Olanzapine Side Effects And Wnt Signaling

Many drugs have unintended side effects.  A perfect example of this is weight gain and insulin resistance (metabolic syndrome characteristics) resulting from use of the antipsychotic drug olanzapine.  Aberrant Wnt signaling is associated with these effects, which can be reversed (in mice) by metformin (which of course has its own set of side effects; we are at a point in which people will be on sets of medications, some of which are to reverse the side effects of other medications). Abstract:

Olanzapine is a widely used atypical antipsychotic medication for treatment of schizophrenia and is often associated with serious metabolic abnormalities including weight gain and impaired glucose tolerance. These metabolic side effects are severe clinical problems but the underpinning mechanism remains poorly understood. Recently, growing evidence suggests that Wnt signaling pathway has a critical role in the pathogenesis of schizophrenia and molecular cascades of antipsychotics action, of which Wnt signaling pathway key effector TCF7L2 is strongly associated with glucose homeostasis. In this study, we aim to explore the characteristics of metabolic disturbance induced by olanzapine and to elucidate the role of TCF7L2 in this process. C57BL/6 mice were subject to olanzapine (4 mg/kg/day), or olanzapine plus metformin (150 mg/kg/day), or saline, respectively, for 8 weeks. Metabolic indices and TCF7L2 expression levels in liver, skeletal muscle, adipose, and pancreatic tissues were closely monitored. Olanzapine challenge induced remarkably increased body weight, fasting insulin, homeostasis model assessment-insulin resistance index, and TCF7L2 protein expression in liver, skeletal muscle, and adipose tissues. Notably, these effects could be effectively ameliorated by metformin. In addition, we found that olanzapine-induced body weight gain and insulin resistance actively influence the expression of TCF7L2 in liver and skeletal muscle, and elevated level of insulin determines the increased expression of TCF7L2 in adipose tissue. Our results demonstrate that TCF7L2 participates in olanzapine-induced metabolic disturbance, which presents a novel mechanism for olanzapine-induced metabolic disturbance and a potential therapeutic target to prevent the associated metabolic side effects.

Fad Diets Not Necessary

More support for the ides that “fad” diets – like low carb – are not necessary for weight control and dealing with metabolic syndrome. Take home point: “any diet type resulting in reduced energy intake will result in weight loss and related favorable metabolic and functional changes.”  Abstract:

In the past, different types of diet with a generally low-carbohydrate content (< 50-< 20 g/day) have been promoted, for weight loss and diabetes, and the effectiveness of a very low dietary carbohydrate content has always been a matter of debate. A significant reduction in the amount of carbohydrates in the diet is usually accompanied by an increase in the amount of fat and to a lesser extent, also protein. Accordingly, using the term "low carb-high fat" (LCHF) diet is most appropriate. Low/very low intakes of carbohydrate food sources may impact on overall diet quality and long-term effects of such drastic diet changes remain at present unknown. This narrative review highlights recent metabolic and clinical outcomes of studies as well as practical feasibility of low LCHF diets. A few relevant observations are as follows: (1) any diet type resulting in reduced energy intake will result in weight loss and related favorable metabolic and functional changes; (2) short-term LCHF studies show both favorable and less desirable effects; (3) sustained adherence to a ketogenic LCHF diet appears to be difficult. A non-ketogenic diet supplying 100-150 g carbohydrate/day, under good control, may be more practical. (4) There is lack of data supporting long-term efficacy, safety and health benefits of LCHF diets. Any recommendation should be judged in this light. (5) Lifestyle intervention in people at high risk of developing type 2 diabetes, while maintaining a relative carbohydrate-rich diet, results in long-term prevention of progression to type 2 diabetes and is generally seen as safe.

More Dangers From Fructose

By That kiwi guy - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=32395910

Whatever we want to say about glucose consumption, it is still better than consuming fructose, as yet another animal study makes clear; abstract:

Overconsumption of high-fat diet (HFD) and sugar-sweetened beverages are risk factors for developing obesity, insulin resistance, and fatty liver disease. Here we have dissected mechanisms underlying this association using mice fed either chow or HFD with or without fructose- or glucose-supplemented water. In chow-fed mice, there was no major physiological difference between fructose and glucose supplementation. On the other hand, mice on HFD supplemented with fructose developed more pronounced obesity, glucose intolerance, and hepatomegaly as compared to glucose-supplemented HFD mice, despite similar caloric intake. Fructose and glucose supplementation also had distinct effects on expression of the lipogenic transcription factors ChREBP and SREBP1c. While both sugars increased ChREBP-β, fructose supplementation uniquely increased SREBP1c and downstream fatty acid synthesis genes, resulting in reduced liver insulin signaling. In contrast, glucose enhanced total ChREBP expression and triglyceride synthesis but was associated with improved hepatic insulin signaling. Metabolomic and RNA sequence analysis confirmed dichotomous effects of fructose and glucose supplementation on liver metabolism in spite of inducing similar hepatic lipid accumulation. Ketohexokinase, the first enzyme of fructose metabolism, was increased in fructose-fed mice and in obese humans with steatohepatitis. Knockdown of ketohexokinase in liver improved hepatic steatosis and glucose tolerance in fructose-supplemented mice. Thus, fructose is a component of dietary sugar that is distinctively associated with poor metabolic outcomes, whereas increased glucose intake may be protective.

