Elevated fasting vs post-load glucose levels and pregnancy outcomes in gestational diabetes: a population-based study.

AIMS: To examine the relative association between fasting plasma glucose vs post-load (1-h and 2-h) glucose levels based on the oral glucose tolerance test in pregnancy and large-for-gestational-age and hypertensive disorders of pregnancy outcomes. METHODS: All live singleton births between October 2008 and December 2014 in Alberta, Canada were included. Gestational diabetes mellitus was diagnosed using Diabetes Canada criteria. Logistic regression models were used to examine the association between fasting plasma glucose vs post-load values and large-for-gestational-age infants and hypertensive disorders of pregnancy after adjusting for maternal characteristics and pharmaceutical intervention in gestational diabetes pregnancies. RESULTS: Among 257 547 pregnancies, 208 344 (80.9%) had negative 50-g glucose challenge tests, 36 261 (14.1%) had negative 75-g oral glucose tolerance tests, and 12 942 (5.0%) had gestational diabetes based on either elevated fasting plasma glucose (n=4130, 1.6%) or elevated 1-h and/or 2-h oral glucose tolerance test values (n=8812, 3.4%). Large-for-gestational-age and hypertensive disorders of pregnancy rates were 8.1% and 5.1% in negative glucose challenge test pregnancies, 11.0% and 7.0% in negative oral glucose tolerance test pregnancies, 22.4% and 11.9% in gestational diabetes pregnancies with elevated fasting plasma glucose, and 9.1% and 8% in gestational diabetes pregnancies with elevated post-load levels, respectively. Among gestational diabetes pregnancies, those with elevated fasting plasma glucose were at higher risk of large-for-gestational age (adjusted odds ratio 2.66, 95% CI 2.39-2.96) and hypertensive disorders of pregnancy (adjusted odds ratio 1.51, 95% CI 1.33-1.72) outcomes relative to pregnancies with post-load glucose elevations only. Fasting plasma glucose remained significantly associated with adverse outcomes in gestational diabetes pregnancies with and without pharmacological intervention. CONCLUSIONS: Elevated fasting plasma glucose in women with gestational diabetes is a stronger predictor of large-for-gestational-age and hypertensive disorders of pregnancy outcomes than elevated post-load glucose.

Patterns of glucose-lowering therapies and neonatal outcomes in the treatment of gestational diabetes in Canada, 2009-2014.

AIM: To examine patterns of use of different glycaemic control agents for treating gestational diabetes mellitus. METHODS: This was a large, retrospective, population-based cohort study of pregnant women with gestational diabetes from Alberta, Canada. We linked data from the Alberta Vital Statistics - Birth database with administrative claims data. Alberta Vital Statistics - Birth data were used to identify births that occurred between 1 January 2009 and 31 December 2014. We used International Classification of Diseases version 9/10 codes to identify women with gestational diabetes, and we excluded women with pre-existing diabetes. RESULTS: Our cohort consisted of 16 857 women with gestational diabetes, with a total of 18 761 birth events between 2009 and 2014. Over the study period, the proportion of women with gestational diabetes who were treated with glycaemic control therapies increased from 25.0% to 31.4% (P<0.0001). The number of pregnancies treated with insulin only increased (from 23.6% to 28.3%; P<0.0001), as did the number treated with metformin, +/- insulin (from 1.4% to 3.2%; P<0.0001). Rates of large-for-gestational-age infants were significantly higher among pregnancies treated with insulin only (17%) or metformin (16.5%) than among pregnancies that did not receive any pharmacological treatment (12.8%). CONCLUSIONS: Our findings show increasing use of insulin and metformin in women with gestational diabetes. Rates of large-for-gestational-age infants were similar among pregnant women receiving either pharmacological treatment, and higher than among pregnant women who did not receive any pharmacological treatment. Future research should explore the long-term outcomes and safety of metformin as an alternative for treating gestational diabetes.

Impact of gestational diabetes mellitus and high maternal weight on the development of diabetes, hypertension and cardiovascular disease: a population-level analysis.

