Diabetes Care

Published by American Diabetes Association
Online ISSN: 0149-5992
Publications
Article
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 …
 
Article
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.
 
ariability between practices regarding change in weight, 2-h plasma glucose, energy intake, and physical activity after 1.5 years in both study groups. P = 0.01 (BMI), P # 0.0001 (2-h plasma glucose [2-h PG]), P = 0.48 (energy intake), and P = 0.78 (physical activity) for the ANCOVA analyses for differences between practices of individuals in the intervention group completing the 1.5-year intervention period (n = 393). □, intervention group; ○, usual-care group. 
Article
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.
 
Article
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.
 
Article
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.
 
Article
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, …
 
-Plasmid lipid levels (mg/dl) before and during CS-045 treatment BEFORE DURING 
Article
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.
 
Article
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.
 
Kaplan-Meier estimates of time to serious heart failure. 
Kaplan-Meier estimates of time from serious heart failure to all-cause mortality (A) and the main secondary end point (B). HF, heart failure. 
Article
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.
 
dA1C over time: (A) through Week 14 (primary efficacy time point) in the full analysis set and (B) through Week 30 in patients with results at Week 30 (n per group is 43 for placebo, 45 for 10 mg, 52 for 20 mg, 44 for 30 mg, and 41 for 40 mg). For both figures, ○ = placebo, c = MK-0941 10 mg t.i.d. a.c., ▼ = MK-0941 20 mg t.i.d. a.c., △ = MK-0941 30 mg t.i.d. a.c., ▪ = MK-0941 40 mg t.i.d. a.c. Data are expressed as mean 6 SE.  
Article
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.
 
Article
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.
 
Mean systolic and diastolic blood pressure during daytime and nighttime related to height in 354 patients with type 1 diabetes. The 10th, 50th, and 90th percentiles taken from a multicenter study in healthy control children (13) are displayed as dashed lines. A: Boys (n = 167); B: girls (n = 187). 
Mean difference of 24-h blood pressure parameters in diabetic patients from the respective normal values based on height and sex during a prospective follow-up for 4 years in 117 pediatric patients. The mean chronological age at the time of each measurement is indicated in parentheses. Bars represent means ± SEM. No significant changes during the follow-up period were noted for systolic or diastolic blood pressure during daytime and nighttime. 
Article
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.
 
Article
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.
 
Cumulative incidence of renal end point stratified by the number of risk alleles of the z2 allele of the 5-(CA) n microsatellite and C-106T promoter polymorphisms of the ALR2 gene (P trend 0.003, log-rank test) in type 2 diabetes. ve, positive;-ve, negative. 
Cumulative incidence of cardiorenal end point stratified by the number of risk alleles of the z2 allele of the 5-(CA) n microsatellite and C-106T promoter polymorphisms of the ALR2 gene (P trend 0.002, log-rank test) in type 2 diabetes. ve, positive;-ve, negative. 
-HRs of predictors for cardiorenal end points in type 2 diabetes Predictors CHD Renal end point* Cardiorenal end point HR (95% CI) P value HR (95% CI) P value HR (95% CI) P value 
Article
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.
 
Article
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.
 
ROC curves illustrating discriminative capacity of unadjusted 1,5AG to distinguish between diabetes subgroups. A: GCK-MODY and type 2 diabetes. B: HNF1A-MODY and type 2 diabetes. C: GCK-MODY and HNF1A-MODY. 
Article
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.
 
Article
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 …
 
ndividual value plot of 1,5-AG concentrations against A1C levels in HNF-1 MODY and type 2 diabetic groups. , adult MODY patients; f, type 2 diabetic patients; E, nondiabetic HNF-1 mutation carriers. 
ROC curve analysis for the diabetic patients with normal serum creatinine concentrations and A1C levels 6.5 and 9.0%. A: ROC curve. Marker represents optimal value. B: Sensitivity and specificity plotted against a cutoff value of plasma 1,5-AG concentration. Additional vertical gridlines represent the optimal cutoff value of 6.5 g/ml. 
Article
1,5-anhydroglucitol (1,5-AG) is a short-term marker of metabolic control in diabetes. Its renal loss is stimulated in hyperglycemic conditions by glycosuria, which results in a lowered plasma concentration. As a low renal threshold for glucose has been described in hepatocyte nuclear factor-1alpha (HNF-1alpha) maturity-onset diabetes of the young (MODY), the 1,5-AG level may be altered in these patients. The purpose of this study was to assess the 1,5-AG levels in patients with HNF-1alpha MODY and in type 2 diabetic subjects with a similar degree of metabolic control. In addition, we aimed to evaluate this particle as a biomarker for HNF-1alpha MODY. We included 33 diabetic patients from the Polish Nationwide Registry of MODY. In addition, we examined 43 type 2 diabetic patients and 47 nondiabetic control subjects. The 1,5-AG concentration was measured with an enzymatic assay (GlycoMark). Receiver operating characteristic (ROC) curve analysis was used to evaluate 1,5-AG as a screening marker for HNF-1alpha MODY. The mean 1,5-AG plasma concentration in diabetic HNF-1alpha mutation carriers was 5.9 microg/ml, and it was lower than that in type 2 diabetic patients (11.0 microg/ml, P = 0.003) and in nondiabetic control subjects (23.9 microg/ml, P < 0.00005). The ROC curve analysis revealed 85.7% sensitivity and 80.0% specificity of 1,5-AG in screening for HNF-1alpha MODY at the criterion of <6.5 microg/ml in patients with an A1C level between 6.5 and 9.0%. 1,5-AG may be a useful biomarker for differential diagnosis of patients with HNF-1alpha MODY with a specific range of A1C, although this requires further investigation. However, the clinical use of this particle in diabetic HNF-1alpha mutation carriers for metabolic control has substantial limitations.
 
