Real-world use of once-weekly semaglutide in patients with type 2 diabetes: pooled analysis of data from four SURE studies by baseline characteristic subgroups

INTRODUCTION: This post hoc pooled analysis of four real-world studies (SURE Canada, Denmark/Sweden, Switzerland and UK) aimed to characterize the use of once-weekly (OW) semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), in patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: The Semaglutide Real-world Evidence (SURE) studies had a duration of ~30 weeks. Changes in glycated hemoglobin (HbA1c) and body weight (BW) were analyzed for the overall population and the following baseline subgroups: GLP-1RA-naïve/GLP-1RA switchers; body mass index 8-≤9%/>9%; T2D duration <5/≥5-<10/≥10 years. Data for patients achieving treatment targets were analyzed in the overall population and the baseline HbA1c ≥7% subgroup. RESULTS: Of 1212 patients, 960 were GLP-1RA-naïve and 252 had switched to semaglutide from another GLP-1RA. In the overall population, HbA1c was reduced from baseline to end of study (EOS) by -1.1% point and BW by -4.7 kg; changes were significant for all subgroups. There were significantly larger reductions of HbA1c and BW in GLP-1RA-naïve versus GLP-1RA switchers and larger reductions in HbA1c for patients with higher versus lower baseline HbA1c. At EOS, 52.6% of patients in the overall population achieved HbA1c <7%. No new safety concerns were identified in any of the completed SURE studies. CONCLUSIONS: In this pooled analysis, patients with T2D initiating OW semaglutide showed significant improvements from baseline to EOS in HbA1c and BW across various baseline subgroups, including patients previously treated with a GLP-1RA other than semaglutide, supporting OW semaglutide use in clinical practice. TRAIL REGISTRATION NUMBERS: NCT03457012; NCT03631186; NCT03648281; NCT03876015

Repression of hypoxia-inducible factor-1 contributes to increased mitochondrial reactive oxygen species production in diabetes

Background: Excessive production of mitochondrial reactive oxygen species (ROS) is a central mechanism for the development of diabetes complications. Recently, hypoxia has been identified to play an additional pathogenic role in diabetes. In this study, we hypothesized that ROS overproduction was secondary to the impaired responses to hypoxia due to the inhibition of hypoxia-inducible factor-1 (HIF-1) by hyperglycemia. Methods: The ROS levels were analyzed in the blood of healthy subjects and individuals with type 1 diabetes after exposure to hypoxia. The relation between HIF-1, glucose levels, ROS production and its functional consequences were analyzed in renal mIMCD-3 cells and in kidneys of mouse models of diabetes. Results: Exposure to hypoxia increased circulating ROS in subjects with diabetes, but not in subjects without diabetes. High glucose concentrations repressed HIF-1 both in hypoxic cells and in kidneys of animals with diabetes, through a HIF prolyl-hydroxylase (PHD)-dependent mechanism. The impaired HIF-1 signaling contributed to excess production of mitochondrial ROS through increased mitochondrial respiration that was mediated by Pyruvate dehydrogenase kinase 1 (PDK1). The restoration of HIF-1 function attenuated ROS overproduction despite persistent hyperglycemia, and conferred protection against apoptosis and renal injury in diabetes. Conclusions: We conclude that the repression of HIF-1 plays a central role in mitochondrial ROS overproduction in diabetes and is a potential therapeutic target for diabetic complications. These findings are timely since the first PHD inhibitor that can activate HIF-1 has been newly approved for clinical use. Funding: This work was supported by grants from the Swedish Research Council, Stockholm County Research Council, Stockholm Regional Research Foundation, Bert von Kantzows Foundation, Swedish Society of Medicine, Kung Gustaf V:s och Drottning Victorias Frimurarestifelse, Karolinska Institute's Research Foundations, Strategic Research Programme in Diabetes, and Erling-Persson Family Foundation for S-B.C.; grants from the Swedish Research Council and Swedish Heart and Lung Foundation for T.A.S.; and ERC consolidator grant for M.M.Peer reviewe