While glucose increased triglycerides, it at least seemed somewhat protective with respect to certain metabolic syndrome phenotypes, while fructose consumption was simply devastating.

BMI, Metabolic Syndrome, And Pancreatic Cancer

Here is study linking higher BMI, and higher fasting insulin levels (metabolic syndrome, insulin resistance), with an increased risk for pancreatic cancer.  The burden of morbidity and mortality caused by overweight/obesity is staggering, something to keep in mind when reading all the popular stories on the Internet that attempt to normalize obesity and rant about “fat shaming” and “body shaming.”  Being overweight is literally killing people, why normalize it?  Abstract:

BACKGROUND:

Risk factors for pancreatic cancer include a cluster of metabolic conditions such as obesity, hypertension, dyslipidemia, insulin resistance, and type 2 diabetes. Given that these risk factors are correlated, separating out causal from confounded effects is challenging. Mendelian randomization (MR), or the use of genetic instrumental variables, may facilitate the identification of the metabolic drivers of pancreatic cancer.

METHODS:

We identified genetic instruments for obesity, body shape, dyslipidemia, insulin resistance, and type 2 diabetes in order to evaluate their causal role in pancreatic cancer etiology. These instruments were analyzed in relation to risk using a likelihood-based MR approach within a series of 7110 pancreatic cancer patients and 7264 control subjects using genome-wide data from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Potential unknown pleiotropic effects were assessed using a weighted median approach and MR-Egger sensitivity analyses.

RESULTS:

Results indicated a robust causal association of increasing body mass index (BMI) with pancreatic cancer risk (odds ratio [OR] = 1.34, 95% confidence interval [CI] = 1.09 to 1.65, for each standard deviation increase in BMI [4.6 kg/m2]). There was also evidence that genetically increased fasting insulin levels were causally associated with an increased risk of pancreatic cancer (OR = 1.66, 95% CI = 1.05 to 2.63, per SD [44.4 pmol/L]). Notably, no evidence of a causal relationship was observed for type 2 diabetes, nor for dyslipidemia. Sensitivity analyses did not indicate that pleiotropy was an important source of bias.

CONCLUSIONS:

Our results suggest a causal role of BMI and fasting insulin in pancreatic cancer etiology.

The Real Headless Horseman: Obesity

By John Quidor - aQHCpcwsbaMXQA at Google Cultural Institute maximum zoom level, Public Domain, https://commons.wikimedia.org/w/index.php?curid=22126482

For Halloween, we need to remember that much of the “treats” that children are getting are extremely unhealthy. Most treats are sugar/fat/high fructose corn syrup laden candy.  As a once-a-year event, this might be fine (in moderation), but with childhood obesity and metabolic syndrome on the rise, and colon cancer diagnosed at ever-younger ages (possibly due to weight problems), consuming such junk food should not be a habit.  It’s not “The Headless Horseman” stalking the land, but the obesity epidemic, and fewer and fewer of us are as slim as Ichabod Crane.

Insulin Analogs And Breast Cancer Risk

By Bakerstmd - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=39243250

Long-acting insulin analogs are used in the treatment of type 2 diabetes.  Given the possible effects of such drugs on cell signaling pathways, the cancer risk needs to be ascertained.  It has been shown that the drug glargine leads to increased risk of breast cancer for women with type 2 diabetes. Assuming various confounding variables were accounted for, this is a serious issue, and drug side effects always need to be considered when planning treatment.  Abstract:

Purpose The association between long-acting insulin analogs and increased breast cancer risk is uncertain, particularly with the short follow-up in previous studies. We assessed this risk long term in women with type 2 diabetes. Methods A population-based cohort of women 40 years or older, all of whom were treated with long-acting (glargine, detemir) or neutral protamine Hagedorn (NPH) insulin between 2002 and 2012, was formed using the United Kingdom's Clinical Practice Research Datalink. Women were followed until February 2015 or breast cancer diagnosis. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) and 95% CIs of incident breast cancer, comparing long-acting insulin analogs with NPH overall, as well as by duration and cumulative dose. Results The cohort included 22,395 women who received insulin treatment, with 321 incident breast cancer events occurring during up to 12 years of follow-up (incidence rate 3.3 per 1,000 person-years). Compared with NPH insulin, insulin glargine was associated with an increased risk of breast cancer (HR, 1.44; 95% CI, 1.11 to 1.85), mainly increasing 5 years after glargine initiation (HR, 2.23; 95% CI, 1.32 to 3.77) and after > 30 prescriptions (HR, 2.29; 95% CI, 1.26 to 4.16). The risk was particularly elevated among prior insulin users (HR, 1.53; 95% CI, 1.10 to 2.12) but not for new users, which included fewer patients and for which one cannot rule out an HR of 1.81. The risk associated with insulin detemir was not significantly elevated (HR, 1.17; 95% CI, 0.77 to 1.77). Conclusion Long-term use of insulin glargine is associated with an increased risk of breast cancer in women with type 2 diabetes. The risk associated with insulin detemir remains uncertain because there are fewer users of this insulin.

