Nano Does a Mega Tango: FETs To Change The Fate Of Diabetics

The role of electronics in medicine or physiology is a very important one. Ranging from CT scan, fMRI, PET scan or electron microscopes and a variety of other medical investigations, medical science depends on electronics and its allied disciplines.

A simple illustration is as follows. Everyone knows that the estimation of blood glucose is the cornerstone in the diagnosis and therapy of diabetes mellitus and other hyperglycemic illnesses such as hyperthyroidism, hyperpituitarism and others. Even hypoglycemic ailments (conditions where the blood glucose levels are less than normal) like hypothyroidism, hypopituitarism or hyperinsulinemia, hypoadrenocorticism need the estimation or quantitation (quantification) of blood glucose, in order to clinch their diagnosis.

Glucose may be estimated in the blood in a variety of methods. One of the easiest methods rely on the simple reaction of glucose with potassium per-manganate. Glucose is a reducing monosachharide; while potassium permanganate is a strong oxidizing agent, so much so that it produces frank fire when added to glycerine not to mention of its emanation of oxygen (O2) when heated. When KMnO4 (potassium permanganate) is added to glucose, it (KMnO4) is reduced to manganese ions (Mn++). The colour changes from purple pink to colorless. This can be seen by the naked eye, giving us an estimate of the amount of total glucose that is present.

Another approach that is adopted nowadays is the enzymatic oxidation of glucose and their quantitation thereof. Here enzyme glucose oxidase (GOD) is used to oxidize glucose to D-gluconic acid and hydrogen peroxide (H2O2). In the presence of H2O2, hydrogen peroxidase (POD) oxidizes phenol, which combines with 4-amino antipyrine to form a red dye (quinone imine). The intensity of the red dye is linearly proportional (upto 500 mg% i.e. 500 mg per dl) to the glucose concentration in the specimen. The intensity of the color that is formed is measured by using a colorimeter; a device that measures the transmittivity of light (through the liquid) by employing LDR (Light Dependent Resistor) or phototransistors or similar devices.

Recently, advances in nanotechnology and nanoscience as a whole, is offering a brand new hope of determining blood glucose within the patients blood itself. That is you don't need to prick the guy. They are using a device called ISFET (Ion Sensitive Field Effect Transistor). It is variant of FET devices (a picture of a MOSFET i.e metal oxide semiconductor FET, is shown on the left). In a ordinary bipolar transistor, we forward bias the emitter-base junction by applying a current and make the collector strongly reverse biased. Thus any input current in the base emitter circuit is amplified several times when the electrons 'rushes' towards the attracting collector. A FET also works in much the same way. The difference is that the flow of charge carriers are controlled by a electric field applied in the Gate (G) Source (S) junction. This electric field is generated by a voltage: VGS. Thus while bipolar junction transistors (BJT) are current controlled, the FET devices are voltage controlled.

Recently, a team of physicists led by Raj Mohanty from Boston University has made a nanoscale glucose sensor using ISFETs and nanowires consisting of silicon. The silicon nanowires were primed with glucose oxidase on their surfaces and these nanowires bridged the source and the drain electrode of the MOS device. The conductivity of the 'wire' would change depending upon the glucose concentration in blood as it is reacted upon by the enzyme present on its surface. A voltage drop will ensue between the source and the drain electrodes, which may be read and interpreted by a voltage comparator. The researchers claimed that these could be put in vivo with virtually no risk. Humans do have the habit of carrying silicon on their bodies and that hardly do them any harm! We may be able to noninvasively monitor the blood glucose of diabetic persons, may even be able to act upon it, by incorporating a feedback circuit that would actuate an insulin pump, in times of hyperglycemia.

Diagnosing Diabetes Mellitus

You may wonder, why I am putting so much stress on diabetes. It is because it is a major cause of morbidity (ill health) and mortality (death), in present society. Also our stressful lifestyles, eating habits, sedentary lives (lack of exercise) and many others have pushed ourselves to the brink of a major health disaster. Diabetes is a major contender among them. Adding to this, there are complications like cardiovascular diseases, renal, neural and retinal diseases; apart from obesity, which also reinforces diabetes (in addition to it being reinforced by diabetes).

To put it succinctly, diabetes can be diagnosed on the following criteria; a person meeting any of the three criteria described below, is said to have diabetes.

1. A random plasma glucose test result of 200mg/dL (11.1 mmol/L) or more in a patient who already has symptom of diabetes (such as polydipsia or excessive thirst, polyuria or excessive urination or progressive unexplained weight loss).

