GLUT4-overexpressing engineered muscle constructs as a therapeutic platform to normalize glycemia in diabetic mice.

Skeletal muscle insulin resistance is a main defect in type 2 diabetes (T2D), which is associated with impaired function and content of glucose transporter type 4 (GLUT4). GLUT4 overexpression in skeletal muscle tissue can improve glucose homeostasis. Therefore, we created an engineered muscle construct (EMC) composed of GLUT4-overexpressing (OEG4) cells. The ability of the engineered implants to reduce fasting glucose levels was tested in diet-induced obesity mice. Decrease and stabilization of basal glucose levels were apparent up to 4 months after implantation. Analysis of the retrieved constructs showed elevated expression of myokines and proteins related to metabolic processes. In addition, we validated the efficiency of OEG4-EMCs in insulin-resistant mice. Following high glucose load administration, mice showed improved glucose tolerance. Our data indicate that OEG4-EMC implant is an efficient mode for restoring insulin sensitivity and improving glucose homeostasis in diabetic mice. Such procedure is a potential innovative modality for T2D therapy.

Personalized epigenetic management of diabetes.

The novel genome-wide assays of epigenetic marks have resulted in a greater understanding of how genetics and the environment interact in the development and inheritance of diabetes. Chronic hyperglycemia induces epigenetic changes in multiple organs, contributing to diabetic complications. Specific epigenetic-modifying compounds have been developed to erase these modifications, possibly slowing down the onset of diabetes-related complications. The current review is an update of the previously published paper, describing the most recent advances in the epigenetics of diabetes.

Challenges of implementing personalized (precision) medicine: a focus on diabetes.

The concept of personalized (precision) medicine (PM) emphasizes the scientific and technological innovations that enable the physician to tailor disease prediction, diagnosis and treatment to the individual patient, based on a personalized data-driven approach. The major challenge for the medical systems is to translate the molecular and genomic advances into clinical available means. Patients and healthcare providers, the pharmaceutical and diagnostic industries manifest a growing interest in PM. Multiple stakeholders need adaptation and re-engineering for successful clinical implementation of PM. Drawing primarily from the field of 'diabetes', this article will summarize the main challenges to implementation of PM into current medical practice and some of the approaches currently being implemented to overcome these challenges.

Depressive symptoms prior to and following insulin initiation in patients with type 2 diabetes mellitus: Prevalence, risk factors and effect on physician resource utilisation.

AIMS: To study the frequency and intensity of depressive symptoms and associations with physician resource utilisation following insulin initiation in patients with type 2 diabetes mellitus. METHODS: SOLVE was a 24-week observational study. In this sub-analysis of data from Poland, depressive symptoms were evaluated using the Patient Health Questionnaire (PHQ)-9. RESULTS: PHQ-9 was completed by 942 of 1169 patients (80.6%) at baseline, and 751 (64.2%) at both baseline and final (24-week) visit. PHQ-9 scores indicated depressive symptoms in 45.6% (n=430) at baseline, and 27.2% (n=223) at final visit. Mean PHQ-9 change was -2.38 [95% CI -2.73, -2.02], p<0.001. Depressive symptoms at baseline (OR 6.32, p<0.001), microvascular disease (OR 2.45, p=0.016), number of physician contacts (OR 1.16, p=0.009), and change in HbA1c (OR 0.60, p=0.025) were independently associated with moderate/severe depressive symptoms at final visit. Patients with more severe depressive symptoms spent more time training to self-inject (p=0.0016), self-adjust (p=0.0023) and manage other aspects of insulin delivery (p<0.0001). Patients with persistent depressive symptoms had more telephone contacts and dose changes at final visit than those without (both p<0.05). CONCLUSIONS: Depressive symptoms are common with type 2 diabetes and associated with increased healthcare utilisation, reinforcing the need for holistic interdisciplinary management approaches.

Personalized epigenetic management of diabetes.

