Swasthya

Diabetes Mellitus is a serious metabolic disorder that places patients at increased risk of coronary and vascular disease, as well as debilitating conditions such as retinopathy, nephropathy, and neuropathy (Table-1)(1-4). The attainment of tight glucose control can reduce the occurrence of deleterious long-term complications associated with the progression of both type1 and type2 diabetes mellitus. (5-10) This relationship has been most convincingly demonstrated with microvascular complications (i.e., retinopathy, neuropathy, and nephropathy).

In the Diabetes Control and Complications Trial (DCCT), intensive therapy reduced the overall risk of developing microvascular complications by 60% in-patients with type 1 diabetes mellitus. (5) The United Kingdom Prospective Diabetes Study (UKPDS) showed a 25% risk reduction in microvascular endpoints with intensive therapy for type 2 diabetes, (9) and every 1% decrease in HbA1c correlated with a 37% reduction in the risk of microvascular complications. (11) Data are less definitive for macrovascular complications such as coronary heart disease and peripheral vascular disease, but current evidence suggests that hyperglycemia is associated with negative cardiovascular outcomes.(11-13)

In turn, improved control of blood glucose can reduce the costs associated with the treatment and long-term management of the common complications of diabetes. In the DCCT, the annual cost of therapy aimed at intensive control was approximately threefold the cost of conventional therapy but it was estimated that intensive treatment would begin to show savings within 5-7 years by decreasing the incidence of future complications. (14)

In order to achieve strict metabolic control, however, patients must monitor their blood glucose levels repeatedly during the day and adapt their insulin therapy accordingly. Insulin injections have become easier and less painful to administer. Intensive insulin therapy in the DCCT was given by insulin pump or at least three insulin injections per day guided by finger-prick glucose determinations.

It is recognized that self-monitoring of blood glucose (SMBG) can play an important role in achieving and maintaining glycemic control, especially for type1 diabetes patients and insulin-using type 2 diabetes patients. (15-17) Current American Diabetes Association (ADA) guidelines recommend SMBG testing at least three to four times each day in patients with type 1 diabetes and at least once a day in patients with type 2 diabetes who cannot be managed with diet and exercise alone. (18) In fact, even highly motivated patients with type 1 diabetes probably only perform one or two spot determinations of blood glucose per day. Thus, maintaining blood glucose levels within the target range can be an elusive goal especially in the paediatric population. Varying and unpredictable physical activity and eating habits, combined with some young patient’s reluctance to undergo or perform glucose testing, lead to a high risk of hypoglycemia for this group. In addition, current methods for SMBG have limitations, especially for detection of nocturnal hypoglycemia, and may be misleading, due to monitor accuracy problems or patient errors in monitoring technique. (19,20)

Number of people with diabetes

According to WHO, number of people with diabetes in India in the year 1995 were 19.4 millions. In the year 2025, it will be 57.2 millions. For both 1995,2025 the country with the highest number of people with diabetes is India (1)

Diabetic retinopathy

Leading cause of blindness in adults ages 20-74(20-44)People with diabetes are twice as likely to develop cataracts or glaucoma than those without diabetes (3)

Diabetic nephropathy

10-21% of all people with diabetes develops severe kidney diseases due to diabetic nephropathy (2)About 40% of people with IDDM develop severe kidney disease and end-stage renal disease (ESRD) by the age of 50. (4)

Diabetic neuropathy

60-70% of people with diabetes has mild to severe forms of diabetic nerve damage (2)Leading cause of non traumatic lower limb amputation (2)15-40-folds increased risk for leg amputation in the diabetic compared to non-diabetic population (2)

Diabetic vascular disease

2-6-fold more likely to have heart disease (2)2-4-fold more likely to have a stroke (2)75% of all diabetes –related deaths are associated with cardiovascular disease.

