed that LDL-C control using statins reduced the risk of kidney events in patients with diabetic kidney disease6. In addition to statin therapy, proprotein convertase subtilisin/kexin type 9 inhibitors and ezetimibe therapies reduced CV event risk7-9.
Although these LDL-C-lowering therapies can decrease the risk of ASCVD, the risk rate reduction is only 30–40%, suggesting the presence of residual risk factors, such as hypertriglyceridemia, low HDL-C levels and highly oxidized or small dense LDL particles. Interestingly, a recent prospective study showed the TG/HDL-C ratio to be correlated with an increased risk of major ASCVD events, suggesting that the TG/HDL-C ratio can be a parameter for assessing atherogenic dyslipidemia10. Furthermore, in addition to fasting hypertriglyceridemia, postprandial hypertriglyceridemia is a risk factor for CV events11.
Several epidemiological, genetic and clinical studies have shown that a high TG level is a residual risk factor; however, neither the Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial nor the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study reported reduced CV events in patients with type 2 diabetes12. A meta-analysis of fibrate users in 11,590 patients with type 2 di
In this modern era, numerous innovative glucose-lowering medications have emerged, leading to a wide range of treatment options for type 2 diabetes mellitus. While pharmacologic interventions are crucial for achieving glycemic control in type 2 diabetes mellitus, it is essential to recognize the fundamental role of lifestyle modifications in attaining glycemic targets. Among various lifestyle modifications, dietary adjustments and exercise hold significant importance in the management of type 2 diabetes mellitus, offering numerous benefits such as improved glycated hemoglobin (HbA1c) levels and a reduced risk of cardiovascular events.
Appropriate medical nutrition therapy has been shown to reduce HbA1c levels by 0.3–2.0% in patients with type 2 diabetes mellitus1. Even after initiating medication, nutrition therapy continues to play a crucial role in the overall management of diabetes. In an animal study involving mice, it was observed that the use of sodium–glucose cotransporter 2 inhibitors (SGLT-2i) in conjunction with controlled feeding led to weight loss and a decrease in hepatic gluconeogenic response. However, these effects were diminished in a group of mice with unrestricted access to food2. This suggests that dietary control remains essential when combined with glucose-lowering medications such as SGLT-2i for optimal glycemic control.
Currently, there is no specific recommendation for the ideal percentage of calories from carbohydrates, proteins, and fats for individuals with diabetes based on existing evidence. Instead, the emphasis is on developing individualized nutrition plans. While there is no specific ideal percentage for the nutritional components in the diet of individuals with type 2 diabetes mellitus, there are general recommendations that can be followed. These recommendations emphasize the importance of consuming non-starchy vegetables, minimizing the intake of added sugars and refined grain, and opting for whole foods instead of highly processed foods3, 4. Some studies have revealed that exogenous ketone ingestion would decrease the blood sugar level which may be related to an increase of early phase insulin5, 6. Still, evidence for prolonged ketone ingestion for blood glucose is limited6. There are also several eating patterns that have been proposed for individuals with type 2 diabetes mellitus. These include the Mediterranean diet, low-carbohydrate diet, fiber-rich diet, intermittent very-low-calorie diet, and vegetarian or plant-based diet (Table 1)7-16. Some of these eating patterns have also been associated with a lower risk of developing type 2 diabetes mellitus in healthy individuals8, 10.
Excessive alcohol intake should be avoided in individuals with type 2 diabetes mellitus due to several reasons. First, it increases the risk of
A 25-year-old man was diagnosed with diabetic ketoacidosis (DKA) at the onset of fulminant type 1 diabetes. After acute-phase DKA treatment including placement of a central venous catheter, a massive deep vein thrombosis (DVT) and pulmonary embolism (PE) were detected on hospital day 15. His protein C (PC) activity and antigen levels were low even 33 days after completing the DKA treatment, indicating partial type I PC deficiency. Severe PC dysfunction, due to overlapping of partial PC deficiency and hyperglycemia-induced PC suppression, concomitant with dehydration and catheter treatment, may have induced the massive DVT with PE. This case suggests that anti-coagulation therapy should be combined with acute-phase DKA treatment in patients with PC deficiency, even those who have been asymptomatic. As patients with partial PC deficiency should perhaps be included among those with severe DVT complications of DKA, venous thrombosis should always be considered as a potential complication of DKA.
Hyperglycemia accelerates the development of diabetic nephropathy (DN) by inducing renal tubular injury. Nevertheless, the mechanism has not been elaborated fully. Here, the pathogenesis of DN was investigated to seek novel treatment strategies.
A model of diabetic nephropathy was established in vivo, the levels of blood glucose, urine albumin creatinine ratio (ACR), creatinine, blood urea nitrogen (BUN), malondialdehyde (MDA), glutathione (GSH), and iron were measured. The expression levels were detected by qRT-PCR and Western blotting. H&E, Masson, and PAS staining were used to assess kidney tissue injury. The mitochondria morphology was observed by transmission electron microscopy (TEM). The molecular interaction was analyzed using a dual luciferase reporter assay.
SNHG1 and ACSL4 were increased in kidney tissues of DN mice, but miR-16-5p was decreased. Ferrostatin-1 treatment or SNHG1 knockdown inhibited ferroptosis in high glucose (HG)-treated HK-2 cells and in db/db mice. Subsequently, miR-16-5p was confirmed to be a target for SNHG1, and directly targeted to ACSL4. Overexpression of ACSL4 greatly reversed the protective roles of SNHG1 knockdown in HG-induced ferroptosis of HK-2 cells.
