Tuesday, September 10, 2013

METFORMIN: IS THIS DIABETIC DRUG AIDING LIFE SPAN BY MEANS OTHER THAN JUST GLYCEMIC CONTROL?

Metformin is a hypoglycemia-inducing drug of the biguanide family that has been used to treat the hyperglycemia associated with type 2 diabetes for over 50 years. Indeed, metformin is the most frequently prescribed diabetes treatment drug.

For more information on the effects of metformin go the the Diabetes page of themedicalbiochemistrypage.org

Metformin exerts several effects in several cell types but with respect to overall glucose homeostasis its effects on hepatic metabolism include an induction of glucose metabolism (glycolysis) and repression of glucose synthesis (gluconeogenesis). Combined, these two effects significantly contribute to the promotion of an increase in whole body insulin sensitivity. Over the years studies with metformin have shown that this drug mimics some of the benefits of calorie restriction, such as improved physical performance, increased insulin sensitivity, and reduced low-density lipoprotein (LDL) and cholesterol levels without a decrease in caloric intake. Examination of gene expression profiles demonstrated that metformin induces a gene expression profile highly similar to that induced by calorie restriction. At a molecular level, one of the most important effects of metformin is an increase in AMP-activated protein kinase (AMPK) activity. Increased AMPK activity is associated with increased antioxidant protection, resulting in reductions in both oxidative damage accumulation and chronic inflammation, both of which are hallmarks of aging processes. Despite all these important observations there is still controversy regarding whether or not metformin is involved in lifespan extension.

A recent study published in the journal Nature Communications indicates that long-term metformin administration in laboratory animals does indeed lead to increases in lifespan:


In this study adult mice were treated with two different doses of metformin continuously until the mice died naturally. The results demonstrated two critical facts. The first is that too much metformin (the mice treated with the higher of the two doses) was toxic and led to a shortened lifespan compared to control untreated mice. The other observation was that mice given the lower dose of metformin exhibited an extension of their lifespan by 5-6% over that of control mice. Additionally significant findings were that when these mice died (at around 115 weeks of age) they showed no obvious pathology that would account for why they died compared to untreated control mice. Another important finding was that the low dose metformin treated mice were healthier than the untreated mice in the measure of body mass. As humans and animals age there is a progressive change in body mass, and in animal studies the ability to maintain a youthful body mass is associated with healthier parameters. In this study the metformin treated mice maintained a healthy weight even at 124 weeks of age even though they actually ate more calories than untreated mice. This indicated that metformin treatment altered the metabolic profiles of the mice. Indeed, metformin treatment was associated with increased fat oxidation rates and reduced lipid synthesis even though there was no significant increase in the activity level of the treated mice. Similar examinations in short-term metformin studies have shown that the drug partially inhibits mitochondrial functions but this study indicates that long-term there is an adaptation to beneficial metformin effects. Detailed molecular studies in these metformin treated mice showed that the drug inhibited inflammation and preserved mitochondrial functions by inducing a pattern of gene expression that was very similar to that observed in mice on a calorie restricted diet.


The TAKE HOME from this study is that chronic metformin treatment, in type 2 diabetics, may actually have unforeseen benefits unrelated to the prescribed benefit of reduced serum glucose. However, it should be noted although the dose associated with the beneficial effects in the mice was well tolerated, the dose used was an order of magnitude higher than that conventionally used in human patients. Therefore, it is clear that although promising, further studies on the dose and length of metformin treatment in humans is necessary to fully ascertain the effects and potential benefits of chronic exposure to biguanides in health and aging in humans.

Sunday, September 8, 2013

GASTRIC BYPASS: ITS ROLE IN TREATING DIABETES IS MORE THAN JUST FORCED FOOD INTAKE REDUCTION

Bariatric surgery is an extreme procedure involving gastric bypass as a means of treatment for morbid obesity and obesity. There are many different types of gastric bypass with the Roux-en-Y procedure (RYGB) being one of the more common. The RYGB procedure involves surgically reducing the size of the stomach to a small pouch by stapling off a section of the stomach then attaching this pouch directly to the small intestine, bypassing most of the rest of the stomach and the upper part of the small intestine. RYGB has been shown to induce substantial and sustained weight loss. An interesting and unexpected finding in patients who underwent the RYGB is that the observed improvement in overall glucose homeostasis occurs early after the RYGB procedure, before any appreciable weight loss, and as a result these patients are often able to discontinue their antidiabetic medications before hospital discharge. However, the means by which the RYGB effected these changes in glucose homeostasis have not been determined.
In a recent study published in the prestigious journal Science it has been determined that a major metabolic consequence of the RYGB procedure is an increase in glucose utilization by the intestines resulting in increased disposal of glucose from the blood, thereby, rapidly reducing the hyperglycemia of type 2 diabetes.


The authors of this study hypothesized that that the beneficial effect of RYGB on glucose homeostasis might likely be due to the fact that the jejunum (the middle section of the small intestine), which normally does not see undigested food, now has an altered metabolism necessary to meet the increased bioenergetic demands of tissue growth and maintenance, possibly in response to exposure of this section of the intestine to undigested nutrients.
These studies were carried out in rats and the initial work centered on a comparative analysis of the metabolic profiles in sham operated jejunal tissue versus RYGB jejunal tissue. The results of metabolomic profiling showed increased concentrations of intermediates of the oxidative phase of the pentose phosphate pathway, increased intermediates of the pyrimidine and purine biosynthetic path-ways, increased lactate production was increased, there was increased serine biosynthesis and hexosamine biosynthetic activity (the HBP), two metabolic pathways that branch off from glycolysis. In addition, the glutamine/glutamate pathway was enhanced as was the metabolism of several other amino acids. The observed changes in metabolic profiles following the RYGB indicates that glycolysis may be up-regulated in in order to shunt glucose carbons into metabolic pathways that support the accumulation of biomass necessary for cellular growth and proliferation. Metabolomic changes in the RYGB rats were also mirrored by examination of transcriptomic profiles that demonstrated increased expression of key glycolytic enzymes.

