The History Of Diabetes Health And Social Care Essay

Aulus Cornelius Celsus made the first clinical description of diabetes but it was Aretaeus of Cappadocia who gave a detailed account and introduced the name diabetes from the Greek word for "siphon". Aretaeus described diabetes with the following words, "Diabetes is a dreadful affliction, not very frequent among men, being a melting down of the flesh and limbs into the urine. The patients never stop making water and the flow is incessant, like the opening of aqueducts. Life is short, unpleasant and painful, thirst is unquenchable, drinking excessive, and disproportionate to the large quantity of urine for yet more urine is passed ….. the patients are affected by nausea, restlessness and burning thirst, and within a short time they expire".

In the European medical literature the existence of sugar in the urine of diabetes was not mentioned until the seventeenth century, when Thomas Willis (1621-1675) in Oxford, England noted the sweet taste of urine. The doctors had to subsequently resort to tasting the urine of patients for sweetness in order to detect the disease. In 1766 Mathew Dobson proved that the sweet taste of diabetic urine was due to sugar and also stated that there was excess of sugar in blood.

During the 18th century and early 19th century glucosuria was accepted as a diagnostic feature of diabetics and the disease was recognised as a metabolic derangement. Claude Bernard was of the view that diabetes was caused by glycogenolysis from the glycogen stored in the liver, which secreted sugary substances into the blood. He postulated that it was an excess of this secretion that caused diabetes. In 1969 the islets of cells were discovered in pancreatic tissue by Paul Langerhans (1849-1888) and were later given his name. One year later Von Mering and Oscar Minkowski observed that removal of the pancreas led to the development of diabetes in dogs.

HISTORY OF HbA1C

For the past many decades many diagnostic criteria were put forward by the various organizations regarding the diagnosis of diabetes. The recent trend is to focus on the HbA1C values for the diagnosis as it has so many advantages over the conventional fasting plasma glucose and 2-hour plasma glucose values. Looking back into the history of HbA1C, it was in 1958 a paper was first published about the heterogeneity of haemoglobin A by Allen et al..The term 'minor haemoglobins' or 'fast haemoglobins' were used to refer the fractions that eluted at more acidic pH on the anion exchanger carboxymethyl cellulose and migrated more rapidly on electrophoresis. At that time they were subfractionated into the species A1a, A1b, A1c, A1d. Later in 1968 Samuel Rahbar on a survey of 1200 hospital patients found that two diabetic patients in this group had a fast moving haemoglobin on starch gel electrophoresis. This fast haemoglobin was identified as Allen's HbA1C and the charge difference were localised to the β chain. Homquist et al. published the data on βchain N terminally blocking group of HbA1C. The definitive structure of HbA1C was elucidated by Bunn et al. Anthony Cerami, Ronald Koenig and co-workers in 1976 first proposed the use of HbA1C for monitoring the degree of control of glucose metabolism in diabetic patient.Later ADA in 2010 and WHO in 2011 adopted using HbA1C for the diagnosis of diabetes.

DIAGNOSING DIABETES BASED ON THE DISTRIBUTION OF GLUCOSE LEVELS

Historically,glucose measurement has been the means of diagnosing diabetes.The clinical presentation of Type 1 and Type 2 diabetes are different. Type 1 diabetes has a characteristic clinical onset,often with relatively acute, extreme elevations in blood glucose concentrations ,usually accompanied by symptoms, so that specific blood glucose cutoff points are not required for diagnosis in most clinical settings. On the other hand, type 2 diabetes has a more gradual onset, blood glucose levels slowly rise over time, and its diagnosis is based on specified glucose values to distinguish pathologic glucose concentrations from the distribution of glucose concentrations in the non -diabetic population. The classification and diagnosis of diabetes in modern times is based on the measure of plasma (or blood or serum) glucose concentrations in timed samples, such as fasting glucose; in random samples ; or after a standardised metabolic stress test, such as the 75g oral glucose tolerance test (OGTT).

