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Prediabetes: trouble in the offing


Prediabetes defined

A high-risk condition considered to be a forerunner of diabetes in which beta cell dysfunction and insulin resistance lead to diverse alterations in glucose metabolism manifesting as increased blood glucose levels above the normal values but below the diabetic range.


The beta cells explained





The beta cells are located in the Islets of Langerhans of the pancreas. Also called Islands of Langerhans, true to its name, these are tiny irregular islands of assorted cell clusters amounting to millions, that lie scattered throughout the pancreatic tissue. The native cells of this cluster include alpha cells, beta cells, delta cells, epsilon cells and pancreatic polypeptide (PP) cells with beta cells dominating the group. Each of these cells release separate hormones with specified functions pertaining to glucose metabolism, fat metabolism and digestion.

The Islets of Langerhans has been under the radar of scientific research not only due to its association with diabetes, but also due to insulin, the principal hormone produced by the beta cells.It helps keep the blood glucose (sugar) levels at bay by driving glucose into the liver, muscle and fat tissues. Though the insulin is released by the beta cells uninterruptedly, the amount that is let out depends on the blood glucose levels i.e., in an unfed state the releases are small while insulin surge happens following a meal. The insulin secretion happens in two phases. The ‘first phase’ is a rapid phase wherein the insulin gets released within a minute of food ingestion and lasts for about 10 minutes. The insulin that is released in this phase is produced and stored as granules in the beta cells. The ‘second phase’ is a sustained phase and lasts till normal blood sugars are accomplished. The insulin that is released in the second phase represents the stored as well as the newly produced insulin. Though this phasic response differs with intravenous glucose, oral glucose and a mixed meal, overall, it represents how well the beta cells respond to glucose.Since insulin also encourages constructive metabolism in the body with respect to energy fuels namely carbohydrates, proteins and fats,it takes the mark as a key anabolic hormone.


Troubleshooting

The deviation in the glucose and insulin parameters driven by progressive reduction of beta cell function in combination with insulin resistance is the hall mark of prediabetes. Insulin resistance is a state in which the biological action of insulin is reduced in certain types of tissues in the body at normal levels thus necessitating the need for higher insulin levels in order to keep up with the expected insulin action.The tissues in question are the skeletal muscles (these muscles are attached to the bone and hence the name. They help in movement and posture), liver and adipose (fat) tissue. As the skeletal muscle is the major site in terms of insulin mediated absorption of glucose from the ingested food and liver as well as adipose tissue are crucial with regard to activating ‘insulin signalling' to store the ingested glucose, these three tissues make up the principal areas while refereeing to insulin resistance.Though in all these three major sites the glucose gets stored, the way in which it is processed shows certain type of predominance site wise.

The development of beta cell disruption in relation to insulin resistance goes through a multistage process with most of the changes commencing well before reaching the prediabetic phase.Initially the beta cells make up the need for higher insulin levels by dual compensatory mechanism involving increased insulin production (compensatory hyperinsulinemia) as well as beta cell mass. The next stage is when the beta cells lose their ability to supply extra insulin though not to the full extent. This is the stage wherein glucose disruptions appear. In the final step towards diabetic phase, the beta cells are incapacitated to an extent wherein the compensatory mechanism fails reflecting as high blood sugar levels.


The glucose intolerance

Glucose intolerance is the general term that describes the metabolic state in which the blood glucose levels are elevated above the expected normal range. It includes the glucose alterations that are defined in relation to the caloric intake. These are

Impaired fasting glucose (IFG):This refers to the blood glucose levels measured after withholding food and drink (except water) for a specified period of time which is usually 8 -12 hours. Fasting blood glucose levels reflect the endogenous glucose production (EGP) which means that the liver is the major site for glucose production during long hours of fasting. The liver produces the glucose from two sources i.e., carbohydrate and non-carbohydrate sources. Glucose from the food which is stored as glycogen in the liver to be released when the blood glucose levels fall forms the carbohydrate source. This process is called glycogenolysis. In addition to this the liver also produces glucose from lactate, glycerol and amino acids which form the non-carbohydrate source. This process is called gluconeogenesis.Both these processes are regulated by a hormone called glucagon produced by the alpha cells of the pancreas. Basically, this hormone opposes the action of insulin. During an overnight fast, a sudden increase of cortisol and growth hormone levels signal the liver to release more glucose to provide energy for the body during waking up. In people with normal glucose tolerance, extra insulin released from the pancreas balances the blood glucose levels on waking up. For those with impaired glucose tolerance, the ineffectiveness of the liver to respond to insulin (hepatic insulin resistance) makes the blood glucose to go high on waking up. There is a varied opinion regarding the exact duration of fasting for IFG measurement. More studies are needed to define the accurate fasting time.

