Diabetes Care

In this issue of Diabetes Care , Massing et al. (1) present the results of their review of Medicare claims from 13,660 diabetic patients who received regular outpatient care from a primary care physician ( n = 1,749). During a 24-month period, 31% received no lipid profile, 24% received only one lipid profile, and 45% of the diabetic patients received two or more lipid profiles. Further analysis revealed that Caucasians compared with African Americans were 1.6 times more likely to receive a lipid panel, and patients with stroke or heart failure were also less likely to receive a lipid profile. There are clinical decisions pertaining to lipid screening made by the primary care physician that are not captured with Medicare claims data and may partially account for an under-representation of the adherence rates. One situation is a patient’s refusal to obtain a lipid profile. Another situation, which is rare, is the individual with a total cholesterol <100 mg/dl. In this case, the primary care physician may not request …

OBJECTIVE Identifying glucokinase monogenic diabetes (GCK-MODY) in pregnancy is important, as management is different from management for other forms of gestational diabetes mellitus (GDM) and there is no increased maternal risk of type 2 diabetes. We calculated the population prevalence of GCK-MODY in pregnancy and determined the clinical characteristics that differentiate pregnant women with GCK-MODY from those with GDM.RESEARCH DESIGN AND METHODS We calculated the population prevalence of GCK-MODY in pregnancy by testing a subset of patients from the population-based Atlantic Diabetes in Pregnancy (Atlantic DIP) study (n = 5,500). We sequenced for GCK mutations in 247 women with a fasting glucose ≥5.1 mmol/L and 109 randomly selected control subjects with normal fasting glucose. Using data from the cases found and 40 previously identified GCK-MODY pregnancies, we analyzed whether clinical criteria could be used to differentiate GCK-MODY from GDM.RESULTSFour women with fasting glucose ≥5.1 mmol/L were diagnosed with GCK-MODY. No cases were identified with normal fasting glucose. The population prevalence of GCK-MODY is 1.1 in 1,000 (95% CI 0.3-2.9 in 1,000) and prevalence in GDM is 0.9% (95% CI 0.3-2.3). Fasting glucose and BMI significantly differentiate GCK-MODY from GDM (P < 0.0001). Combined criteria of BMI <25 kg/m(2) and fasting glucose ≥5.5 mmol/L has a sensitivity 68%, specificity 96%, and number needed to test of 2.7 women with GDM to find one case of GCK-MODY.CONCLUSIONS Our large population cohort of pregnant women tested estimates the population prevalence of GCK-MODY of 1.1 in 1,000. We have shown routine clinical criteria that can identify which women should be tested for GCK-MODY in pregnancy.

OBJECTIVE To study the overall effect of the Active Prevention in High-Risk Individuals of Diabetes Type 2 in and Around Eindhoven (APHRODITE) lifestyle intervention on type 2 diabetes risk reduction in Dutch primary care after 0.5 and 1.5 years and to evaluate the variability between general practices. RESEARCH DESIGN AND METHODS Individuals at high risk for type 2 diabetes (Finnish Diabetes Risk Score ≥13) were randomly assigned into an intervention group (n = 479) or a usual-care group (n = 446). Comparisons were made between study groups and between general practices regarding changes in clinical and lifestyle measures over 1.5 years. Participant, general practitioner, and nurse practitioner characteristics were compared between individuals who lost weight or maintained a stable weight and individuals who gained weight. RESULTS Both groups showed modest changes in glucose values, weight measures, physical activity, energy intake, and fiber intake. Differences between groups were significant only for total physical activity, saturated fat intake, and fiber intake. Differences between general practices were significant for BMI and 2-h glucose but not for energy intake and physical activity. In the intervention group, the nurse practitioners’ mean years of work experience was significantly longer in individuals who were successful at losing weight or maintaining a stable weight compared with unsuccessful individuals. Furthermore, successful individuals more often had a partner. CONCLUSIONS Risk factors for type 2 diabetes could be significantly reduced by lifestyle counseling in Dutch primary care. The small differences in changes over time between the two study groups suggest that additional intervention effects are modest. In particular, the level of experience of the nurse practitioner and the availability of partner support seem to facilitate intervention success.

