Diabetes Part I: Biology and molecular dynamics of diabetes

This is the first of two related blog posts on diabetes.  Here I review the nature of diabetes, and a commonly occurring biomolecular processes underlying the development of Type 2 diabetes.  I quote from several recent research papers relating diabetes to its closely-associated risk factors like obesity, metabolic syndrome and insulin resistance.  A Part 2 post will look at what research has to say relating the impacts on the underlying disease process of lifestyle activities and substances known to control diabetes.  That post will review lifestyle measures, dietary measures and supplements known to prevent or control diabetes.  A number of suggestions already in the anti-aging firewalls lifestyle regimen  and the combined supplement regimen are exactly ones that the research shows can avert or help control Type 2 diabetes. 

About Type 2 diabetes  Type 2 diabetes (diabetes mellitus) is the most common type representing about 90% of cases; it is a disease of high blood sugar connected with inability of cells to absorb sufficient glucose from the blood.  Insulin is required for such absorption and the problem can be either that the body does not produce sufficient insulin or, more likely, that the body cells cannot properly absorb the glucose due to insulin resistance(ref)(ref).  Insulin resistance is a state in which a given concentration of insulin produces a less-than-expected biological effect. Insulin resistance has also been arbitrarily defined as the requirement of 200 or more units of insulin per day to attain glycemic control and to prevent ketosis. — The syndromes of insulin resistance actually make up a broad clinical spectrum, which includes obesity, glucose intolerance, diabetes itself, and metabolic syndrome, as well as an extreme insulin-resistant state. Many of these disorders are associated with various endocrine, metabolic, and genetic conditions. These syndromes may also be associated with immunological diseases and may exhibit distinct phenotypic characteristics(ref).” 

The excess blood sugar, in turn, can eventually lead to several disease conditions associated with diabetes including heart disease and stroke, high blood pressure, eye problems including cataracts, glaucoma, retinopathy and blindness, kidney damage. nerve damage, infections, gum disease, problems in pregnancy and dementia.Type 2 diabetes is traditionally viewed as a disease of aging, normally diagnosed in people 45 and over.  However it is increasingly being discovered in people of all ages including adolescents and children.

Risk factors for Type 2 diabetes include metabolic syndrome (itself a collection of risk factors for diabetes, heart disease and stroke — including abdominal obesity, high blood pressure, high blood sugar, low levels of “good” HDL cholesterol and high triglycerides, a sedentary lifestyle and insufficient exercise, obesity again, high-fat diet, and age over 45. Variations in some 38 genes have been identified with increased susceptibility to Type 2 diabetes(ref)(ref)(ref).  For example, see the blog post The “skinny” about the “fatso” gene FTO.

According to the American Diabetes Association Data from the 2007 National Diabetes Fact Sheet (the most recent year for which data is available): Total: 23.6 million children and adults in the United States—7.8% of the population—have diabetes. Diagnosed: 17.9 million people, Undiagnosed: 5.7 million people,  Pre-diabetes: 57 million people,  New Cases: 1.6 million new cases of diabetes are diagnosed in people aged 20 years and older each year(ref).”  About 200 million people are directly affected worldwide.  Because of the dietary and lifestyle patterns that typically lead to Type 2 diabetes, it has sometimes been characterized as a disease of poverty(ref).Details of the multiple consequences of diabetes are grim.  They include vascular and cardiovascular problems, blindness dementia, loss of extremities, severe disability and premature death.    

According to the CDC, “If current trends continue, 1 in 3 Americans will develop diabetes sometime in their lifetime, and those with diabetes will lose, on average, 10–15 years of life. — Diabetes is the leading cause of new cases of blindness, kidney failure, and nontraumatic lower-extremity amputations among adults. –Diabetes was the sixth leading cause of death on U.S. death certificates in 2006. Overall, the risk for death among people with diabetes is about twice that of people without diabetes of similar age(ref).” 