Impaired glucose tolerance (IGT):This refers to the blood glucose measured 2 hours after the administration of standardized dose of 75 g oral glucose dissolved in 200-300 ml water in adults.In children the glucose dose is calculated based on the body weight. The 2-hourglucose values reflect the efficiency of glucose clearance from the blood. Following a meal, the glucose from the intestines enters the blood stream leading to an increase in the blood glucose levels. This sets off increased insulin production from the beta cells leading to suppression of liver glycogenolysis, gluconeogenesis as well as encouraging the glucose entry into the adipose tissue and skeletal muscle. Studies have shown that the skeletal muscle accounts for taking up 70%-90% of glucose from the blood in normal metabolic state. There are special proteins called the transport proteins located in the muscle that are responsible for transferring the glucose from the blood into the muscle. Among the many proteins that are present, GLUT4 takes the lead in terms of responding to the insulin stimulus. This protein which is stored inside the muscle cells moves on to the surface to aid the transport of glucose. It is this process that gets impaired leading to elevated blood glucose levels. Under normal conditions the glucose levels are back to normal within 2 hours after food.


The HbA1c described

The HbA1c also called glycated hemoglobin, glycosylated hemoglobin, hemoglobin A1c or A1c is a test that measures the average glucose values for the previous three months or 90 days. It is expressed as a percentage. Hemoglobin is a special iron containing protein that is exclusive to the red blood cells. Apart from giving bright red color to the blood, it conveys oxygen from the lungs to all the tissues of the body. While passing through the blood stream, the glucose that is present clings on to the hemoglobin. The amount of glucose that adheres to the hemoglobin increases with elevated blood sugar levels. This process is called glycation and hence the name. The red blood cells live for an average of three months, and the glucose stuck to the hemoglobin remains as long as the red blood cells are alive. The normal A1c value should be less than 5.7%.


The diagnostic numbers and variables

Based on the recommendations of ADA and European Association for the Study of Diabetes (EASD), prediabetes is diagnosed based on the following values

· Fasting plasma glucose (FPG) 100-125mg/dl (5.6-6.9 mmol/l) - indicates IFG and/or

· Plasma glucose level 140-199mg/dl (7.8-11.1 mmol/l) measured 2 hours after the administration of 75 g of glucose orally called oral glucose tolerance test (OGTT) – indicates IGT and/or

· A1c 5.7% - 6.4%.

The WHO recommendations are based on the following values

· Fasting plasma glucose (FPG) 110-125mg/dl (6.1-6.9 mmol/l) and/or

· Plasma glucose level 140-199mg/dl (7-8-11.1 mmol/l) measured 2 hours after the administration of 75 g of glucose orally.

The diagnosis of prediabetes on the basis of IFG and IGT has certain drawbacks. First of all, the blood glucose values (both fasting and 2-hour glucose) show discrepancy on a daily basis. The ability of these tests to reflect the abnormalities related to diabetes and the likelihood of developing diabetes though open to debate, have been considered to have a better predictive value. Recent studies have indicated diabetes risk at a level of blood glucose regarded as normal. While the evidence-based discussion regarding the cut off values continues, it is worth noting that the existence of IFG and IGT indicate a significant metabolic derangement.

The use of HbA1c for the diagnosis of prediabetes was introduced by ADA more than a decade ago. The notion that HbA1c is a precise tool to diagnose prediabetes has its own downside. Despite indicating average blood glucose values, and having an edge over the blood glucose tests in terms of convenience and less daily variations, the presence of hemoglobin disorders, anemia and kidney disease can affect the values. Besides not being cost effective, the testing needs to be carried out using a standardized method approved by the National Glycohemoglobin Standardization Program (NGSP). But compared to the blood glucose values, the HbA1cis less sensitive in detecting glucose abnormalities that define a prediabetic state. However, the diagnostic precision can be enhanced if A1c is used along with IGT and OGTT values.While WHO does not include A1c criteria and has a higher FPG cut off, ADA suggests that the risk of developing diabetes starts at values (IFG, IGT, A1c) below the lower limit and significantly rises as the numbers reach the upper range.