To evaluate the efficacy and safety of four doses of pioglitazone monotherapy in the treatment of patients with type 2 diabetes. There were 408 patients randomized in this multicenter double-blind placebo-controlled clinical trial. Patients who had HbA1c > or = 7.0%, fasting plasma glucose (FPG) > or = 140 mg/dl, and C-peptide > 1 ng/ml were randomized to receive placebo or 7.5, 15, 30, or 45 mg pioglitazone administered once a day for 26 weeks. Patients treated with 15, 30, or 45 mg pioglitazone had significant mean decreases in HbA1c (range -1.00 to -1.60% difference from placebo) and FPG (-39.1 to -65.3 mg/dl difference from placebo). The decreases in FPG were observed as early as the second week of therapy; maximal decreases occurred after 10-14 weeks and were maintained until the end of therapy (week 26). In the 15-, 30-, or 45-mg pioglitazone groups, there were significant mean percent decreases in triglycerides, significant mean percent increases in HDL cholesterol, and only small percent changes in total cholesterol and LDL. The subset of patients naive to therapy had greater improvements in HbA1c and FPG (difference from placebo of -2.55% and -79.9 mg/dl for the 45-mg group) compared with previously treated patients. The overall adverse event profile of pioglitazone was similar to that of placebo. There was no evidence of drug-induced hepatotoxicity or drug-induced elevations of alanine aminotransferase levels in this study Pioglitazone monotherapy significantly improves HbA1c and FPG while producing beneficial effects on serum lipids in patients with type 2 diabetes with no evidence of drug-induced hepatotoxicity.

The overlap between genetic susceptibility to celiac disease (CD) and to type 1 diabetes is incomplete; therefore, some genetic polymorphisms may significantly modify the risk of CD in subjects with type 1 diabetes. This study aimed to investigate whether the susceptibility to CD in diabetic children is modified by positivity for HLA-DQB1*02-DQA1*05 and DQB1*0302-DQA1*03 and by alleles of single nucleotide polymorphisms within the genes encoding CTLA4, transforming growth factor (TGF)-beta, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-1, IL-2, IL-6, and IL-10. Genotypic data were compared between 130 case subjects (children with type 1 diabetes and CD diagnosed using endomysium antibodies) and 245 control subjects (children with type 1 diabetes only, optimally two per case, matched for center, age at type 1 diabetes onset, and type 1 diabetes duration). The subjects were recruited from 10 major European pediatric diabetes centers performing regular screening for CD. The polymorphisms were determined using PCR with sequence-specific primers, and the risk was assessed by building a step-up conditional logistic regression model using variables that were significantly associated with CD in the univariate analysis. The best-fitted model showed that risk of CD is increased by presence of HLA-DQB1*02-DQA1*05 (odds ratio 4.5 [95% CI 1.8-11], for homozygosity, and 2.0 [1.1-3.7], for a single dose) and also independently by TNF -308A (1.9 [1.1-3.2], for phenotypic positivity), whereas IL1-alpha -889T showed a weak negative association (0.6 [0.4-0.9]). The results indicate that the risk of CD in children with type 1 diabetes is significantly modified both by the presence of HLA-DQB1*02-DQA1*05 and by a variant of another gene within the major histocompatibility complex, the TNF -308A.