Simple linear regression analyses demonstrated that 1,5-AG levels had significantly inverse correlations with HbA1c levels in normal renal function (A), in CKD stages 1–2 (B) and 3 (C), but not in CKD stages 4–5 (D).
Simple linear regression analyses demonstrated that 1,5-AG levels had significantly inverse correlations with FPG levels in normal renal function (A), in CKD stages 1–2 (B) and 3 (C), but not in CKD stages 4–5 (D).
Baseline characteristics of the subjects according to CKD stages
Stepwise multivariate linear regression analyses as independent determinants of ln(1,5-AG) according to CKD stages
Article
To assess the relationship between 1,5-anhydroglucitol (AG) levels, which are a marker of glycemic control, and stages of chronic kidney disease (CKD). This was a cross-sectional study with 269 subjects with type 2 diabetes who were divided into four groups based on estimated glomerular filtration rate (eGFR) using Modification of Diet in Renal Disease (eGFR(MDRD)) formula: 57 in control, 111 in CKD stages 1-2, 78 in stage 3, and 23 in stages 4-5. The study groups differed significantly with respect to 1,5-AG and fasting plasma glucose (FPG), age, duration of diabetes, blood pressure, HDL, and percentage of antihypertension or antidyslipidemia medication use. Stepwise multivariate regression analyses showed that 1,5-AG levels in the control group, the CKD stages 1-2 group, and the CKD stage 3 group could be explained by HbA(1c), age, duration of diabetes, FPG, and antihypertension medication. However, eGFR(MDRD) was the only independent determinant of 1,5-AG levels in CKD stages 4-5. Logarithmic transformed 1,5-AG values (ln[1,5-AG]) had significant inverse correlations with HbA(1c) and FPG levels for CKD stages 1-2 and CKD stage 3 (all P < 0.001). However, associations between ln(1,5-AG) and HbA(1c) or FPG were insignificant for CKD stages 4-5 (P = 0.274 and P = 0.080, respectively). This study demonstrated that 1,5-AG levels do not appear to be influenced by mild or moderate renal dysfunction, suggesting it is a reliable glycemic marker in type 2 diabetes with CKD stages 1-3.
 
Article
This prospective study was designed to elucidate the relationship between the serum level of 1,5-anhydroglucitol (1,5AG) and the urinary excretion of N-acetylglucosaminidase (NAG) and albumin in patients who were in the early stages of diabetes. A total of 1,062 male nondiabetic subjects with impaired glucose tolerance were monitored for blood glucose level once every 2-3 months, and the values were evaluated. Of these 1,062 subjects, 112 showed a worsening of glycemia during the observation period to the level seen in diabetes. We began to monitor the glycemia and parameters of renal damage in the 112 patients from the onset of diabetes. The urinary excretion of NAG and albumin were elevated even at the onset of diabetes. The abnormal excretion of NAG and albumin was associated with a change in serum 1,5AG and was quickly reversible when the serum 1,5AG improved. In the 3 years after the onset of diabetes, we obtained at least 18 measurements of one parameter for each patient and calculated the mean. Urinary NAG was found to be significantly correlated with the fasting plasma level of glucose (FPG; r = 0.512, P < 0.0001), the level of HbA1 (r = 0.351, P = 0.001), and the level of 1,5AG (r = -0.790, P < 0.0001). The urinary excretion of albumin was weakly but significantly correlated with levels of FPG (r = 0.383, P < 0.0001) and HbA1 (r = 0.337, P < 0.0001), but it was more strongly correlated with 1,5AG (r = -0.632, P < 0.0001). The level of 1,5AG was significantly correlated with FPG (r = -0.681, P < 0.0001) and HbA1 (r = -0.609, P < 0.0001). When the renal damage is not severe, the serum level of 1,5AG appeared to be an indicator of the reversible renal damage caused by hyperglycemia, as well as of the severity of the glycemia itself.
 