Epigenetic regulation of gene expression allows the organism to respond/adapt to environmental conditions without changing the gene coding sequence. Epigenetic modifications have also been found to control gene expression in various diseases, including diabetes. Epigenetic changes induced by hyperglycemia in multiple target organs contribute to metabolic memory of diabetic complications. The long-lasting development of diabetic complications even after achieving glucose control has been partly attributed to epigenetic changes in target cells. Specific epigenetic drugs might rescue chromatin conformation associated to hyperglycemia possibly slowing down the onset of diabetes-related complications. The current review will describe the updated epigenetics in diabetes that can be used to personalize a more focused treatment.

Introduction to personalized medicine in diabetes mellitus.

The world is facing an epidemic rise in diabetes mellitus (DM) incidence, which is challenging health funders, health systems, clinicians, and patients to understand and respond to a flood of research and knowledge. Evidence-based guidelines provide uniform management recommendations for "average" patients that rarely take into account individual variation in susceptibility to DM, to its complications, and responses to pharmacological and lifestyle interventions. Personalized medicine combines bioinformatics with genomic, proteomic, metabolomic, pharmacogenomic ("omics") and other new technologies to explore pathophysiology and to characterize more precisely an individual's risk for disease, as well as response to interventions. In this review we will introduce readers to personalized medicine as applied to DM, in particular the use of clinical, genetic, metabolic, and other markers of risk for DM and its chronic microvascular and macrovascular complications, as well as insights into variations in response to and tolerance of commonly used medications, dietary changes, and exercise. These advances in "omic" information and techniques also provide clues to potential pathophysiological mechanisms underlying DM and its complications.

Preventing type 2 diabetes mellitus: a call for personalized intervention.

In parallel with the rising prevalence of obesity worldwide, especially in younger people, there has been a dramatic increase in recent decades in the incidence and prevalence of metabolic consequences of obesity, in particular prediabetes and type 2 diabetes mellitus (DM2). Although approximately one-third of US adults now meet one or more diagnostic criteria for prediabetes, only a minority of those so identified as being at risk for DM2 actually progress to diabetes, and some may regress to normal status. Given the uncertain prognosis of prediabetes, it is not clear who is most likely to benefit from lifestyle change or medication interventions that are known to reduce DM2 risk. We review the many factors known to influence risk of developing DM2 and summarize treatment trials demonstrating the possibility of preventing DM2. Applying the concepts of personalized medicine and the potential of "big data" approaches to analysis of massive amounts of routinely gathered clinical and laboratory data from large populations, we call for the development of tools to more precisely estimate individual risk of DM2.

Observational study of once-daily insulin detemir in people with type 2 diabetes aged 75 years or older: a sub-analysis of data from the Study of Once daily LeVEmir (SOLVE).

OBJECTIVES: Older patients are particularly vulnerable to hypoglycaemia. The aim of this study was to evaluate the response to initiation of once-daily insulin detemir in patients aged ≥75 years with type 2 diabetes mellitus (T2DM) treated with one or more oral antidiabetic drugs (OADs). METHODS: A sub-analysis was conducted using data from SOLVE (Study of Once daily LeVEmir), a 24-week observational study involving 3,219 investigators and 2,817 project sites from ten countries. Routine clinical practice was followed; there were no study-prescribed procedures. The total cohort comprised 17,374 participants, of whom 2,398 (14 %) were aged ≥75 years. The physicians collected information from patient recall, the patients' medical records and their self-monitored blood glucose diaries (if kept). RESULTS: Pre-insulin glycated haemoglobin (HbA(1c)) was similar between participants aged ≥75 years and those aged <75 years (HbA(1c) 8.8 ± 1.5 % vs. 8.9 ± 1.6 % [mean ± SD], respectively). After 24 weeks of treatment, similar reductions in HbA(1c) were observed in the two subgroups: 7.6 ± 1.1 % and 7.5 ± 1.2 % in participants aged ≥75 years and those aged <75 years, respectively. The incidence of severe hypoglycaemia (episodes per patient-year) decreased during the study in both age groups (from 0.057 to 0.007 in patients aged ≥75 years; from 0.042 to 0.005 in patients aged <75 years), while minor hypoglycaemia increased from 1.1 to 2.0 and from 1.7 to 1.8 episodes per patient-year in the older and younger age groups, respectively. Average weight reduction was similar in both groups: -0.5 kg (≥75 years) and -0.6 kg (<75 years). CONCLUSION: In both the older and younger age groups, the addition of once-daily insulin detemir to existing OAD regimens was effective and safe. In older patients, an improvement in HbA(1c) of 1.2 % was not associated with an increased risk of severe hypoglycaemia or weight gain.

