Restoring insulin creation in diabetes type I sufferers

Type I diabetes is very manageable by taking daily doses of exogenous insulin. However, researchers of the University of South Dakota pulled together a method utilizing G-protein coupled receptor 119 (GPR119) and dipeptidylpeptidase-IV (DPP-IV) to regenerate lost ß-islet cells of diabetics and restore insulin production in the body.

ß-cells are the insulin generators of the body, but in type I diabetes patients, they don’t exist or don’t work. GPR119, when activated by an agonist such as PSN632408, stimulates ß-cell replication, increases GLP-1 secretion, reduces food intake, and decreases body weight gain. If hyperstimulated in type I diabetes sufferers the level of insulin reached would be closer to that of normal body levels, which is why this was a target of this study. Contrarily, DPP-IV works to degrade or breakdown GLP-1, which is a protein that stimulates insulin release from ß-cells, enhances ß-cell proliferation, and prevents ß-cell programmed cell death.

In the study, diabetic mice with blood glucose levels of 400 to 500 mg/dL were treated with PSN632408 and/or sitagliptin for 7 weeks. The former acted as a GPR119 agonist and the latter as a DPP-IV inhibitor. After treatment ended, the three different treatment groups obtained the following percentages of normoglycemia (blood glucose < 200 mg/dL) mice:

– PSN632408, 32% mice with normoglycemia
– Sitagliptin, 36% mice with normoglycemia
– PSN632408 & sitagliptin, 59% mice with normoglycemia

The average drop in blood glucose was 257 mg/dL after seven weeks. The treatment actively reversed type I diabetes in these mice.

Further tests showed increased levels of GLP-1 (7.6±0.4 pmol/L in control mice, 14.8±1.0, 35.9±8.6, 44.2±10.5 pmol/L in mice treated with PSN632408, Sitagliptin, or both respectively), ß-cell replication, and ß-cell regeneration.

Mice treated with a GRP119 agonist and DPP-IV inhibitor showed increased ß-cell regeneration and overall insulin production. As mice have similar GRP119/DPP-IV pathways to humans, these results are very exciting for the diabetes scene.

Drinking (or painfully auto-injecting) daily insulin may no longer be necessary for diabetics if the GRP119 agonist/DPP-IV inhibitor treatment is approved for clinical use.

Reference:
Ansarullah, Yan Lu, Martha Holstein, Brittany DeRuyter, Alex Rabinovitch, Zhiguang Guo. Stimulating β-Cell Regeneration by Combining a GPR119 Agonist with a DPP-IV Inhibitor. PLoS ONE, 2013. http://dx.doi.org/10.1371/journal.pone.0053345

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PICU infections reduced by a shared procedure

Photo credits audi_insperation

Hospital procedures are improving daily and one such measure may have just decreased pediatric intensive care patient bacterial infections by 35%. Researchers of Baltimore, Philadelphia, Seattle, and Washington recently found that chlorhexidine gluconate baths for pediatric intensive care unit (PICU) patients reduces bacteremia (bacteria in the blood) by 35%.

Infants of the intensive care unit have immune systems that are not fully equipped to deal with infections they may face. As such, infections such as MRSA, a hospital born pathogen, can prove lethal.

Chlorhexidine gluconate (CHG) is an anti-bacterial agent that kills gram-negative and gram-positive bacteria. It is also the antiseptic physicians clean their hands with before invasive procedures.

To test the efficacy of bathing PICU patients with CHG, five hospitals across the U.S. participated in either standard bathing procedures or 2% CHG cloth wipes over 6 months for patients and switching to the other bathing procedure for 6 months thereafter. 4947 participants were included in this study.

The population receiving standard bathing showed incidence of infection as 4.93 cases per 1,000 days (95% CI 3.91 – 6.15) while those receiving the CHG bath showed 3.52 cases per 1,000 days (95% CI 2.64 – 4.61). That was a 35% reduction in bacteremia cases in the CHG group compared to the standard bathing group. Furthermore, no serious adverse events caused by bathing were seen in those receiving the CHG.

The PICU adopting the pre-procedure wash habits of physicians has shown to significantly decrease bacterial infections. This easy to implement solution to bacteremia is just one such case of shared ideas improving the quality of life.

