The fact that obesity, a major risk factor for type 2 diabetes, and diabetes itself, are inflammatory conditions, led to investigations exploring whether inflammatory mediators
predict the development of type 2 diabetes in populations at risk. Several such studies have now confirmed that the presence of inflammation predicts the development of type 2 diabetes. The first of these studies by Schmidt et al. showed that the presence of inflammatory mediators predicted the future occurrence of type 2 diabetes in adults [11] and was part of the larger Atherosclerosis Risk in Communities Study (ARIC). A recent paper from the same study continues this theme by showing that elevated plasma concentrations of sialic acid, orosomucoid, IL-6 and CRP predict type 2 diabetes [12]. An overall inflammation score based on these four indices, the total leucocyte count and plasma fibrinogen concentration, provided an increased
risk of 3.7 (when comparing the highest and the lowest quintiles) in white non-smokers for the development of type 2 diabetes [13]. There are at least three other prospective studies confirming the fact that an increase in inflammatory indices at baseline predicts type 2
diabetes and insulin resistance [14–17]. Similarly, there is also a correlation between fasting insulin concentrations and CRP concentrations in plasma [5,18,19], indicating that insulin resistance and inflammatory processes are related and that in association with the other facts
discussed there might be a causal link. Novel data have now appeared showing that the concomitant presence of promoter polymorphisms of TNF-a (G-308A) and IL-6 (C-124G) in obese subjects with impaired glucose tolerance carry twice the risk of conversion to type 2 diabetes when compared with other genotypes. A G-308A mutation of the TNF-a promoter is associated with increased plasma TNF-a concentrations and a 1.8 higher risk of developing diabetes compared to noncarriers. A C-124G mutation of the IL-6 promoter increases the risk for insulin resistance [20].
TRENDS in Immunology Vol.25 No.1 January 2004
14 September 2009
13 September 2009
Milk Products, Insulin Resistance Syndrome and Type 2 Diabetes
A growing body of evidence suggests an inverse relationship between calcium and vitamin D status and dairy food intake and the development of the insulin resistance syndrome (IRS) and type 2 diabetes mellitus (t2DM). Observational studies show a consistent inverse association between dairy intake and the prevalence of IRS and
t2DM. In a systematic review of the observational evidence, the odds for developing the IRS was 0.71 for the highest dairy intake (3–4 servings/d) vs. the lowest intake (0.9 –1.7 servings/d). Few interventional studies have been conducted to evaluate the effects of dairy food intake on the management of prevention of IRS or t2DM. Intervention studies that have examined the independent effects of dairy intake on
specific metabolic components of the IRS including blood pressure and obesigenic parameters have shown favorable effects that support the observational findings albeit the results have been less consistent. Many metabolic and dietary factors appear to influence the degree to which dairy affects IRS metabolic parameters
including calcium and vitamin D intake status, BMI, ethnicity and age. Overall, the intake of low-fat dairy products is a feature of a healthy dietary pattern which has been shown to contribute to a significant extent to the prevention of IRS.
Journal of the American College of Nutrition, Vol. 28, No. 1, 91S–102S (2009)
What is pointed out by this paper I think is really good. This doesn't mean that people should be consuming more dairy servings than what is suggested for their age and gender, but consuming the adequate amount would help them if they have insulin resistance. But I think, they should also be aware of their renal function as if there is a dysfunction it might increase the formation of renal stones.
t2DM. In a systematic review of the observational evidence, the odds for developing the IRS was 0.71 for the highest dairy intake (3–4 servings/d) vs. the lowest intake (0.9 –1.7 servings/d). Few interventional studies have been conducted to evaluate the effects of dairy food intake on the management of prevention of IRS or t2DM. Intervention studies that have examined the independent effects of dairy intake on
specific metabolic components of the IRS including blood pressure and obesigenic parameters have shown favorable effects that support the observational findings albeit the results have been less consistent. Many metabolic and dietary factors appear to influence the degree to which dairy affects IRS metabolic parameters
including calcium and vitamin D intake status, BMI, ethnicity and age. Overall, the intake of low-fat dairy products is a feature of a healthy dietary pattern which has been shown to contribute to a significant extent to the prevention of IRS.
Journal of the American College of Nutrition, Vol. 28, No. 1, 91S–102S (2009)
What is pointed out by this paper I think is really good. This doesn't mean that people should be consuming more dairy servings than what is suggested for their age and gender, but consuming the adequate amount would help them if they have insulin resistance. But I think, they should also be aware of their renal function as if there is a dysfunction it might increase the formation of renal stones.
