Advantages and Disadvantages of the Ketogenic Diet: A Review Article.

The ketogenic diet (KD) has gained immense popularity during the last decade, primarily because of its successful short-term effect on weight loss. In the United States, KD is utilized in a variety of patient populations for weight management, despite limited evidence regarding its efficacy and risks. This literature review provides an evaluation of data on the benefits and risks associated with the chronic use of KD, including its metabolic, endocrinological, and cardiovascular effects.

Intermittent Fasting: The Choice for a Healthier Lifestyle.

Obesity is a worldwide epidemic due to the availability of many unhealthy food options and limited physical exercise. Restriction of the daily food intake results in weight loss, which is also associated with better health outcomes including triglycerides, total cholesterol, low-density lipoprotein cholesterol, blood pressure, glucose, insulin, and C-reactive protein. Our aim is to briefly discuss the effects of intermittent fasting on weight and other biochemical markers mentioned previously. The study is designed as a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. To assess the effectiveness of intermittent fasting, related studies were reviewed between 2000 and 2018 and 815 studies were identified. Only four articles met the preset inclusion and exclusion criteria. All four studies have shown a significant decrease in fat mass with P-values <0.01. It was also noted that some biochemical markers were significantly reduced such as the reduction in low-density lipoprotein and triglyceride with P-values < 0.05. Other biochemical markers had inconsistent results. Based on the qualitative analysis, intermittent fasting was found to be efficient in reducing weight, irrespective of the body mass index. Further studies are needed to assess the ability to maintain the lost weight without regaining it and the long-term effects of such dietary changes.

Transdermal Testosterone in Female Hypoactive Sexual Desire Disorder: A Rapid Qualitative Systematic Review Using Grading of Recommendations Assessment, Development and Evaluation.

Female hypoactive sexual desire disorder (HSDD) is a multifactorial sexual dysfunction disorder characterized by a decrease in sexual desire and personal distress. HSDD occurs in naturally occurring postmenopausal women or secondary to oophorectomy. Multiple studies have assessed the use of transdermal testosterone (TDT) as a management option for patients with HSDD. Our aim is to assess published studies using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework for the quality of evidence regarding testosterone use as a short- and long-term therapy for HSDD. We implemented this qualitative systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. We set a GRADE score of 4 (high evidence) as a cutoff point for the quality measure of published studies assessing the use of TDT in HSDD. The outcomes of interest were the efficacy of TDT on the total number of satisfying sexual activity, number of orgasms, sexual desire and distress level in patients with HSDD. These outcomes were evaluated through Sexual Activity Log (SAL), Profile of Female Sexual Function (PFSF), and Personal Distress Scale (PDS) evaluation tools. Five randomized controlled trials were identified to meet the inclusion criteria. The selected studies were of high evidence based on the GRADE score as two of the studies scored 4 points, the other two studies scored 5 points and one study scored 6 points. All of the high quality selected studies had similar outcomes suggesting high effectiveness for the use of 300 µg/d TDT with or without estrogen for the management of HSDD with minimal side effects. One study showed a trend for higher risk of breast cancer in long-term use (0.37%). The use of 300 µg/d of TDT in surgical and natural menopause is an effective plan to manage HSDD in the short- and long-term. Although side effects are minimal, further prospective research is needed to assess the more severe side effects such as breast cancer in the long-term use of TDT.

SGLT-2 inhibitors and their potential in the treatment of diabetes.

Diabetes remains a burgeoning global problem, necessitating ongoing efforts on the part of pharmaceutical and device manufacturers, patients, and society to curb the frightening trends in morbidity and mortality attributable to the malady. Since 1835 when phlorizin was discovered, sodium glucose co-transporter 2 (SGLT-2) inhibitors have rested tantalizingly on the horizon, promising a more physiological approach to glucose control. These agents lower glucose by enhancing its excretion by blocking reabsorption in the renal tubules, thus eliminating glucose from the body along with the molecules' attendant effects on caloric balance, plasma osmolality, and lipids. Consequently, SGLT-2 inhibitors improve glucose control to an extent comparable to other hypoglycemic agents while simultaneously reducing body weight, blood pressure, and cholesterol - an admirable portfolio. One agent, canagliflozin, has recently been approved by the US Food and Drug Administration (FDA) and two other agents have progressed through Phase III trials, including dapagliflozin and empagliflozin. Collectively, when used as monotherapy, these agents have demonstrated reductions in hemoglobin A1c (HbA1c), body weight, and blood pressure of -0.34% to -1.03%, -2.0 to -3.4 kg, and -1.7 to -6.4 mmHg/-0.3 to -2.6 mmHg (systolic blood pressure/diastolic blood pressure), respectively. SGLT-2 inhibitors have been well tolerated, with hypoglycemia (0.9% to 4.3%) occurring infrequently in clinical trials. Safety signals related to breast and bladder cancer have arisen with dapagliflozin, though these are unsubstantiated and likely ascribed to the presence of preexisting cancer. As these agents emerge, clinicians should embrace the addition to the formulary for treating type 2 diabetes, but must also weight the risk-benefit of this new class in deciding which patient types are most likely to benefit from their novel mechanism of action.