Reference:
Aaron M. Milstone, Alexis Elward, Xiaoyan Song, Dianielle M. Zerr, Rachel Orscheln, Kathleen Speck, Daniel Obeng, Nicholas G. Reich, Susan E. Coffin, Trish M. Perl. Daily chlorhexidine bathing to reduce bacteraemia in critically ill children: a multicentre, cluster-randomised, crossover trial. The Lancet, 2013.
http://dx.doi.org/10.1016/S0140-6736(12)61687-0

Powerful Sleep Apnea Treatment (Proof of Concept)

Photo courtesy of Primarily Inspired

A small study was recently done to prove Dronabinol safe, tolerable, and effective in treating obstructive sleep apnea. Researchers of the University of Illinois found that Dronabinol was able to lower the apnea hypopnea index (AHI) of participants by an average of 14 points.

Photo courtesy of Healthwsie Inc.

Obstructive sleep apnea (OSA) is a sleep disorder in which one stops breathing (for seconds or minutes at a time) or experiences abnormally low breathing during sleep due to low muscle tone or obstructive tissue that blocks the airway. Hypopnea similarly is a sleep disorder but is characterized by abnormally shallow breathing during sleep. Additionally, the AHI is a tool used to categorize the severity of sleep apnea. The measurements are average apnea episodes per hour with a scale of 5-15/hr (mild), 16-30/hr (moderate), and above 30/hr (severe).

Participants age 21-65 with moderate or severe OSA were to self administer pills of 2.5, 5.0, or 10.0 mg of dronabinol nightly before sleep (at least 8 hour sleep) for 3 weeks. Doses were increased each step as tolerated (defined by no adverse events).

As per safety, the most common adverse event seen was somnolence (drowsiness and/or hypersomnia). This was seen in 29% of participants at 2.5 mg, 14% at 5 mg, and 50% at 10 mg. Overall, adverse events were seen in 67% of participants across all doses. All but two participants completed the study as these two were withdrawn due to severe adverse events.

Efficacy wise, dronabinol resulted in a reduction in AHI of participants by 14.1 ± 17.5 (P = 0.003) during the study. The effect in treating OSA was dose and position (supine vs. non-supine) independent. The effect was hypothesized to be due to dronabinol binding cannabinoid type 1 and 2 receptors to improve respiratory stability, block serotonergic activity, and prevent airway collapse.

Overall dronabinol seems safe and effective in treating obstructive sleep apnea and by extension hypopnea in humans. As this study was only a proof that the drug works, larger studies will need to be performed before dronabinol is available as a treatment for sleep apnea.

Reference:
Bharati Prasad, Miodrag G. Radulovacki, David W. Carley. Proof of Concept Trial of Dronabinol in Obstructive Sleep Apnea. Frontiers in Psychiatry, 2013.
http://dx.doi.org/10.3389/fpsyt.2013.00001

Liver Cancer’s worst nightmare, Docosahexaenoic acid

Human liver. Photo credits: HealthHabbits

Human liver.
Photo credits: HealthHabbits

Hepatocellular carcinoma (HCC) or liver cancer might have finally been met with an agent that blocks its growth and isn’t harmful to human health. Docosahexaenoic acid (DHA), an ω-3 fatty acid, was used by researchers of Anhui Province, China to stop the migration of and induce apoptosis in hepatocellular carcinoma cells.

Epidemiologically, liver cell cancer usually affects more men than women, those over the age of 50, and people in Asia and Africa and is usually caused by alcohol abuse, chronic liver inflammation, or hepatitis B/C infection.

Omega (ω) 3 fatty acids are commonly found in fish oils and known to have beneficial effects for the body. An example is the incidence of breast cancer being four to five times higher in western countries than in Japan, a country that eats much more seafood daily than the west. DHA specifically was used in this study to test the effects of ω-3 polyunsaturated fatty acids on HCC and search for the mechanism of action.

HCC cells were cultured then treated with varying levels of DHA for 72 hours. Using between 25 and 200 µmol/L DHA an increasing trend of decreased cell density was seen between time 0 and 72 hours.(so, less cells with more DHA and time). After treating HCC cell cultures for 72 hours with 200 µmol/L DHA the following was seen:

– Just over 20% of cancer cells survived
– An over 30 fold increase in apoptosis (cell suicide) was seen

The pathway behind the significant increase in cell apoptosis was attributed to modified activity of the Bim gene, Bcl-2 protein, Bax protein, and caspase-3 protein effector. Bcl-2 and Bim, two factors that protect cells against apoptosis, both showed decreased activity with increasing DHA. Also, caspase-3 and Bax, two pro-apoptotic factors, showed increased activity.

