Thursday, September 13, 2012

Diabetes and Chronic Inflammation - connecting the dots, Part Un

Nature Medicine has recently featured studies dealing with obesity-related insulin resistance which leads to a type of diabetes, called Type 2 diabetes. Of these papers, one by Pal et al. (Nature Medicine, 18(8):1284, August 2012) highlights some specific aspects of the disease, including prospects for future therapeutics. I found it interesting - for various reasons* - enough to spur me to write about diabetes in the context of their observations. I shall make it a 2-part series; in the first post, I would talk a bit about diabetes in general, and follow it up with a review of the main findings of their elegant studies. (Full disclosure: I have parents and grandparents who are/were diabetic.)

I'd probably be hard pressed to find an adult person in an industrialized country, who hasn't heard of the dreaded metabolic disease, diabetes, short for Diabetes Mellitus or DM. Diabetes is the condition of hyperglycemia (hyper = over the limit; glyc = referring to sugar, generally simple sugars such as glucose; emia = in blood; that is, high blood sugar) with glycosuria (uria = in urine); this means, that the level of sugar in the blood is so much, that the kidney filtration system is overwhelmed and the sugar literally spills into the urine.
How does this happen? In the healthy body, Insulin - a hormone produced by the β-cells of pancreas - moves glucose from blood into muscles, fat and liver cells, where they are either used up in form of fuel or stored in a complex form called glycogen. This works in a feed-forward/feed-back loop. More glucose is detected in the blood, more insulin is produced; when the glucose level in blood is normal, Insulin production decreases. Another hormone, glucagon, produced by α-cells of pancreas, does the exact opposite function, moving glucose from tissues and organs back to blood when required, but that is the subject of another discussion.

Why does the disease occur? In some people, the pancreas simply does not make enough insulin - leading to Type 1 diabetes, a.k.a. Juvenile Onset diabetes, because it is often diagnosed in children, adolescents, or young adults. Although the exact cause of Type 1 diabetes is unclear, it is often considered an autoimmune disorder in which the body itself erroneously attacks and destroys the pancreatic β-cells, and it can be familial in origin. Exogenous insulin - delivered intramuscularly or subcutaneously - can often help in this situation. However, in most people, the body cannot use the insulin properly - leading to Type 2 diabetes, a.k.a. Adult Onset diabetes, in which the usual targets of insulin - hepatocytes (liver cells), cells of both skeletal and smooth muscles, and adipocytes (lipid/fat-containing cells of the adipose tissue; yup, we all have 'em!!) - do not respond at all, or adequately, to insulin. This is known as Insulin Resistance, and it is a chronic metabolic disorder, developing over many years.

Why is diabetes bad? Well, as a metabolic disorder, diabetes has widespread consequences in the body.
  • Extra glucose in blood can make the blood more concentrated than normal (hyperosmolarity), which in turn - following laws of Physics - draws more water out of tissues and organs, including the brain. This can cause severe dehydration and associated illnesses.
  • Diabetes can also cause severe damage to blood vessels at various places in different ways; uncontrolled diabetes attacks blood vessels supplying the retina of the eye, causing diabetic retinopathy and eventual blindness.
  • Diabetes can lead to hardening of the wall of arteries (arteriosclerosis) leading to peripheral artery disease, usually along with high blood pressure (hypertension), or even coronary heart disease, in conjunction with a dysfunction in cholesterol metabolism.
  • In chronic diabetes, the nephrons - functional units of the kidneys - thicken and scar over time, losing their functions (a condition called diabetic nephropathy).
  • Chronic diabetes can cause severe damage to central and peripheral nerves of the body (diabetic neuropathy).
All in all, not a pretty disease to have, particularly since there is yet no cure, only management, once diabetes sets on; currently, treatment involves medicines (injectable insulin and/or glucose-lowering medications, such as thiazolidinediones, biguanides and sulfonylureas), diet, and exercise to control blood sugar and secondary management of symptoms and long-term complications. For those who are interested, the US National Library of Medicine - "PubMed" to the rest of us - has excellent basic information on Type 1 and Type 2 diabetes, including causes, risk factors, symptoms, tests and treatment modalities; it's a great resource.
Diabetes is recognized as a public health menace. Based on global population statistics, the global prevalence of diabetes among adults (aged 20–79 years) would increase from 6.4% in 2010 (affecting 285 million adults) to 7.7% (affecting 439 million adults) by 2030; it is predicted that between 2010 and 2030, there will be a 69% increase in numbers of adults with diabetes in developing countries and a 20% increase in developed countries (Shaw et al., Diabetes Research and Clinical Practice, 87:4–14, 2010). Suffice it to say, the statistics amply illustrate the severity of this disease.

Let me now dive into some mechanistic details of this disease, beginning with the definition of certain related terms.