Longitudinal changes in 1,5AG (A), HbA 1c (B), fructosamine (FA; C), and glucose (D) in individual patients. 
Article
1,5-Anhydroglucitol (1,5AG) is a major circulating polyol arising primarily from ingestion and excreted competitively with glucose. Japanese studies have demonstrated reduced concentrations of 1,5AG in serum in hyperglycemic patients in comparison with euglycemic subjects and a gradual normalization of 1,5AG values for patients responding to antihyperglycemic therapies. In this first U.S. study, we assessed the ability of 1,5AG measurements to monitor glycemic control in a cohort of 77 patients with diabetes (22 with type 1 diabetes, 55 with type 2 diabetes) who presented with suboptimal glycemic control at baseline (defined as HbA(1c) >or=7%). Each patient received therapies consisting of combinations of diabetes education, nutritional counseling, and addition or dose adjustment of various insulins or oral antihyperglycemic medications. Therapy was targeted to reduce mean HbA(1c) by >or=1.0% over the monitoring period. 1,5AG, HbA(1c), fructosamine, and random glucose measurements were performed at baseline and at 2, 4, and 8 weeks after the initiation of therapy. 1,5AG, fructosamine, and glucose values progressed significantly toward euglycemia by week 2 of monitoring (Wilcoxon's signed-rank test, P < 0.05), with median changes of 93, -7, and -13% for 1,5AG, fructosamine, and glucose, respectively. In contrast, HbA(1c) values did not respond significantly to therapy until week 4. On an individual patient basis, 89.6% of patients displayed longitudinal changes of 1,5AG from baseline to week 8 in concordance with HbA(1c). 1,5AG was also highly correlated with HbA(1c) and fructosamine (Spearman rho = -0.6459 and -0.6751, respectively; both P < 0.0001). We conclude that 1,5AG responds sensitively and rapidly to changes in glycemia and monitors glycemic control in accordance with established markers.
 
Article
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.
 
Article
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.
 
Article
To evaluate the usefulness of plasma 1,5-anhydro-D-glucitol (1,5-AG) as a possible marker for daily glycemic excursion, we measured plasma 1,5-AG, HbA1c, fasting plasma glucose (FPG) level, and daily excursion of glycemia, from which the M-value (after Schlichtkrull) was calculated as an index of daily glycemic excursion. The subjects were 76 patients with well-controlled non-insulin-dependent diabetes mellitus (NIDDM) treated with diet therapy only (diet, n = 17), oral hypoglycemic agents (OHA, n = 28), conventional insulin therapy (CIT, n = 16), or multiple insulin injection therapy (MIT, n = 15). HbA1c values were similar among all the groups (diet, 6.9 +/- 0.6; OHA, 7.2 +/- 0.5; CIT, 7.1 +/- 0.6; MIT, 7.2 +/- 0.5%). The MIT group showed a significantly higher 1,5-AG concentration (11.5 +/- 5.3 micrograms/ml), a significantly lower M-value (9.2 +/- 5.2), and little risk of hypoglycemia ( < 4 mmol/l) and hyperglycemia ( > 10 mmol/l) (1.3 +/- 1.1 times/24 h) compared with the CIT group (6.9 +/- 3.3 micrograms/ml, 15.7 +/- 8.9, 2.2 +/- 1.6 times/24 h, respectively). Insulin doses (22.4 +/- 4.5 vs. 22.0 +/- 8.9 U/day), FPG (6.6 +/- 2.2 vs. 7.4 +/- 2.4 mmol/l), and HbA1c concentrations were not significantly different between the CIT and MIT groups. M-values significantly correlated with 1,5-AG concentrations (r = 0.414, P < 0.05), but not with HbA1c concentrations. The findings suggest that the plasma 1,5-AG concentration can be a useful index of the daily excursion of blood glucose, especially in patients with well-controlled NIDDM.
 
Article
To assess the association of 1,5-anhydroglucitol (1,5-AG) with 2-h postprandial glucose values in type 2 diabetic patients followed over 12 months in an outpatient setting. In 55 patients, we examined self-measured postprandial blood glucose values for correlations with 1,5-AG values over prespecified preceding time periods (3 days, 1 week, and weekly up to 12 weeks). The correlation coefficients for postprandial glucose values were -0.34 (P < 0.05) for 3 days, -0.38 (P < 0.001) for 1 week, and -0.40 (P < 0.001) for 2 weeks preceding the measurement of 1,5-AG. Correlations declined for time periods >2 weeks before measurement of 1,5-AG. The correlation was lower with fasting/preprandial plasma glucose levels. There was no time dependency for the correlation between A1C and fasting or postprandial glucose. 1,5-AG best reflected the 2-h postprandial glucose values of the 2 previous weeks.
 