AIMS: To examine the association between gestational diabetes mellitus (GDM) and high maternal weight and the risk of development of chronic disease. METHODS: Women with singleton deliveries between April 1999 and March 2010 in Alberta, Canada, were categorized according to pre-pregnancy weight (overweight ≥ 91 kg) and GDM status. Obstetric and neonatal outcomes, as well as the long-term incidence of maternal diabetes, hypertension and cardiovascular disease were examined. RESULTS: Of 240 083 women, 213 765 (89%) had no GDM and were not overweight (reference group), 17 587 (7.3%) were overweight only, 7332 (3%) had GDM only and 1399 (0.6%) had GDM and were overweight. Significant differences in Caesarean section rates, induction rates and birthweight were observed across the four groups. During a median follow-up of 5.3 years, diabetes incidence was 36% in the GDM and overweight, 18.8% in the GDM only, 4.8% in the overweight only and 1.1% in the reference group. With respect to hypertension and cardiovascular disease, the GDM and overweight group had the highest rates (26.8% and 3.1%, respectively) and the reference group had the lowest rates (5.8% and 1.0%, respectively). However, rates were similar in the GDM only (14.9% and 1.9%, respectively) and overweight only groups (14.9% and 1.5%, respectively). CONCLUSIONS: Not surprisingly, the presence of both high maternal weight and GDM compounds the risk of developing diabetes. However, the association between overweight alone and GDM alone and hypertension and cardiovascular disease appears similar suggesting a need for effective interventions to manage both these conditions to improve the health of these patients.

What effect does mammographic breast density have on lesion detection in digital mammography?

Effective detection of breast cancer using mammography is an important public health issue worldwide. Breasts that contain higher levels of fibroglandular compared with fatty tissue increase breast radio-opacity making it more difficult to differentiate between normal and abnormal findings. The higher prevalence of breast cancer amongst women with denser breasts demands the origination of effective solutions to manage this common radiographic appearance. This brief review considers the impact of higher levels of density on cancer detection and the importance of digital technology in possibly reducing the negative effects of increased density.

Altering source or amount of dietary carbohydrate has acute and chronic effects on postprandial glucose and triglycerides in type 2 diabetes: Canadian trial of Carbohydrates in Diabetes (CCD).

BACKGROUND AND AIMS: Nutrition recommendations for type 2 diabetes (T2DM) are partly guided by the postprandial responses elicited by diets varying in carbohydrate (CHO). We aimed to explore whether long-term changes in postprandial responses on low-glycemic-index (GI) or low-CHO diets were due to acute or chronic effects in T2DM. METHODS AND RESULTS: Subjects with diet-alone-treated T2DM were randomly assigned to high-CHO/high-GI (H), high-CHO/low-GI (L), or low-CHO/high-monounsaturated-fat (M) diets for 12-months. At week-0 (Baseline) postprandial responses after H-meals (55% CHO, GI = 61) were measured from 0800 h to 1600 h. After 12 mo subjects were randomly assigned to H-meals or study diet meals (L, 57% CHO, GI = 50; M, 44% CHO, GI = 61). This yielded 5 groups: H diet with H-meals (HH, n = 34); L diet with H- (LH, n = 17) or L-meals (LL, n = 16); and M diet with H- (MH, n = 18) or M meals (MM, n = 19). Postprandial glucose fluctuations were lower in LL than all other groups (p < 0.001). Changes in postprandial-triglycerides differed among groups (p < 0.001). After 12 mo in HH and MM both fasting- and postprandial-triglycerides were similar to Baseline while in MH postprandial-triglycerides were significantly higher than at Baseline (p = 0.028). In LH, triglycerides were consistently (0.18-0.34 mmol/L) higher than Baseline throughout the day, while in LL the difference from Baseline varied across the day from 0.04 to 0.36 mmol/L (p < 0.001). CONCLUSION: Low-GI and low-CHO diets have both acute and chronic effects on postprandial glucose and triglycerides in T2DM subjects. Thus, the composition of the acute test-meal and the habitual diet should be considered when interpreting the nutritional implications of different postprandial responses.

Diagnosing gestational diabetes.

