Diabetes mellitus is a complex metabolic disorder associated with an increased risk of microvascular and macrovascular disease; its main clinical characteristic is hyperglycaemia. The last century ...has been characterised by remarkable advances in our understanding of the mechanisms leading to hyperglycaemia. The central role of insulin in glucose metabolism regulation was clearly demonstrated during the early 1920s, when Banting, Best, Collip and Macleod successfully reduced blood glucose levels and glycosuria in a patient treated with a substance purified from bovine pancreata. Later, during the mid-1930s, clinical observations suggested a possible distinction between 'insulin-sensitive' and 'insulin-insensitive' diabetes. Only during the 1950s, when a reliable measure of circulating insulin was available, was it possible to translate these clinical observations into pathophysiological and biochemical differences, and the terms 'insulin-dependent' (indicating undetectable insulin levels) and 'non-insulin-dependent' (normal or high insulin levels) started to emerge. The next 30 years were characterised by pivotal progress in the field of immunology that were instrumental in demonstrating an immune-mediated loss of insulin-secreting β-cells in subjects with 'insulin-dependent' diabetes. At the same time, new experimental techniques allowing measurement of insulin 'impedance' showed a reduced peripheral effect of insulin in subjects with 'non-insulin-dependent' diabetes (insulin resistance). The difference between the two types of diabetes emerging from decades of observations and experiments was further formally recognised in 1979, when the definitions 'type I' and 'type II' diabetes were introduced to replace the former 'insulin-dependent' and 'non-insulin-dependent' terms. In the following years, many studies elucidated the natural history and temporal contribution of insulin resistance and β-cell insulin secretion in 'type II' diabetes. Furthermore, a central role for insulin resistance in the development of a cluster of cardiometabolic alterations (dyslipidaemia, inflammation, high blood pressure) was suggested. Possibly as a consequence of the secular changes in diabetes risk factors, in the last 10 years the limitation of a simple distinction between 'type I' and 'type II' diabetes has been increasingly recognised, with subjects showing the coexistence of insulin resistance and immune activation against β-cells. With the advancement of our cellular and molecular understanding of diabetes, a more pathophysiological classification that overcomes the historical and simple 'glucocentric' view could result in a better patient phenotyping and therapeutic approach.
Diets that boost ketone production are increasingly used for treating several neurological disorders. Elevation in ketones in most cases is considered favorable, as they provide energy and are ...efficient in fueling the body's energy needs. Despite all the benefits from ketones, the above normal elevation in the concentration of ketones in the circulation tend to illicit various pathological complications by activating injurious pathways leading to cellular damage. Recent literature demonstrates a plausible link between elevated levels of circulating ketones and oxidative stress, linking hyperketonemia to innumerable morbid conditions. Ketone bodies are produced by the oxidation of fatty acids in the liver as a source of alternative energy that generally occurs in glucose limiting conditions. Regulation of ketogenesis and ketolysis plays an important role in dictating ketone concentrations in the blood. Hyperketonemia is a condition with elevated blood levels of acetoacetate, 3-β-hydroxybutyrate, and acetone. Several physiological and pathological triggers, such as fasting, ketogenic diet, and diabetes cause an accumulation and elevation of circulating ketones. Complications of the brain, kidney, liver, and microvasculature were found to be elevated in diabetic patients who had elevated ketones compared to those diabetics with normal ketone levels. This review summarizes the mechanisms by which hyperketonemia and ketoacidosis cause an increase in redox imbalance and thereby increase the risk of morbidity and mortality in patients.
•Hyperketonemia can lead to beneficial or detrimental effects based on the metabolic state of the patient.•Hyperketonemia can cause redox imbalance and activate pro-inflammatory signaling pathways, and is associated with neurological and other complications.•Continuous monitoring of ketonemia is essential in preventing ketone buildup and associated complications.
BackgroundViral infections may trigger type 1 diabetes (T1D), and recent reports suggest an increased incidence of paediatric T1D and/or diabetic ketoacidosis (DKA) during the COVID-19 ...pandemic.ObjectiveTo study whether the number of children admitted to the paediatric intensive care unit (PICU) for DKA due to new-onset T1D increased during the COVID-19 pandemic, and whether SARS-CoV-2 infection plays a role.MethodsThis retrospective cohort study comprises two datasets: (1) children admitted to PICU due to new-onset T1D and (2) children diagnosed with new-onset T1D and registered to the Finnish Pediatric Diabetes Registry in the Helsinki University Hospital from 1 April to 31 October in 2016–2020. We compared the incidence, number and characteristics of children with newly diagnosed T1D between the prepandemic and pandemic periods.ResultsThe number of children admitted to PICU due to new-onset T1D increased from an average of 6.25 admissions in 2016–2019 to 20 admissions in 2020 (incidence rate ratio IRR 3.24 95% CI 1.80 to 5.83; p=0.0001). On average, 57.75 children were registered to the FPDR in 2016–2019, as compared with 84 in 2020 (IRR 1.45; 95% CI 1.13 to 1.86; p=0.004). 33 of the children diagnosed in 2020 were analysed for SARS-CoV-2 antibodies, and all were negative.ConclusionsMore children with T1D had severe DKA at diagnosis during the pandemic. This was not a consequence of SARS-CoV-2 infection. Instead, it probably stems from delays in diagnosis following changes in parental behaviour and healthcare accessibility.