Multivariable risk-adjusted HR for CAD extent and severity on a per-vessel basis for matched individuals with and without DM. 1VD, one-vessel obstructive CAD >50% stenosis; 2VD, two-vessel obstructive CAD >50% stenosis; 3VD, three-vessel obstructive CAD >50% stenosis; Nonobst, nonobstructive CAD <50% maximal per-patient stenosis.
Baseline characteristics and coronary artery findings of matched DM and non-DM individuals
SSS for matched DM and non-DM individuals
Univariable and multivariable HRs for all-cause mortality for clinical variables in matched DM and non-DM individuals
Article
We examined the prevalence, extent, severity, and prognosis of coronary artery disease (CAD) in individuals with and without diabetes (DM) who are similar in CAD risk factors. We identified 23,643 consecutive individuals without known CAD undergoing coronary computed tomography angiography. A total of 3,370 DM individuals were propensity matched in a 1-to-2 fashion to 6,740 unique non-DM individuals. CAD was defined as none, nonobstructive (1-49% stenosis), or obstructive (≥ 50% stenosis). All-cause mortality was assessed by risk-adjusted Cox proportional hazards models. At a 2.2-year follow-up, 108 (3.2%) and 115 (1.7%) deaths occurred among DM and non-DM individuals, respectively. Compared with non-DM individuals, DM individuals possessed higher rates of obstructive CAD (37 vs. 27%) and lower rates of having normal arteries (28 vs. 36%) (P < 0.0001). CAD extent was higher for DM versus non-DM individuals for obstructive one-vessel disease (19 vs. 14%), two-vessel disease (9 vs. 7%), and three-vessel disease (9 vs. 5%) (P < 0.0001 for comparison), with higher per-segment stenosis in the proximal and mid-segments of every coronary artery (P < 0.001 for all). Compared with non-DM individuals with no CAD, risk of mortality for DM individuals was higher for those with no CAD (hazard ratio 3.63 [95% CI 1.67-7.91]; P = 0.001), nonobstructive CAD (5.25 [2.56-10.8]; P < 0.001), one-vessel disease (6.39 [2.98-13.7]; P < 0.0001), two-vessel disease (12.33 [5.622-27.1]; P < 0.0001), and three-vessel disease (13.25 [6.15-28.6]; P < 0.0001). Compared with matched non-DM individuals, DM individuals possess higher prevalence, extent, and severity of CAD. At comparable levels of CAD, DM individuals experience higher risk of mortality compared with non-DM individuals.
 
dAssociations between fatty liver and CAC score .0 according to group. The association (OR 6 95% CIs) between fatty liver and CAC .0 score in various subgroups from stratified multivariable regression analyses including variables listed in Table 2. 
Article
Objective: Nonalcoholic fatty liver disease (NAFLD) coexists with insulin resistance (IR), but it is uncertain whether NAFLD and IR contribute independently to atherosclerosis. We tested whether fatty liver, IR, and metabolic syndrome (MetS) features (waist, glucose, triglyceride, HDL cholesterol [HDL-C], and blood pressure) were associated with a marker of atherosclerosis (coronary artery calcium [CAC] score >0), independently of cardiovascular risk factors and cardiovascular disease (CVD). Research design and methods: Data were analyzed from a South Korean occupational cohort of 10,153 people who all received ultrasound measurements of fatty liver and a cardiac computed tomography CAC score. IR was defined by homeostasis model assessment of IR (HOMA-IR) ≥75th percentile. Odds ratios (ORs) (95% CIs) for the presence of a CAC score >0 were estimated using logistic regression. Results: There were 915 people with a CAC score >0. MetS features were increased (glucose, blood pressure, triglyceride, and waist) or decreased (HDL-C) among people with a CAC score >0 (all comparisons against CAC score ≤0; P < 0.0001). Of subjects with a CAC score >0, 55% had fatty liver and 33.7% were insulin resistant. Fatty liver (OR 1.21 [95% CI 1.01-1.45]; P = 0.04) and HOMA-IR (1.10 [1.02-1.18]; P = 0.02) were associated with CAC score >0, independently of all MetS features, conventional cardiovascular risk factors, and prior evidence of CVD. The presence of IR and fatty liver combined was associated with CAC score >0 (1.53 [1.20-1.95]; P = 0.001). Conclusions: Fatty liver and HOMA-IR are both associated with a CAC score >0 (independently of each other), features of MetS, conventional cardiovascular risk factors, and existing CVD.
 