Finally, a scratch wound assay testing how quickly HCC cells migrated to the wound in the presence/absence of DHA showed blunted migration of cells when DHA was included. Immunofluorescence showed decreased MMP-9, a protein required for HCC cell migration, levels based on DHA concentration.

Wrapping all together, the modified Bim, Bcl-2, caspase-3, and Bax levels showing increased apoptosis, decreased MMP-9 levels indicating less cell migration, and overall decreased cell density seen with more DHA used yields significant evidence for DHA being effective in stopping liver cancer.

Since DHA is an ω-3 and essential fatty acid, it may be a shorter task to move it into the clinic as a treatment for hepatocellular carcinoma.

Reference:
Si-Nan Sun, Wei-Dong Jia, Hao Chen, Jin-Liang Ma, Yong-Sheng Ge, Ji-Hai Yu, Jian-Sheng Li. Docosahexaenoic acid (DHA) induces apoptosis in human hepatocellular carcinoma cells. International Journal of Clinical and Experimental Pathology, 2013.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3544235/

Fainting genes exist

A 'fainted' fainting goat Photo credits: 6sketchers

A ‘fainted’ fainting goat
Photo credits: 6sketchers

An Australian study of 2012 has linked vasovagal syncope, fainting, predisposition to genetics. Samuel Berkovic and colleagues suggest that fainting must have a strong genetic component involving multiple genes and used a twin study to prove it.

Vasovagal syncope or fainting is a loss of consciousness usually brought on by the sight of blood, injury, pain, or the like. This is due to hypoperfusion and resulting low oxygenation of the brain. Common presyncope signs include sweating, nausea, weakness, and temporary loss of feeling.

Twins that participated in this study were monozygotic, “identical twins” that came from one egg and sperm, or dizygotic, twins that came from two separate egg/sperm combinations.

In the study, fifty-one same sex twin pairs where at least one twin had syncope were interviewed via phone questionnaire. Questions were asked about their family history and prevalence of syncope. The researchers assigned a score of 1 to 5 for syncopic features of  each participant.

– 1 = Presyncope episodes exclusively
– 2 = One syncope episode
– 3 = Two syncope episodes & at least one occurring in exceptional circumstances (ie. malnourishment)
– 4 = Up to three syncope episodes
– 5 = More than three syncope episodes

57% of the individuals exhibited typical vasovagal syncope triggers. Monozygotic twins presented with more scores of 4 and 5 indicating higher rates of syncope than did dizygotic twins (P=0.06). 12 of 19 pairs of monozygotic twins indicated few to no close relatives having syncopic episodes.

With higher rates of vasovagal syncope shown between monozygotic twins and not individuals with more distant genetic parallels, this study strong supports the notion of a genetic component behind fainting. Further studies may be done to find those genes, so gene therapy targets can be identified.

Then even med students who just can’t watch a patient’s leg get cut open (no matter how many times they see it) will be able to continue pursuing their dream without fear of fainting.

Reference:
Karl Martin Klein, San San Xu, Kate Lawrence, Alexandra Fischer, Samuel F. Berkovic. Evidence for genetic factors in vasovagal syncope, A twin-family study. Neurology, 2012.
http://dx.doi.org/10.1212/WNL.0b013e3182635789

Vitamins and Anti-oxidants don’t stop CV disease

Antioxidants Photo credits: Gloria Tsang, RD

Antioxidants
Photo credits: Gloria Tsang, RD

Contrary to popular belief, vitamins and antioxidant supplements may not actually be effective in preventing cardiovascular diseases. Researchers of the Republic of Korea recently conducted a large meta-analysis of randomized control trials using data from public research databases to show there is no link between these supplements and reduced risk of major cardiac events.

The analysis included data from 2,240 articles of 50 randomized control trials with 294,478 participants found using the databases of PubMed, EMBASE, the Cochrane Library, Scopus, CINAHL, and ClinicalTrials.gov. The supplements studied included vitamin A, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, ß carotene, folic acid, and selenium. The range of time participants took supplements and study followup was six months to 12 years. Finally, there were 39 trials with vitamins only, and 22 trials with antioxidants only.

