| 1. |
- DAddio, Francesca, et al.
(författare)
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The IGFBP3/TMEM219 pathway regulates beta cell homeostasis
- 2022
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Ingår i: Nature Communications. - : Nature Portfolio. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- In this new study the Authors demonstrated that the IGFBP3/TMEM219 pathway is a physiological regulator of pancreatic beta cell homeostasis and it is dysregulated in diabetes. IGFBP3/TMEM219 targeting may therefore serve as a therapeutic option in diabetes. Loss of pancreatic beta cells is a central feature of type 1 (T1D) and type 2 (T2D) diabetes, but a therapeutic strategy to preserve beta cell mass remains to be established. Here we show that the death receptor TMEM219 is expressed on pancreatic beta cells and that signaling through its ligand insulin-like growth factor binding protein 3 (IGFBP3) leads to beta cell loss and dysfunction. Increased peripheral IGFBP3 was observed in established and at-risk T1D/T2D patients and was confirmed in T1D/T2D preclinical models, suggesting that dysfunctional IGFBP3/TMEM219 signaling is associated with abnormalities in beta cells homeostasis. In vitro and in vivo short-term IGFBP3/TMEM219 inhibition and TMEM219 genetic ablation preserved beta cells and prevented/delayed diabetes onset, while long-term IGFBP3/TMEM219 blockade allowed for beta cell expansion. Interestingly, in several patients cohorts restoration of appropriate IGFBP3 levels was associated with improved beta cell function. The IGFBP3/TMEM219 pathway is thus shown to be a physiological regulator of beta cell homeostasis and is also demonstrated to be disrupted in T1D/T2D. IGFBP3/TMEM219 targeting may therefore serve as a therapeutic option in diabetes.
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| 2. |
- de Valk, Harold W., et al.
(författare)
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Switching to Degludec is Associated with Reduced Hypoglycaemia, Irrespective of Definition Used or Patient Characteristics : Secondary Analysis of the ReFLeCT Prospective, Observational Study
- 2020
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Ingår i: Diabetes Therapy. - : Springer. - 1869-6953 .- 1869-6961. ; 11:9, s. 2159-2167
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Hypoglycaemia is a common side effect of insulin therapy; low or high glycated haemoglobin (HbA(1c)) levels, history of hypoglycaemia or long diabetes duration are known modifiers of hypoglycaemia risk. In randomised clinical trials, lower rates of hypoglycaemia have been observed with the new-generation insulin analogue, long-acting insulin degludec, compared with other basal insulins.Methods: The ReFLeCT study was a prospective observational study over 12 months. Patient-reported diary data on hypoglycaemia were collected from patients with type 1 diabetes (T1D) or type 2 diabetes (T2D) who were switching from other basal insulins to insulin degludec (degludec) at their physician's discretion in routine clinical care. Two secondary analyses were undertaken to investigate the change in number of hypoglycaemic events: a post hoc analysis using the updated American Diabetes Association (ADA) level 1, 2 and 3 hypoglycaemia definitions, and a pre-specified analysis using patient characteristics (baseline HbA(1c), diabetes duration, and physician's rationale for initiating degludec).Results: Switching to degludec was associated with significantly fewer hypoglycaemic events for all definitions in T1D, and level 1 and 2 in T2D (too few level 3 events for statistical comparison). Moreover, patient characteristics did not influence the observed reduction in hypoglycaemia in T1D and T2D.Conclusion: These results demonstrate that switching to degludec from other basal insulins was associated with reduced rates of hypoglycaemia, irrespective of the definition used or baseline patient characteristics.Plain Language Summary: Low blood sugar levels (hypoglycaemia) are a common, and sometimes serious, side effect of treatment with insulin in people with diabetes. In the ReFleCT study, adults with type 1 (T1D) and type 2 diabetes (T2D) were asked to complete a diary for 12 months when their doctor changed their previous long-acting insulin treatment to insulin degludec (degludec). The key outcome of the study was whether the frequency of hypoglycaemia changed when a patient's insulin treatment was switched. Here, we used the diary information from the ReFLeCT study to investigate whether the change in the rate of hypoglycaemia was related to the way hypoglycaemia was defined, or to patients' characteristics at the time their insulin was switched. These characteristics included the length of time that patients had had diabetes, their blood sugar control, and their doctor's reason for changing their medication. Our findings showed that the way hypoglycaemia was defined, and patients' characteristics, did not generally influence the frequency of hypoglycaemia for patients with T1D or T2D. However, the most severe hypoglycaemia in patients with T2D occurred too infrequently to be assessed. Patients in all groups had less hypoglycaemia overall after switching compared with their previous treatment, suggesting that degludec may be a treatment option for a broad range of patients with diabetes.