The terminology debates

The term prediabetes has been the center of controversy as there has been inconsistencies in the way it has been defined by various expert organizations. The Expert committee on the Diagnosis and Classification of Diabetes Mellitus first reported prediabetes as a medical condition with IFG as a distinct feature. While some have conveyed the fact that prediabetes be considered as a clinal state rather than a diagnostic condition, others including the expert bodies such as American Diabetes Association (ADA), World Health organization (WHO) and National Institute for Health and Care Excellence (NICE) have voiced about the varying definitions of prediabetes and the influence it has on the identification, diagnosis and management of at-risk population.The terminologies ‘Intermediate Hyperglycemia’ and ‘High Risk State of Developing Diabetes’ as recommended by the WHO and the International expert committee though sound closer, for the sake of being concise the term prediabetes is applied while referring to IFG, IGT and a higher-than-normal HbA1c. But based on the recommendations of WHO and International Diabetes Federation (IDF), risk evaluation should be done not only in accordance with the glycemic numbers but also considering the risk factors.


The risk elements

Adults

· Genetics: Family history of type 2 diabetes, especially a first degree relative, either parent or sibling.

· Ethnicity: Non-Caucasians (African American, Native American, Latino, Asian American, Pacific Islander)

· Life style: Sedentary habits (less than 90 min or 3 times /week of aerobic activity).

· Overweight/obesity: With a body mass index (BMI) of more than 25 kg/m2.

· Female factors: Gestational diabetes (diabetes that develops during pregnancy), Polycystic ovary syndrome (also called PCOS, this is a hormonal disorder characterized by the irregular periods, high levels of male hormones –androgens, multiple cysts- fluid filled sacs in the ovaries).

· Hypertension: Blood pressure above or equal to 140/90 mm Hg or on medication for the same.

· Cholesterol: HDL cholesterol above 35 mg/dl and/or triglyceride above 250mg/dl.

· Insulin resistance manifestations: Severe/morbid obesity with a BMI above 40 kg/m2, acanthosis nigricans (presence of dark, thick velvety skin in the folds and creases).

· Cardiovascular diseases: conditions involving heart and blood vessels.

Children

· Overweight/obesity: BMI above the 85th percentile for overweight and above the 95th percentile for obesity for the age and sex of the child

· Genetics: Family history of type 2 diabetes in a first or second degree relative.

· Ethnicity/minority race: African American, Native American, Asian American, Latino, Pacific Islander.

· Maternal factors:Presence of maternal gestational diabetes or maternal diabetes during the child’s pregnancy.

· Insulin resistance: Presence of signs of insulin resistance like acanthosis nigricans, lipid profile abnormalities, hypertension, PCOS.

· Birth Weight: Small for gestational age are the fetuses or newborn infants who are smaller in size than the expected normal for their gestational age or those whose weight falls under the 10th percentile for the gestational age.


Looking into the sub-types

Based on the glucose intolerance the following sub types have been identified

· Isolated IFG (i-IFG):The main defect lies with the glucose processing leading to elevated fasting blood glucose levels even after an overnight fast. Here the main site of insulin resistance is the liver with normal insulin sensitivity in the muscle. The combination of beta cell dysfunction, insulin resistance in the liver and impaired first phase insulin release results in a sharp rise in the fasting blood glucose levels. However, the blood glucose levels return to normal as the second phase insulin response and the normal response of the muscles to insulin is preserved. This is more seen in younger people with males taking the lead.

· Isolated IGT (i-IGT): The main defect lies with the glucose uptake following a meal leading to elevated post prandial blood glucose levels. Here the main site of insulin resistance is the muscle with a marginal reduction in the liver insulin resistance and the first phase insulin release. This along with severely affected second phase insulin release together with moderate to severe muscle insulin resistance leads to an increase in the blood sugar levels for an extended period. This is more seen in older people with females taking the lead.

· Combined IFG/IGT: This has the defects relating to both IFG and IGT and reflects a profound derangement of glucose metabolism.

Recent studies conducted by the German researchers which was started 25 years ago have reported six sub types of prediabetes. This study was conducted on 899 individuals who were at risk for diabetes, followed up by a series of tests. The same study was extended to include 7000 individuals. On the basis of parameters including blood glucose levels, liver fat, body fat distribution, blood lipid levels and genetics, six clusters were recognized. Researchers have proposed that this classification would make the interventions more efficient.

· Clusters 1,2 &4:consisted of healthy people with low probability of developing diabetes. Cluster 2 consisted of slim individuals who had a low probability of complications. Cluster 4 had overweight individuals with a somewhat normal metabolism. The mortality rate was low in these three clusters.