Article
OBJECTIVES Endogenous insulin secretion, measured by C-peptide area under the curve (AUC), can be tested using both the glucagon stimulation test (GST) and the mixed-meal tolerance test (MMTT). This study compares these two stimulation methods using long-term data from patients newly diagnosed with type 1 diabetes or with latent autoimmune diabetes.RESEARCH DESIGN AND METHODSA recently completed phase 3 intervention study with DiaPep277 demonstrated improved glycemic control and a significant treatment effect of glucagon-stimulated C-peptide secretion. Unexpectedly, MMTT failed to detect differences between the treated and control groups. Data from 343 patients in two balanced-randomized, double-blind, placebo-controlled, parallel-group trials of DiaPep277 were used to compare and correlate between GST- and MMTT-derived C-peptide AUC. Pearson's correlations were calculated for absolute C-peptide AUC at baseline and 12 and 24 months and for long-term changes in AUC (AUC).RESULTSThe absolute AUC values obtained at any single time point by the two tests were well correlated in both data sets (r = 0.74-0.9). However, the correlations between the AUC were much weaker (r = 0.39-0.58). GST-stimulated C-peptide secretion was stable over the fasting glucose range permitted for the test (4-11.1 mmol/L), but MMTT-stimulated C-peptide secretion decreased over the same range, implying differences in sensitivity to glucose.CONCLUSIONS Measurement of long-term changes in stimulated C-peptide, reflecting endogenous insulin secretion, during the course of intervention trials may be affected by the method of stimulation, possibly reflecting different sensitivities to the physiological status of the tested subject.
 
-Selected weight-loss drugs available in the U.S. Drug Mechanism of action FA Labeling
Article
Medical nutrition therapy (MNT) is important in preventing diabetes, managing existing diabetes, and preventing, or at least slowing, the rate of development of diabetes complications. It is, therefore, important at all levels of diabetes prevention. MNT is also an integral component of diabetes self-management education (or training). This position statement provides evidence-based recommendations and interventions for diabetes MNT. The previous position statement with accompanying technical review was published in 2002 and modified slightly in 2004. This statement updates previous position statements, focuses on key references published since the year 2000, and uses grading according to the level of evidence available...
 
Article
The Diabetes Prevention Program demonstrated the ability to delay or prevent type 2 diabetes in participants with impaired glucose tolerance (IGT). Participants with IGT are at high risk for cardiovascular disease (CVD), with a marked increase in the number and severity of CVD risk factors. We prospectively assessed the impact of our interventions on hypertension, dyslipidemia, and CVD events. The study group consisted of 3,234 individuals with IGT randomly assigned to receive intensive lifestyle intervention, metformin, or placebo. Annual assessment of blood pressure, lipids, electrocardiogram, and CVD events was undertaken. Hypertension was present in 30% of participants at study entry and then increased in the placebo and metformin groups, although it significantly decreased with intensive lifestyle intervention. Triglyceride levels fell in all treatment groups, but fell significantly more with intensive lifestyle intervention. Total cholesterol and LDL cholesterol levels were similar among treatment groups. Intensive lifestyle intervention significantly increased the HDL cholesterol level and reduced the cumulative incidence of the proatherogenic LDL phenotype B. At 3 years of follow-up, the use for pharmacologic therapy to achieve established goals in the intensive lifestyle group was 27-28% less for hypertension and 25% less for hyperlipidemia compared with placebo and metformin groups. Over an average of 3 years, 89 CVD events from 64 participants were positively adjudicated studywide, with no differences among treatment groups. Lifestyle intervention improves CVD risk factor status compared with placebo and metformin therapy. Although no differences in CVD events were noted after 3 years, achieved risk factor modifications suggest that longer intervention may reduce CVD event rates.
 
Article
OBJECTIVE To evaluate safety and efficacy of DiaPep277 in preserving -cell function in type 1 diabetic patients.RESEARCH DESIGN AND METHODSDIA-AID 1 is a multinational, phase 3, balanced-randomized, double-blind, placebo-controlled, parallel-group clinical study. Newly diagnosed patients (N = 457, aged 16-45 years) were randomized to subcutaneous injections of DiaPep277 or placebo quarterly for 2 years. The primary efficacy end point was the change from baseline in the area under the glucagon-stimulated C-peptide curve. Secondary end points were the change from baseline in mixed-meal stimulated C-peptide secretion and in fasting C-peptide and achieving target HbA(1c) 7% (53 mmol/mol). Partial remission (target HbA(1c) on insulin 0.5 units/kg/day) and hypoglycemic event rate were exploratory end points.RESULTSDiaPep277 was safe and well tolerated. Significant preservation of C-peptide secretion was observed in the DiaPep277-treated group compared with the placebo (relative treatment effects of 23.4%, P = 0.037, and 29.2%, P = 0.011, in the modified intent-to-treat [mITT] and per-protocol [PP] populations, respectively). The mixed-meal stimulation failed to distinguish between the groups. There was a trend toward efficacy in fasting C-peptide levels, though not statistically significant. Significantly more DiaPep277-treated than placebo-treated patients maintained target HbA(1c) (mITT 56% versus 44%, P = 0.03; PP 60% versus 45%, P = 0.0082) and entered partial remission (mITT 38% versus 29%, P = 0.08; PP 42% versus 30%, P = 0.035). DiaPep277 treatment reduced the relative hypoglycemic event risk (mITT by 20%; PP by 28%).CONCLUSIONS DiaPep277 safely contributes to preservation of -cell function and to improved glycemic control in patients with type 1 diabetes.
 