The cost of diabetes to the U.S. in 2007 was $174 billion, according to the CDC.  Direct medical costs accounted for $116 billion, and indirect costs, such as disability, work loss and premature mortality, were listed at $58 billion. The biological and molecular roots of Type 2 diabetes In highly-simplified language the selected research publications quoted below as well as many other related publications provide the following picture:  In most cases of obesity there is a low level of inflammation in the white fat resulting in part from the in-migration of macrophages and resulting in the overproduction  of highly inflammatory cytokine molecules (adipokines) and overproduction of substances implicated in generating insulin resistance (e.g. resistin and leptin) and the underproduction of substances required for insulin sensitization (e.g. adiponectin).  Insufficient oxygen in the fat tissue due to lower capillary density in the fat tissue could source the inflammation and macrophage in-migration.  The result is an extensive re-organization of the adipose tissue and, too-often, insulin resistance, a chronic state of too-much sugar in the blood, and Type 2 diabetes.   This description is important because in the Part 2 blog post, I will characterize how certain of the lifestyle, dietary habits and supplements in the anti-aging firewalls regimens work on a molecular level to disrupt the described diabetes-creating process.  Note that there is both white fat where the insulin sensitivity problem initiates and “good” brown fat which accelerates metabolism and weight control.  See the blog entry Getting skinny from brown fat. Of the hundreds or thousands of research publications related to diabetes, I have selected a few that illustrate how obesity leads to Type 2 diabetes. 

An elegant explanation of how insulin resistance and diabetes can follow from a low-level inflammatory process present in obesity is given in the 2006 publication Recent advances in the relationship between obesity, inflammation, and insulin resistance.  It now appears that, in most obese patients, obesity is associated with a low-grade inflammation of white adipose tissue (WAT) resulting from chronic activation of the innate immune system and which can subsequently lead to insulin resistance, impaired glucose tolerance and even diabetes. WAT is the physiological site of energy storage as lipids. In addition, it has been more recently recognized as an active participant in numerous physiological and pathophysiological processes. In obesity, WAT is characterized by an increased production and secretion of a wide range of inflammatory molecules including TNF-alpha and interleukin-6 (IL-6), which may have local effects on WAT physiology but also systemic effects on other organs. Recent data indicate that obese WAT is infiltrated by macrophages, which may be a major source of locally-produced pro-inflammatory cytokines. Interestingly, weight loss is associated with a reduction in the macrophage infiltration of WAT and an improvement of the inflammatory profile of gene expression. Several factors derived not only from adipocytes but also from infiltrated macrophages probably contribute to the pathogenesis of insulin resistance. Most of them are overproduced during obesity, including leptin, TNF-alpha, IL-6 and resistin. Conversely, expression and plasma levels of adiponectin, an insulin-sensitising effector, are down-regulated during obesity. Leptin could modulate TNF-alpha production and macrophage activation. TNF-alpha is overproduced in adipose tissue of several rodent models of obesity and has an important role in the pathogenesis of insulin resistance in these species. However, its actual involvement in glucose metabolism disorders in humans remains controversial. IL-6 production by human adipose tissue increases during obesity. It may induce hepatic CRP synthesis and may promote the onset of cardiovascular complications. Both TNF-alpha and IL-6 can alter insulin sensitivity by triggering different key steps in the insulin signaling pathway. In rodents, resistin can induce insulin resistance, while its implication in the control of insulin sensitivity is still a matter of debate in humans. Adiponectin is highly expressed in WAT, and circulating adiponectin levels are decreased in subjects with obesity-related insulin resistance, type 2 diabetes and coronary heart disease. Adiponectin inhibits liver neoglucogenesis and promotes fatty acid oxidation in skeletal muscle. In addition, adiponectin counteracts the pro-inflammatory effects of TNF-alpha on the arterial wall and probably protects against the development of arteriosclerosis. In obesity, the pro-inflammatory effects of cytokines through intracellular signaling pathways involve the NF-kappaB and JNK systems. Genetic or pharmacological manipulations of these effectors of the inflammatory response have been shown to modulate insulin sensitivity in different animal models. In humans, it has been suggested that the improved glucose tolerance observed in the presence of thiazolidinediones or statins is likely related to their anti-inflammatory properties. Thus, it can be considered that obesity corresponds to a sub-clinical inflammatory condition that promotes the production of pro-inflammatory factors involved in the pathogenesis of insulin resistance.” 