OGTT was used to standardise the definition of diabetes in the early period. But the performance and interpretation of the test were inconsistent and the number of subjects studied to define abnormal values was very small. Studies in the high-risk Pima Indian population that demonstrated a bimodal distribution of glucose levels following the OGTT helped to establish the 2-hour value as the diagnostic value of choice, even though most populations had a unimodal distribution of glucose levels1,2.However, a discrete fasting plasma glucose (FPG) or 2-h plasma glucose (2-HPG) level that separated the bimodal distributions in the Pimas was difficult to identify, with potential FPG and 2-HPG cut points ranging from 120 to 160 mg/dl (6.7 - 8.9 mmol/dL) and from 200 to 250 mg /dL ( 11.1 - 13.9 mmol/l), respectively.

The National Diabetes Data Group (NDDG) provided the diagnostic criteria for diabetes in 1979 that served as the blueprint for nearly two decades. The NDDG relied on distributions of glucose levels to diagnose diabetes rather than on the relationship of glucose levels with complications, eventhough there was emerging evidence that the high range of fasting and OGTT glucose values were associated with microvascular diabetic complications. The diagnostic glucose values chosen by the NDDG were based on their association3,4,5 with decompensation to "overt" or symptomatic diabetes.

The diagnosis of diabetes was made when

Classic symptoms were present

The venous FPG was ≥ 140mg/dL (≥7.8 mmol/l)

After a 75-g glucose load, the venous 2-HPG and levels from an earlier sample before 2h were ≥ 200 mg/dL (≥ 11.1 mmol/l)

An intermediate group was also identified as having "impaired glucose tolerance " (IGT) with FPG < 140mg/dL (7.8 mmol/l) and a 2-HPG value between 140 and 200 mg/dL (7.8 - 11.1 mmol/l). IGT group is having a relatively higher risk of progression to diabetes compared with that of "normal" glucose tolerance.They have low frequency of "diabetic symptoms" .In patients with impaired glucose tolerance there is high probability of their glycemic status getting reverted to normal glucose tolerance or they may continue to have IGT. "Clinically significant" microvascular disease rarely develops in patients with impaired glucose tolerance.The NDDG recommendations were also promulgated by the contemporaneous report of the World Health Organization (WHO)6.

DIAGNOSING DIABETES BASED ON THE RELATIONSHIP BETWEEN GLUCOSE LEVELS AND LONG TERM COMPLICATIONS

In 1997, the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus7 examined the basis for diagnosing diabetes. This committee made two very important contributions. First, they focused attention on the relationship between glucose levels and the occurrence of long-term complications as the basis for diagnosing diabetes. Second, they negated the widespread hypothesis that the 2-HPG was the gold-standard test for diagnosing diabetes. The committee examined data from three cross-sectional epidemiological studies that included an Egyptian population (n=1,018), Pima Indians (n = 960) and the US National Health & Nutrition Examination Survey (NHANES) population ( n=2,821). Each of these studies assessed retinopathy with the aid of fundus photography or direct ophthalmoscopy and measured glycemia as FBS, 2-HPG and HbA1C. These studies demonstrated that the prevalence of retinopathy increased in an apparently linear fashion above certain glycemic levels. The prevalence of retinopathy was expressed by deciles of glycemia for each of the three measures and the deciles at which retinopathy began to increase were the same for each measure within each population.These data showed a clear relationship between glycemia and risk for retinopathy,a diabetic microvascular complication. This firmly supported the previous notion of risk of progression to overt, symptomatic diabetes as the basis for diagnosing diabetes.

The relationship between FPG and 2-HPG values and retinopathy was compared and it was found that the previous FPG cutoff point of ≥ 140 mg/dl (7.8 mmol/l) was substantially above the glucose level at which the prevalence of retinopathy began to increase. Based on this the committee recommended to lower the FPG cutoff point to ≥126mg/dL (7.0mmol/l). The 1997 committee report acknowledged that even at the lower FPG cutoff point,there was no perfect concordance between the FPG and OGTT (2-HPG). An individual may be diagnosed to have diabetes using one test but not the other. This discrepancy between the two tests has been confirmed in numerous subsequent reports. Although both the tests are measures of glycemia, this type of discrepancy may be because of the fact that they reflect different physiological measures of acute glucose metabolism8.