Mediterranean Diet And Metabolic Syndrome

By popsique - Dieta Mediterranea, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=1380032

Take a look at this paper.  Key points: First, rather than concentrate on effects of specific nutrients in isolation, it is better to consider a diet as a whole, with all its components working together.  Second, conformation that the typical Western diet contributes to metabolic syndrome. Third, we again see the virtues of the Mediterranean diet.  Fourth, the benefits of that latter diet may be in large part due to "high amounts of mono- and polyunsaturated fatty acids, bioactive polyphenols and dietary fiber."   These are things hopefully we all already know, but confirmation is comforting.  And it should be clear that "high consumption of meat or meat products, snacks, baked desserts and sugar-sweetened beverages" is absolutely no good for anyone's health.  Abstract:

Metabolic syndrome (MetS) is a cluster of risk factors that significantly increases the risk of cardiovascular disease. The lack of universally accepted diagnosis criteria makes it difficult to know the real prevalence of MetS in both adult and pediatric population. Lifestyle, especially nutritional habits and physical activity, have been suggested to be independent risk factors for the development of MetS. Recent studies highlight the need to prioritize overall dietary patterns, rather than isolated nutrients, to better appraise the associations between nutritional habits and MetS. In this review we summarize recently published intervention trials and systematic reviews that evaluated the association between overall dietary patterns and the risk of MetS. Westernized dietary patterns, characterized by a high consumption of meat or meat products, snacks, baked desserts and sugar-sweetened beverages, which provide high amounts of saturated fatty acids and simple carbohydrates as added sugars, have been associated with higher risk of MetS. In contrast, more traditional dietary patterns, including the Mediterranean dietary pattern (MDP), characterized by a high consumption of vegetables, fruits, whole cereals and fish are associated with a reduced risk of MetS. The main characteristics of the MDP include a high consumption of nuts and olive oil, resulting in a relatively fat-rich pattern that provides high amounts of mono- and polyunsaturated fatty acids, bioactive polyphenols and dietary fiber. Strong evidence is accumulating to support that a closer conformity with the MDP is inversely associated with the incidence of MetS, cardiovascular risk factors, diabetes and cardiovascular disease.

Fructose - Your Foe

We all know that sugar is bad for us. This is why the World Health Organization recommends us to limit our sugar (sucrose) intake to six teaspoons a day. But did you know that fructose, one of the individual types of sugar, is toxic for you? You may not be aware that you consume fructose every day. It is present in regular sugar “sucrose” (composed by glucose and fructose at a ratio of 1:1); however, its main source in the diet is the omnipresent high fructose corn syrup. This “syrup” is added to almost everything: from soft drinks, candy, bread, to tomato soup and ketchup. It is even in some potato and macaroni salads in the neighborhood deli. The fruit juices also contain considerable levels of fructose.
 
Whereas the sugar glucose is used as an energy source by every single cell in the body, fructose is not. Be aware, however, that excess of glucose intake could be converted into fructose in the body. Unlike glucose, fructose can be utilized only by liver cells, where fructose processing results in increased levels of the toxic uric acid and fat. Thus, excess of fructose intake from the diet results in excess fat in the liver (and “fatty liver” disease) and excess fat circulating in the blood. The increased fat in the blood accumulates in the body, and leads to obesity, cardiovascular (heart) diseases, and type 2 diabetes. In fact, fructose is the main culprit for metabolic syndrome, the condition in which high blood pressure, high blood sugar, excess body fat around the waist, and high cholesterol levels co-occur.


Actionable

• Read the ingredients of each food product in your refrigerator and pantry. If “high fructose corn syrup” is one of the ingredients, discard the product. Stop buying such products.

• Stop drinking soft drinks and fruit juices. Instead, eat fruit and drink water.

• Do not allow your children to drink anything else but water and plain milk.

• Laugh with this Coca Cola video. Coca Cola is one of the companies that have drowned us in drinks with high fructose corn syrup and sugar.

• Next time you want to eat out, think twice: do you know what is in your meal? The only way to be sure is to cook it yourself. Learn how to cook with these affordable recipes from the free Good and Cheap cookbook.

• If you do eat out and you are served in a plate larger than 9 inches in diameter, chances are that there is too much food. Eat only half of the meal and take the other half home.