Microdialysis as a tool for the management of diabetes mellitus

Diabetes complications are the result of impaired metabolic control. A continuous glucose monitoring system could be a tool to improve metabolic control. Microdialysis is a minimal invasive method for investigating tissue metabolism in-vivo and provides a novel opportunity for glucose monitoring in patients with diabetes (DM). The general aim of this thesis was to investigate if microdialysis technique can be used for reliable monitoring of glucose and other metabolites in abdominal subcutaneous (sc) adipose tissue during everyday activity in patients with DM. Moreover, we wanted to investigate if the microdialysis technique can be used for assessment of insulin sensitivity in subcutaneous adipose tissue. Methodological studies Comparing the effect of different microdialysis flow rates (0.3, 1, 2 and 5 µL/min) on the interstitial metabolites measured in subcutis we found that at the basal fasting state the dialysate glucose obtained by 0.3 µL/min was equal to capillary glucose concentration. A decrease in dialysate glucose levels during the basal state was observed for higher flow rates but not for 0.3 µL/min when no glucose was added to the perfusion fluid. This indicates a depleting effect for higher flow rates (> 0.3 µL/min). The relative increase in glucose after OGTT was similar for capillary glucose and dialysate glucose measured with flow rate 0.3 µL/min but not for higher flow rates (I). In long term studies with microdialysis the changes in dialysate glucose and other metabolites over eight days differed significantly in rats and humans. Caution should therefore be used when extrapolating data from subcutaneous tissue in Sprague Dawley rat to human applications. In healthy subjects and in patients with DM significant increases in dialysate glucose levels and glucose recovery were observed over five days. Histological signs of local inflammation in sc adipose tissue were observed around the microdialysis catheters. However, when using a flow rate of 0.3 µL/min over a period of 5 days no changes were observed in dialysate glucose levels or glucose recovery. These data suggest that the measurements are not affected by inflammation around the catheter when using a microdialysis flow rate of 0.3 µL/min. The actual glucose concentration can be measured using a flow rate of 0.3 µL/min without any calibration adjustments that would be needed for 2 µL/min. Using a flow rate of 0.3 µL/min the dialysate glucose measured by microdialysis catheters which had been rinsed prior to the insertion were significantly higher compared to the levels measured by dry catheters. We recommend that the low flow rate should be used in a microdialysis-based glucose sensor (II, III). In fasting and hyperglycemic state the dialysate and capillary glucose levels correlated in healthy subjects and patients with type 1 DM but not in patients with type 2 DM. The correlation increased over time with the highest correlation being observed at the last measurements in all three groups. This indicates stronger correlation over time between capillary and interstitial glucose in type 2 DM (IV). Metabolic studies. Using a low flow rate (0.3 µL/min) the true concentrations of interstitial metabolites can be determined. We use the term interstitial (instead of dialysate) metabolite in our metabolic studies. Our studies showed that the microdialysis technique can be used for assessment of insulin sensitivity in sc adipose tissue. Moreover, there were significant correlations between insulin sensitivity in sc adipose tissue, whole body and liver (M. A mixed meal resulted in lower capillary and interstitial glucose as well as lactate levels compared to OGTT. There were no differences in relative glucose recovery after mixed meal compared to OGTT. The microdialysis technique was reliable also for studies after mixed meal on the insulin effect in sc adipose tissue. (V) In conclusion microdialysis technique can used for reliable monitoring of glucose and other metabolites in sc abdominal adipose tissue during everyday activity in patients with DM. Pre-rinsing the microdialysis catheter in combination with a low (0.3 µL/min) perfusion flow rate gave similar interstitial and capillary glucose levels during fasting state, after oral glucose test and standardized mixed meal and two hours after meals in healthy subjects and patients with type 1 and type 2 DM. The low flow rate is also recommended for long term (five days) measurements of sc interstitial glucose, since at this flow rate the measurements were not affected by the inflammation around the catheter. Furthermore, the microdialysis technique can be used for studying the effect of insulin on glucose utilization and lipolysis in abdominal sc adipose tissue

Protective Effect of the HIF-1A Pro582Ser Polymorphism on Severe Diabetic Retinopathy