This paper has been widely cited and its findings confirmed.  For example, the 2007 publication Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance reports on the same theme: “Obesity and insulin resistance, the cardinal features of metabolic syndrome, are closely associated with a state of low-grade inflammation. In adipose tissue chronic overnutrition leads to macrophage infiltration, resulting in local inflammation that potentiates insulin resistance. For instance, transgenic expression of Mcp1 (also known as chemokine ligand 2, Ccl2) in adipose tissue increases macrophage infiltration, inflammation and insulin resistance. Conversely, disruption of Mcp1 or its receptor Ccr2 impairs migration of macrophages into adipose tissue, thereby lowering adipose tissue inflammation and improving insulin sensitivity. These findings together suggest a correlation between macrophage content in adipose tissue and insulin resistance. — Using mice with macrophage-specific deletion of the peroxisome proliferator activated receptor-gamma (PPARgamma), we show here that PPARgamma is required for maturation of alternatively activated macrophages. Disruption of PPARgamma in myeloid cells impairs alternative macrophage activation, and predisposes these animals to development of diet-induced obesity, insulin resistance, and glucose intolerance. Furthermore, gene expression profiling revealed that downregulation of oxidative phosphorylation gene expression in skeletal muscle and liver leads to decreased insulin sensitivity in these tissues. Together, our findings suggest that resident alternatively activated macrophages have a beneficial role in regulating nutrient homeostasis and suggest that macrophage polarization towards the alternative state might be a useful strategy for treating type 2 diabetes.”  

The message in the 2010 publication Adipose tissue as an endocrine organ is completely consistent: “Obesity is characterized by increased storage of fatty acids in an expanded adipose tissue mass and is closely associated with the development of insulin resistance in peripheral tissues such as skeletal muscle and the liver. In addition to being the largest source of fuel in the body, adipose tissue and resident macrophages are also the source of a number of secreted proteins. Cloning of the obese gene and the identification of its product, leptin, was one of the first discoveries of an adipocyte-derived signaling molecule and established an important role for adipose tissue as an endocrine organ. Since then, leptin has been found to have a profound role in the regulation of whole-body metabolism by stimulating energy expenditure, inhibiting food intake and restoring euglycemia, however, in most cases of obesity leptin resistance limits its biological efficacy. In contrast to leptin, adiponectin secretion is often diminished in obesity. Adiponectin acts to increase insulin sensitivity, fatty acid oxidation, as well as energy expenditure and reduces the production of glucose by the liver. Resistin and retinol binding protein-4 are less well described. Their expression levels are positively correlated with adiposity and they are both implicated in the development of insulin resistance. More recently it has been acknowledged that macrophages are an important part of the secretory function of adipose tissue and the main source of inflammatory cytokines, such as TNFalpha and IL-6. An increase in circulating levels of these macrophage-derived factors in obesity leads to a chronic low-grade inflammatory state that has been linked to the development of insulin resistance and diabetes. These proteins commonly known as adipokines are central to the dynamic control of energy metabolism, communicating the nutrient status of the organism with the tissues responsible for controlling both energy intake and expenditure as well as insulin sensitivity.” 

The processes involved in inflammation of adipose tissue and consequent steps leading to insulin resistance and diabetes are complex involving many factors.  For example, adipose tissue may not receive sufficient oxygen as suggested in the 2009 publication Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. “Compared with lean subjects, overweight/obese subjects had 44% lower capillary density and 58% lower VEGF, suggesting AT rarefaction (capillary drop out).” 

The 2010 publication Plasma adipokine and inflammatory marker concentrations are altered in obese, as opposed to non-obese, type 2 diabetes patients further amplifies the picture.  It would be possible to continue quoting other sources and generate a book on the subject, but that depth of treatment is not appropriate for this blog. 

