The polyol pathway is an evolutionarily conserved system for sensing glucose uptake

SummaryCells must adjust the expression levels of metabolic enzymes in response to fluctuating nutrient supply. For glucose, such metabolic remodeling is highly dependent on a master transcription factor ChREBP/MondoA. However, it remains elusive how glucose fluctuations are sensed by ChREBP/MondoA despite the stability of major glycolytic pathways. Here we show that in both flies and mice, ChREBP/MondoA activation in response to glucose ingestion depends on an evolutionarily conserved glucose-metabolizing pathway: the polyol pathway. The polyol pathway converts glucose to fructose via sorbitol. It has been believed that this pathway is almost silent, and its activation in hyperglycemic conditions has deleterious effects on human health. We show that the polyol pathway is required for the glucose-induced nuclear translocation of Mondo, a Drosophila homologue of ChREBP/MondoA, which directs gene expression for organismal growth and metabolism. Likewise, inhibition of the polyol pathway in mice impairs ChREBP’s nuclear localization and reduces glucose tolerance. We propose that the polyol pathway is an evolutionarily conserved sensing system for the glucose uptake that allows metabolic remodeling.

Insulin-Related Lipohypertrophy: Ultrasound Characteristics, Risk factors, and Impact of Glucose Fluctuations

BackgroundLipohypertrophy (LHT) has been suggested as an outcome of adipogenic effects of insulin injection-related tissue trauma. It is common clinically, but the current understanding of LHT by medical staff and diabetic patients is still insufficient, and it has not attracted attention as a research topic.ObjectiveThe aim of this study was to investigate the ultrasound characterization of LHT, to identify factors associated with the development of LHT by assessing the prevalence of LHT compared to both clinical palpation and ultrasound detection methods, and to further evaluate the possible impact of LHT on patients' blood glucose fluctuations.MethodA cross-sectional study was established, in which 120 patients with type 2 diabetes were selected. General information was registered in the form of a questionnaire, and the patients were evaluated for LHT by ultrasonography and clinical palpation of the abdomen. Patients were instructed to inject equal amounts of insulin in LHT and normal adipose tissue (NAT) on a non-consecutive 2 d in a selected week, and the possible effect of LHT on patients' blood glucose fluctuations was assessed using a continuous glucose monitoring system. .ResultsLHT has special ultrasonic signs. We found a high rate of missed clinical palpation of LHT compared with ultrasonography (P < 0.05). The duration of insulin treatment, whether to rotate the injection site, frequency of needle use, and number of insulin injections per day were the main factors influencing the development of LHT (P < 0.05). Compared to NAT, LHT resulted in elevated largest amplitude of glycemic excursion, mean blood glucose, standard deviation of blood glucose, and postprandial glucose excursion, and large fluctuations in blood glucose (P < 0.05).ConclusionUltrasonography can detect more LHT than can clinical palpation. The development of LHT is related to many factors and can lead to significant blood glucose fluctuations; thus, LHT should be given sufficient attention.

Pathophysiological Association between Diabetes Mellitus and Endothelial Dysfunction

Endothelial dysfunction plays a critical role in atherosclerosis progression, leading to cardiovascular complications. There are significant associations between diabetes mellitus, oxidative stress, and endothelial dysfunction. Oxidative stress is increased by chronic hyperglycemia and acute glucose fluctuations induced by postprandial hyperglycemia in patients with diabetes mellitus. In addition, selective insulin resistance in the phosphoinositide 3-kinase/Akt/endothelial nitric oxide (NO) synthase pathway in endothelial cells is involved in decreased NO production and increased endothelin-1 production from the endothelium, resulting in endothelial dysfunction. In a clinical setting, selecting an appropriate therapeutic intervention that improves or augments endothelial function is important for preventing diabetic vascular complications. Hypoglycemic drugs that reduce glucose fluctuations by decreasing the postprandial rise in blood glucose levels, such as glinides, α-glucosidase inhibitors and dipeptidyl peptidase 4 inhibitors, and hypoglycemic drugs that ameliorate insulin sensitivity, such as thiazolidinediones and metformin, are expected to improve or augment endothelial function in patients with diabetes. Glucagon-like peptide 1 receptor agonists, metformin, and sodium-glucose cotransporter 2 inhibitors may improve endothelial function through multiple mechanisms, some of which are independent of glucose control or insulin signaling. Oral administration of antioxidants is not recommended in patients with diabetes due to the lack of evidence for the efficacy against diabetic complications.

Multi-Timescale Rhythmicity of Blood Glucose and Insulin Delivery Reveals Key Advantages of Hybrid Closed Loop Therapy

Background: Blood glucose and insulin exhibit coordinated daily and hourly rhythms in people without diabetes (nonT1D). Although the presence and stability of these rhythms are associated with euglycemia, it is unknown if they (1) are preserved in individuals with type 1 diabetes (T1D) and (2) vary by therapy type. In particular, Hybrid Closed Loop (HCL) systems improve glycemia in T1D compared to Sensor Augmented Pump (SAP) therapies, but the extent to which either recapitulates coupled glucose and insulin rhythmicity is not well described. In HCL systems, more rapid modulation of glucose via automated insulin delivery may result in greater rhythmic coordination and euglycemia. Such precision may not be possible in SAP systems. We hypothesized that HCL users would exhibit fewer hyperglycemic event, superior rhythmicity, and coordination relative to SAP users. Methods: Wavelet and coherence analyses were used to compare glucose and insulin delivery rate (IDR) within-day and daily rhythms, and their coordination, in 3 datasets: HCL (n = 150), SAP (n = 89), and nonT1D glucose (n = 16). Results: Glycemia, correlation between normalized glucose and IDR, daily coherence of glucose and IDR, and amplitude of glucose oscillations differed significantly between SAP and HCL users. Daily glucose rhythms differed significantly between SAP, but not HCL, users and nonT1D individuals. Conclusions: SAP use is associated with greater hyperglycemia, higher amplitude glucose fluctuations, and a less stably coordinated rhythmic phenotype compared to HCL use. Improvements in glucose and IDR rhythmicity may contribute to the overall effectiveness of HCL systems.

Reading between the (Genetic) Lines: How Epigenetics is Unlocking Novel Therapies for Type 1 Diabetes

Type 1 diabetes (T1D) is an autoimmune condition where the body’s immune cells destroy their insulin-producing pancreatic beta cells leading to dysregulated glycaemia. Individuals with T1D control their blood glucose through exogenous insulin replacement therapy, often using multiple daily injections or pumps. However, failure to accurately mimic intrinsic glucose regulation results in glucose fluctuations and long-term complications impacting key organs such as the heart, kidneys, and/or the eyes. It is well established that genetic and environmental factors contribute to the initiation and progression of T1D, but recent studies show that epigenetic modifications are also important. Here, we discuss key epigenetic modifications associated with T1D pathogenesis and discuss how recent research is finding ways to harness epigenetic mechanisms to prevent, reverse, or manage T1D.