Insulin autoimmune syndrome (IAS) is characterized by frequent hypoglycemic attacks associated with the presence of autoantibodies to insulin in patients who have not received insulin injections. Approximately half of IAS patients have a medication history before onset, and over 90% of the agents are sulfydryl compounds such as methimazole, mercaptopropionyl glycine, or glutathione. In addition to these compounds, α-lipoic acid (ALA), which is widely used as a health supplement, …

To study the metabolic effects of a new oral antidiabetic agent, CS-045, in subjects with non-insulin-dependent diabetes mellitus (NIDDM). Eleven NIDDM subjects (mean age 59 yr and body mass index 32.3) were treated with 400 mg/day CS-045 for 6-12 wk. Patients were hospitalized before and at the end of the drug-treatment period for metabolic studies, including oral glucose tolerance test (OGTT), meal tolerance test (MTT), euglycemic glucose-clamp studies, and lipid analyses. Eight subjects showed a marked clinical response to the drug, whereas 3 were nonresponders. The data were analyzed both for the total group and for the responders. Fasting plasma glucose (FPG) fell from 12.5 +/- 0.7 to 10.7 +/- 1.0 mM in the total group but fell more dramatically from 12.7 +/- 0.5 to 8.3 +/- 0.6 mM in the responder group. The area under the OGTT glucose curve improved by 17% in the total group and by 29% in the responders. The area under the MTT glucose curve improved by 38 and 52%, respectively. MTT levels of insulin, free fatty acids, and glucagon were significantly lower after treatment. Glucose disposal rates during glucose-clamp studies were increased in all subjects after CS-045 treatment. Mean increases were 63% at 120 mU.m-2.min-1 and 41% at 300 mU.m-2.min-1. Basal hepatic glucose production fell by 17% in the total group and by 28% in the responders. CS-045 improves insulin resistance, reduces insulinemia, lowers hepatic glucose production, and improves both fasting and postprandial glycemia in NIDDM subjects. CS-045 may represent a new therapeutic option for NIDDM.

To study the effects of CS-045, a newly developed thiazolidine analogue, on glucose tolerance and insulin response to oral glucose load in patients with non-insulin-dependent diabetes mellitus (NIDDM). Nineteen NIDDM patients (mean +/- SD age 48.9 +/- 9.4 yr) whose previous glycemic control on diet and/or sulfonylurea (SU) therapy was judged stable but unsatisfactory (greater than 7.8 mM) were selected for this study. CS-045 (400 mg/day p.o.) was given alone or together with the previous SU drugs for 12 wk. A 75-g oral glucose tolerance test (OGTT) was performed before and after CS-045 treatment. The following results were found after CS-045 treatment. 1) Fasting plasma glucose (FPG) and HbA1c decreased (n = 19, FPG, 11.0 +/- 2.4 vs. 8.4 +/- 2.7 mM [before vs. after], P less than 0.001; HbA1c, 8.0 +/- 1.1 vs. 7.4 +/- 1.3%, P less than 0.005), and glucose tolerance markedly improved. 2) Fasting insulin (immunoreactive insulin [IRI]) and insulin response during OGTT decreased (n = 19, fasting IRI, 77.4 +/- 49.8 vs. 56.5 +/- 24.6 pM [before vs. after], P less than 0.05; area under the curve of IRI, 540.3 +/- 350.5 vs. 426.4 +/- 216.3 pM.h, P less than 0.05). CS-045 is effective in improving glucose tolerance without stimulation of insulin secretion in NIDDM, suggesting an effect in improving insulin sensitivity.

PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) enrolled patients with type 2 diabetes and preexisting cardiovascular disease. These patients were at high risk for heart failure, so any therapeutic benefit could potentially be offset by risk of associated heart failure mortality. We analyzed the heart failure cases to assess the effects of treatment on morbidity and mortality after reports of serious heart failure. PROactive was an outcome study in 5,238 patients randomized to pioglitazone or placebo. Patients with New York Heart Association Class II-IV heart failure at screening were excluded. A serious adverse event of heart failure was defined as heart failure that required hospitalization or prolonged a hospitalization stay, was fatal or life threatening, or resulted in persistent significant disability or incapacity. Heart failure risk was evaluated by multivariate regression. More pioglitazone (5.7%) than placebo patients (4.1%) had a serious heart failure event during the study (P = 0.007). However, mortality due to heart failure was similar (25 of 2,605 [0.96%] for pioglitazone vs. 22 of 2,633 [0.84%] for placebo; P = 0.639). Among patients with a serious heart failure event, subsequent all-cause mortality was proportionately lower with pioglitazone (40 of 149 [26.8%] vs. 37 of 108 [34.3%] with placebo; P = 0.1338). Proportionately fewer pioglitazone patients with serious heart failure went on to have an event in the primary (47.7% with pioglitazone vs. 57.4% with placebo; P = 0.0593) or main secondary end point (34.9% with pioglitazone vs. 47.2% with placebo; P = 0.025). Although the incidence of serious heart failure was increased with pioglitazone versus placebo in the total PROactive population of patients with type 2 diabetes and macrovascular disease, subsequent mortality or morbidity was not increased in patients with serious heart failure.

