Faculty Bibliography

AIMS: The relationship between 1- and 2 h glucose levels following an oral glucose tolerance test (OGTT) and long-term mortality was evaluated. METHODS: Over a 33 year period, 2138 individuals were followed for all-cause mortality. Fasting and post-OGTT glucose parameters categorized the cohort according to baseline glycaemic status. Four categories were established according to 1- and 2 h glucose levels (in mg/dl): group A = 1 h 155 and 2 h < 140; group C = 1 h 155 and 2 h = 140-199 (impaired glucose tolerance). Individuals with diabetes at baseline were excluded from the cohort. RESULTS: By August 2013, 51% of the study cohort had died. The worst prognosis occurred in group D (73.8%), followed by groups C (67.5% mortality), B and A (57.9% and 41.6%, respectively). When the 2 h glucose value is 'normal' (<140mg/dl), the 1 h glucose value >155mg/dl is an important predictor of mortality (28% increased risk) compared with group A, controlling for sex, age, smoking, BMI, systolic and diastolic blood pressures. A gradual increased hazard for mortality was seen by study group(hazard ratio = 1.28, 1.60 and 1.76, for groups B, C and D, respectively; group A = reference). CONCLUSIONS: A 1 h glucose value > 155 mg/dl predicts mortality even when the 2 h level is < 140 mg/dl. However, when the 2 h level is in the impaired glucose tolerance range, the hazard for mortality rises significantly independent of the 1 h value. Individuals at risk for developing diabetes could be identified earlier using the 1 h threshold value of 155 mg/dl, which could avert progression to diabetes and increased mortality

AIM: To assess the performance of HbA1c and the 1-h plasma glucose (PG >/= 155 mg/dl; 8.6 mmol/l) in identifying dysglycemia based on the oral glucose tolerance test (OGTT) from a real-world clinical care setting. METHODS: This was a diagnostic test accuracy study. For this analysis, we tested the HbA1c diagnostic criteria advocated by the American Diabetes Association (ADA 5.7-6.4 %) and International Expert Committee (IEC 6.0-6.4 %) against conventional OGTT criteria. We also tested the utility of 1-h PG >/= mg/dl; 8.6 mmol/l. Prediabetes was defined according to ADA-OGTT guidelines. Spearman correlation tests were used to determine the relationships between HbA1c, 1-h PG with fasting, 2-h PG and indices of insulin sensitivity and beta-cell function. The levels of agreement between diagnostic methods were ascertained using Cohen's kappa coefficient (Kappa). Receiver operating characteristic (ROC) curve was used to analyze the performance of the HbA1c and 1-h PG test in identifying prediabetes considering OGTT as reference diagnostic criteria. The diagnostic properties of different HbA1c thresholds were contrasted by determining sensitivity, specificity and likelihood ratios (LR). RESULTS: Of the 212 high-risk individuals, 70 (33 %) were identified with prediabetes, and 1-h PG showed a stronger association with 2-h PG, insulin sensitivity index, and beta-cell function than HbA1c (P < 0.05). Furthermore, the level of agreement between 1-h PG >/= 155 mg/dl (8.6 mmol/l) and the OGTT (Kappa[95 % CI]: 0.40[0.28-0.53]) diagnostic test was stronger than that of ADA-HbA1c criteria 0.1[0.03-0.16] and IEC criteria (0.17[0.04-0.30]). The ROC (AUC[95 % CI]) for HbA1c and 1-h PG were 0.65[0.57-0.73] and 0.79[0.72-0.85], respectively. Importantly, 1-h PG >/= 155 mg/dl (8.6 mmol/l) showed good sensitivity (74.3 % [62.4-84.0]) and specificity 69.7 % [61.5-77.1]) with a LR of 2.45. The ability of 1-h PG to discriminate prediabetes was better than that of HbA1c (AUC: -0.14; Z value: 2.5683; P = 0.01022). CONCLUSION: In a real-world clinical practice setting, the 1-h PG >/= 155 mg/dl (8.6 mmol/l) is superior for detecting high-risk individuals compared with HbA1c. Furthermore, HbA1c is a less precise correlate of insulin sensitivity and beta-cell function than the 1-h PG and correlates poorly with the 2-h PG during the OGTT.

The public health outcry toward infectious entities appears to dwarf chronic diseases such as diabetes. This disparity is particularly astonishing given the considerable prevalence of diabetes and prediabetes. Diseases associated with short-term morbidity and mortality therefore seem to garner attention and demand an immediate public health response, whereas chronic illnesses, which can be considerably more devastating in the longer term, receive relatively less notoriety. It should not, however, be misconstrued that one disease entity is more important than the other-it is critical that both acute and chronic entities are given balanced attention in the public health, governmental, and scientific realms. The current perspective reflects on the disparate public health purviews toward acute and chronic illnesses, describes why prevention is so difficult and challenging, and addresses what can be done to reverse this trend. If there is any hope of conquering the spiraling prediabetes and diabetes epidemics, the medical community must grapple with the complex issues herein raised.