A novel endocrinology-based wellness program to reduce medication expenditures and improve glycemic outcomes.

AIMS: The purpose of this study was to determine the difference in diabetes-related medication expenditures as a result of a 16-week lifestyle intervention program. Medical expenditures for patients with diabetes are twice as high compared to patients without this condition. Secondary objectives were changes in HbA1C, BMI, weight, body fat, and program satisfaction. METHODS: The Wellness Life! Program includes educational sessions focused on nutrition, fitness, and behavioral therapy. Medication costs were based on Average Wholesale Prices, tabulated from the 2010 Red Book. RESULTS: A total of 36 patients (49-80 years old) enrolled, of which 27 patients have diabetes mellitus (Type 2=26, Type 1=1). Mean 30-day anti-diabetic medication costs decreased by $142.92. Clinical mean parameters improved in both the overall group and the diabetic subgroup, respectively: HbA1C (%) -0.69, -0.82; weight (lbs) -16.94, -17.11; BMI -2.73, -2.88; and body fat (%) -1.71, -1.79. Participants were generally satisfied with the program. CONCLUSIONS: Employing a multidisciplinary wellness program within an endocrinology practice can reduce anti-diabetic medication expenses; however, long term follow-up is needed to determine if medication reductions and improved clinical parameters persist.

Nicotinic acid induces apolipoprotein A-I gene expression in HepG2 and Caco-2 cell lines.

The objective was to test the effect of nicotinic acid on apolipoprotein A-I (apo A-I) gene expression in hepatic (HepG2) and intestinal (Caco-2) cell lines. HepG2 and Caco-2 cells were treated with 0.1, 0.3, 1.0, 3.0, and 10 mmol/L of nicotinic acid; and apo A-I concentrations in conditioned media were measured with Western blots. Relative apo A-I messenger RNA (mRNA) levels, normalized to glyceraldehyde-3-phosphate dehydrogenase mRNA, were measured with quantitative real-time polymerase chain reaction method. The nicotinic acid response element in the apo A-I promoter was identified using a series of apo A-I reporter plasmids containing deletion constructs of the promoter. In other experiments, HepG2 cells were also transfected with the apo A-I reporter plasmid and the hepatocyte nuclear factors 3α and ß expression plasmids. The apo A-I levels in conditioned media from HepG2 cells, apo A-I mRNA levels, and apo A-I promoter activity increased significantly following treatment with 1.0, 3.0, and 10 mmol/L nicotinic acid. Nicotinic acid-induced promoter activity required a region of the apo A-I gene located between -170 and -186 base pairs. Exogenous overexpression of the hepatocyte nuclear factors 3α and ß had no additive effect on apo A-I promoter. Apolipoprotein A-I concentrations in conditioned media and the apo A-I promoter activity were also significantly increased in Caco-2 intestinal cells. Nicotinic acid may increase apo A-I protein synthesis in the liver and small intestine. Induction of apo A-I gene by nicotinic acid requires a nicotinic acid responsive element in the apo A-I promoter.

24, 25-dihydroxycholecalciferol but not 25-hydroxycholecalciferol suppresses apolipoprotein A-I gene expression.