Daily SMBG meter readings may not provide enough information to guide therapy modifications (21,22) Self-monitoring, even at the recommended four times per day, leaves gaps of time when glucose levels are not sufficiently monitored, leading to undetected hyperglycemic and hypoglycemic events, the latter especially at night.

Clinicians are expected to make therapeutic decisions based on a small number of finger pricks, for example, that represent but a few minutes of the day and do not indicate direction or trends for glucose levels. Thus, it can be difficult, if not impossible, to calibrate the patient’s therapeutic regimen to avoid episodes of excessive hyperglycemia or hypoglycemia.

In addition, tight glucose control at near-normal levels increases the risk of hypoglycemic events. The blood glucose goals of the DCCT were accomplished in a highly motivated group of patients who had benefits of extensive, ongoing, support and education from a diabetes healthcare team. But despite performing four or more SMBG tests each day, the incidence of hypoglycemia tripled with intensive therapy. More than half of hypoglycemic events occurred during sleeping hours, and one third occurred without symptoms when patients were awake. In the UKPDS, 2.3% of type 2 diabetes patients receiving insulin therapy experienced major hypoglycemic events. Clearly, for both major forms of diabetes, hypoglycemia is an important complication of intensive therapy.

From the perspective of people with diabetes, little has changed with regard to blood glucose self-monitoring over the last three decades. It remains an invasive procedure, especially if repeated many times during the day, and the patient requires motivation to perform these spot glucose measurements.

*Measurement*		Minimally invasive		Non-invasive
*Continuous*		· Microdialysis (Accu-Chek) Open-tissue microperfusion · Glucose electrodes (MiniMed, 5 min)	· Transdermal (Abbott)	· Non-optical and optical approaches
*Semi-continuous*			· Transdermal (Cygnus, 20 min)
*Spot*	· Test strips			· Optical sensing (Diasensor)
	Blood	Subcutaneous interstitial fluid	Intradermal interstitial fluid	Skin

Continuous glucose monitoring offers the possibility of 24-hour glucose control. It would help to avoid hypoglycemic episodes by providing a complete picture of glucose fluctuations over a 24-hour period, which cannot be achieved even by frequent spot measurements.

Non-invasive approaches being investigated include near-infrared absorption and scattering, polarimetry, far-infrared radiation spectroscopy, radio-wave impedance, and pulsed photoacoustic and fluorescence spectroscopy. Despite many years of research and development, it is still uncertain whether optical glucose sensors can achieve sufficient precision within the clinically relevant blood glucose range and over prolonged periods of time.

The only optical glucose sensor marketed (Diasensor) allows only spot measurements, so it does not allow continuous glucose measurement. Other promising non-optical technologies are currently under development (23).

Minimally invasive methods involve placing a sensor subcutaneously with assess to interstitial fluid, or transferring interstitial fluid outside the body for measurement. The advantages of this approach are that glucose can be measured specifically and, in principle, absolute concentrations can be measured. The main disadvantages include breaking the skin (risk of infection), the limited time for which the sensor can be applied, and the body’s inflammatory response to the inserted sensor.

The CGMS consists of the sensor which is inserted subcutaneously and is capable of reliable operation for up to 3 days Data are collected once every 5 min by a pager-sized monitor device and can be periodically downloaded into a computer for analysis and interpretation

The SCGM system consists of a microdialysis catheter and a portable extracorporal electrochemical glucose sensor. It displays a new glucose value every minute.

The Glucowatch is consisting of biographer and autosensor. Following a 3 hour warming up period, it can provide automatic glucose reading as frequently as every 20 minutes for up to 12 hours.