The use of continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) systems has gained wide acceptance in diabetes care. These devices have been demonstrated to be ...clinically valuable, improving glycemic control and reducing risks of hypoglycemia in ambulatory patients with type 1 diabetes and type 2 diabetes. Approximately 30-40% of patients with type 1 diabetes and an increasing number of insulin-requiring patients with type 2 diabetes are using pump and sensor technology. As the popularity of these devices increases, it becomes very likely that hospital health care providers will face the need to manage the inpatient care of patients under insulin pump therapy and CGM. The American Diabetes Association advocates allowing patients who are physically and mentally able to continue to use their pumps when hospitalized. Health care institutions must have clear policies and procedures to allow the patient to continue to receive CSII treatment to maximize safety and to comply with existing regulations related to self-management of medication. Randomized controlled trials are needed to determine whether CSII therapy and CGM systems in the hospital are associated with improved clinical outcomes compared with intermittent monitoring and conventional insulin treatment or with a favorable cost-benefit ratio.
Loss of functional β-cell mass is the key mechanism leading to the two main forms of diabetes mellitus - type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Understanding the ...mechanisms behind β-cell failure is critical to prevent or revert disease. Basic pathogenic differences exist in the two forms of diabetes mellitus; T1DM is immune mediated and T2DM is mediated by metabolic mechanisms. These mechanisms differentially affect early β-cell dysfunction and eventual fate. Over the past decade, major advances have been made in the field, mostly delivered by studies on β-cells in human disease. These advances include studies of islet morphology and human β-cell gene expression in T1DM and T2DM, the identification and characterization of the role of T1DM and T2DM candidate genes at the β-cell level and the endoplasmic reticulum stress signalling that contributes to β-cell failure in T1DM (mostly IRE1 driven) and T2DM (mostly PERK-eIF2α dependent). Here, we review these new findings, focusing on studies performed on human β-cells or on samples obtained from patients with diabetes mellitus.
The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy reduced the development and progression of retinopathy in type 1 diabetes (T1D) compared with conventional ...therapy. The Epidemiology of Diabetes Interventions and Complications (EDIC) study observational follow-up showed persistent benefits. In addition to glycemia, we now examine other potential retinopathy risk factors (modifiable and nonmodifiable) over more than 30 years of follow-up in DCCT/EDIC.
The retinopathy outcomes were proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), and ocular surgery. The survival (event-free) probability was estimated using the Kaplan-Meier method. Cox proportional hazards models assessed the association between risk factors and subsequent risk of retinopathy. Both forward- and backward-selection approaches determined the multivariable models.
Rate of ocular events per 1,000 person-years was 12 for PDR, 14.5 for CSME, and 7.6 for ocular surgeries. Approximately 65%, 60%, and 70% of participants remained free of PDR, CSME, and ocular surgery, respectively. The greatest risk factors for PDR in descending order were higher mean HbA
, longer duration of T1D, elevated albumin excretion rate (AER), and higher mean diastolic blood pressure (DBP). For CSME, risk factors, in descending order, were higher mean HbA
, longer duration of T1D, and greater age and DBP and, for ocular surgeries, were higher mean HbA
, older age, and longer duration of T1D.
Mean HbA
was the strongest risk factor for the progression of retinopathy. Although glycemic control is important, elevated AER and DBP were other modifiable risk factors associated with the progression of retinopathy.
Viruses are implicated in autoimmune destruction of pancreatic islet β cells, which results in insulin deficiency and type 1 diabetes (T1D)
. Certain enteroviruses can infect β cells in vitro
, have ...been detected in the pancreatic islets of patients with T1D
and have shown an association with T1D in meta-analyses
. However, establishing consistency in findings across studies has proven difficult. Obstacles to convincingly linking RNA viruses to islet autoimmunity may be attributed to rapid viral mutation rates, the cyclical periodicity of viruses
and the selection of variants with altered pathogenicity and ability to spread in populations. β cells strongly express cell-surface coxsackie and adenovirus receptor (CXADR) genes, which can facilitate enterovirus infection
. Studies of human pancreata and cultured islets have shown significant variation in enteroviral virulence to β cells between serotypes and within the same serotype
. In this large-scale study of known eukaryotic DNA and RNA viruses in stools from children, we evaluated fecally shed viruses in relation to islet autoimmunity and T1D. This study showed that prolonged enterovirus B rather than independent, short-duration enterovirus B infections may be involved in the development of islet autoimmunity, but not T1D, in some young children. Furthermore, we found that fewer early-life human mastadenovirus C infections, as well as CXADR rs6517774, independently correlated with islet autoimmunity.