The effectiveness of RYGB, not only at the level of weight loss, but in the resolution of hyperglycemia and insulin resistance in type 2 diabetes attests to the important role of the gastrointestinal tract in overall glucose homeostasis. Most previous studies suggested that these effects of RYGB were due to changes gastrointestinal hormones that control glucose homeostasis such as glucagon-like peptide-1 (GLP-1). Other animal studies have also demonstrated that changes in intestinal gluconeogenesis following a different type of gastric bypass resulted in reduced hepatic gluconeogenesis. However, studies in humans who underwent the RYGB procedure did not show appreciable induction of intestinal gluconeogenesis so there is some controversy as to the role of intestinal gluconeogenesis in the efficacy of gastric bypass in ameliorating the hyperglycemia of type 2 diabetes.


The TAKE HOME from this study first confirms the physiological benefits of the use of the RYGB procedure in the treatment of obesity and type 2 diabetes. Specifically, this study demonstrated that changes in overall metabolism in the jejunal limb of the bypass structure may be primarily responsible for improved glucose homeostasis following RYGB. The resulting reprogrammed intestinal glucose metabolism leads to the intestine becoming a major organ for glucose disposal which in turn contributes to the overall improvement in glycemic control following RYGB and the associated improvement in the hyperglycemia associated with type 2 diabetes.

Saturday, September 7, 2013

GUT BACTERIA FROM THIN HUMANS MAY BE THE CURE FOR OBESITY IN FAT HUMANS

More and more research is demonstrating the beneficial roles played by the bacteria that reside within our intestines in the control, regulation, and modulation of normal physiological status and that disruption in the ratios of certain types of bacteria are associated with disease states such as obesity and type 2 diabetes, and the associated increase in intestinal inflammation and gut barrier disruption this causes. Indeed, I have written about this area of research in the pages of this blog earlier this year:


As always you can read more about the correlation between obesity and gut bacteria in the Obesity page of themedicalbiochemistrypage.org


A recent paper just published in the prestigious journal Science demonstrates that administration of bacteria from thin human feces prevents obesity in mice even when they are fed a high-fat diet.



This most elegant study study compared the effects of the administration of uncultured (feces) or culturable bacteria from twins that were both obese or who were both lean, to mice. These types of studies are designed to ascertain precisely what types of bacteria, and especially how these bacteria, effect the differences in metabolism observed in lean versus obese individuals. Previous work, for example, has shown that transplanting fecal bacteria from healthy donors to recipients with metabolic syndrome (MetS) results in the amelioration of insulin-resistance. In this current study, the bacteria (feces) from obese twins resulted in significantly greater increases in body mass and adiposity (fat) in the mice than did the bacteria (feces) from lean twins. These changes in overall metabolism in the mice were correlated to differences in the metabolic profiles of the bacteria. Bacteria in the gut metabolize (ferment) undigested fiber into short-chain fatty acids (SCFA) which exert important metabolic effects on host tissue such as the intestine. These SCFA were increased in the mice fed bacteria from lean twins relative to those fed bacteria from obese twins. The mice fed obese bacteria also showed higher levels of amino acid metabolism including essential and branched-chain amino acids (BCAA). This pattern of amino acid metabolism by the obese bacteria in these mice is very similar to elevations seen in BCAA and related amino acids observed in obese and insulin-resistant versus lean and insulin-sensitive humans. In addition, bacterial metabolism of bile acids into molecules that down-regulated host FXR receptorsignaling was significantly higher with lean bacteria than with the obese bacteria. The significance of this latter observation relates to the role of FXR-regulated bile acid synthesis and how this relates to serum cholesterol levels since bile acid synthesis is the major means for excretion of cholesterol. Activation of intestinal FXR induces expression of intestinal fibroblast growth factor 15 (FGF15) which is then secreted to the portal circulation where it binds to, and activates the liver fibroblast growth factor receptor 4 (FGFR4). This activation then results in inhibited expression of the rate-limiting enzyme in bile acid biosynthesis, cholesterol 7-a-hydroxylase (CYP7A1) resulting in lower rates of bile acid synthesis. Therefore, the observation that mice fed lean bacteria have reduced levels of activated FXR in the gut can be directly correlated to increased bile acid synthesis and increased disposition of cholesterol. Indeed, studies have shown that over-expression of CYP7A1 can prevent diet-induced obesity and insulin resistance. An additional finding in this study was that when mice fed lean twin bacteria were housed with mice fed obese twin bacteria the latter mice had reduced fat mass and adiposity accumulation compared to mice fed obese twin bacteria that were not co-housed with lean bacteria fed mice.



TAKE HOME from this study: it could be argued that an easy (but potentially distasteful, pun intended) solution to obesity is just to consume a small amount of feces from skinny humans. Given that most, if not all, of the bacteria in our guts are anaerobic, due to the lack of oxygen in the gut, it is difficult to culture the beneficial strains so that they can be delivered in the diet. In addition, there are 500 to 1000 different species of bacteria in the gut making it highly laborious to separate and culture each and every individual strain. However, in spite of these limitations it is clear that very soon there will be available methods to treat obese and type 2 diabetic individuals with cocktails of beneficial gut microbiota. Look for this to be the next HUGE market in the alternative medical and dietary supplement market. Already, numerous yogurt manufacturers are making claims to the health benefits of the probiotic cultures in their yogurt.