Dapagliflozin enhances fat oxidation and ketone production in patients with type 2 diabetes

OBJECTIVE Insulin resistance is associatedwithmitochondrial dysfunction and decreased ATP synthesis. Treatment of individuals with type 2 diabetes mellitus (T2DM) with sodium-glucose transporter 2 inhibitors (SGLT2i) improves insulin sensitivity. However, recent reports have demonstrated development of ketoacidosis in subjects with T2DM treated with SGLT2i. The current study examined the effect of improved insulin sensitivity with dapagliflozin on 1) mitochondrial ATP synthesis and 2) substrate oxidation rates and ketone production. RESEARCH DESIGN AND METHODS The study randomized 18 individuals with T2DMto dapagliflozin (n = 9) or placebo (n = 9). Before and after 2 weeks, subjects received an insulin clamp with tritiated glucose, indirect calorimetry, and muscle biopsies. RESULTS Dapagliflozin reduced fasting plasma glucose (167 ± 13 to 128 ± 6 mg/dL) and increased insulin-stimulated glucose disposal by 36% (P < 0.01). Glucose oxidation decreased (1.06 to 0.80 mg/kg · min, P < 0.05), whereas nonoxidative glucose disposal (glycogen synthesis) increased (2.74 to 4.74 mg/kg · min, P = 0.03). Dapagliflozin decreased basal glucose oxidation and increased lipid oxidation and plasma ketone concentration (0.05 to 0.19 mmol/L, P < 0.01) in association with an increase in fasting plasma glucagon (77 ± 8 to 94 ± 13, P < 0.01). Dapagliflozin reduced the ATP synthesis rate, which correlated with an increase in plasma ketone concentration. CONCLUSIONS Dapagliflozin improved insulin sensitivity and caused a shift from glucose to lipid oxidation, which, together with an increase in glucagon-to-insulin ratio, provide the metabolic basis for increased ketone production

Human Embryonic Stem Cell Differentiation Toward Regional Specific Neural Precursors

Human embryonic stem cells (hESCs) are self-renewing pluripotent cells that have the capacity to differentiate into a wide variety of cell types. This potentiality represents a promising source to overcome many human diseases by providing an unlimited supply of all cell types, including cells with neural characteristics. Therefore, this review summarizes early neural development and the potential of hESCs to differentiate under in vitro conditions, examining at the same time the potential use of differentiated hESCs for therapeutic applications for neural tissue and cell regeneration

The Individualized Target HbA1c: A New Method for Improving Macrovascular Risk and Glycemia Without Hypoglycemia and Weight Gain

Both the DCCT and UKPDS trials demonstrated that improved glycemic control reduces microvascular complications. Inconclusive evidence, however, has remained on the question of the effect of glycemic control on macrovascular disease (with special emphasis on cardiovascular morbidity and mortality). In the last year, the data from four large trials were published, directly addressing this question (ACCORD, ADVANCE, VADT and UKPDS-80), yet the results were conflicting. Close inspection of the structure of three of these trials (ACCORD, ADVANCE and VADT) revealed inadequacies that may explain the unfavorable results, such as the inclusion of mainly elderly patients with previous macrovascular complications. It is not surprising that intensive glycemic control resulted in a rise of hypoglycemic events yet did not decrease macrovascular morbidity or mortality in these cohorts. On the other hand, the UKPDS-80 trial, a follow-up of the original UKPDS, showed that intensive glycemic control was beneficial when initiated in newly diagnosed patients. These results led us to develop a new individualized method of determining the target HbA1c based on the characteristics of the individual. This method considers the patient’s possible benefit from glycemic control, the risk of suffering hypoglycemic events and consequences suffered from the hypoglycemic event. It is essential that the target HbA1c be tailored to the patient, with different goals set for the recently diagnosed “healthy” and young patient on the one hand, and the elderly patient with co-morbidities and polypharmacy on the other hand. We further suggest a method of comparing and choosing between the different hypoglycemic drugs available. Drugs should be considered not only based on their hypoglycemic effect but also on several other attributes such as effects on weight, glycemic durability, cardiovascular protection, individual experience with the drug, method of delivery and side effect profiles. Scoring the different attributes allows us to compare between different preparations and choose the most suitable drugs for each individual patient. Using our newly suggested system, a physician will first calculate the adequate HbA1c goal for his patient and then choose the drug that will best suit him, thus tailoring the treatment to the patients needs

Hand Grip Strength Relative to Waist Circumference as a Means to Identify Men and Women Possessing Intact Mobility in a Cohort of Older Adults with Type 2 Diabetes