Diagnosis of type 2 diabetes and prediabetes is mandatory. Chronic hyperglycemia in diabetes is associated with long-term micro- and macrovascular as well as with neurological complications. Prediabetes predisposes patients to develop diabetes and macrovascular disease. Diagnosis of diabetes is established on (at least) one of the following criteria: a fasting plasma glucose >/= 126 mg/dl (7.0 mmol/l), a casual plasma glucose >/= 200 mg/dl (11.1 mmol/l) in the presence of symptoms, a 2-h plasma glucose during the 75-g oral glucose tolerance test (OGTT) >/= 200 mg/dl (11.1 mmol/l) and/or an HbA1c >/= 6.5%. Prediabetes is defined by the Position Statement of the American Diabetes Association as a fasting plasma glucose between 100 and 125 mg/dl (5.6 - 6.9 mmol/l) [a condition called Impaired Fasting Glucose] and/or by a 2-h plasma glucose during OGTT 140 - 199 mg/dl (7.8 - 11.0 mmol) [Impaired Glucose Tolerance] and/or a HbA1c level 5.7 - 6.4%, with however some potential discordance between tests. The threshold of fasting plasma glucose defining Impaired Fasting Glucose as well as the adequacy of HbA1c as a correct diagnostic tool for prediabetes is still debated.

BACKGROUND: We describe the relationship between dysglycemia and long-term mortality and elucidate the relationship between blood glucose levels during an oral glucose tolerance test (OGTT) and haemoglobin A1 (HbA1) and mortality. METHODS: A cohort of 1410 individuals was followed for 33 years since 1980. Fasting and post-OGTT glucose parameters were used to categorize the cohort according to baseline glycemic status. RESULTS: The mortality rate increased from 43% in normoglycemic individuals to 53.3, 61.7, 72.9 and 88.0% in those with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG/IGT and diabetes, respectively. The highest mortality rate, compared with the normoglycemic category, was observed in individuals with IFG/IGT and diabetes according to a Cox proportional hazard model (HR = 1.38, 95%CI 1.10-1.74 and HR = 2.14, 95%CI 1.70-2.70, respectively), followed by individuals with IGT and IFG, but this did not reach statistical significance. We speculate that the IFG group may represent a mixture of individuals en route from normal to the next two categories as well as another cohort whose glucose levels are stably set at the upper reaches of the normal distribution. Significant differences were found between 1 and 2 h glucose values (p < 0.001). Fasting, 60 and 120 min glucose values were positively associated with increasing HbA1 quintiles (p < 0.05). The mean HbA1 was significantly higher in those who died (p = 0.01). The highest mortality (58.8%) was observed in the upper HbA1 quintile that was also associated with the highest prevalence of the metabolic syndrome (17.2%). CONCLUSIONS: This study shows a continuous relationship between the severity of dysglycemia and long-term mortality and should promote the early recognition of prediabetes. The 1 h post-load glucose level was continuously associated with increasing HbA1 concentrations and may therefore serve as an early marker for abnormalities in glucose tolerance. An elevated 1 h post-load glucose level may potentially identify at-risk individuals well before the traditional 2 h glucose value

Prediabetes represents an elevation of plasma glucose above the normal range but below that of clinical diabetes. Prediabetes includes individuals with IFG, IGT, IFG with IGT and elevated HbA1c levels. Insulin resistance and beta-cell dysfunction are characteristic of this disorder. The diagnosis of prediabetesis is vital as both IFG and IGT are indeed well-known risk factors for type 2 diabetes with a greater risk in the presence of combined IFG and IGT. Furthermore, as will be illustrated in this review, prediabetes is associated with associated disorders typically only considered in with established diabetes. These include cardiovascular disease, periodontal disease, cognitive dysfunction, microvascular disease, blood pressure abnormalities, obstructive sleep apnea, low testosterone, metabolic syndrome, various biomarkers, fatty liver disease, and cancer. As the vast majority of individuals with prediabetes are unaware of their diagnosis, it is therefore vital that the associated conditions are identified, particularly in the presence of mild hyperglycemia, so they may benefit from early intervention.

This Commentary briefly reviews the background of prediabetes including its definition and pathophysiology and describes as well the natural course of glycemic deterioration as it follows a continuum. Research efforts in identifying glucose and other biomarkers for the early detection of high-risk individuals are summarized.