Objective. Hypoxia is central in the pathogenesis of diabetic retinopathy (DR). Hypoxia-inducible factor-1 (HIF-1) is the key mediator in cellular oxygen homeostasis that facilitates the adaptation to hypoxia. HIF-1 is repressed by hyperglycemia contributing by this to the development of complications in diabetes. Recent work has shown that the HIF-1A Pro582Ser polymorphism is more resistant to hyperglycemia-mediated repression, thus protecting against the development of diabetic nephropathy. In this study, we have investigated the effect of the HIF-1A Pro582Ser polymorphism on the development of DR and further dissected the mechanisms by which the polymorphism confers a relative resistance to the repressive effect of hyperglycemia. Research Design and Method. 703 patients with type 1 diabetes mellitus from one endocrine department were included in the study. The degree of retinopathy was correlated to the HIF-1A Pro582Ser polymorphism. The effect of glucose on a stable HIF-1A construct with a Pro582Ser mutation was evaluated in vitro. Results. We identified a protective effect of HIF-1A Pro582Ser against developing severe DR with a risk reduction of 95%, even when adjusting for known risk factors for DR such as diabetes duration, hyperglycemia, and hypertension. The Pro582Ser mutation does not cancel the destabilizing effect of glucose but is followed by an increased transactivation activity even in high glucose concentrations. Conclusion. The HIF-1A genetic polymorphism has a protective effect on the development of severe DR. Moreover, the relative resistance of the HIF-1A Pro582Ser polymorphism to the repressive effect of hyperglycemia is due to the transactivation activity rather than the protein stability of HIF-1α

The impact of macronutrient composition on metabolic regulation : An Islet-Centric view

Aim: The influence of dietary carbohydrates and fats on weight gain is inconclusively understood. We studied the acute impact of these nutrients on the overall metabolic state utilizing the insulin:glucagon ratio (IGR). Methods: Following in vitro glucose and palmitate treatment, insulin and glucagon secretion from islets isolated from C57Bl/6J mice was measured. Our human in vivo study included 21 normoglycaemia (mean age 51.9 ± 16.5 years, BMI 23.9 ± 3.5 kg/m2, and HbA1c 36.9 ± 3.3 mmol/mol) and 20 type 2 diabetes (T2D) diagnosed individuals (duration 12 ± 7 years, mean age 63.6 ± 4.5 years, BMI 29.1 ± 2.4 kg/m2, and HbA1c 52.3 ± 9.5 mmol/mol). Individuals consumed a carbohydrate-rich or fat-rich meal (600 kcal) in a cross-over design. Plasma insulin and glucagon levels were measured at −30, −5, and 0 min, and every 30 min until 240 min after meal ingestion. Results: The IGR measured from mouse islets was determined solely by glucose levels. The palmitate-stimulated hormone secretion was largely glucose independent in the analysed mouse islets. The acute meal tolerance test demonstrated that insulin and glucagon secretion is dependent on glycaemic status and meal composition, whereas the IGR was dependent upon meal composition. The relative reduction in IGR elicited by the fat-rich meal was more pronounced in obese individuals. This effect was blunted in T2D individuals with elevated HbA1c levels. Conclusion: The metabolic state in normoglycaemic individuals and T2D-diagnosed individuals is regulated by glucose. We demonstrate that consumption of a low carbohydrate diet, eliciting a catabolic state, may be beneficial for weight loss, particularly in obese individuals

Triggering of a Dll4–Notch1 loop impairs wound healing in diabetes

Diabetic foot ulcerations (DFUs) represent a major medical, social, and economic problem. Therapeutic options are restricted due to a poor understanding of the pathogenic mechanisms. The Notch pathway plays a pivotal role in cell differentiation, proliferation, and angiogenesis, processes that are profoundly disturbed in diabetic wounds. Notch signaling is activated upon interactions between membrane-bound Notch receptors (Notch 1-4) and ligands (Jagged 1-2 and Delta-like 1, 3, 4), resulting in cell-context-dependent outputs. Here, we report that Notch1 signaling is activated by hyperglycemia in diabetic skin and specifically impairs wound healing in diabetes. Local inhibition of Notch1 signaling in experimental wounds markedly improves healing exclusively in diabetic, but not in nondiabetic, animals. Mechanistically, high glucose levels activate a specific positive Delta-like 4 (Dll4)-Notch1 feedback loop. Using loss-of-function genetic approaches, we demonstrate that Notch1 inactivation in keratinocytes is sufficient to cancel the repressive effects of the Dll4-Notch1 loop on wound healing in diabetes, thus making Notch1 signaling an attractive locally therapeutic target for the treatment of DFUs