With rising obesity, it is becoming increasingly difficult to distinguish between type 1 diabetes (T1D) and type 2 diabetes (T2D) in young adults. There has been substantial recent progress in ...identifying the contribution of common genetic variants to T1D and T2D. We aimed to determine whether a score generated from common genetic variants could be used to discriminate between T1D and T2D and also to predict severe insulin deficiency in young adults with diabetes.
We developed genetic risk scores (GRSs) from published T1D- and T2D-associated variants. We first tested whether the scores could distinguish clinically defined T1D and T2D from the Wellcome Trust Case Control Consortium (WTCCC) (n = 3,887). We then assessed whether the T1D GRS correctly classified young adults (diagnosed at 20-40 years of age, the age-group with the most diagnostic difficulty in clinical practice; n = 223) who progressed to severe insulin deficiency <3 years from diagnosis.
In the WTCCC, the T1D GRS, based on 30 T1D-associated risk variants, was highly discriminative of T1D and T2D (area under the curve AUC 0.88 95% CI 0.87-0.89; P < 0.0001), and the T2D GRS added little discrimination (AUC 0.89). A T1D GRS >0.280 (>50th centile in those with T1D) is indicative of T1D (50% sensitivity, 95% specificity). A low T1D GRS (<0.234, <5th centile T1D) is indicative of T2D (53% sensitivity, 95% specificity). Most discriminative ability was obtained from just nine single nucleotide polymorphisms (AUC 0.87). In young adults with diabetes, T1D GRS alone predicted progression to insulin deficiency (AUC 0.87 95% CI 0.82-0.92; P < 0.0001). T1D GRS, autoantibody status, and clinical features were independent and additive predictors of severe insulin deficiency (combined AUC 0.96 95% CI 0.94-0.99; P < 0.0001).
A T1D GRS can accurately identify young adults with diabetes who will require insulin treatment. This will be an important addition to correctly classifying individuals with diabetes when clinical features and autoimmune markers are equivocal.
Cognitive decline is a common symptom at advanced stage of type 1 diabetes (T1D), but its potential pathogenesis remains unclear. In this study, therefore, we investigated changes in the gut ...microbiome and metabolome in serum and hippocampus between advanced-stage T1D (AST1D) rats with cognitive decline and age-matched controls (AMC), and explored the possible mechanism of the gut-microbiota-metabolite axis in T1D-induced cognitive dysfunction. The results demonstrated that AST1D rats possessed peculiar metabolic phenotypes in serum and hippocampus relative to AMC rats, as characterized by decreases in tricarboxylic acid (TCA) cycle and amino acid and choline metabolism as well as disturbances in glutamate/GABA-glutamine cycle and astrocyte-neuron metabolism. We also found that AST1D rats had higher relative abundances of Prevotella_9, Bacteroides and Lachnospiraceae_NK4A136_group as well as lower relative abundances of Clostridium_sensu_stricto_1, Romboutsia and Turicibacter than AMC rats. Microbiota-host metabolic correlation analysis suggests that metabolic alterations in serum and hippocampus may be modulated by the gut microbiota, especially Clostridium_sensu_stricto_1, Romboutsia and Turicibacter. Therefore, our study implies that the modification of host metabolism by targeting the gut microbiota may be a novel avenue for prevention and treatment of diabetic encephalopathy in the future.
•Learning and memory ability is impaired in advanced-stage T1D (AST1D) rats.•AST1D rats have peculiar metabolic phenotypes in serum and hippocampus.•AST1D rats show a disrupted gut microbiota relative to age-matched controls.•Gut microbiota dysbiosis correlates with host metabolic changes.•Targeting gut microbiota may be a possible therapy for diabetic encephalopathy.
Abstract Background Vascular complications are the leading cause of morbidity and mortality among patients with type 1 and type 2 diabetes mellitus. These vascular abnormalities result of a chronic ...hyperglycemic state, which leads to an increase in oxidative stress and inflammatory responses. Aim This review addresses the relationships among endothelial dysfunction, hypercoagulability and inflammation and their biomarkers in the development of vascular complications in type 1 and type 2 diabetes. Results Inflammation, endothelial dysfunction, and hypercoagulability are correlated to each other, playing an important role in the development of vascular complications in diabetic patients. Moreover, it has been observed that several endothelial, inflammatory and pro-coagulant biomarkers, such as VWF, IL-6, TNF-α, D-dimer and PAI-1, are increased in diabetic patients who have microvascular and macrovascular complications, including nephropathy or cardiovascular disease. Conclusion It is promising the clinical and laboratory use of endothelial, inflammatory and pro-coagulant biomarkers for predicting the risk of cardiovascular and renal complications in diabetic patients and for monitoring these patients.
PDF