To assess the efficacy and safety of MK-0941, a glucokinase activator (GKA), when added to stable-dose insulin glargine in patients with type 2 diabetes. In this double-blind study, 587 patients taking stable-dose insulin glargine (±metformin ≥1,500 mg/day) were randomized (1:1:1:1:1) to MK-0941 10, 20, 30, or 40 mg or matching placebo t.i.d. before meals (a.c.). This study included an initial 14-week, dose-ranging phase followed by a 40-week treatment phase during which patients were to be uptitrated as tolerated to 40 mg (or placebo) t.i.d. a.c. The primary efficacy end point was change from baseline in A1C at Week 14. At Week 14, A1C and 2-h postmeal glucose (PMG) improved significantly versus placebo with all MK-0941 doses. Maximal placebo-adjusted least squares mean changes from baseline in A1C (baseline A1C 9.0%) and 2-h PMG were -0.8% and -37 mg/dL (-2 mmol/L), respectively. No significant effects on fasting plasma glucose were observed at any dose versus placebo. By 30 weeks, the initial glycemic responses noted at 14 weeks were not sustained. MK-0941 at one or more doses was associated with significant increases in the incidence of hypoglycemia, triglycerides, systolic blood pressure, and proportion of patients meeting criteria for predefined limits of change for increased diastolic blood pressure. In patients receiving stable-dose insulin glargine, the GKA MK-0941 led to improvements in glycemic control that were not sustained. MK-0941 was associated with an increased incidence of hypoglycemia and elevations in triglycerides and blood pressure.

Several well-accepted classification systems are available for diabetic foot ulcers. However, there are only a few and scientifically not validated severity scores. The aim of this study was to establish a new wound-based clinical scoring system for diabetic foot ulcers suitable for daily clinical practice anticipating chances for healing and risk of amputation. Four clinically defined parameters, namely palpable pedal pulses, probing to bone, ulcer location, and presence of multiple ulcerations, were prospectively assessed in 1,000 consecutive patients. In the next step, a new diabetic ulcer severity score (DUSS) was created from these parameters. Palpable pedal pulses were categorized by the absence (scored as 1) or presence (scored as 0) of pedal pulses, while probing to bone was defined as yes (scored as 1) or no (scored as 0). The site of ulceration was defined as toe (scored as 0) or foot (scored as 1) ulcer. Patients with multiple ulcerations were graded as 1 compared with those with single ulcers (scored as 0). The DUSS was calculated by adding these separate gradings to a theoretical maximum of 4. Wounds were followed-up for 365 days or until healing or amputation if earlier. Probability of healing and risk of amputation were calculated by the Kaplan-Meier method. Uni- and multivariate analyses showed a significantly higher probability of healing for patients with palpable pulses, no probing to bone, toe ulcers, and absence of multiple ulcerations. When patients were divided into subgroups with the same DUSS, we found significantly different probabilities for healing. We showed a decreasing probability of healing for ulcers with a high DUSS, concurrent with increasing amputation rates. An increase in the DUSS by one score point reduced the chance for healing by 35%. Similarly, the higher the ulcer score, the larger the initial wound area, the longer the wound history, and the more likely the need for surgery or hospitalization. The DUSS categorizes different ulcers into subgroups with specific severity and similar clinical outcome. Using this score, the probabilities for healing, amputation, need for surgery, and hospitalization are predictable with high accuracy. This might be useful for the anticipation of health care costs and for comparison of subgroups of patients in clinical studies.