Possessing intact mobility in older adults assures their continued independence. The early identification of reduced mobility in older adults with type 2 diabetes (T2DM) is paramount for preventing their future physical deterioration. Hand grip strength (HGS), relative to body size, is associated with mobility in older T2DM patients. This study aims to identify an HGS index that best identifies mobilityintact older T2DM patients, along with its optimal cut-off point. The baseline data are from a cohort of 122 older T2DM patients (59% women) (mean age of 70.2 ± 4.4 years). Three mobility tests encompassing three main mobility domains were measured, including usual gait speed (UGS), timed up and go (TUG), and a two-minute walk test (2MWT). Passing scores were defined as those either above the established cut-off points or above the 25th percentile of population norms. Passing all three tests was considered as possessing intact mobility. Receiver operating characteristic (ROC) curves of the most relevant HGS indices were constructed to determine the area under the curve (AUC) that best identifies patients with intact mobility. In a sample of 122 older adults with T2DM, 63.9% of women and 60% of men were found to possess intact mobility. HGS relative to waist circumference (WC) was found to have the strongest association with intact mobility, presenting the highest AUC in both men (0.78) and women (0.72) for discriminating mobility status, with an optimal cut-off of 0.355 (kg/cm) and 0.245 (kg/cm) in men and women, respectively. HGS relative to WC best differentiated between mobility-intact older adults with T2DM and those with mobility limitations, especially in men. Using HGS/WC as a simple and safe screening mode for mobility in a clinical setting could potentially identify older patients with T2DM that require therapeutic interventions

Inhibition of nuclear factor-κB activation in pancreatic β-cells has a protective effect on allogeneic pancreatic islet graft survival.

Pancreatic islet transplantation, a treatment for type 1 diabetes, has met significant challenges, as a substantial fraction of the islet mass fails to engraft, partly due to death by apoptosis in the peri- and post-transplantation periods. Previous evidence has suggested that NF-κB activation is involved in cytokine-mediated β-cell apoptosis and regulates the expression of pro-inflammatory and chemokine genes. We therefore sought to explore the effects of β-cell-specific inhibition of NF-κB activation as a means of cytoprotection in an allogeneic model of islet transplantation. To this end, we used islets isolated from the ToI-β transgenic mouse, where NF-κB signalling can specifically and conditionally be inhibited in β-cells by expressing an inducible and non-degradable form of IκBα regulated by the tet-on system. Our results show that β-cell-specific blockade of NF-κB led to a prolonged islet graft survival, with a relative higher preservation of the engrafted endocrine tissue and reduced inflammation. Importantly, a longer delay in allograft rejection was achieved when mice were systemically treated with the proteasome inhibitor, Bortezomib. Our findings emphasize the contribution of NF-κB activation in the allograft rejection process, and suggest an involvement of the CXCL10/IP-10 chemokine. Furthermore, we suggest a potential, readily available therapeutic agent that may temper this process

Glucose-Reducing Effect of the ORMD-0801 Oral Insulin Preparation in Patients with Uncontrolled Type 1 Diabetes: A Pilot Study

<div><p>The unpredictable behavior of uncontrolled type 1 diabetes often involves frequent swings in blood glucose levels that impact maintenance of a daily routine. An intensified insulin regimen is often unsuccessful, while other therapeutic options, such as amylin analog injections, use of continuous glucose sensors, and islet or pancreas transplantation are of limited clinical use. In efforts to provide patients with a more compliable treatment method, Oramed Pharmaceuticals tested the capacity of its oral insulin capsule (ORMD-0801, 8 mg insulin) in addressing this resistant clinical state. Eight Type I diabetes patients with uncontrolled diabetes (HbA1c: 7.5–10%) were monitored throughout the 15-day study period by means of a blind continuous glucose monitoring device. Baseline patient blood glucose behavior was monitored and recorded over a five-day pretreatment screening period. During the ensuing ten-day treatment phase, patients were asked to conduct themselves as usual and to self-administer an oral insulin capsule three times daily, just prior to meal intake. CGM data sufficient for pharmacodynamics analyses were obtained from 6 of the 8 subjects. Treatment with ORMD-0801 was associated with a significant 24.4% reduction in the frequencies of glucose readings >200 mg/dL (60.1±7.9% pretreatment vs. 45.4±4.9% during ORMD-0801 treatment; <i>p</i> = 0.023) and a significant mean 16.6% decrease in glucose area under the curve (AUC) (66055±5547 mg/dL/24 hours vs. 55060±3068 mg/dL/24 hours, <i>p</i> = 0.023), with a greater decrease during the early evening hours. In conclusion, ORMD-0801 oral insulin capsules in conjunction with subcutaneous insulin injections, well tolerated and effectively reduced glycemia throughout the day.</p><p>Trial Registration</p><p>Clinicaltrials.gov <a href="http://clinicaltrials.gov/show/NCT00867594" target="_blank">NCT00867594</a>.</p></div

Mean glucose concentrations before and during ORMD-0801 oral insulin support therapy.

<p>A. Mean blood glucose levels of six Type I diabetic subjects, continuously monitored throughout the pretreatment (blue) and ORMD-0801, oral insulin-treatment (red) phases (dotted lines represent the corresponding standard errors). The greatest reduction (21.2%) is noted between 5–7pm. B. ORMD-0801 treatment was associated with a mean 16.6% decrease in glucose area under the curve (AUC) (66055±5547 mg/dL/24 hours before treatment vs. 55060±3068 mg/dL/24 hours during ORMD-0801 treatment,*- <i>p</i> = 0.023).</p

Study flow diagram.

<p>Study flow diagram.</p