Folic acid supplementation on insulin sensitivity and inflammatory markers
Inflammation plays a pivotal role in the atherosclerotic process, and some chemokines seem to be crucial in the pathogenesis of vascular damage. High-serum homocysteine, recently recognized as an independent risk factor for vascular disease might increase cytokine and chemokine levels, thus amplifying endothelial damage; moreover, it might worse insulin resistance, thus further contributing to enhance cardiovascular risk. The effect of folic acid supplementation in improving in vivo endothelial function is still debated.
Subjects receiving folic acid supplementation showed a decrement of homocysteine and an amelioration of insulin sensitivity; this treatment was also associated with a significant drop in the circulating concentration of monocyte chemoattractant protein-1, interleukin-8 and C-reactive protein, in the absence of any significant variation of BMI or fat mass.
In healthy overweight subjects a short-term folic acid supplementation reduces the circulating level of some inflammatory mediators independently of weight change, thus suggesting a potential therapeutic role for folic acid in the protection from atherogenesis and cardiovascular diseases.
International Journal of Obesity (2006) 30, 1197–1202.
On the other hand it has been shown that increased folic acid supplementation can increase the chance of colorectal and prostate cancer. Specially if a person already has a precancerous lesion, folic acid supplementation would increase the chance of malignancy in these lesions.
For this study, I think, we can't just tell people to consume more folic acid. We already know about the increase of the risk of cancer, which is a big problem and most of the breads and cereals are already fortified with folic acid in U.S. So we can't have people increase their folic acid intake.
Subjects receiving folic acid supplementation showed a decrement of homocysteine and an amelioration of insulin sensitivity; this treatment was also associated with a significant drop in the circulating concentration of monocyte chemoattractant protein-1, interleukin-8 and C-reactive protein, in the absence of any significant variation of BMI or fat mass.
In healthy overweight subjects a short-term folic acid supplementation reduces the circulating level of some inflammatory mediators independently of weight change, thus suggesting a potential therapeutic role for folic acid in the protection from atherogenesis and cardiovascular diseases.
International Journal of Obesity (2006) 30, 1197–1202.
On the other hand it has been shown that increased folic acid supplementation can increase the chance of colorectal and prostate cancer. Specially if a person already has a precancerous lesion, folic acid supplementation would increase the chance of malignancy in these lesions.
For this study, I think, we can't just tell people to consume more folic acid. We already know about the increase of the risk of cancer, which is a big problem and most of the breads and cereals are already fortified with folic acid in U.S. So we can't have people increase their folic acid intake.
Klotho, atherosclerosis
Disruption of klotho gene expression causes multiple aging phenotypes including arteriosclerosis, pulmonary emphysema, osteoporosis, infertility, and skin atrophy. Although klotho supplementation has been shown to improve the aging phenotype of klotho deficient mice which as would be expected , it remained to be addressed whether klotho supplementation in a heterogeneous experimental animal of vascular dysfunction would improve vascular function which is a prerequisite to address the generality of the effects of klotho on the vasculature.klotho gene transfer improves endothelial function and increases NO metabolites strongly suggests a direct and possibly cooperative regulatory pathway between NO and klotho in the vasculature. Equally important is the finding that klotho gene expression improved blood pressure and induced vascular remodeling.
These findings strongly suggest an underlying role of the klotho gene product in the regulation of endothelial function and of atherosclerosis. Vasodilatation induced by endothelium-derived NO has been reported to be impaired in hypertension , diabetes mellitus and hyperlipidemia . These observations lead to the hypothesis that a decrease in the klotho gene expression may be atherogenic due to direct or indirect involvement with reduced NO production in these common diseases. findings collectively show a coupling between klotho gene expression and NO as a general phenomenon in vascular diseased states which establishes and confirms a regulatory interactive pathway between NO and klotho in the vasculature. Although the cellular and molecular mechanisms of the relationship between klotho and regulation of NO need to be clarified in further studies, involvement of the klotho gene in decreased NO formation by down-regulated eNOS or accelerated degeneration of NO by NO scavenger such as superoxide anion are plausible regulatory pathways.