Continuous glucose monitoring generates a large amount of data, which is presented in a form that can be easily and adequately interpreted by patients and physicians. The glucose sensor data can be presented in several ways (Table-3)

Actual glucose reading· Glucose trend analysis· Warning signals when approaching or trasngressing preset hypo-and hyperglycemic limits· 24-hour profiles· Longer-term glucose profiles

At its most basic level, continuous glucose monitoring can replace self-monitoring blood glucose by finger-prick methods (except for calibration). This can give the patient a feeling of safety, because a glucose reading is available at any time without any pain. A warning signal can be generated if the actual glucose level is above or below pre-set values for the individual patient, and this is particularly relevant at night, when patients do not regularly measure blood glucose. It must be remembered, however, that the glucose level measured reflects the glucose level of proceeding few minutes. (Depending upon the time lag of the continuous monitoring system)

At the next level, continuous glucose monitoring can allow comparison of an actual glucose reading with readings over a previous period, thus allowing the trend in concentration to be determined. This provides the diabetic patient with important additional information (rising, falling, or stable values) as a basis for decisions on insulin requirement. Because rapidly falling blood glucose is a potentially dangerous situation, the alarm for impending hypoglycemia should be set for a glucose reading well above the critical threshold to allow time for appropriate action.

At present, the limited numbers of self-measurements performed by most diabetic patients do not provide a precise overview of the glucose profile during the day and especially at night. This profile, of course, consists not only of postprandial glucose excursions, but also of variations in glucose levels due to exercise, changes in routine at the weekend, and during holidays, travel or illness. Continuous monitoring over 24 hours usually detects larger glucose swings than anticipated, and hypoglycemic and hyperglycemic periods may be common even in-patients with acceptable or good glycated haemoglobin levels (25)

Superimposing several 24-hour glucose profiles allows any diurnal pattern present to be characterized. The patient (and the physician) can then make more informed decisions about the appropriate therapy.

What is the advantage of continuous glucose monitoring in terms of maintaining strict glycemic control?

Continuous glucose monitoring allows a series of 24-hour glucose profiles to identify each patient’s personal pattern of blood glucose variation. This means that an insulin regimen can be tailored to the patient’s individual needs to maintain blood glucose concentration within acceptable limits. Continuous glucose monitoring also means that situations that change the usual pattern, such as illness, travel, weekends and holidays, can be followed closely, and insulin administration can be adjusted accordingly. Continuous glucose monitoring therefore offers for the first time the opportunity to translate in to reality the new therapeutic goals of strict metabolic control without increased risk of hypoglycemic episodes.(26)

What are the practical advantages of continuous glucose monitoring for the diabetic patient?

Many diabetic patients find spot determinations using finger-prick methods both painful and inconvenient, and this reduces their compliance. Continuous glucose monitoring reduces the need for finger-pricking, yet provides glucose values at any time so that the patient can avoid both hypoglycemic and hyperglycemic episodes, particularly if an alarm is set at predefined levels of glycemia. This type of system could also give patients a greater sense of security that they will not be taken unawares by a hypoglycemic episode.(26)

Although the eventual aim is that all patients with type1 diabetes should be able to perform continuous glucose monitoring, the present target group is patients who need intensive treatment to achieve the glycemic control that they are currently failing to master. These patients would include those, whose glycemic control is labile, who often have nighttime hypoglycemic episodes, or whose compliance with spot determinations is poor.

Continuous glucose monitoring is also appropriate in patients starting insulin therapy, in order to define their diurnal blood glucose pattern during their normal daily life as a basis for optimizing insulin therapy.(26)

Special circumstances, such as myocardial infarction, pregnancy and surgery, increase the risk of acute metabolic deterioration. How continuous glucose monitoring can minimize these risks?