Effect of baseline glycosylated hemoglobin A1c on glycemic control and diabetes management following initiation of once-daily insulin detemir in real-life clinical practice.

OBJECTIVE: The SOLVE study investigated the initiation of basal insulin in patients with type 2 diabetes on oral antidiabetic (OAD) treatment and outcomes in patients with varying levels of glycemic control at baseline. METHODS: This was an observational cohort study conducted in 10 countries using insulin detemir. Data were collected at 3 clinic visits (baseline, 12-week interim, and 24-week final visit). RESULTS: A total of 13,526 (77.9%) patients were included in the glycosylated hemoglobin A1c (HbA1c) subset analysis. Patients were grouped according to pre-insulin HbA1c values as follows: HbA1c <7.6% (n = 2,797); HbA1c 7.6-9% (n = 5,366), and HbA1c >9% (n = 5,363). A total of 27 patients experienced serious adverse drug reactions (SADRs) and/or severe hypoglycemia (3, 10, and 11 patients with pre-insulin HbA1c <7.6%, 7.6-9.0%, and >9.0%, respectively). All patient subgroups realized improvements in HbA1c, with the pre-insulin HbA1c >9% subgroup having the largest HbA1c reduction (-2.4% versus -0.9% and -0.2% for HbA1c subgroups 7.6-9% and <7.6%, respectively). In the total cohort (n = 17,374), the incidence of severe hypoglycemia decreased from 4 events per 100 person years to <1 event per 100 person years by final visit; the incidence of minor hypoglycemia increased from 1.6 to 1.8 events per person year. CONCLUSIONS: In this study, insulin initiation was delayed until late in disease course, and overall concordance with internationally recognized guidelines was low. The initiation of once-daily insulin detemir was associated with substantial improvements in glycemic control and was not associated with an increase in severe hypoglycemia or weight gain.

Initiation of once daily insulin detemir is not associated with weight gain in patients with type 2 diabetes mellitus: results from an observational study.

BACKGROUND: Obesity is common in type 2 diabetes (T2DM) and is associated with increased risk of morbidity and all-cause mortality. This analysis describes weight changes associated with insulin detemir initiation in real-life clinical practice. METHODS: Study of Once-Daily Levemir (SOLVE) was a 24-week international observational study of once-daily insulin detemir as add-on therapy in patients with T2DM receiving oral hypoglycaemic agents (OHAs). RESULTS: 17,374 participants were included in the analysis: mean age 62 ± 12 years; weight 80.8 ± 17.6 kg; body mass index (BMI) 29.2 ± 5.3 kg/m2; diabetes duration 10 ± 7 years; HbA1c 8.9 ± 1.6%. HbA1c decreased by 1.3 ± 1.5% during the study, with insulin doses of 0.27 ± 0.17 IU/kg. Patients with higher BMI had higher pre-insulin HbA1c, and similar reductions in HbA1c with insulin therapy. Weight decreased from 80.8 ± 17.6 kg to 80.3 ± 17.0 kg (change of -0.6 [95% CI -0.65; -0.47] kg), with 35% of patients losing >1 kg. Patients with the highest pre-insulin BMI lost the greatest amount of weight: BMI < 25: +0.8 [95% CI: 0.6; 0.9] kg, 25 ≤ BMI < 30: -0.2 [95% CI: -0.3; -0.8] kg, 30 ≤ BMI < 35: -1.0 [95% CI: -1.1; -0.8] kg; BMI ≥ 35: -1.9 [95% CI: -2.2; -1.6] kg. Minor hypoglycaemia decreased with increasing BMI: 2.3 and 1.3 events per patient year for BMI <25 and ≥ 35, respectively. CONCLUSIONS: Overall, patients with poorly controlled T2DM achieved significant reductions in HbA1c after initiation of once-daily insulin detemir therapy, without weight gain. The favourable impact of insulin detemir on weight may not apply to other insulin preparations. TRIAL REGISTRATIONS: ClinicalTrials.gov, NCT00825643 and NCT00740519.