Little information is available on the early course of hypertension in type 1 diabetes. The aim of our study, therefore, was to document circadian blood pressure profiles in patients with a diabetes duration of up to 20 years and relate daytime and nighttime blood pressure to duration of diabetes, BMI, insulin therapy, and HbA1c. Ambulatory profiles of 24-h blood pressure were recorded in 354 pediatric patients with type 1 diabetes (age 14.6 +/- 4.2 years, duration of diabetes 5.6 +/- 5.0 years, follow-up for up to 9 years). A total of 1,011 profiles were available for analysis from patients not receiving antihypertensive medication. Although daytime mean systolic pressure was significantly elevated in diabetic subjects (+3.1 mmHg; P < 0.0001), daytime diastolic pressure was not different from from the height- and sex-adjusted normal range (+0.1 mmHg, NS). In contrast, both systolic and diastolic nighttime values were clearly elevated (+7.2 and +4.2 mmHg; P < 0.0001), and nocturnal dipping was reduced (P < 0.0001). Systolic blood pressure was related to overweight in all patients, while diastolic blood pressure was related to metabolic control in young adults. Blood pressure variability was significantly lower in girls compared with boys (P < 0.01). During follow-up, no increase of blood pressure was noted; however, diastolic nocturnal dipping decreased significantly (P < 0.03). Mean daytime blood pressure was significantly related to office blood pressure (r = +0.54 for systolic and r = +0.40 for diastolic pressure); however, hypertension was confirmed by ambulatory blood pressure measurement in only 32% of patients with elevated office blood pressure. During the early course of type 1 diabetes, daytime blood pressure is higher compared with that of healthy control subjects. The elevation of nocturnal values is even more pronounced and nocturnal dipping is reduced. The frequency of white-coat hypertension is high among adolescents with diabetes, and ambulatory blood pressure monitoring avoids unnecessary antihypertensive treatment.

To study if there is an association between mildly elevated body iron and glucose homeostasis indexes. A cross-sectional population study was conducted in 1,013 middle-aged men, and an association of serum ferritin with concentrations of serum insulin, blood glucose, and serum fructosamine was tested. The mean concentration of fasting serum insulin was 21.6% higher (95% CI 7.3-37.9%, P < 0.001) in the 5th quintile of serum ferritin compared with the 1st quintile. The elevation in blood glucose was 6.1% (95% CI 2.3-9.9%, P < 0.001) and in serum fructosamine 3.9% (1.5-6.9%, P < 0.01). Mildly elevated body iron stores are associated with statistically significant elevations in glucose homeostasis indexes.

We report the independent risk association of type 2 diabetic nephropathy with the z-2 allele of the 5'-(CA)(n) microsatellite and C-106T promoter polymorphisms of the aldose reductase gene (ALR2) using a case-control design. In this expanded cohort, we examined their predictive roles on new onset of cardiorenal complications using a prospective design. In this 8-year prospective cohort of 1,074 type 2 diabetic patients (59% male, median age 61 years; disease duration 7 years) with an observation period of 8,592 person-years, none had clinical evidence of coronary heart disease (CHD) or chronic kidney disease at recruitment. The renal end point was defined as new onset of estimated glomerular filtration rate <60 ml/min per 1.72 m(2) or hospitalizations with dialysis or death due to renal disease, and CHD was defined as hospitalizations with myocardial infarction, ischemic heart disease, or related deaths. After controlling for baseline risk factors and use of medications, we found that the ALR2 z-2 allele of (CA)(n) microsatellite carriers had increased risk of renal (hazard ratio 1.53 [95% CI 1.14-2.05], P = 0.005) or combined cardiorenal (1.31 [1.01-1.72], P = 0.047) end points. Carriers of the ALR2 C-106T polymorphism also had increased risk of renal (1.54 [1.15-2.07], P = 0.004) and cardiorenal (1.49 [1.14-1.95], P = 0.004) end points. Compared with noncarriers, patients with two risk-conferring genotypes had a twofold increased risk of renal (2.41 [1.57-3.70], P < 0.001) and cardiorenal (1.94 [1.29-2.91], P = 0.002) end points. In Chinese type 2 diabetic patients, genetic polymorphisms of ALR2 independently predicted new onset of renal and cardiorenal end points, with the latter being largely mediated through renal disease.