Another interesting finding is that klotho gene transfer significantly prevented perivascular fibrosis in the coronary arteries as chronic inhibition of NOS with L-NAME has been reported to be associated with an increase in wall thickening and coronary perivascular fibrosis in the rat heart. These histological findings also further support an association between NO and klotho. NO and klotho, although speculation, an increase in systemic NO production may be involved in reduction in medial hypertrophy of aorta and coronary perivascular fibrosis.Some studies indicate that supplementation of the klotho gene restores endothelial-dependent aortic dilatation and accelerates systemic NO production, resulting in a decrease in blood pressure and vascular remodeling. klotho gene therapy is a potentially viable and novel therapeutic strategy for preventive treatment of atherosclerotic cardiovascular diseases.
Vol. 276, No. 2, 2000 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
These findings strongly suggest an underlying role of the klotho gene product in the regulation of endothelial function and of atherosclerosis. Vasodilatation induced by endothelium-derived NO has been reported to be impaired in hypertension , diabetes mellitus and hyperlipidemia . These observations lead to the hypothesis that a decrease in the klotho gene expression may be atherogenic due to direct or indirect involvement with reduced NO production in these common diseases. findings collectively show a coupling between klotho gene expression and NO as a general phenomenon in vascular diseased states which establishes and confirms a regulatory interactive pathway between NO and klotho in the vasculature. Although the cellular and molecular mechanisms of the relationship between klotho and regulation of NO need to be clarified in further studies, involvement of the klotho gene in decreased NO formation by down-regulated eNOS or accelerated degeneration of NO by NO scavenger such as superoxide anion are plausible regulatory pathways.
Another interesting finding is that klotho gene transfer significantly prevented perivascular fibrosis in the coronary arteries as chronic inhibition of NOS with L-NAME has been reported to be associated with an increase in wall thickening and coronary perivascular fibrosis in the rat heart. These histological findings also further support an association between NO and klotho. NO and klotho, although speculation, an increase in systemic NO production may be involved in reduction in medial hypertrophy of aorta and coronary perivascular fibrosis.Some studies indicate that supplementation of the klotho gene restores endothelial-dependent aortic dilatation and accelerates systemic NO production, resulting in a decrease in blood pressure and vascular remodeling. klotho gene therapy is a potentially viable and novel therapeutic strategy for preventive treatment of atherosclerotic cardiovascular diseases.
Vol. 276, No. 2, 2000 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Serum FGF21 ,Obesity
Serum FGF21 levels in overweight/obese subjects are significantly higher than in lean
individuals.
Serum FGF21 correlates positively with adiposity, fasting insulin, and triglycerides but negatively with HDL cholesterol . The increased risk of the metabolic
syndrome associated with high serum FGF21 is over and above the effects of individual components of the metabolic syndrome. In vitro study detected a differentiation-dependent expression of FGF21 in 3T3-L1 adipocytes and human adipocytes. In db/db obese mice, FGF21 mRNA expression was markedly increased in both the liver and adipose tissue compared with that in their lean littermates. Furthermore, FGF21 expression in subcutaneous fat correlated well with its circulating concentrations
in human.FGF21 is a novel adipokine associated with obesity-related metabolic complications in humans. Diabetes 57:1246–1253,2008
individuals.
Serum FGF21 correlates positively with adiposity, fasting insulin, and triglycerides but negatively with HDL cholesterol . The increased risk of the metabolic
syndrome associated with high serum FGF21 is over and above the effects of individual components of the metabolic syndrome. In vitro study detected a differentiation-dependent expression of FGF21 in 3T3-L1 adipocytes and human adipocytes. In db/db obese mice, FGF21 mRNA expression was markedly increased in both the liver and adipose tissue compared with that in their lean littermates. Furthermore, FGF21 expression in subcutaneous fat correlated well with its circulating concentrations
in human.FGF21 is a novel adipokine associated with obesity-related metabolic complications in humans. Diabetes 57:1246–1253,2008
Interesting Quote.
So while we were having our discussion two weeks ago about people expecting a 'wonder' drug of some sort that would cure obesity and/or diabetes (which seems to be in the pipes if you read some of the other blogs) I kept thinking of a quote that I had heard of a few years back and wanted to share it all with you:
“Formerly, when religion was strong and science weak, men mistook magic for medicine; now, when science is strong and religion weak, men mistake medicine for magic.”
-Thomas Szasz
Just some food for thought.
“Formerly, when religion was strong and science weak, men mistook magic for medicine; now, when science is strong and religion weak, men mistake medicine for magic.”