Toll-like Receptors (TLRs) are protein structures present on the surface of cells, responsible for recognizing unique molecules that serve as signatures for pathogens releasing them. Different TLRs recognize different signatures; for example, microbial cell wall components containing polysaccharides are recognized by TLR4, whereas nucleic acids from bacteria and viruses are picked up by TLR3, 7, 8 and 9. These signature molecules, called ligands, bind to specific regions, called domains, on the part of TLRs outside the cell. Ligand binding induces two such TLRs to attach to each other (a process called dimerization). Sometimes, this process requires help from additional molecules (called co-receptors); for example, TLR4 often needs a small lipid-binding glycoprotein, known as myeloid differentiation factor 2 (MD-2), and attaches to another copy of itself, making a 'homodimer'. This, in turn, initiates biochemical processes (called signaling) inside the cell. The intracellular part of the TLR dimers, called the signaling domain, is comprised of a specific structure, called the Toll-IL-1 receptor (TIR) domain, which is also present in the certain other intracellular proteins that act as adaptors and bridge factors in the process, namely, MyD88, TRIF (a.k.a. TICAM1), Mal (a.k.a. TIRAP), and/or TRAM. It strikes me, biochemists and cell biologists are entirely too fond of their acronyms, aren't they?
TLR4-ligand signalling
Click here to embiggen
Schema of ligand-mediated TLR4 function in health and disease
Figure © Elsevier; modified and adapted for educational purpose from Figures 1 & 4 of
Gangloff M, Trends in Biochemical Sciences, volume 37 issue 3, March 2012, pages 92-98
Forget the acronyms; suffice it to say that the activation of these adapters and bridging factors leads to the organization of signaling - a complex process involving other protein factors and enzymes; also referred to as 'signal transduction' - eventually leading to the activation of certain transcription factors (such as nuclear factor (NF)-κB), which are proteins with the ability of crossing the nuclear membrane in order to cause changes in the expression of certain genes. In this way, TLRs function as key regulators of the innate immune response to specific pathogens; the signaling process, that is initiated with a ligand binding to TLRs, eventually allows host immune defences to be activated for clearance of the infection and for creating a molecular immune memory for long-term protection.
However, as often happens in the physiological system, the same pathways and mechanisms that work in health can cause disease, too. TLR4, an important molecule for innate immune defences, also happens to be active in various pathological conditions, including septic shock, inflammatory and autoimmune diseases, allergy and cancer. In recent times, it has come to light that TLR4-mediated inflammatory processes are involved in certain metabolic disorders, such as Type 2 diabetes (Fessler et al., Current Opinions in Lipidology, 20(5):379–385, 2009). Let's delve into how that happens.

Non-esterified ('Free') fatty acids (FFAs) are lipid molecules produced during breakdown of fat (a process called lipolysis) stored in adipocytes; although lipolysis is a common process releasing various types of lipid molecules, the saturated fatty acids (long-chain carboxylic acids with 12-24 carbon atoms and no double bonds, i.e. 'saturated' with hydrogen atoms) are of particular problem, and have a long history of association with various diseases. For the purpose of this discussion, therefore, 'FFA' refers mainly to saturated fatty acids. Although FFA levels have similar effects on both diabetic and non-diabetic individuals, obese individuals, having larger depots of fat, likely produce more FFAs, which - when released into the bloodstream and circulating throughout the body - cause a number of negative effects.

High levels of circulating FFAs counteract multiple actions of insulin. They inhibit insulin-stimulated glucose uptake/transport (i.e., reduce the ability of hepatocytes and muscle cells to take up glucose from blood); inhibit synthesis of glycogen (i.e., the insoluble form in which glucose is stored in liver and muscle, a process promoted by insulin); and inhibit insulin-mediated suppression of glycogenolysis (i.e., breakdown of glycogen and release of glucose into blood, a process that insulin normally suppresses, and glucagon promotes). This FFA-mediated inhibition of insulin action, therefore, causes more glucose to move to blood, maintaining hyperglycemia.

In addition, studies have shown that FFAs may inhibit insulin-signaling or transduction of insulin signal in skeletal muscle cells, hepatocytes and adipocytes, by -
  1. Increasing a substance called diacylglycerol (DAG) which activates an enzyme called Protein Kinase C (PKC); PKC suppresses the activation of insulin receptors;
  2. Stimulating inflammation in the adipocytes via TLR4 and pro-inflammatory NF-kB pathways, leading to the release of several inflammation-inducing molecules called cytokines, such as TNF-α, IL1β, IL6 and MCP1;
  3. Producing oxidative and cellular organelle stress in adipocytes, hepatocytes and pancreatic β-cells, which activates an enzyme called JNK that leads to insulin resistance. These three processes are not independent of each other, since oxidative stress results in dysregulation of cytokine production, and cytokines can induce JNK and indirectly suppress the activation of insulin receptors. (Boden. Current Opinion in Endocrinology, Diabetes, and Obesity, 18(2):139–143, 2011)
However, many aspects of this process are not well-understood. For example, FFA-induced chronic inflammation seen in Type 2 diabetes may be mediated by TLR4, but how are the two physically linked? Current evidence suggests that FFAs do not bind to the usual TLR4-MD2 complex directly (Erridge & Samani. Arteriosclerosis, Thrombosis, and Vascular Biology, 29:1944–1949, 2009), as do other ligands (such as pathogen signature molecules I mentioned above). It appears that a different ligand may be involved, an endogenous TLR4 ligand that allows FFA to communicate with TLR4, and the identification of that ligand is the exciting prospect explored in the Nature Medicine paper by Pal et al. that I am going to discuss in the part 2 of this series. See you there!

* Note: My academic interest in diabetes and inflammatory diseases aside, I was also attracted to the article by Durba Pal and her colleagues, because this is excellent work (plaudits to the researchers), published in a Nature journal (a laudable achievement), from a group of scientists based entirely in India (a rare and important achievement) - a fabulous example of great collaboration between some established and some relatively new institutions in that corner of the world. I, being born and brought up in the same place, feel a justifiable pride in this accomplishment.

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