To investigate the independent contributions of waist circumference, physical activity, and sedentary behavior on glycemia in South Asians living in Scotland. Participants were 1,228 (523 men and 705 women) adults of Indian or Pakistani origin screened for the Prevention of Type 2 Diabetes and Obesity in South Asians (PODOSA) trial. All undertook an oral glucose tolerance test, had physical activity and sitting time assessed by International Physical Activity Questionnaire, and had waist circumference measured. Mean ± SD age and waist circumference were 49.8 ± 10.1 years and 99.2 ± 10.2 cm, respectively. One hundred ninety-one participants had impaired fasting glycemia or impaired glucose tolerance, and 97 had possible type 2 diabetes. In multivariate regression analysis, age (0.012 mmol ⋅ L⁻¹ ⋅ year⁻¹ [95% CI 0.006-0.017]) and waist circumference (0.018 mmol ⋅ L⁻¹ ⋅ cm⁻¹ [0.012-0.024]) were significantly independently associated with fasting glucose concentration, and age (0.032 mmol ⋅ L⁻¹ ⋅ year⁻¹ [0.016-0.049]), waist (0.057 mmol ⋅ L⁻¹ ⋅ cm⁻¹ [0.040-0.074]), and sitting time (0.097 mmol ⋅ L⁻¹ ⋅ h⁻¹ ⋅ day⁻¹ [0.036-0.158]) were significantly independently associated with 2-h glucose concentration. Vigorous activity time had a borderline significant association with 2-h glucose concentration (-0.819 mmol ⋅ L⁻¹ ⋅ h⁻¹ ⋅ day⁻¹ [-1.672 to 0.034]) in the multivariate model. These data highlight an important relationship between sitting time and 2-h glucose levels in U.K. South Asians, independent of physical activity and waist circumference. Although the data are cross-sectional and thus do not permit firm conclusions about causality to be drawn, the results suggest that further study investigating the effects of sitting time on glycemia and other aspects of metabolic risk in South Asian populations is warranted.

In their very elegant study, Stettler et al. (1) assessed the association between 1,5-anhydroglucitol (1,5-AG) and postprandial glucose during different time periods, varying from 3 days to 12 weeks long, in patients with type 2 diabetes. They found the strongest association during a 2-week period. Although the authors excluded patients with overt renal insufficiency or proteinuria, it is as yet unknown whether additional adjustments for …

Assignment of the correct molecular diagnosis in diabetes is necessary for informed decisions regarding treatment and prognosis. Better clinical markers would facilitate discrimination and prioritization for genetic testing between diabetes subtypes. Serum 1,5 anhydroglucitol (1,5AG) levels were reported to differentiate maturity-onset diabetes of the young due to HNF1A mutations (HNF1A-MODY) from type 2 diabetes, but this requires further validation. We evaluated serum 1,5AG in a range of diabetes subtypes as an adjunct for defining diabetes etiology. 1,5AG was measured in U.K. subjects with: HNF1A-MODY (n = 23), MODY due to glucokinase mutations (GCK-MODY, n = 23), type 1 diabetes (n = 29), latent autoimmune diabetes in adults (LADA, n = 42), and type 2 diabetes (n = 206). Receiver operating characteristic curve analysis was performed to assess discriminative accuracy of 1,5AG for diabetes etiology. Mean (SD range) 1,5AG levels were: GCK-MODY 13.06 microg/ml (5.74-29.74), HNF1A-MODY 4.23 microg/ml (2.12-8.44), type 1 diabetes 3.09 microg/ml (1.45-6.57), LADA 3.46 microg/ml (1.42-8.45), and type 2 diabetes 5.43 (2.12-13.23). Levels in GCK-MODY were higher than in other groups (P < 10(-4) vs. each group). HNF1A-MODY subjects showed no difference in unadjusted 1,5AG levels from type 2 diabetes, type 1 diabetes, and LADA. Adjusting for A1C revealed a difference between HNF1A-MODY and type 2 diabetes (P = 0.001). The discriminative accuracy of unadjusted 1,5AG levels was 0.79 for GCK-MODY versus type 2 diabetes and 0.86 for GCK-MODY versus HNF1A-MODY but was only 0.60 for HNF1A-MODY versus type 2 diabetes. In our dataset, serum 1,5AG performed well in discriminating GCK-MODY from other diabetes subtypes, particularly HNF1A-MODY. Measurement of 1,5AG levels could inform decisions regarding MODY diagnostic testing.

