COVID-19 and metabolic disease: mechanisms and clinical management.

Up to 50% of the people who have died from COVID-19 had metabolic and vascular disorders. Notably, there are many direct links between COVID-19 and the metabolic and endocrine systems. Thus, not only are patients with metabolic dysfunction (eg, obesity, hypertension, non-alcoholic fatty liver disease, and diabetes) at an increased risk of developing severe COVID-19 but also infection with SARS-CoV-2 might lead to new-onset diabetes or aggravation of pre-existing metabolic disorders. In this Review, we provide an update on the mechanisms of how metabolic and endocrine disorders might predispose patients to develop severe COVID-19. Additionally, we update the practical recommendations and management of patients with COVID-19 and post-pandemic. Furthermore, we summarise new treatment options for patients with both COVID-19 and diabetes, and highlight current challenges in clinical management.

Metabolic and Non-Metabolic Peripheral Neuropathy: Is there a Place for Therapeutic Apheresis?

As the rate of obesity and the incidence of diabetes mellitus have been increasing, diabetic neuropathy has become the most common cause of peripheral neuropathy in developed countries. In addition, a variety of pathogenetically heterogeneous disorders can lead to impairment of the peripheral nervous system including amyloidosis, vitamin deficiencies, uremia and lipid disorders, alcohol abuse, autoimmune and infectious diseases as well as exposure to environmental toxins. We have noted that a combination of these disorders may aggravate the manifestations of peripheral diabetic neuropathy, an effect, which is most pronounced when metabolic and non-metabolic pathologies lead to cumulative damage. Current treatment options are limited and generally have unsatisfactory results in most patients. Therapeutic apheresis (INUSpherese®) allows the removal of metabolic, inflammatory, immunologic and environmental contributors to the disease process and may be an effective treatment option. We reviewed the developments in therapeutic apheresis for metabolic and non-metabolic peripheral neuropathy, including the current literature as well as data from our university diabetes center.

Current aspects in the pathophysiology and treatment of chronic wounds in diabetes mellitus.

Impaired wound healing is a frequent and very severe problem in patients with diabetes mellitus, yet little is known about the underlying pathomechanisms. In this paper we review the biology of wound healing with particular attention to the pathophysiology of chronic wounds in diabetic patients. The standard treatment of diabetic ulcers includes measures to optimize glycemic control as well as extensive debridement, infection elimination by antibiotic therapy based on wound pathogen cultures, the use of moisture dressings, and offloading high pressure from the wound bed. In this paper we discuss novel adjuvant therapies with particular reference to the use of autologous skin transplants for the treatment of diabetic foot ulcers which do not respond to standard care.

Self-adjustment of insulin dose using graphically depicted self-monitoring of blood glucose measurements in patients with type 1 diabetes mellitus.

BACKGROUND: There is a need for patients to be able to adjust their insulin doses accurately and independently during continuous subcutaneous insulin infusion (CSII) therapy in order to avoid glycemic excursions and improve glycemic control. Use of new technology has the potential to aid patients in visualizing their circadian patterns and improving their understanding of data provided by self-monitored blood glucose (SMBG) measurements. METHODS: A 24-week crossover study was performed in 25 patients with type 1 diabetes mellitus using CSII and SMBG. Patients were randomized either to entering blood glucose data into handwritten logbooks or to using the Accu-Chek SmartPix information management system (IMS) coupled with instructions from a training manual to aid interpretation of the IMS readings. Patients analyzed these chart readings every 2 weeks, and outpatient visits were scheduled for both arms every 6 weeks. RESULTS: There was a significantly lower mean overall blood glucose level with the IMS compared with use of a logbook (139 ± 16.2 versus 150 ± 19.8 mg/dl; Δ = 10.8 mg/dl; p < .01), and a significantly higher proportion of blood glucose values was in the target range compared with use of a logbook (43.6% versus 38.5%; p < .001). Hypoglycemic events were also significantly lower with the IMS compared with logbooks (3.7 fewer events/6 weeks; p < .05). There was no significant difference between groups in the daily frequency of SMBG measurements. CONCLUSIONS: The use of an IMS, coupled with an easily understood training manual, enables patients to improve glycemic control by performing accurate and timely self-adjustments to their insulin regimens.

Noninvasive management of the diabetic foot with critical limb ischemia: current options and future perspectives.