· Clusters 3,5&6: Consisted of people with a high probability of developing diabetes. Cluster 3 consisted of individuals who produced very little insulin. Cluster 5 consisted of individuals with fatty liver and insulin resistance. Cluster 6 had individuals with high visceral fat (belly fat) and kidney damage even before being diagnosed with diabetes. The mortality rate was high in these three clusters.


The sign of trouble

Most of the individuals with prediabetes do not show any symptoms. The diagnosis is made during screening and evaluation of high-risk individuals. However, a small proportion of them might have symptoms such as increased thirst, hunger and urination, in-explainable weight loss/gain, excessive tiredness, sweating, blurring of vision, slow healing of wounds and frequent skin infections.


The diabetes threat

Prediabetes is a risky state with a high possibility for evolution into type 2 diabetes. Recent studies have shown that the annual conversion rate ranges from 3.5%-7%. The ADA expert panel states that the progression from prediabetes to diabetes can happen in 70% of individuals. Some of the factors which influence the progression to type 2 diabetes are

· Presence of combined IFG and IGT wherein the annual risk rate is 15%-19%.

· In i-IGT the risk is marginally lower than i-IFG.

· HbA1c values- The annual conversion rates are 5% with an A1c range of 5.7-6% and doubles with A1c of 6.1%-6.4%.

· Presence of risk factors other than higher glucose values increases the annual risk to 30%.

· Current evidence points to the fact that the diabetes risk is higher in the middle age compared to the elderly people.


Future obstacles

Prediabetes, contrary to the term ‘pre’ doesn’t come without consequences. The complications seen in prediabetes are similar to those seen in diabetes but occurring at a lesser frequency. Evidence based studies not only indicate the possibility of complications even at prediabetic blood sugar values, but also point to the presence of other risk elements.

Micro vascular complications (relating to small blood vessels)

· Kidneys: Diabetic kidney disease (DKD) or nephropathy is a condition wherein there is a progressive decline in the kidney function leading to the development of end stage kidney disease (ESKD) or kidney failure. Depending upon the rate of progression DKD can be either acute or chronic kidney disease (CKD). The presenting features of DKD are albuminuria (presence of albumin a type of protein in urine) and gradual decline in the glomerular filtration rate (GFR- a measure that indicates how well the kidneys are removing the waste). Studies have shown a link between prediabetes and kidney disease.

· Nerves: Diabetic neuropathy is a condition related to nerve damage as a consequence of high blood sugar. Because it involves the peripheral nerves outside the brain and spinal cord, it is also called peripheral neuropathy. Diabetic neuropathy can involve the autonomic nerves (their function is to regulate the vital functions such as heartbeat, blood pressure, respiration and digestion) or sensory/motor nerves (sensory nerves transmit signals to the brain and help with touch, taste, smell, vision. Motor nerves transmit signals to the muscles and glands and helps them function). In prediabetes, autonomic neuropathy has been found to manifest as low heart rate variability (means there is less variation in the time difference between each beat and indicates future heart problems) and erectile dysfunction in men. Sensorimotor neuropathy leading to alterations in sensations and nerve pain has been detected in prediabetic individuals with IGT.

· Eyes:Diabetic retinopathy is an eye condition wherein damage to the retinal blood vessels leads to progressive visual changes. There is limited evidence pointing to the link between prediabetes and retinopathy.

Macro vascular complications (relating to large blood vessels)

Studies have shown that prediabetes overall escalates the risk of cardiovascular disease (CVD) by 20% without taking into consideration the sub type of prediabetes i.e., IFG or IGT. But when looking into the specific sub type, IGT takes an edge over IFG. Furthermore, an interesting fact from the recent studies show that there is a correlation in the incidence of myocardial infarction and stroke irrespective of prediabetes or diabetes. Though this gives an impression that CVD shares the same frequency in both prediabetes and diabetes, it should be noted that while considering prediabetes there is an element of doubt as to whether it is the elevated blood glucose or the presence of other risk factors that increases the possibility of CVD in prediabetes.


Plan of action

· Center of focus:Treatment should aim at achieving a normal blood glucose level as a prevention strategy against diabetes and its complications. Recent data from the Diabetes Prevention Program Outcomes Study (DPPOS) states that normal blood sugar reduces the diabetes risk by 56% including the development of micro vascular and macro vascular complications in spite of reduction in the usage of medication for the same.