Postprandial hyperglycemia is often inadequately assessed in diabetes management. Serum 1,5-anhydroglucitol (1,5-AG) drops as serum glucose rises above the renal threshold for glucose and has been proposed as a marker for postprandial hyperglycemia. The objective of this study is to demonstrate the relationship between 1,5-AG and postprandial hyperglycemia, as assessed by the continuous glucose monitoring system (CGMS) in suboptimally controlled patients with diabetes. Patients with type 1 or type 2 diabetes and an HbA(1c) (A1C) between 6.5 and 8% with stable glycemic control were recruited from two sites. A CGMS monitor was worn for two consecutive 72-h periods. Mean glucose, mean postmeal maximum glucose (MPMG), and area under the curve for glucose above 180 mg/dl (AUC-180), were compared with 1,5-AG, fructosamine (FA), and A1C at baseline, day 4, and day 7. 1,5-AG varied considerably between patients (6.5 +/- 3.2 mug/ml [means +/- SD]) despite similar A1C (7.3 +/- 0.5%). Mean 1,5-AG (r = -0.45, P = 0.006) correlated with AUC-180 more robustly than A1C (r = 0.33, P = 0.057) or FA (r = 0.38, P = 0.88). MPMG correlated more strongly with 1,5-AG (r = -0.54, P = 0.004) than with A1C (r = 0.40, P = 0.03) or FA (r = 0.32, P = 0.07). 1,5-AG reflects glycemic excursions, often in the postprandial state, more robustly than A1C or FA. 1,5-AG may be useful as a complementary marker to A1C to assess glycemic control in moderately controlled patients with diabetes.

To investigate the effect of a family history of NIDDM on HbAlc and serum 1,5-anhydroglucitol (AG) in nondiabetic subjects. A 75-g oral glucose tolerance test was performed; 258 subjects with normal glucose tolerance and 106 subjects with impaired glucose tolerance (IGT) were selected HbAlc and serum AG were compared between subjects with and without a family history of NIDDM. The relationships between age, BMI, HbAlc, serum AG, fasting and 2-h plasma glucose, and urinary glucose were also examined using principal component analysis with a varimax rotation. In the normal group, only serum AG was lower in subjects with a positive family history than in those with no family history. On the other hand, in the IGT group, subjects with a positive family history were younger and had a higher 2-h plasma glucose, a higher urinary glucose, and a lower serum AG than those with no family history, whereas there was no difference in HbAlc. Principal component analysis identified three factors. The first factor, a linear combination of HbAlc and fasting plasma glucose, was labeled an average glycemic factor. The second factor, which included serum AG, 2-h plasma glucose, and urinary glucose, was labeled an oscillatory glycemic factor. The third factor, which contrasted age against BMI, was labeled an environmental factor. Serum AG is related to glycosuria even among nondiabetic subjects, and its concentrations are decreased in those with a family history of NIDDM. Our results suggest that serum AG rather than HbAlc reflects early metabolic abnormalities in these subjects.