What causes obesity in the first place?  The blog entry Obesity in the news again discusses the skyrocketing rate of obesity in the US and delves into that question.   Obviously, there are lifestyle factors like not moving much and eating a high-fat high-calorie diet and drinking a lot of sugar-infused sodas. Many biolgical factors can be involved like the abnormal expression of ghrelin, the “hunger protein.”  See the blog entry Ghrelin hunger, obesity and aging.  The metabolic pathways that can lead to obesity are also significant.  The AMPK pathway is particularly relevant to diabetes and metabolic syndrome.  See the subsection AMPK and Type 2 Diabetes in the recent blog post AMPK and longevity.  Finally, once there is an established state of metabolic syndrome or obesity, the changes brought about tend to lock in the metabolic syndrome or obesity through multiple channels.  Severely obese people may find it very difficult to exercise and experience abnormal hunger, for example.   

I have characterized a process of how Type 2 diabetes arises from obesity.  The characterization can also be applied where the problem arises in people with metabolic syndrome and large stomach paunches but who are otherwise lean.  In less-frequent cases such a when there is significant genetic susceptibility; type 2 diabetes also can arise in lean subjects through other processes too complex to cover here. 

Having in mind the pathological process through which diabetes arises from obesity or metabolic syndrome, the next blog entry, Diabetes Part 2: Lifestyle, dietary and supplemental interventions for diabetes will discuss research findings showing how the suggested interventions and certain diabetes medications interfere with the pathological process leading to diabetes. Please see the medical disclaimer for this blog.

About Vince Giuliano

Being a follower, connoisseur, and interpreter of longevity research is my latest career. I have been at this part-time for well over a decade, and in 2007 this became my mainline activity. In earlier reincarnations of my career. I was founding dean of a graduate school and a university professor at the State University of New York, a senior consultant working in a variety of fields at Arthur D. Little, Inc., Chief Scientist and C00 of Mirror Systems, a software company, and an international Internet consultant. I got off the ground with one of the earliest PhD's from Harvard in a field later to become known as computer science. Because there was no academic field of computer science at the time, to get through I had to qualify myself in hard sciences, so my studies focused heavily on quantum physics. In various ways I contributed to the Computer Revolution starting in the 1950s and the Internet Revolution starting in the late 1980s. I am now engaged in doing the same for The Longevity Revolution. I have published something like 200 books and papers as well as over 430 substantive.entries in this blog, and have enjoyed various periods of notoriety. If you do a Google search on Vincent E. Giuliano, most if not all of the entries on the first few pages that come up will be ones relating to me. I have a general writings site at www.vincegiuliano.com and an extensive site of my art at www.giulianoart.com. Please note that I have recently changed my mailbox to vegiuliano@agingsciences.com.
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5 Responses to Diabetes Part I: Biology and molecular dynamics of diabetes

  1. Res says:

    great post.
    I am forwarding this to two of my friends who suffer from diabetes.

    Thanks as always

  2. admin says:

    Thanks Res

    I am spending a lot more time on blog entries recently and writing fewer of them. Did you see the Part 2 entry?


  3. liew says:

    Back in May, there was an exciting documentary showing on the Australian channel 7 TV Sunday night about a medical revolution concerning diabetes 1, using a pure breed of pigs in New Zealand sub-Antarctic island for xenotransplantation. See links below

    Sub Antarctic Pigs and a Medical Revolution – a blog by Dr John D’Arcy.

    A blog by Dr John D’Arcy
    “The pigs used must be free of any disease that’s capable of being transmitted to man,” Professor Elliot said.
    “By good fortune we lit upon a herd of pigs that had been abandoned in a sub-Antarctic island some 200 years ago, and in that 200 years they have lost any form of infection capable of being transmitted to man.
    “The pigs we used are derived from those. They’re not currently housed on that island, they’re housed in a very special containment facility which keeps that nice pristine, infection-free, bug-free status.”
    With no moratorium in place, Living Cell Technologies hopes to conduct more human trials in Australia by the end of the year.”

    Juvenile diabetes research foundation:
    “For type 1 diabetes, xenotransplantation involves taking insulin-producing islets from animals —in this case, pigs—and transplanting them into people. Pigs are considered the best species for xenotransplantation because pig organs are similar in size and physiology to human organs and pig insulin has been shown to work effectively in humans.”
    Latest news of trials by Living cells technologies

  4. admin says:


    Fascinating contribution. thanks.


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