The 1997 report also gave recommendation in favour of FPG level as the preferred test to diagnose diabetes,rather than 2-HPG because it was more convenient for patients. Moreover it is less costly and time consuming.The repeat test reproducibility was also superior. The committee also introduced the term "impaired fasting glucose" (IFG).This was to differentiate the metabolic state between normal state (FPG < 110 mg/dL or < 6.1 mmol/l) and diabetes (≥ 126 mg/dL or ≥ 7.0 mmol/l) when the FPG test was used.The intermediate glycemic state was continued to be called as IGT when an OGTT was performed, with the 2-HPG (between 140 and 200 mg/dL) the same as that as in the NDDG report. A WHO consultation9 adopted most of the above recommendations with one exception. They recommended that, whenever feasible, individuals with IFG should undergo an OGTT to exclude the presence of diabetes that would otherwise be missed and that the OGTT should remain the "gold standard" in the diagnosis of diabetes. A 2003 follow-up report from the expert committee refined the fasting glucose value range for IFG from ≥ 110 but < 126 mg/dL to ≥ 100 but < 126 mg/dL (≥ 6.1 but < 7.0mml/l to ≥ 5.6 but < 7.0 mmol/l ) to make it more comparable with the IGT value . The WHO did not change its previous recommendations10.

THE ROLE OF HbA1C TEST IN THE DIAGNOSIS OF DIABETES

The hall-mark of diabetes is the chronic hyperglycemia which is sufficient to cause diabetes-specific complications. Common sense would then dictate that laboratory measures that are capable of capturing long-term glycemic exposure should provide a better marker for the presence and severity of the disease than single measures of glucose concentration. Observational studies that have assessed glycemia with measures that capture longer -term exposure (i.e.HbA1C ) or with single or longitudinal measurements of glucose level have consistently demonstrated a strong and clear correlation between retinopathy and HbA1C levels11,12,13 but a less consistent relationship with fasting glucose levels and retinopathy14. The correlation between HbA1C levels and complications has also been shown in the setting of controlled clinical trials in type 115 and type 216 diabetes, and these findings have been used to establish the HbA1C treatment goals for diabetic care17.

All these observations from various studies suggest that HbA1C is a reliable measure of chronic glycemic levels and it captures the degree of glucose exposure over time and is related more intimately to the risk of complications than single or episodic measures of glucose levels. Hence it may serve as a better biochemical marker of diabetes and should be considered a diagnostic tool. The 1997 expert committee report considered this option, but it recommended against using HbA1C values for diagnosis in part because of the lack of standardisation in assay. The National Glycohaemoglobin Standardisation Program succeeded in standardising the various assays in US .The 2003 follow-up report of the expert committee noted that, eventhough the standardisation had succeeded, the use of HbA1C for diagnosis still had disadvantages, and it stuck on to the previous recommendation that A1C should not be used to diagnose diabetes.

With the advances in instrumentation and standardization, the accuracy and precision of HbA1C assays matched with those of glucose assays, as viewed by the current International Expert Committe. The accuracy and precision of glucose measurement itself is low. This fact is beyond the realisation of most of the clinicians. The performance of a variety of clinical laboratory instruments and methods that measure plasma glucose level was recently analyzed and it revealed that 41% of instruments have a significant bias from the reference method that would result in potential misclassification of >12% of patients18. A lot of potential pre analytic errors can also occur. Most of these are due to improper sample handling. The lability of glucose in the collection tube at room temperature is a well known fact. When the whole blood samples are collected in sodium fluoride to inhibit in vitro glycolysis, if we store the blood sample at room temperature for as little as 1 to 4 hours before analysis, it may result in decreases in glucose levels by 3-10 mg/dL in non-diabetic individuals19,20.

HbA1C values are relatively stable after collection21, and the medical science experts are of the view that the recent introduction of a new reference method to calibrate all HbA1C assay instruments would further improve HbA1C assay standardization in most of the world. Another advantage of HbA1C measurement over glucose measurement is that, between- and within- subject coefficients of variation is substantially lower for HbA1C than for glucose measurements. The variability of HbA1C values is also considerably less than that of FPG levels. The day-to-day within person variance is <2% for HbA1C but 12-15% for FPG. The most attractive advantage of HbA1C testing is the convenience for the patient and the care of sample collection for HbA1C testing (which can be obtained at any time, requires no patient preparation , and is relatively stable at room temperature) compared with that of FPG testing (which requires a timed sample after at least an 8-hour fast and which is unstable at room temperature).These facts support the use of HbA1C assay to diagnose diabetes.