Article
There is increasing evidence for the use of hyperbaric oxygen therapy (HBOT) in selected patients with chronic diabetic foot ulcers (1). However, several issues still need to be answered, including health economics. In an editorial commenting on our study, Lipsky and Berendt (2) reported costs between $50,000 and $200,000 for a full course of HBOT treatment in the U.S. Van der Staal et al. (3) report significantly lower cost/reimbursement in the Netherlands at €6,916 for 40 HBOT sessions. Our Hyperbaric Centre in the southern part of Sweden is reimbursed €9,462 for 40 HBOT sessions, whereas at another Swedish center, the same treatment schedule is reimbursed with €21,505. It must further be stated that these European figures only include HBOT. Accompanying expenses such as traveling and hotel costs are not included. In summary, the cost of a full course HBOT treatment for diabetic foot ulcer varies considerably from one center to another and might depend on set-up costs, ongoing costs, reimbursement systems, and number of patients treated per center. Of more importance than the actual cost is the full health economical evaluation of a treatment. Some health economic analyses evaluating the cost-effectiveness of HBOT in diabetic foot ulcer treatment have been published, but they are limited by deficient primary clinical data and should be interpreted with caution (4–6). Still, these studies suggest a potential cost-effectiveness of HBOT, i.e., a crude analysis of the small but high-quality double-blind randomized clinical trial by Abidia et al. (5), only taking HBOT and dressing costs into account, suggests a saving of £2,960 per patient during the 1st year of follow-up (4). However, the cost-effectiveness of HBOT could not be considered as established as long as robust health economic data—based on evaluation of large placebo-controlled randomized clinical trials evaluating the effect of HBOT as adjunctive treatment in a selected and specified population of patients with chronic diabetic foot ulcers—is lacking. The health economic analysis of HBOT in the setting of the Hyperbaric Oxygen Therapy in Diabetics with Chronic Foot Ulcers (HODFU) study is ongoing, hopefully making some more information available.
 
Article
Current understanding of the role of hepatic glucokinase activity in hepatic glucose disposal has emerged largely from studies on hepatocytes and animal models. The lack of availability of simple noninvasive methods for determining hepatic glucokinase flux in vivo has been a major hurdle for studying glucokinase in man. Thus the recent report of a noninvasive method for determining glucokinase flux from lactate kinetics after intravenous glucose loading is an exciting new development (1). In hepatocyte models, glucokinase activity is a major determinant of both glycogen synthesis and glycolysis (2,3). Glucokinase is regulated acutely by adaptive interaction with a glucokinase regulatory protein (GCKR), which sequesters glucokinase in the nucleus …
 
Article
We are pleased to respond to the comment by Loranne Agius (1) relating to our recent article in Diabetes Care (2). Overall, we are in agreement with Agius that further well-designed studies are needed to validate the underlying assumptions of the model. For that purpose, we are already performing studies that will help clarify these questions. Nevertheless, a point was raised in Agius’s letter that we wanted to comment on further. As stated by Agius, one possible explanation for the 50% difference in our estimates of glucokinase activity and that of Iozzo et al. (3) may be …
 
Article
We appreciate the interest of Sawicki and Bastian (1) in our study. They propose an alternative explanation of our results, namely, that parents with a high education level would have better controlled diabetes, leading to lesser complications during pregnancy, which, in turn, would lead to stronger liability for autoimmunity in the offspring. Although such a scenario cannot be completely ruled out, we feel that it is unlikely based on the following grounds: Firstly, an association between low social status and negative influence on pregnancy complications has been documented by the references given by Sawicki and Bastian only for parents with type 1 diabetes (2–4), and parents with type 1 diabetes constitute only a small minority of the parents of current patients with type 1 diabetes or latent autoimmune diabetes in adults. Secondly, that there exists preferential passage of autoimmunity with well-controlled versus poorly controlled diabetes from mother to child is, to our knowledge, an unproven concept. Information on educational level and on type of diabetes for some of the parents of our cases might be available by coupling our data to the Norwegian Family Registry, but there would be too few cases to answer this question properly.
 
Article
Olsson et al. (1) describe an association between high levels of education and an increased risk of autoimmune diabetes in adults. They propose “the hygiene hypothesis” as an explanation for their results indicating that childhood environment and a low prevalence of childhood infections might contribute to the evolution of autoimmune diabetes. We would like to draw the attention to an alternative explanation of the results, and we wonder whether additional data available from the HUNT (Nord-Trøndelag Health Study) surveys might further clarify these phenomena.Children of parents with a higher level of education are more likely to have a higher level of education themselves (2). Patients with type 1 diabetes and a higher educational social status tend to have a better metabolic control and consequently a higher conception rate and better pregnancy outcomes when compared with patients with type 1 diabetes and a lower level of education and social status (3–5). Hence, we hypothesize that parents with type 1 diabetes/latent autoimmune diabetes in adults and a higher educational level might have had a higher probability of passing the autoimmune predisposition to type 1 diabetes to their offspring compared with parents with lower levels of education. Olsson et al. seem to have adjusted the results to family history of diabetes, but apparently without differentiating between type 1 and type 2 diabetes (1). We wonder whether the data of the HUNT survey would allow such a differentiation between the types of parental diabetes and if the level of education was assessed in parents.
 