Foot ulcers are a major complication in patients with diabetes mellitus and involve dramatic restrictions to quality of life and also lead to enormous socio-economical loss due to the high amputation rate. The poor and slow wound healing is often aggravated by the frequent comorbidity of foot ulcers with peripheral arterial disease, making the treatment of this condition even more complicated. While the local treatment of foot ulcers is mainly based on mechanical relief and prevention or treatment of infection, improving perfusion of the impaired tissue remains the major challenge in peripheral arterial disease. While focal arterial stenosis is the domain of interventional angioplasty or vascular surgery, patients with critical limb ischemia and lacking options for revascularization have a much worse prognosis, because current treatment options avoiding amputation are scarce. However, based on recent research efforts, there is rising hope for promising and more-effective therapeutic approaches for these patients. Here, we discuss the current improvements of established therapies aimed at an improvement of limb perfusion, as well as the development of novel cutting-edge therapies based on stem-cell technology. The experiences of a 'high-volume center' for treatment of diabetic foot syndrome with a current major amputation rate of 4% are discussed.

Intermittent intravenous urokinase for critical limb ischemia in diabetic foot ulceration.

Patients with diabetic foot ulceration and critical limb ischemia have a high risk of major amputation, especially if limbs can not be revascularized. Urokinase is effective in improving microcirculation in critical limb ischemia and might improve outcomes. There are no data on the efficacy and safety of urokinase treatment (survival free of major amputation, ulcer healing and the rate of minor and major bleeding). Therefore, we aimed to investigate the effect of urokinase treatment in a phase II clinical trial. We performed an open, prospective, non-controlled, multicenter phase II cohort study in 77 type-2 diabetic patients with critical limb ischemia and diabetic foot ulceration. Patients had no surgical or endovascular treatment option based on interdisciplinary consensus. Urokinase (1 Mio IU if plasma fibrinogen >or=2.5 g/l, 0.5 Mio IU if fibrinogen <2.5 g/l) was administered for 21 days as an intravenous infusion over 30 minutes. Each patient was followed up for 12 months. Treatment for a median of 21 days resulted in 33% of patients being alive, having no major amputation and completely healed ulcers after 12 months. Total survival rate was 84.6%, amputation-free survival 69.2% and rate of major amputation 21.1%. Eighty-two percent of patients experienced at least once a complete ulcer healing within the course of study. Three serious adverse events were urokinase-related. Urokinase treatment in diabetic patients with critical limb ischemia appears to be effective, feasible and safe. Although this calls for a larger, randomized and controlled trial, the results are highly relevant for clinical practice to prevent these patients from receiving major amputation due to diabetic foot syndrome.

Association of the calpain-10 gene with type 2 diabetes in Europeans: results of pooled and meta-analyses.

We conducted pooled and meta-analyses of the association of the calpain-10 gene (CAPN10) polymorphisms SNP-43, Indel-19 and SNP-63 individually and as haplotypes with type 2 diabetes (T2D) in 3237 patients and 2935 controls of European ancestry. In the pooled analyses, the common SNP-43*G allele was associated with modest but statistically significant increased risk of T2D (odds ratio (OR)=1.11 (95% confidence interval (CI), 1.02-1.20), P=0.01). Two haplotype combinations were associated with increased risk of T2D (1-2-1/1-2-1, OR=1.20 (1.03-1.41), P=0.02; and 1-1-2/1-2-1, OR=1.26 (1.01-1.59), P=0.04) and one with decreased risk (1-1-1/2-2-1, OR=0.86 (0.75-0.99), P=0.03). The meta-analysis also showed a significant effect of the 1-2-1/1-2-1 haplogenotype on risk (OR=1.25 (1.05-1.50), P=0.01). However, there was evidence for heterogeneity with respect to this effect (P=0.06). The heterogeneity appeared to be due to data sets in which the cases were selected from samples used in linkage studies of T2D. Using only the population-based case-control samples removed the heterogeneity (P=0.89) and strengthened the evidence for association with T2D in both the pooled (SNP-43*G, OR=1.19 (1.07-1.32), P=0.001; 1-2-1/1-2-1 haplogenotype, OR=1.46 (1.19-1.78), P=0.0003; 1-1-2/1-2-1 haplogenotype, OR=1.52 (1.12-2.06), P=0.007; and 1-1-1/2-2-1 haplogenotype, OR=0.83 (0.70-0.99), P=0.03) and the meta-analysis (SNP-43*G, OR=1.18 (1.05-1.32), P=0.005; 1-2-1/1-2-1 haplogenotype, OR=1.68 (1.33-2.11), P=0.00001). The pooled and meta-analyses as well as the linkage disequilibrium and haplotype diversity studies suggest a role for genetic variation in CAPN10 affecting risk of T2D in Europeans.