Major cardiac events studied were cardiovascular death, myocardial infarction (heart attack), angina, sudden cardiac death, stroke, and transient ischaemic attack.

Compiled data showed the use of vitamin and/or antioxidant supplements was not associated with reduced risks of major cardiovascular events. The risk of developing a cardiovascular (CV) disease relative to exposure of participants was 1.00 with 95% CI from 0.98 to 1.02. This meant there was no average increase or decrease in major cardiac event risk after taking these supplements. Data on each individual supplement vs. risk of CV event can be found in table 2, table 3, and table 4 of the source article.

Analysis was done using participants who were not deficient in the supplements studied. Perhaps further research meta-analysis from the deficient perspective will yield results more in favor of supplements.

This study shows that there is currently no reason to take antioxidant or vitamin supplements if one is trying to prevent cardiovascular disease and isn’t deficient. Government agencies may want to reevaluate the efficacy and safety of such supplements before allowing them to be marketed as colloquial cardiovascular necessities.

Reference:
Seung-Kwon Myung, Woong Ju, Belong Cho, Seung-Won Oh, Sang Min Park, Bon-Kwon Koo, and Byung-Joo Park. Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: systematic review and meta-analysis of randomised controlled trials. British Medical Journal, 2013.
http://dx.doi.org/10.1136/bmj.f10

Vitamin D deficiency causes cardiovascular complications

Photo Credits: Jennifer McMenamin

Photo Credits: Jennifer McMenamin

Hypertension, high blood pressure, and atherosclerosis, thickening of the arteries due to plaque build up, are two leading  causes of or relative causes of mortality in the United States. Researchers of Washington University recently found a link between vitamin D deficiency and increased blood pressure as well as atherosclerosis.

One billion people worldwide have low levels of vitamin D’s storage form.

The way vitamin D contributes to the two aforementioned conditions was what researchers wanted to see; therefore, low density lipoprotein receptor knockout (LDLR−/−) and apolipoprotein E knockout (ApoE−/−) mice were studied as models of human hypertension and atherosclerosis. The study involved feeding both groups of mice vitamin D deficient or sufficient food for  six weeks followed by high fat vitamin D deficient or sufficient food for 8-10 weeks.

LDL, commonly known as “bad cholesterol,” and ApoE, a class of molecules that helps break down fat constituents, are two major players in plaque build up and prevention in the cardiovascular system.

The results showed both LDLR−/− and ApoE−/− mice on the vitamin D deficient diets (FoodD) had increased blood pressure and progression of atherosclerosis. Specifically, compared to mice on FoodD+, the following was seen:

– Normal FoodD, blood pressure increased an average of 13mmHg (P< 0.04)
– High fat FoodD, blood pressure increased an average of 11.5mmHg (P< 0.003)
– FoodD, arterial blood pressure increased 14mmHg (P<0.04)
– FoodD, serum renin activity increased 1.5 fold (P<0.02)
– Normal FoodD, Urinary sodium excretion decreased 37% (P<0.05)
– FoodD, 2.3 to 8 fold bigger atherosclerotic lesions (plaque build up) in aortic regions (P<0.05)

This showed increased blood pressure, increased renin activity, decreased sodium elimination, and increased plaque build ups during vitamin D deficient diets. Two notes for context: Normal blood pressure for humans is 90-140 systolic and 60-90 diastolic. Also, renin is a hormone that increases arterial blood pressure and sodium excretion. The effects of the FoodD was shown as reversible by giving the mice vitamin D sufficient diets.

– FoodD+, blood pressure decreased by an average of 14.5mmHg
– FoodD+, renin activity decreased 50%

Vitamin D seems to be a powerful regulator of hypertension and atherosclerosis severity with low levels worsening the conditions. Vitamin D replacement therapy may become a commonplace treatment to combat high blood pressure and plaque filled arteries one day.

Reference:
Sherry Weng, Jennifer E. Sprague, Jisu Oh, Amy E. Riek, Kathleen Chin, Miguel Garcia, Carlos Bernal-Mizrachi. Vitamin D Deficiency Induces High Blood Pressure and Accelerates Atherosclerosis in Mice. PloS ONE, 2013.
http://dx.doi.org/10.1371/journal.pone.0054625