Cytochrome P-450 CYP2E1 knockout mice are protected against high-fat diet-induced obesity and insulin resistance.

Conventional (whole body) CYP2E1 knockout mice displayed protection against high-fat diet-induced weight gain, obesity, and hyperlipidemia with increased energy expenditure despite normal food intake and spontaneous locomotor activity. In addition, the CYP2E1 knockout mice displayed a marked improvement in glucose tolerance on both normal chow and high-fat diets. Euglycemic-hyperinsulinemic clamps demonstrated a marked protection against high-fat diet-induced insulin resistance in CYP2E1 knockout mice, with enhanced adipose tissue glucose uptake and insulin suppression of hepatic glucose output. In parallel, adipose tissue was protected against high-fat diet-induced proinflammatory cytokine production. Taken together, these data demonstrate that the CYP2E1 deletion protects mice against high-fat diet-induced insulin resistance with improved glucose homeostasis in vivo.

The metabolic syndrome--from insulin resistance to obesity and diabetes.

In today's society with the escalating levels of obesity, diabetes, and cardiovascular disease, the metabolic syndrome is receiving considerable attention and is the subject of much controversy. Greater insight into the mechanism(s) behind the syndrome may improve our understanding of how to prevent and best manage this complex condition.

GLUT4 in murine bone growth: from uptake and translocation to proliferation and differentiation.

Skeletal growth, taking place in the cartilaginous growth plates of long bones, consumes high levels of glucose for both metabolic and anabolic purposes. We previously showed that Glut4 is present in growing bone and is decreased in diabetes. In the present study, we examined the hypothesis that in bone, GLUT4 gene expression and function are regulated via the IGF-I receptor (IGF-IR) and that Glut4 plays an important role in bone growth. Insulin and IGF-I actions on skeletal growth and glucose uptake were determined using mandibular condyle (MC) organ cultures and MC-derived primary cell cultures (MCDC). Chondrogenesis was determined by following proliferation and differentiation activities using immunohistochemical (IHC) analysis of proliferating cell nuclear antigen and type II collagen expression, respectively. Overall condylar growth was assessed morphometrically. GLUT4 mRNA and protein levels were determined using in situ hybridization and IHC, respectively. Glut4 translocation to the cell membrane was assessed using confocal microscopy analysis of GFP-Glut4 fusion-transfected cells and immunogold and electron microscopy on MC sections; glucose uptake was assayed by 2-deoxyglucose (2-DOG) uptake. Both IGF-I and insulin-stimulated glucose uptake in MCDC, with IGF-I being tenfold more potent than insulin. Blockage of IGF-IR abrogated both IGF-I- and insulin-induced chondrogenesis and glucose metabolism. IGF-I, but not insulin, induced Glut4 translocation to the plasma membrane. Additionally, insulin induced both GLUT4 and IGF-IR gene expression and improved condylar growth in insulin receptor knockout mice-derived MC. Moreover, silencing of GLUT4 gene in MCDC culture abolished both IGF-I-induced glucose uptake and chondrocytic proliferation and differentiation. In growing bone, the IGF-IR pathway stimulates Glut4 translocation and enhances glucose uptake. Moreover, intact Glut4 cellular levels and translocation machinery are essential for early skeletal growth.