2. A fasting (=at least 8 hours of no caloric intake, i.e. no carbohydrates, proteins or fats: water may be allowed) plasma glucose level of 126mg/dL (7.0mmol/L) or more

3. A oral glucose tolerance test value of 200mg/dL (11.1 mmol/L) or more. This test is carried out by giving the patient 75 grams of glucose orally, and then taking the plasma glucose values of the patient.

When the person satisfies any of the above criteria, he is automatically considered a patient of the disease. However, in presence of any doubts the test/s may have to be repeated, on a separate occasion.

Thus, it behooves upon us to get ourselves checked at regular intervals. Better forewarning is better forearming.

Related topics: insulin, type2DM, water water..

Treating Type2 DM

So far, we have discussed about insulin, its actions, type 1 diabetes mellitus and its treatment. In contrast to type 1 DM, type 2 DM is characterized by end organ (tissue level) insensitivity to insulin. Thus insulin is present in normal or more than normal quantity, but somehow it can not deliver its message across the cell. Obviously such a state cannot be addressed by giving more insulin, but in making the cell more responsive to its effects. This is done by administering oral hypoglycemic drugs (OHD). (Although, in complicated type2DM or when there is an added stress like a fracture, emotional trauma, surgery; insulin has to be administered, in addition).

Sulfonylurea group of drugs act by closing the SUR (Sulfonylurea) channel, which is in fact, a part of the ATP sensitive potassium channel. Closing this channel would mean build up of potassium inside the cell, thus neutralizing the electro negativity inside, making the cell depolarized. This in turn will lead to influx of calcium ions from outside, which in turn will lead to release of stored insulin. Thus these groups of drugs are also referred to as insulin releasers. Of these, short acting sulfonylureas like glimiperide or glyclazide are preferred over their long acting cousins like chlorpropamide. This is due to the adverse effect of hypo glycemia, which, naturally tend to be long and more profound with long acting sulfonylureas.

Biguanides like metformin are very helpful, specially in obese diabetics. It acts in various ways, though its exact mechanism of action hasn't yet been worked out. It is also effective in the treatment of PCOD (poly cystic ovarian syndrome). Phenformin, a biguanide, which caused fatal lactic acidosis, was withdrawn from the market.

Meglitinides are a group of drugs which act by releasing insulin, in much the same manner as the sulfonylurea drugs. Repaglinide and nateglinide are examples of this group.

Thiazolidinediones, which include pioglitazone and rosiglitazone, are novel drugs which target PPAR-gamma (peroxisome proliferator-activator receptor-gamma), an intracellular receptor.
The Tzds as they are better known, combine with the intra nuclear receptor, thereby modifying gene activation and thus bring about their actions. PPAR-gamma are located in muscle cells, fat cells, liver and other organs. Their effects take time, since they act through genetic transcription, translation etc. In addition to sensitizing the tissues to insulin, they also lower LDL, increase HDL in those taking it. Thus, they also correct, to some extent, the metabolic disorders which usually accompany diabetes.

Then there are also alpha glucosidase inhibitors, like acarbose and miglitol, which prevent the breakdown of polysaccharides in the intestine, to smaller molecules like glucose or fructose. As the intestine cannot absorb carbohydrate molecules other than simple sugars, blocking polysaccharide breakdown in the gut will thus reduce the sugar load into the blood stream.

RELATED POST: Water water everywhere..

INSULIN : Take the pen to beat the pain

One of the greatest discoveries of the twentieth century which led to their discoverers having the Nobel prize (and sharing it!), this molecule, insulin, is secreted by the beta cells of the islets of Langerhans in the pancreas. It is produced as pre- pro-insulin by genes located on the chromosome 11. It is cleaved and folded to give insulin and C peptide before its release into blood. The pancreatic beta cells have a glucose transporter, called GLUT2 in their cell membrane which senses the blood glucose level and acts accordingly. When blood glucose level goes high, as after meals, glucose enters the beta cells through GLUT2. Thereafter, it is converted to ATP within the cell by metabolism (TCA cycle). This ATP then chokes (inhibits) the ATP sensitive potassium channel located in the cell membrane. Since there is more potassium inside than on the outside, the channel when open allows potassium to go out of the cell. Thus, glucose entry would mean more ATP, and more ATP will close this channel resulting in potassium build up with in the cell. Potassium (K+) being a positively charged ion (cation) will thus decrease the electronegativity inside, causing the cell to fire. As a result, voltage gated calcium channels open. Ca+ plays instrumental role in the exocytosis of insulin (insulin now comes out of the cell into the bloodstream).