In summary, the HbA1C assay is at least as good as glucose measurement in defining the level of hyperglycemia at which retinopathy prevalence increases. Moreover it has superior technical attributes, including less pre-analytic instability and less biologic variability ; and is more clinically convenient. HbA1C is a more stable biological index than FPG. The glucose concentrations are known to fluctuate within and between days whereas HbA1C gives a measure of chronic glycemia levels.

THE MOST APPROPRIATE HbA1C CUTOFF POINT FOR THE DIAGNOSIS OF DIABETES

The 1997 committee report viewed a substantial increase in the prevalence of retinopathy at HbA1C values starting between 6.0 and 7.0 %. A recent analysis derived from DETECT-222 and including the 3 that were included in the 1997 report examined the association between HbA1C and retinopathy. Retinopathy was objectively assessed and graded by fundus photography. This analysis included 28,000 subjects from nine countries and showed that at the glycemic level of 6.5% the prevalence of diabetes-specific "moderate" retinopathy begins to rise. Among the >20,000 subjects who had HbA1C values <6.5%, "moderate" retinopathy was found in none. The receiver operating characteristic curve analysis of the same data indicated that optimal cut off point for detecting at least moderate retinopathy was an HbA1C of 6.5%.

In summary, the large volume of data derived from diverse populations established an HbA1C level which is associated with an increase in the prevalence of moderate retinopathy(taken as a specific marker of diabetes) and it provided strong justification for assigning an HbA1C cut off point of >6.5% for the diagnosis of diabetes. A population based study of 3190 adults of Malay ethnicity was done recently and it concluded that "HbA1C levels in the range 6.6 to 7% were optimal for detecting microvascular complications."

The relationship between chronic glycemic levels and the long term complications of diabetes is better expressed as a continuum. There is a low prevalence of "any" retinopathy(which includes minor changes that can be due to other conditions,such as hypertension) at A1C levels <6.5% that may reflect a continuum of risk. The substantial increase in the prevalence of moderate retinopathy at HbA1C of ≥6.5% supports the selection of this level as the threshold level of glycemia that results in retinopathy, most characteristic of diabetes.

The cut off point of 6.5% should not be taken as an absolute dividing line between normal glycemia and diabetes. However, the HbA1C level of 6.5% is sufficiently sensitive and specific in identifying individuals who are at risk of developing retinopathy and who should be diagnosed as diabetic. The HbA1C level is predictive as the conventional FPG and 2HPG values. The International Expert Committee has balanced the stigma and costs of mistakenly identifying individuals as diabetic in selecting a diagnostic HbA1C level ≥6.5% against the minimal clinical consequences of delaying the diagnosis in someone with an A1C level <6.5% The committee agreed to emphasize specificity rather than sensitivity.Effective prevention strategies were recommended for at-risk group with an HbA1C between 6.0% and 6.5%.

HISTORY, SCIENCE AND POLITICS OF HbA1C STANDARDISATION

Since the introduction of glycated haemoglobin (GHb), measured as total HbA1, in clinical laboratories for diabetes monitoring around 1977, it is fascinating to consider the analytical improvements that have occurred. At the initial period various methods displayed poor precision and there were no calibrators or material with assayed values for quality control purpose.

Many methods making use of charge or structural differences between the glycated and non-glycated species of haemoglobin for the measurement of glycated haemoglobin have been developed.

[A] Methods based on charge difference

The major assays in use from the late 1970s to the mid 1980s were either electrophoretic or mini-column assays for the chromatographic fraction HbA1 and later the more specific subfraction HbA1C. The mini-column assays were rapid "short column" variations of the original 1971 Trivelli macro-column procedure that took several days to perform23. Hb1a, Hb1b, HbF, HbA1c, HbAo and HbA2 was the order in which fractions eluted, with buffers of varying ionic strength.

Multilevel lyophilised bloods were used with values assigned by manufactures using their own kit methods to improve the laboratory comparability. Better precision was achieved with the use of temperature control than the use of calibrators for correcting temperature variation.The current HbA1C HPLC assays based on cation exchange incorporate both thermosttated temperature control and the use of calibrators.

Other assays based on charge differences are

Agar gel electroendosmosis

Agarose gel electrophoresis

Isoelectric focusing

Capillary electrophoresis

These methods have now become obsolete.

