scholarly journals HIF-1 mediated activation of antimicrobial peptide LL-37 in type 2 diabetic patients

Author(s):  
Soumitra Mohanty ◽  
Witchuda Kamolvit ◽  
Silvia Zambrana ◽  
Eduardo Gonzales ◽  
Jonas Tovi ◽  
...  

Abstract Infections are common in patients with diabetes, but increasing antibiotic resistance hampers successful bacterial clearance and calls for alternative treatment strategies. Hypoxia-inducible factor 1 (HIF-1) is known to influence the innate immune defense and could therefore serve as a possible target. However, the impact of high glucose on HIF-1 has received little attention and merits closer investigation. Here, we show that higher levels of proinflammatory cytokines and CAMP, encoding for the antimicrobial peptide cathelicidin, LL-37, correlate with HIF-1 in type 2 diabetic patients. Chemical activation of HIF-1 further enhanced LL-37, IL-1β, and IL-8 in human uroepithelial cells exposed to high glucose. Moreover, HIF-1 activation of transurethrally infected diabetic mice resulted in lower bacterial load. Drugs activating HIF-1 could therefore in the future potentially have a therapeutic role in clearing bacteria in diabetic patients with infections where antibiotic treatment failed. Key messages • Mohanty et al. “HIF-1 mediated activation of antimicrobial peptide LL-37 in type 2 diabetic patients.” • Our study highlights induction of the antimicrobial peptide, LL-37, and strengthening of the innate immunity through hypoxia-inducible factor 1 (HIF-1) in diabetes. • Our key observations are: 1. HIF-1 activation increased LL-37 expression in human urothelial cells treated with high glucose. In line with that, we demonstrated that patients with type 2 diabetes living at high altitude had increased levels of the LL-37. 2. HIF-1 activation increased IL-1β and IL-8 in human uroepithelial cells treated with high glucose concentration. 3. Pharmacological activation of HIF-1 decreased bacterial load in the urinary bladder of mice with hereditary diabetes. • We conclude that enhancing HIF-1 may along with antibiotics in the future contribute to the treatment in selected patient groups where traditional therapy is not possible.

Author(s):  
Maria Saveria Gilardini Montani ◽  
Marisa Granato ◽  
Laura Cuomo ◽  
Sandro Valia ◽  
Livia Di Renzo ◽  
...  

Author(s):  
Giuseppe Derosa ◽  
Angela D’Angelo ◽  
Chiara Martinotti ◽  
Maria Chiara Valentino ◽  
Sergio Di Matteo ◽  
...  

Abstract. Background: to evaluate the effects of Vitamin D3 on glyco-metabolic control in type 2 diabetic patients with Vitamin D deficiency. Methods: one hundred and seventeen patients were randomized to placebo and 122 patients to Vitamin D3. We evaluated anthropometric parameters, glyco-metabolic control, and parathormone (PTH) value at baseline, after 3, and 6 months. Results: a significant reduction of fasting, and post-prandial glucose was recorded in Vitamin D3 group after 6 months. A significant HbA1c decrease was observed in Vitamin D3 (from 7.6% or 60 mmol/mol to 7.1% or 54 mmol) at 6 months compared to baseline, and to placebo (p < 0.05 for both). At the end of the study period, we noticed a change in the amount in doses of oral or subcutaneous hypoglycemic agents and insulin, respectively. The use of metformin, acarbose, and pioglitazone was significantly lower (p = 0.037, p = 0.048, and p = 0.042, respectively) than at the beginning of the study in the Vitamin D3 therapy group. The units of Lispro, Aspart, and Glargine insulin were lower in the Vitamin D3 group at the end of the study (p = 0.031, p = 0.037, and p = 0.035, respectively) than in the placebo group. Conclusions: in type 2 diabetic patients with Vitamin D deficiency, the restoration of value in the Vitamin D standard has led not only to an improvement in the glyco-metabolic compensation, but also to a reduced posology of some oral hypoglycemic agents and some types of insulin used.