Metabolic profiling in personalized medicine: bridging the gap between knowledge and clinical practice in Type 2 diabetes.

Type 2 diabetes mellitus (DM2) is the most commonly diagnosed metabolic disease and its prevalence is expected to increase. Epidemiological studies clearly show excess mortality associated with DM2, as well as an increased risk of DM2-related complications. Advances in personalized medicine would greatly improve patient care in the field of diabetes and other metabolic diseases. Prediction of the disease in asymptomatic patients as well as its harsh complications in patients already diagnosed is becoming a necessity, with the considerable increase in the cost of the treatment. In the current article, we review the known clinical, molecular metabolic and genetic biomarkers that should be integrated in a future bioinformatic platform to be used at the point-of-care, and discuss the challenges we face in applying this vision of personalized medicine for diabetes into reality.

Insulin resistance in obesity as the underlying cause for the metabolic syndrome.

The metabolic syndrome affects more than a third of the US population, predisposing to the development of type 2 diabetes and cardiovascular disease. The 2009 consensus statement from the International Diabetes Federation, American Heart Association, World Heart Federation, International Atherosclerosis Society, International Association for the Study of Obesity, and the National Heart, Lung, and Blood Institute defines the metabolic syndrome as 3 of the following elements: abdominal obesity, elevated blood pressure, elevated triglycerides, low high-density lipoprotein cholesterol, and hyperglycemia. Many factors contribute to this syndrome, including decreased physical activity, genetic predisposition, chronic inflammation, free fatty acids, and mitochondrial dysfunction. Insulin resistance appears to be the common link between these elements, obesity and the metabolic syndrome. In normal circumstances, insulin stimulates glucose uptake into skeletal muscle, inhibits hepatic gluconeogenesis, and decreases adipose-tissue lipolysis and hepatic production of very-low-density lipoproteins. Insulin signaling in the brain decreases appetite and prevents glucose production by the liver through neuronal signals from the hypothalamus. Insulin resistance, in contrast, leads to the release of free fatty acids from adipose tissue, increased hepatic production of very-low-density lipoproteins and decreased high-density lipoproteins. Increased production of free fatty acids, inflammatory cytokines, and adipokines and mitochondrial dysfunction contribute to impaired insulin signaling, decreased skeletal muscle glucose uptake, increased hepatic gluconeogenesis, and ß cell dysfunction, leading to hyperglycemia. In addition, insulin resistance leads to the development of hypertension by impairing vasodilation induced by nitric oxide. In this review, we discuss normal insulin signaling and the mechanisms by which insulin resistance contributes to the development of the metabolic syndrome.

Using multi-perspective methodologies to study users' interactions with the prototype front end of a guideline-based decision support system for diabetic foot care.

PURPOSE: Clinical practice guidelines are important instruments for improving the quality of care; in paper form, however, they are not used as effectively as possible. In order to develop a guideline-based decision support system (DSS) prototype to help clinicians deal with diabetic patients' foot problems, we drew on methodologies from qualitative research, cognitive science, and information systems. This multi-perspective approach was intended to facilitate user-centered design and evaluation. METHODS: We employed field observations, structured interviews, and document analyses to collect and analyze users' workflow patterns, decision support goals, and preferences regarding interactions with a DSS. Next, we aligned their requirements with sequence diagrams and followed Nielsen's heuristics to develop a DSS prototype. We then performed think-aloud analyses and used the technology acceptance model to direct our evaluation of users' perceptions of the prototype. RESULTS: Users had a positive response to the DSS prototype in terms of its clarity of design and ease of use. They expressed a high intention of using the system in the future. CONCLUSION: Applying multi-perspective methodologies is an effective way to study and design user interactions with the front end of a guideline-based DSS.