[B] Methods based on structural difference

(1) Affinity separation

In 1981 a method was described by Mallia et al. that separated glycated haemoglobin based on the binding of the cisdiol groups of the glucose to m-amino phenylboronic acid cross linked on agarose24. Glycated haemoglobin binds to the affinity resin, while non-glycated haemoglobin does not bind. Quantitation of the glycated and non glycated fractions is by spectrophotometry at 415 nm.

This method is much less temperature sensitive and the presence HbF and carbamylated haemoglobin do not cause any analytical interference, and is the preferred method of choice in patients with haemoglobin variants . Calibration did not exist.

(2) Immuno assays

The first commercial immunoassay, Novoclone HbA1C, was marketed by Dako Diagnostics Ltd. (Ely,UK) in 1991, which used enzyme linked micro-titre plates with an antibody, specific to the N-terminal eight aminoacids of ketoamine HbA1C. The assay was discontinued within a few years. The DCA 2000 Point of Care HbA1C analyser was introduced subsequently in 1992. This manual immunoassay analyser was originally marketed with an eight minute assay programme, and subsequently converted to a six minute assay25.

By mid 1990 immunological based assays for HbA1C became more widely used and many commercial assays are now available and are targeted against the -N terminal glycated tetrapeptide or hexapeptide group.Various assay designs are variable,ranging from immunoturbidimetry to latex enhanced competitive immunoturbidimetry.

SCIENCE

Once the HbA1C methods were introduced into routine use, it quickly became evident that there was a significant difference in the results produced by different laboratories. The discrepancy in results were due to the range of methods being used by the laboratories and also to the lack of a primary reference material. The new generation HbA1C methods now demonstrate a degree of precision that was beyond our imagination in the mid 1970's, even then the comparison of results from different laboratories was still difficult.

Peterson et al. first proposed the standardization with common calibration in 1984. He examined factors such as inter method correlation and reproducibility between laboratories26. The international standardization of glycated haemoglobin measurements became an important objective for scientists and clinicians only after the publication of the DCCT study in 1993. The lack of international standardization prompted several countries to develop national standardization programmes of their own.

USA: National Glycohaemoglobin Standardization Program (NGSP)27,28

The NGSP was formed in July 1996 to implement the plan developed by the American Association for Clinical Chemistry Glycohaemoglobin Standardisation Subcommittee. A system of reference laboratories was established that would support each other in a network and that would be used in calibrating and standardising the commercial HbA1C methods and analytical systems. The Bio Rex 70 HPLC System, established in the DCCT Central Laboratory, was chosen as the NGSP "reference standard method" .The NGSP is responsible for the calibration of HbA1C methods in many parts of the world and it enabled direct comparison to the DCCT targets. The NGSP has an excellent website and provides up-to-date information on the precision and accuracy of validated commercial methods for HbA1C29.

Japanese Standardization Scheme30,31

In 1995 the Japanese Diabetes Society (JDS) in collaboration with the Japan Society of Clinical Chemistry (JSCC) developed a National Standardization Scheme. Two calibrators (JDS Callibrator Lot 1) were prepared as lyophilised haemolysates. The two most common high pressure liquid chromatography (HPLC) analysers used were Tosh (Tokyo, Japan) and Kyoto Daiichi (Kyoto, Japan). Both of them were very precise cation exchange methods and the HbA1C values were assigned as the mean of both. These two point calibrators are used for the calibration of all routine HbA1C assays in Japan.

Swedish Standardization Scheme32,33

Mono S HPLC (a strong methyl sulfonate cation exchanger on mono beads) is being used as the reference method in the Swedish standardization scheme. Mono S is a relatively specific assay separating HbA1C form all known minor endogenous components except carbamylated haemoglobin and -chains. The HbF fraction is well separated.

Global Standardization

All these national programmes have some common drawbacks like the absence of internationally recognised and accepted reference materials and measurement procedures.As a result the accuracy and comparability of HbA1C measurements at a global level cannot be assured. To overcome these shortcomings, and also to achieve a uniform international standardization of HbA1C measurements, the IFCC established a Working Group on HbA1C standardization (WG - HbA1C).Its aim was to develop a complete reference measurement system based on the concepts of metrological traceability.The essential elements of a comprehensive reference measurements system include the definition of the measurement (including the unit) with regard to the intended clinical use and the individuation of reference laboratories that possibly collaborate in a network.