VASA ◽  
2005 ◽  
Vol 34 (2) ◽  
pp. 113-117 ◽  
Author(s):  
Papanas ◽  
Symeonidis ◽  
Maltezos ◽  
Giannakis ◽  
Mavridis ◽  
...  

Background: The purpose of this study is to evaluate the severity of aortic arch calcification among type 2 diabetic patients in association with diabetes duration, diabetic complications, coronary artery disease and presence of cardiovascular risk factors. Patients and methods: This study included 207 type 2 diabetic patients (101 men) with a mean age of 61.5 ± 8.1 years and a mean diabetes duration of 13.9 ± 6.4 years. Aortic arch calcification was assessed by means of posteroanterior chest X-rays. Severity of calcification was graded as follows: grade 0 (no visible calcification), grade 1 (small spots of calcification or single thin calcification of the aortic knob), grade 2 (one or more areas of thick calcification), grade 3 (circular calcification of the aortic knob). Results: Severity of calcification was grade 0 in 84 patients (40.58%), grade 1 in 64 patients (30.92%), grade 2 in 43 patients (20.77%) and grade 3 in 16 patients (7.73%). In simple regression analysis severity of aortic arch calcification was associated with age (p = 0.032), duration of diabetes (p = 0.026), insulin dependence (p = 0.042) and presence of coronary artery disease (p = 0.039), hypertension (p = 0.019), dyslipidaemia (p = 0.029), retinopathy (p = 0.012) and microalbuminuria (p = 0.01). In multiple regression analysis severity of aortic arch calcification was associated with age (p = 0.04), duration of diabetes (p = 0.032) and presence of hypertension (p = 0.024), dyslipidaemia (p = 0.031) and coronary artery disease (p = 0.04), while the association with retinopathy, microalbuminuria and insulin dependence was no longer significant. Conclusions: Severity of aortic arch calcification is associated with age, diabetes duration, diabetic complications (retinopathy, microalbuminuria), coronary artery disease, insulin dependence, and presence of hypertension and dyslipidaemia.


1992 ◽  
Vol 68 (03) ◽  
pp. 253-256 ◽  
Author(s):  
Thomas Vukovich ◽  
Sylvia Proidl ◽  
Paul Knöbl ◽  
Harald Teufelsbauer ◽  
Christoph Schnack ◽  
...  

SummaryBeside hypercoagulation and hyperactivated platelets disturbances of the fibrinolytic system towards hypofibrinolysis have been reported to be associated with both glycemic and lipidemic derangement in diabetic patients. In the present prospective follow-up study the effect of 16 weeks insulin treatment and glycemic regulation on plasma levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1), the main regulators of fibrinolysis, was investigated in 19 type-2 diabetic patients with secondary failure to sulphonylureas. A similar glycemic regulation was obtained in a control group of 10 type 2 diabetic patients with sufficient metabolic response to strict dietary treatment and continuation of sulphonylurea treatment. Compared to 27 healthy subjects levels of tPA and PAI-1 were not significantly increased in type 2 diabetic patients before metabolic intervention. Although a hypofibrinolytic state due to an increase of PAI-1 levels was previously reported in obese hyperinsulinemic patients, no effect of insulin treatment on both tPA- and PAI-1 levels was observed in the present study including patients with only slightly increased body mass index (median 26.0 kg/m2). By correlation analysis PAI-1 levels were significantly related to serum cholesterol (R = 0.52) and glycemic control (glucose R = 0.41) in the whole group of diabetic patients at entry and in both subgroups after 16 weeks of treatment (insulin group: cholesterol R = 0.46, HbA1c R = 0.51; sulphonylurea group: cholesterol R = 0.59, HbA1c R = 0.58). In healthy subjects tPA and PAI-1 was correlated to serum insulin (R = 0.54, R = 0.56) and triglycerides (R = 0.46, R = 0.40). In conclusion, our results indicate that insulin treatment associated with metabolic improvement has no adverse effect to fibrinolysis in type 2 diabetic patients.


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