Studies have shown that diabetic patients who have a myocardial infarction have a 2-3-fold better chance of survival if their glycemia is under strict control. This can be most easily achieved with continuous glucose monitoring, particularly as the patient’s clinical state may be changing quite rapidly. (26)

Surgery also interferes with the normal diurnal pattern of glucose concentration, and again continuous monitoring during surgery and during the subsequent period of intensive care can help to stabilize the patient’s glycemic control.(26)

It is particularly important to control diabetes in women who develop gestational diabetes (4% of all pregnancy). If glucose levels are high during pregnancy, the risk of having a large baby, with the attendant difficulties at birth is increased. (26)

Many of us have the experience of managing women with gestational diabetes. Inspite of having good glycemic control, based on SMBG and HbA1c, they deliver macrosomic babies. In these women, it may be necessary to measure blood glucose up to 16 times per day to achieve tight glycemic control, which imposes a considerable burden on them. Continuous glucose monitoring would obviously make a considerable difference in this situation. CGMS in these women can reveal high postprandial blood glucose levels that were unrecognised by intermittent SMBG evaluation. CGMS shows undetected hyperglycemia that might be contributing to neonatal complications. It provides a useful tool to help educate patients in behavior modifications. Thereby we can improve compliance with management regimen.(27)

CGMS is also helpful to type 1 diabetes patients who are or wish to become pregnant. CGMS can characterize insulin need, thereby, we can improve the outcome of pregnancy.

How can continuous glucose monitoring help the patients with hypoglycemia unawareness?

Continuous glucose monitoring offers the opportunity not only to determine actual glucose concentrations at any time point, but also to analyse trends. If glucose levels are failing an alarm can be set to warn the patient before actual hypoglycemia occurs, allowing time to correct the impending hypoglycemia by eating and thereby preventing neuroglycopenia and unconsciousness. It has also been shown that when hypoglycemia is prevented for a while, the patient may regain hypoglycemia awareness, which may benefit glycemic control in the longer term.(26)

How continuous glucose monitoring can be helpful in diagnosing diabetes gastroparesis?

Diabetes gastroparesis is a common and often unrecognized complication of diabetes. New studies reveal a spectrum of disease ranging from a mild gastropathy (diagnosable only with sophisticated equipment) in-patients with relatively new-onset diabetes to the easily recognizable syndrome of gastroparesis (with often intractable nausea and vomiting) in patients with long-standing diabetes and other manifestations of autonomic neuropathy. Although gastrointestinal symptoms can often be severe and even debilitating, most patients have few or no symptoms. The presence of delayed gastric emptying can lead to glycemic lability. Insulin / food mismatch in turn, may lead to postprandial hypoglycemia, often followed by hyperglycemia. Patients with this condition are at increased risk for microvascular complications from hyperglycemia as well as from severe and potentially catastrophic hypoglycemia. Compared to standard tests of gastric emptying, the CGMS system offers a simple, and clinically meaningful diagnostic tool for this condition.(28)

Patients with diabetes out of control· Patients prone to severe episodes of hypoglycemia or diabetic ketoacidosis
Newly diagnosed patients· Type 1 diabetes patients who are, or wish to become, pregnant: CGMS can characterize insulin needs
Patients undergoing surgery or who have myocardial infarction, CGMS can improve the outcome by stabilizing the glycemic control
Patients on renal dialysis or who have received transplants: CGMS can identify the effects of dialysis and of various other events or stresses
Patients with hypoglycemia unawareness, CGMS may help in regaining hypoglycemia unawareness
CGMS offers simple and clinically meaningful diagnostic tool for diabetes gastroparesis
Patients who are in denial and nonadherent to therapy may follow their recommended therapeutic regimen more closely after CGMS use

The data obtained with the CGM allow the clinician to diagnose glycemic patterns in a far more precise manner and to assess the post-prandial and nocturnal period for the first time in an ambulatory setting. Furthermore, it is the gold standard to assess whether the treatment regimen really works, since a normal HbA1c with fasting and occasional postprandial SMBG may mask significant glycemic abnormalities. Finally, it educates and it motivates the patient. This heralds a new era in insulin therapy, with new possibilities in self-treatment for people with diabetes. In addition, blood glucose levels could be closely controlled during clinical events, such as pregnancy, surgery, myocardial infarction or dialysis. In the future, it is possible that continuous glucose monitoring could be used diagnose and treat conditions such as gestational diabetes and pre diabetic states, e.g. impaired glucose tolerance.