For this project, HbA1C was defined as haemoglobin molecules having a stable adduct of glucose to the N-terminal valine of the haemoglobin β chain (β N-1-deoxy fructosyl- haemoglobin). The rationale behind this was that this quantity is biochemically well characterised and is the major form of HbA1C in human blood, and most of the commercial HbA1C tests claim to measure only this form. Two equivalent reference methods specifically measuring this hexapeptide were then developed , with a combination of HPLC and electron-spray mass spectrometry (MS) or ,alternatively, a two dimensional approach using HPLC and capillary electrophoresis (CE) with UV detection34. The WG-HbA1C was also successful in preparing primary reference materials (purified HbAo and HbA1C) to calibrate the reference procedures35. In 2001, the National Societies of Clinical Chemistry unanimously accepted the IFCC reference methods and published as approved IFCC reference methods. A network of laboratories was also established using either the HPLC - MS or the HPLC -CE option .

POLITICS

It soon came into notice that there were significant differences between the HbA1C values of the IFCC Network Laboratories and each of the three national networks' designated comparison methods (DCMs) and also significant differences between each of the DCMs. But the relationship between each DCM and the IFCC was linear in each individual case.

The relationships of each DCM with the IFCC method have been stable and reproducible over several years, and are described by the following master equations:36

NGSP HbA1C = 0.915 (IFCC HbA1C) + 2.15

JDS/JSCC HbA1C = 0.927 (IFCC HbA1C) + 1.73

Swedish HbA1C = 0.989 (IFCC HbA1C) + 0.88

"mmol/mol" was proposed as the SI unit of measurement for HbA1C by the Joint IFCC Committee on Nomenclature , Properties and Units and IUPAC (International Union of Pure and Applied Chemistry) Subcommittee on Nomenclature, Properties and Units (C-NPU). This option of using mmol/mol instead of percentage as the unit helps to avoid confusion when recalculating old HbA1C targets to the new IFCC standardized values. This approach has got some more advantages also, which include a positive impact on changing of scale of reported HbA1C results, which helps the clinicians and diabetic patients to conceive the analyte changes in a much better way and increased potential for future use of HbA1C as a diagnostic tool37.This helps to avoid a situation where the clinicians and patients may perceive small changes of HbA1C as unimportant, although they are linked to large health effects.

The changes proposed by IFCC had a great impact in the numeric results provided to clinicians. An initial meeting was held in London in January 2004 between the International Diabetes Federation (IDF), European Association for the Study of Diabetes (EASD), the American Diabetes Association (ADA), the IFCC -WG - HbA1C and a representative of NGSP to discuss a joint approach. The most important outcome of the meeting was the recommendation to report HbA1C in terms of "average plasma glucose" and a study (Mean Blood Glucose Study) was organised to investigate this relationship.

To discuss the progression relating to the new reference method to standardize the HbA1C results, a second meeting was held in Milan, Italy on 4 May 2007, at which a consensus agreement emerged. The following statements have been approved by the ADA, EASD, IDF and IFCC.

HbA1C test results should be standardised world wide, including the reference system and results reporting.

The new IFCC reference system for HbA1C represents the only valid anchor to implement standardization of the measurement.

HbA1C results are to be reported world wide in IFCC units (mmol/mol) and derived NGSP units (%) using the IFCC-NGSP master equation.

If the ongoing 'average plasma glucose study' fulfils its a prior specified criteria, an HbA1C derived average glucose (ADAG) value calculated from the HbA1C result will also be reported as an interpretation of the HbA1C results.

Glycemic goals appearing in clinical guidelines should be expressed in IFCC units, derived NGSP units and as ADAG.

HbA1C : MARKER OF CHRONIC GLYCEMIA

HbA1C is currently the most important biomarker for assessing the glycemic status of people with diabetes.Its use has now been extended for making decisions on the appropriate treatment modifications. HbA1C was discovered more than forty years ago by Samuel Rahbar38 and co-workers. Eventually the breakthrough for HbA1C was achieved in 1993 when it was discovered that the concentration of HbA1C was an excellent predictor of diabetes related long term complications in the Diabetes Control and Complications Trial (DCCT).Since then, many health care providers view the HbA1C value as a "magic number" which comprises all the information required for managing blood glucose concentration in the normal range to prevent complications in people with diabetes.

Existence of glucose is predominantly in a cyclic form. This cyclic form is in chemical equilibrium with a sma