-Thomas Szasz
Just some food for thought.
Systemic Inflammation: whats Obesity got to do with it?
If you find obesity and its associated comorbidities then inflammation is sure to be close by. The connections between these three spin such a web it is hard to tell where the start, middle, and end of the obesity web are. For example, does obesity cause comorbidity and inflammation independently or are the three dominoes in a line. To further complicate the predicament classically associated obesity comorbidities can be caused by inflammation without obesity. For example, the gram negative bacteria cell associated lipopolysaccharide, activating the tried and true TLR->NFKB->gene expression->cytokine pathway ( or down regulation of PAPP-gamma according to the literature you read, both of which suppress GLUT 4 by different means) results in type 2 diabetes. Wow, if that doesn’t make you scratch your head I don’t know what will, and it gets better. Preadipocytes can exhibit phagocytic activity, secrete cytokines, and can become adipocytes or macrophages. At this point you should be having a mid-life immunologic crisis. Rest assured though, with reductionism to the rescue we will tackle the inflammation obesity predicament piece by piece, one at a time. For example obesity can cause fat deposition in the liver. Many proinflammatory cytokines such as CRP are produced by the liver (one possibility for the source of chronic inflammation.).
Sometimes the obesity web actually makes sense. In the obese state a large number of macrophages infiltrate the adipose tissue possibly to clear necrotic adiposity. Secreting TNF-alpha the macrophages inhibit insulin receptors and suppress GLUT 4 expression causing insulin resistance. According to Ping et. al. in the obese state macrophages in adiposity are in the M1 polarization alternatively macrophages in the lean state are of the M2 polarization suggesting obesity is proinflammatory. Macrophages in the proinflammatory state also cause atherosclerosis.
To be a large cell such as a growing adipocyte you need a lot of oxygen. One theory to the systemic inflammation associated with obesity is that as adipocytes get too large they no longer receive adequate oxygen. They might die because of it causing the large influx of macrophages which in turn cause inflammation. Or alternatively they might release cytokines to self induce insulin resistance so they wont get any larger which causes a secondary systemic inflammation.
Systemic inflammation associated with obesity is multifaceted. Macrophages and adipocytes are the primary source of the inflammation but there are many secondary and treachery contributors making pointing the finger to the culprit difficult but this knowledge helps to delineate solutions to the problem.
-Randy, who has a serious case of blogitis and is amused that despite agreeing with his 495 partner Elham to blog on different topics still managed to cover the same material. Seriously, not my bad yall.
Citations:
Jia0, Ping. "Adipose inflammation: cause or consequence of obestiy-related insulin resistance." Diabetes, Metabolic Syndrome, and Obesity Dove Medical Press 2008;1 25-31
O'rourke, Robert. "Inflammation in obesity-related diseases." Surgical Research Review
Mosby inc 2009; 255-259
Sometimes the obesity web actually makes sense. In the obese state a large number of macrophages infiltrate the adipose tissue possibly to clear necrotic adiposity. Secreting TNF-alpha the macrophages inhibit insulin receptors and suppress GLUT 4 expression causing insulin resistance. According to Ping et. al. in the obese state macrophages in adiposity are in the M1 polarization alternatively macrophages in the lean state are of the M2 polarization suggesting obesity is proinflammatory. Macrophages in the proinflammatory state also cause atherosclerosis.
To be a large cell such as a growing adipocyte you need a lot of oxygen. One theory to the systemic inflammation associated with obesity is that as adipocytes get too large they no longer receive adequate oxygen. They might die because of it causing the large influx of macrophages which in turn cause inflammation. Or alternatively they might release cytokines to self induce insulin resistance so they wont get any larger which causes a secondary systemic inflammation.
Systemic inflammation associated with obesity is multifaceted. Macrophages and adipocytes are the primary source of the inflammation but there are many secondary and treachery contributors making pointing the finger to the culprit difficult but this knowledge helps to delineate solutions to the problem.
-Randy, who has a serious case of blogitis and is amused that despite agreeing with his 495 partner Elham to blog on different topics still managed to cover the same material. Seriously, not my bad yall.
Citations:
Jia0, Ping. "Adipose inflammation: cause or consequence of obestiy-related insulin resistance." Diabetes, Metabolic Syndrome, and Obesity Dove Medical Press 2008;1 25-31
O'rourke, Robert. "Inflammation in obesity-related diseases." Surgical Research Review
Mosby inc 2009; 255-259
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