Once it has come out, it circulates in the bloodstream and reaches the target organs/tissues. There it binds with the insulin receptor. The receptor molecule consists of 2 alpha chains (extracellular) and 2 beta chains (partly located extracellularly, partly transmembrane and partly intracellularly). The chains are linked together by sulfur atoms. Insulin binds with the alpha chains (naturally, as they are on the outside) of the receptor molecule, which in turn changes its (receptor) conformation. This triggers tyrosine kinase enzyme activity within the cell. This enzyme is intrinsic to the cell, only its activity is triggered by insulin. Then this enzyme autophosphorylates the receptor (meaning that the receptor itself gets phosphorylated: sounds incestuous!), and molecules such as IRS (insulin receptor substrates) are formed. They in turn phosphorylate/ dephosphorylate cellular proteins to bring about their effects. For example, activation of PI3 kinase (phosphatidyl inositol 3 kinase) results in the translocation of GLUT4 from the cell interior to the cell membrane. This transporter is important in the transport of glucose to the interior of muscle and fat cells. Thus GLUT4 is very important for glucose to enter these cells. Apart from this, insulin also has mitogenic action (by virtue of MAPK activity).

Thus absence of insulin will lead the cells to use fuels other than glucose. Thus the body is depleted of its fat stores, ketone bodies : a byproduct of fat burning are formed, muscles become wasted, and various complications occur.

Previously, insulin from animals (beef, porcine) were used to treat diabetes. Nowadays human insulin from recombinant DNA technology are being increasingly used. They are almost always injected subcutaneously, that too by a device called insulin pen (whence the name of this article). A pen has several disposable needles and a cartridge which may or may not be replaceable. Other routes of insulin administration has been explored, such as nasal, gastric, intrapulmonary by aerosol. Of these, the last mode of delivery holds promise. Insulin has been classified into short acting, intermediate acting and long acting insulins, according to the duration of action, of the type of insulin in question.

Therapy of diabetes often requires more than one component (type) of it (insulin), and is often based on SMBG and HbA1c and clinical parameters, rather than simple calculation on body weight or surface area basis. One example of how different types of insulins are mixed and administered has been sited in my former article, water water everywhere... This is just one example (actual treatment will depend upon SMBG, HbA1c and other informations, as cited above and more).

Diabetes Mellitus: Water Water Everywhere

Samuel Taylor Coleridge in his poem 'The Rime of the Ancient Mariner' said ' Water, water, every where, Nor any drop to drink'. A similar type of situation occurs in a human disease where sugar is plentiful in the blood and other tissues, but the cells themselves go hungry. Diabetes Mellitus is such a disease where there is 'starvation in the midst of plenty'.

Diabetes is a group of disorder in which there is hyperglycemia. This rise in plasma glucose level can be brought about by a decrease in (or absent) insulin levels, insulin resistance (insulin is there or may be even raised-but the cells are refractory to its presence), or counter-regulatory hormone (such as glucagon) excess. Presently diabetes is classified into 4 types, on the basis of the pathologic processes that leads to hyperglycemia. Type2 DM accounts for about 90% of all diagnosed cases while type1 diabetes accounts for about 5-10%.

In type1DM, the pancreatic beta cells of the islets of Langerhans are destroyed. These cells secrete insulin into the blood stream. These cells may die as a result of an autoimmune process (type1A) or the cause of their death may not be known (type1B or idiopathic). In type1A DM the destruction is due to an autoimmune insult on a person genetically predisposed to it (e.g. HLA DR3 and/DR4 haplotype present on chromosome6) or persons exposed to environmental toxins like bovine milk protein etc.

As the insulin forming cells of the pancreas are gone in type1 diabetes, the treatment naturally consists of substituting insulin. It is given by subcutaneous injection. Typically a long acting insulin such as ultralente or glargine insulin is given twice a day. One shot of it is given during breakfast and another during supper. They help maintain a steady basal supply of insulin. Short acting insulins like lispro insulin are added to this regimen during breakfast, lunch and supper time to tide over glucose surges during mealtime (thus mimicking physiological insulin release during these times). The average insulin requirement in type1 diabetes is about 0.5-1.0 unit insulin/kg (weight of the patient)/day. But this is only a rough estimate. The dose should be titrated by taking several (about 6-8 in a day!) measurements of SMBG (self monitoring of blood glucose: using glucowatch or other devices).

The diet should also be carefully watched (strict carbohydrate intake as used to be advocated in the past is no longer recommended) and the patient should be acquainted with the disease and its manifestations and complications, in addition to the pharmacotherapy by insulin.