Article
To assess the efficacy of topically applied CT-102 APST for treating diabetic neurotrophic foot ulcers. Thirteen patients entered a randomized, double-blind trial of topically applied CT-102 APST vs. placebo (normal saline) gauze dressings for the treatment of nonhealing diabetic neurotrophic foot ulcers. CT-102 APST (Curative Technologies, Setauket, NY) was prepared from homologous platelets and contained multiple growth factors including PDGF, PDAF, EGF, PF-4, TGF-beta, aFGF, and bFGF. Inclusion criteria for subjects included diabetes, ulcer of > 8 wk duration, peri-wound transcutaneous oxygen tension > 30 mmHg, platelet count > 100,000/mm3, and no wound infection. Wounds were excised before entry and were > 700 mm3 but < 50,000 mm3 in volume, < 100 cm2 in area, and involved subcutaneous tissue. In the CT-102 group, 5 of 7 ulcers were healed (100% epithelialized) by 15 wk, but only 1 of 6 ulcers was healed by 20 wk with placebo (P < 0.05). Average percent reduction in ulcer area at 20 wk was 94% for CT-102 vs. 73% for placebo. Daily reduction in ulcer volume was 73.8 +/- 42.4 mm3/day (mean +/- SE) for CT-102 vs. 21.8 +/- 8.1 mm3/day for placebo (P < 0.05). Daily reduction in ulcer area was 6.2 +/- 1.8 mm2/day for CT-102 vs. 1.8 +/- 0.4 mm2/day for placebo (P < 0.05). CT-102 significantly accelerated wound closure in diabetic leg ulcers when administered as part of a comprehensive program for the healing of chronic ulcers.
 
Article
A classification of diabetes and other categories of glucose intolerance, based on contemporary knowledge of this heterogeneous syndrome, was developed by an international workgroup sponsored by the National Diabetes Data Group of the NIH. This classification, and revised criteria for the diagnosis of diabetes, were reviewed by the professional members of the American Diabetes Association, and similar versions were circulated by the British Diabetic Association, the Australian Diabetes Society, and the European Association for the Study of Diabetes. The ADA has endorsed the proposals of the international workgroup, and the Expert Committee on Diabetes of the World Health Organization has accepted its substantive recommendations. It is proposed that this classification be used as a uniform framework in which to conduct clinical and epidemiologie research so that more meaningful and comparative data will be obtained on the scope and impact of the various forms of diabetes and other classes of glucose intolerance. Medical treatment of diabetes is not considered in this paper, and the classification is not an attempt to define guidelines for therapy of patients. The salient changes proposed in the classification are that 1. The insulin-dependent, ketosis-prone type of diabetes, which is associated with increased or decreased frequency of certain histocompatibility antigens (HLA) on chromosome 6 and with islet cell antibodies, be considered a distinct subclass of diabetes [insulin-dependent diabetes mellitus (IDDM)]. This type of diabetes has been inappropriately termed juvenile diabetes. Since it can occur at any age, it is recommended that diagnosis based on age of onset be eliminated. 2. The noninsulin-dependent, nonketosis-prone types of diabetes, which are not secondary to other diseases or conditions, be considered a second distinct subclass of diabetes [noninsulin-dependent diabetes mellitus (NIDDM)]. This subclass has been divided-according to whether or not obesity is present (obese NIDDM and nonobese NIDDM, respectively), and patients in this subclass can be further characterized by the type of treatment they receive (insulin, oral hypoglycemie agents, diet) or by other characteristics of interest to the researcher. It is believed that heterogeneity within this subclass, and also within IDDM, will be demonstrated by further research. 3. The types of diabetes caused by other conditions or found in increased frequency with other conditions (implying an etiologie relationship) be considered a third subclass of diabetes mellitus—diabetes associated with certain conditions and syndromes. This subclass has been divided according to the known or suspected etiologie relationships. 4. The class gestational diabetes be restricted to women in whom glucose intolerance develops or is discovered during pregnancy. 5. Individuals with plasma glucose (PG) levels intermediate between those considered normal and those considered diabetic [see (8)] be termed to have impaired glucose tolerance. It is proposed that the terms chemical, latent, borderline, subclinical, and asymptomatic diabetes, which have been applied to persons in this class, be abandoned, since use of the term diabetes invokes social, psychologic, and economic sanctions that are unjustified in light of the lack of severity of their glucose intolerance.
 