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| 3. |
- Fadini, Gian Paolo, et al.
(författare)
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Switching to Degludec from Other Basal Insulins is Associated with Reduced Hypoglycemia Rates : a Prospective Study
- 2019
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197. ; 104:12, s. 5977-5990
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Observational studies of insulin degludec (degludec) with hypoglycemia events prospectively recorded are lacking.OBJECTIVE: To evaluate the safety and effectiveness of degludec in patients with type 1 (T1D) or type 2 diabetes (T2D) switching from other basal insulins in routine care.DESIGN: ReFLeCT was a multinational, multicenter, prospective, observational, single-arm study comprising a 4-week baseline period (pre-switch basal insulin) and 12-month follow-up (degludec).SETTING: Routine clinical practice. Patients or Other Participants: Insulin-treated patients (≥18 years) with T1D (n=556) or T2D (n=611) with treatment plans to initiate degludec.INTERVENTIONS: Switching to degludec from other basal insulins.MAIN OUTCOME MEASURE(S): Change from baseline in number of overall hypoglycemic events recorded in patient diaries.RESULTS: In T1D, the 12-month follow-up/baseline rate ratios [95% CI] of overall (0.80 [0.74;0.88]), non-severe (0.83 [0.76;0.91]), severe (0.28 [0.14;0.56]) and nocturnal (0.61 [0.50;0.73]) hypoglycemia suggested significantly reduced hypoglycemia rates with degludec (all P<0.001). At 12 months, HbA1c, fasting plasma glucose (FPG) and basal insulin dose decreased significantly. Body weight increased and treatment satisfaction improved significantly. In T2D, the hypoglycemia rate ratios were: overall (0.46 [0.38;0.56]), non-severe (0.53 [0.44;0.64]) and nocturnal (0.35 [0.20;0.62]) (all P<0.001; too few events for analysis of severe). At 12 months, HbA1c and FPG decreased significantly. Body weight and insulin doses remained unchanged, and treatment satisfaction was significantly improved.CONCLUSIONS: In a routine clinical care setting, switching to degludec from other basal insulins was associated with significantly reduced rates of hypoglycemia, improved glycemic control, and treatment satisfaction in patients with T1D or T2D.
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| 4. |
- Norgren, Lars, 1942-, et al.
(författare)
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PACE : randomized, controlled, multicentre, multinational, phase III study of PLX-PAD for critical limb ischaemia in patients unsuitable for revascularization: randomized clinical trial
- 2024
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Ingår i: British Journal of Surgery. - : Oxford University Press. - 0007-1323 .- 1365-2168. ; 111:2
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Revascularization is the primary treatment modality for chronic limb-threatening ischaemia (CLTI), but is not feasible in all patients. PLX-PAD is an off-the-shelf, placental-derived, mesenchymal stromal cell-like cell therapy. This study aimed to evaluate whether PLX-PAD would increase amputation-free survival in people with CLTI who were not candidates for revascularization.METHODS: People with CLTI and minor tissue loss (Rutherford 5) who were unsuitable for revascularization were entered into a randomized, parallel-group, placebo-controlled, multinational, blinded, trial, in which PLX-PAD was compared with placebo (2 : 1 randomization), with 30 intramuscular injections (0.5 ml each) into the index leg on days 0 and 60. Planned follow-up was 12-36 months, and included vital status, amputations, lesion size, pain and quality-of-life assessments, haemodynamic parameters, and adverse events.RESULTS: Of 213 patients enrolled, 143 were randomized to PLX-PAD and 70 to placebo. Demographics and baseline characteristics were balanced. Most patients were Caucasian (96.2%), male (76.1%), and ambulatory (85.9%). Most patients (76.6%) reported at least one adverse event, which were mostly expected events in CLTI, such as skin ulcer or gangrene. The probability of major amputation or death was similar for placebo and PLX-PAD (33 and 28.6% respectively; HR 0.93, 95% c.i. 0.53 to 1.63; P = 0.788). Revascularization and complete wound healing rates were similar in the two groups. A post hoc analysis of a subpopulation of 121 patients with a baseline haemoglobin A1c level below 6.5% showed improved 12-month amputation-free survival (HR 0.46, 0.21 to 0.99; P = 0.048).CONCLUSION: Although there was no evidence that PLX-PAD reduced amputation-free survival in the entire study population, benefit was observed in patients without diabetes mellitus or whose diabetes was well controlled; this requires confirmation in further studies. Trial registration: NCT03006770 (http://www.clinicaltrials.gov); 2015-005532-18 (EudraCT Clinical Trials register - Search for 2015-005532-18).
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