SNHG1 knockdown inhibited ferroptosis via the miR-16-5p/ACSL4 axis to alleviate diabetic nephropathy, which provided some new insights for the novel treatment of diabetic nephropathy.
Autoantibodies to pancreatic islet antigens identify young children at high risk of type 1 diabetes. On a background of genetic susceptibility, islet autoimmunity is thought to be driven by environmental factors, of which enteric viruses are prime candidates. We sought evidence for enteric pathology in children genetically at-risk for type 1 diabetes followed from birth who had developed islet autoantibodies (“seroconverted”), by measuring mucosa-associated cytokines in their sera.
Sera were collected 3 monthly from birth from children with a first-degree type 1 diabetes relative, in the Environmental Determinants of Islet Autoimmunity (ENDIA) study. Children who seroconverted were matched for sex, age, and sample availability with seronegative children. Luminex xMap technology was used to measure serum cytokines.
Of eight children who seroconverted, for whom serum samples were available at least 6 months before and after seroconversion, the serum concentrations of mucosa-associated cytokines IL-21, IL-22, IL-25, and IL-10, the Th17-related cytokines IL-17F and IL-23, as well as IL-33, IFN-γ, and IL-4, peaked from a low baseline in seven around the time of seroconversion and in one preceding seroconversion. These changes were not detected in eight sex- and age-matched seronegative controls, or in a separate cohort of 11 unmatched seronegative children.
In a cohort of children at risk for type 1 diabetes followed from birth, a transient, systemic increase in mucosa-associated cytokines around the time of seroconversion lends support to the view that mucosal infection, e.g., by an enteric virus, may drive the development of islet autoimmunity.
Effects of caloric restriction, fasting and circadian alignment on longevity in mice and potential risks and benefits of extrapolation to humans.
Fibrosis is the principle reason for heart failure in diabetes. Regarding the involvement of long non-coding ribonucleic acid zinc finger E-box binding homeobox 1 antisense 1 (ZEB1-AS1) in diabetic myocardial fibrosis, we explored its specific mechanism.
Human cardiac fibroblasts (HCF) were treated with high glucose (HG) and manipulated with plasmid cloning deoxyribonucleic acid 3.1-ZEB1-AS1/microribonucleic acid (miR)-181c-5p mimic/short hairpin RNA specific to sirtuin 1 (sh-SIRT1). ZEB1-AS1, miR-181c-5p expression patterns, cell viability, collagen I and III, α-smooth muscle actin (α-SMA), fibronectin levels and cell migration were assessed by reverse transcription quantitative polymerase chain reaction, cell counting kit-8, western blot and scratch tests. Nuclear/cytosol fractionation assay verified ZEB1-AS1 subcellular localization. The binding sites between ZEB1-AS1 and miR-181c-5p, and between miR-181c-5p and SIRT1 were predicted and verified by Starbase and dual-luciferase assays. The binding of SIRT1 to Yes-associated protein (YAP) and YAP acetylation levels were detected by co-immunoprecipitation. Diabetic mouse models were established. SIRT1, collagen I, collagen III, α-SMA and fibronectin levels, mouse myocardium morphology and collagen deposition were determined by western blot, and hematoxylin–eosin and Masson trichrome staining.
Zinc finger E-box binding homeobox 1 antisense 1 was repressed in HG-induced HCFs. ZEB1-AS1 overexpression inhibited HG-induced HCF excessive proliferation, migration and fibrosis, and diminished collagen I, collagen III, α-SMA and fibronectin protein levels in cells. miR-181c-5p had targeted binding sites with ZEB1-AS1 and SIRT1. SIRT1 silencing/miR-181c-5p overexpression abrogated ZEB1-AS1-inhibited HG-induced HCF proliferation, migration and fibrosis. ZEB1-AS1 suppressed HG-induced HCF fibrosis through SIRT1-mediated YAP deacetylation. ZEB1-AS1 and SIRT1 were repressed in diabetic mice, and miR-181c-5p was promoted. ZEB1-AS1 overexpression improved myocardial fibrosis in diabetic mice, and reduced collagen I, collagen III, α-SMA and fibronectin protein levels in myocardial tissues.
Long non-coding ribonucleic acid ZEB1-AS1 alleviated myocardial fibrosis through the miR-181c-5p–SIRT1–YAP axis in diabetic mice.
Psoriasis is a chronic inflammatory skin disease that is associated with obesity and myocardial infarction. Obesity-induced changes in lipid metabolism promote T helper 17 (Th17) cell differentiation, which in turn promotes chronic inflammation. Th17 cells have central roles in many inflammatory diseases, including psoriasis and atherosclerosis; however, whether treatment of obesity attenuates Th17 cells and chronic inflammatory diseases has been unknown. In this study, we found an increase in Th17 cells in a patient with obesity, type 2 diabetes and psoriasis. Furthermore, weight loss with diet and exercise resulted in a decrease in Th17 cells and improvement of psoriasis. This case supports the hypothesis that obesity leads to an increase in Th17 cells and chronic inflammation of the skin and blood vessel walls, thereby promoting psoriasis and atherosclerosis.
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