Cumulative incidence of hypoglycemia (■), hyperglycemia (○), association hypohyperglycemia (◇), and insulin therapy (●) in 58 patients pancreatectomized for diffuse congenital hyperinsulinism. Patients with both hypo- and hyperglycemia are a subset of both hypo- and hyperglycemia groups. yr, years.
Illustration of changes over time of insulin requirements in 20 of the 33 patients pancreatectomized for diffuse congenital hyperinsulinism. Four upper bars: Patients with insulin immediately after surgery but transiently. The three following bars: Patients with insulin after a delay but transiently. Thirteen lower bars: Patients with insulin after a delay and definitively. The other patients are not presented: eight with insulin immediately after surgery and definitively, with no insulin treatment (including five who received insulin immediately after surgery for 1–16 days). Dark bars, time of insulin therapy; gray bars, time of follow-up, with hyperglycemia but without insulin. yr, years.
Characteristics of 105 children who underwent near-total or partial elective pancreatectomy for congenital hyperinsulinism
Insulin secretion and sensitivity in children who underwent near-total or partial elective pancreatectomy for congenital hyperinsulinism
Article
To describe the long-term metabolic outcome of children with congenital hyperinsulinism after near-total or partial elective pancreatectomy. Patients (n = 105: 58 diffuse and 47 focal congenital hyperinsulinism) received operations between 1984 and 2006. Follow-up consisted of periodic measurements of pre- and postprandial plasma glucose over 24 h, OGTT, and IVGTT. Cumulative incidence of hypo- or hyperglycemia/insulin treatment was estimated by Kaplan-Meier analysis. After near-total pancreatectomy, 59% of children with diffuse congenital hyperinsulinism still presented mild or asymptomatic hypoglycemia that responded to medical treatments and disappeared within 5 years. One-third of the patients had both preprandial hypoglycemia and postprandial hyperglycemia. Hyperglycemia was found in 53% of the patients immediately after surgery; its incidence increased regularly to 100% at 13 years. The cumulative incidence of insulin-treated patients was 42% at 8 years and reached 91% at 14 years, but the progression to insulin dependence was very variable among the patients. Plasma insulin responses to IVGTT and OGTT correlated well with glycemic alterations. In focal congenital hyperinsulinism, hypoglycemia or hyperglycemia were rare, mild, and transient. Patients with focal congenital hyperinsulinism are cured of hypoglycemia after limited surgery, while the outcome of diffuse congenital hyperinsulinism is very variable after near-total pancreatectomy. The incidence of insulin-dependent diabetes is very high in early adolescence.
 
Article
To report the incidence of pancreatitis in type 2 diabetes trials of liraglutide and details of all pancreatitis cases. Data from Novo Nordisk-sponsored trials with liraglutide (phase 2 and 3; NN2211 identifiers) completed by 19 April 2013 were pooled. All pancreatitis cases were reviewed. Total exposure to liraglutide and active comparators was 5,021 and 1,354 patient-years, respectively (n = 6,345 and 1,846, respectively). Eight cases of acute pancreatitis (AP) with liraglutide and one with any comparator (glimepiride) were found. The incidence of AP was 1.6 cases/1,000 patient-years exposure (PYE) for liraglutide vs. 0.7 cases/1,000 PYE for active comparators. One of the eight AP cases reported with liraglutide did not meet diagnostic criteria for AP. In six of these eight cases, recognized risk factors for AP were present and/or the onset of AP occurred >6 months after liraglutide initiation. All patients were receiving multiple medications. Four cases of chronic pancreatitis (CP) with liraglutide and none with comparators were found. One of these four cases fulfilled diagnostic criteria for CP; these criteria were not met or information was missing in the remaining three. Based on the small number of cases observed, the incidences of reported AP and CP were numerically greater with liraglutide than with comparators. Not all cases fulfilled diagnostic criteria, and confounding variables were present in 75% of the AP cases with liraglutide therapy, precluding firm conclusions. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
 
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We aimed at analyzing the frequency, clinical characteristics, and trends associated with the occurrence of diabetic ketoacidosis (DKA) at the onset of type 1 diabetes on the basis of long-term follow-up data. A total of 106 pediatric diabetes centers in Germany and Austria participated in this study. Data from 14,664 patients with type 1 diabetes collected between 1995 and 2007 were suitable for evaluation. DKA was defined and classified according to the International Society for Pediatric and Adolescent Diabetes consensus guidelines. DKA was observed in 21.1% of patients. The frequency of DKA, including the severe form, remained unchanged throughout the 13-year observation period. The frequency of DKA was particularly striking among children <5 years of age (26.5%). Ketoacidosis occurring at diabetes onset continues to be a difficult problem. Our data show no significant change in the frequency and magnitude of DKA over the last 13 years.
 
Top-cited authors
Anders Green
  • Odense University Hospital
Ralph Defronzo
  • University of Texas Health Science Center at San Antonio
George Alberti
  • Imperial College London
Philip Raskin
  • University of Texas Southwestern Medical Center
Robert Rizza
  • Mayo Foundation for Medical Education and Research