AIMS: Ligands for the vitamin D receptor (VDR) regulate apolipoprotein A-I (apo A-I) gene expression in a tissue-specific manner. The vitamin D metabolite 24, 25-dihydroxycholecalciferol (24, 25-(OH)(2)D(3)) has been shown to possess unique biological effects. To determine if 24, 25-(OH)(2)D(3) modulates apo A-I gene expression, HepG2 hepatocytes and Caco-2 intestinal cells were treated with 24, 25-(OH)(2)D(3) or its precursor 25-OHD(3). MAIN METHODS: Apo A-I protein levels and mRNA levels were measured by Western and Northern blotting, respectively. Changes in apo A-I promoter activity were measured using the chlorampenicol acetytransferase assay. KEY FINDINGS: Treatment with 24, 25-(OH)(2)D(3), but not 25-OHD(3), inhibited apo A-I secretion in HepG2 and Caco-2 cells and apo A-I mRNA levels and apo A-I promoter activity in HepG2 cells. To determine if 24, 25-(OH)(2)D(3) represses apo A-I gene expression through site A, the nuclear receptor binding element that is essential for VDRs effects on apo A-I gene expression, HepG2 cells were transfected with plasmids containing or lacking site A. While the site A-containing plasmid was suppressed by 24, 25-(OH)(2)D(3), the plasmid lacking site A was not. Likewise, treatment with 24, 25-(OH)(2)D(3) suppressed reporter gene expression in cells transfected with a plasmid containing site A in front of a heterologous promoter. Finally, antisense-mediated VDR depletion failed to reverse the silencing effects of 24, 25-(OH)(2)D(3) on apo A-I expression. SIGNIFICANCE: These results suggest that the vitamin D metabolite 24, 25-(OH)(2)D(3) is an endogenous regulator of apo A-I synthesis through a VDR-independent signaling mechanism.

Hyperglycemia-induced endoplasmic reticulum stress in endothelial cells.

OBJECTIVE: Hyperglycemia-induced endothelial cell dysfunction in vascular disease can occur due to increased oxidative stress and a concomitant increase in endoplasmic reticulum (ER) stress. To investigate whether these cellular stresses are independent or causally linked, we determined whether or not specific glycolytic intermediates that induce oxidative stress also induce ER stress. METHODS: Human umbilical vein endothelial cells were treated with dextrose, partially metabolizable (e.g., fructose and galactose) and non-metabolizable sugars (e.g., 3-O-methyglucose), and various intermediates of the glycolytic and tricarboxylic acid pathways. Activation of the unfolded protein response and subsequent generation of ER stress was measured by the ER stress-responsive alkaline phosphatase method, and superoxide (SO) generation was measured using the hydro-ethidene-fluorescence method. The mitochondrial origin of the SO and the generation of ER stress by dextrose and the intermediate metabolites were confirmed with experiments using allopurinol and diphenyleneiodonium chloride to block SO generation by xanthine oxidase and nicotinamide adenosine dinucleotide phosphate oxidase, respectively. RESULTS: Although ER stress could be induced by glycolytic intermediates up to and including pyruvate, the SO generation occurred in the presence of glycolytic and mitochondrial metabolites. CONCLUSION: Although the mitochondria are the site of signals generated by dextrose to initiate oxidative stress, the dextrose-induced ER stress, unlike SO generation, does not require pyruvate oxidation in the mitochondria.

Effects of antioxidants on glucose-induced oxidative stress and endoplasmic reticulum stress in endothelial cells.

AIM: Hyperglycemia-induced endothelial cell dysfunction can be the result of increased oxidative stress and concomitant increase in endoplasmic reticulum (ER) stress. To test the extent of coupling between these two stresses, the effect of antioxidant vitamins on glucose-induced oxidative stress and ER stress in endothelial cells were studied. METHODS: Human umbilical vein endothelial cells (HUVEC) were treated with physiological (5.5mM) or supra-physiological (27.5mM) dextrose concentrations, and ER stress and oxidative stress were measured. Additional experiments were carried out in HUVEC over-expressing exogenous glucose transporter-1 (Glut-1) and treated with 5.5mM dextrose. RESULTS: Supra-physiological dextrose concentrations increased both ER stress and oxidative stress. However, while oxidative stress could be effectively inhibited with alpha-tocopherol and ascorbic acid, these antioxidants had no effect on ER stress. Increasing intracellular glucose levels by exogenous expression of Glut-1 in endothelial cells also increased oxidative stress and ER stress. Whereas the oxidative stress in these cells was reduced with alpha-tocopherol and ascorbic acid and dimethylsulfoxide, the ER stress could not be ameliorated with alpha-tocopherol and ascorbic acid. CONCLUSIONS: These results indicate that ER stress can be uncoupled from oxidative stress and antioxidants can ameliorate the latter without altering the ER stress induced by hyperglycemia.