· Reaching the target:There is little less clarity regarding which type of intervention takes the lead to achieving normal blood glucose levels. While the opinions differ regarding independently advocating life style modifications and drugs, growing evidence from a number of studies have expressed the efficacy of both interventions in not only preventing diabetes and its complications but also achieving normal blood sugar levels.

· Changing for the better: Studies like the Diabetes Prevention Study (DPS) have shown that life style modifications in terms of achieving weight loss and escalating the level of physical activity brings about a 58% reduction in the risk for developing diabetes. This study also found that for every 1 kg weight loss, the diabetes risk dropped by 16%. However, fixed targets like weight loss of more than 5%, fat intake constituting less than 30% of the total energy consumption, saturated fat intake less than 10% of the total energy consumption, increased intake of dietary fiber and exercise accounting to more than 4 hours/week, greatly influence the long-term benefits regardless of the ethnicity.It has been shown that physical exercise helps to improve the beta cell function as well as glucose tolerance (a measure of how efficiently glucose gets diverted from the blood stream to the storage organs). Physical exercise also activates GLUT4 and allows glucose to enter the muscle.

· A Peep into the medications:Some of the anti-diabetic medications that possibly prevent the development of diabetes from a pre diabetic state are

Metformin: This is considered to be one of the most preferred drugs and was approved by FDA as an anti-diabetic medication in 1994. It lowers the blood glucose levels by reducing the production of glucose by the liver (gluconeogenesis), reducing the intestinal absorption of glucose and improving the glucose uptake by the skeletal muscles.A number of studies conducted on the efficacy of metformin in prediabetes have produced conflicting results. But one study concluded the effectiveness of the drug in individuals with BMI above 35, age less than 65 years and FPG above 110mg/dl. In general, it is considered a safe drug and has been recommended to people with a BMI of over 35, less than 60 years either having IGT or IFG by ADA. Glitazones: These group of drugs act by improving the uptake of glucose in the adipose (fat) tissue, liver and muscle as well as decreasing the production of glucose by the liver. The drugs of this class include troglitazone, rosiglitazone and pioglitazone. Troglitazone has been discontinued owing to the liver failure caused by the drug. Though the other two glitazones have been found to significantly reduce the risk of developing diabetes, concerns have been raised about their side effects including heart failure and weight gain. However recent studies have confirmed their safety and so these drugs have the potential to gain popularity.

Alpha Glucosidase inhibitors: The drugs of this group like acarbose, voglibose act by extending the carbohydrate digestion time and also reducing the glucose absorption from the small intestine eventually reducing the post-prandial glucose levels. Though studies have shown that these drugs reduce the risk of diabetes by 25%-40% in individuals with IGT, troublesome side effects such as flatulence and diarrhea are a disadvantage. More ever they do not improve insulin sensitivity. So, they are preferred as a combination therapy.

GLP 1 analogs: The incretins are the natural hormones produced by the intestines in response to food intake. They include Gastric inhibitory peptide (GIP) and Glucagon like peptide 1(GLP1). The later stimulates the insulin production by the beta cells, brings down the glucagon production, improves satiety thus helping in weight loss. However, both these incretins get inactivated by an enzyme called Dipeptidyl Peptidase 4 (DPP4). So, enhancing the effects of GLP1 by using GLP 1 analogs like exenatide and liraglutide helps reducing the blood glucose levels. Though studies have shown that these drugs aid weight loss and improve beta cell function, more follow ups are needed regarding their effect in preventing the progression of IGT to diabetes.

SGLT-2 inhibitors: The drugs belonging to this group like canagliflozin, dapagliflozin and empagliflozin are the new add-ons for managing pre-diabetes. The Sodium Glucose Co-transporter-2 (SGLT-2) are special types of proteins present in the kidneys that are responsible for re absorption of filtered glucose. These drugs block the proteins resulting in reduced glucose absorption and increased elimination in the urine. However, owing to their side effects such as urinary infections, genital infections, breast and bladder cancer more studies are needed to establish the safe use of these drugs.

· Challenging obesity: Orlistat is an anti-obesity drug that reduces the absorption of dietary fats by 30%. It acts by blocking digestive enzyme called lipase which helps in the digestion and breakdown of fats. According to the studies, this drug reduces the risk of progression from IGT to diabetes when given along with a low-calorie diet. However, these findings are restricted to IGT.

· Surgical intervention: Bariatric surgery is a surgical procedure that aims to create changes in the digestive system to restrict the calorie intake thus helping in weight loss. This surgery has not only been shown to reduce the risk of developing diabetes, but also reversal of IGT to normoglycemia (having normal blood glucose levels).
















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