The newly proposed criteria for diagnosing gestational diabetes will result in a gestational diabetes prevalence of 17.8%, doubling the numbers of pregnant women currently diagnosed. These new diagnostic criteria are based primarily on the levels of glucose associated with a 1.75-fold increased risk of giving birth to large-for-gestational age infants (LGA) in the Hyperglycemia Adverse Pregnancy Outcome (HAPO) study; they use a single OGTT. Thus, of 23,316 pregnancies, gestational diabetes would be diagnosed in 4,150 women rather than in 2,448 women if a twofold increased risk of LGA were used. It should be recognised that the majority of women with LGA have normal glucose levels during pregnancy by these proposed criteria and that maternal obesity is a stronger predictor of LGA. The expected benefit of a diagnosis of gestational diabetes in these 1,702 additional women would be the prevention of 140 cases of LGA, 21 cases of shoulder dystocia and 16 cases of birth injury. The reproducibility of an OGTT for diagnosing mild hyperglycaemia is poor. Given that (1) glucose is a weak predictor of LGA, (2) treating these extra numbers has a modest outcome benefit and (3) the diagnosis may be based on a single raised OGTT value, further debate should occur before resources are allocated to implementing this change.

Synthesis of specific fatty acids contributes to VLDL-triacylglycerol composition in humans with and without type 2 diabetes.

AIMS/HYPOTHESIS: It is recommended that patients with diabetes reduce their intake of saturated fat and increase their intake of monounsaturated fat or carbohydrate. However, high-carbohydrate diets may result in higher saturated fatty acids in VLDL-triacylglycerol. This is attributed to de novo lipogenesis, although synthesis of specific fatty acids is rarely measured. The objective of this study was to examine the contribution of de novo fatty acid synthesis to VLDL-triacylglycerol composition. It was hypothesised that levels of total and de novo synthesised fatty acids would increase with increased carbohydrate intake in diabetic participants. METHODS: Seven individuals with type 2 diabetes mellitus and seven matched non-diabetic controls consumed two diets differing in fat energy (lower fat <25%, higher fat >35%) for 3 days in a randomised crossover design. Blood samples were drawn before and 24 h after the ingestion of (2)H-labelled water. RESULTS: In the control participants, the higher-fat diet resulted in a 40% reduction in VLDL-triacylglycerol fatty acids because of decreases in myristic, palmitic, palmitoleic and linoleic acids, but the opposite trend occurred in participants with diabetes. The lower-fat diet increased the fractional synthesis rate by 35% and 25% in the control and diabetes participants, respectively (range: 0-33%). Palmitate accounted for 71% of fatty acids synthesised (range: 44-84% total de novo synthesised fatty acids). CONCLUSIONS/INTERPRETATION: (2)H incorporation was used for the first time in humans showing variability in the synthesis rate of specific fatty acids, even palmitic acid. A lower-fat diet stimulated saturated fatty acid synthesis at high rates, but no net stimulation of synthesis of any fatty acid occurred in the diabetes group. The implications of this finding for our understanding of lipid metabolism in diabetes require further investigation.

Population-Level Outcomes with a 2-Step Approach for Gestational Diabetes Screening and Diagnosis.

OBJECTIVES: To examine outcomes associated with alternative glucose thresholds in a 2-step approach for screening and diagnosing gestational diabetes mellitus (GDM). METHODS: We studied 178,527 pregnancies between 2008 and 2012 in Alberta, Canada. They were categorized retrospectively as normal 50 g screen (n=144,191); normal 75 g oral glucose tolerance test (OGTT) (n=21,248); abnormal at glucose thresholds suggested by the International Association of Diabetes and Pregnancy Group (IADPSG) (HAPO 1.75, n=4308); abnormal at glucose thresholds associated with an odds ratio of 2.0 for adverse events in the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study. This latter group, which would have been treated for GDM based on customary care, was further divided into those with 1 (HAPO 2-1 n=5528) or 2 or more abnormal glucose values (HAPO 2-2 n=3252). Main outcomes were large for gestational age (LGA), induced labour and Cesarean-section rates. RESULTS: LGA rates were 8.2%, 10.5%, 14.2%, 11.8% and 16.5% among normal 50 g, normal 75 g OGTT, HAPO 1.75, HAPO 2-1, and HAPO 2-2 groups, respectively. Labour induction and caesarean-section rates were 29.6% and 36.2% in the IADPSG, 38.2% and 36.8% in the HAPO 2-1 group, and 42.3% and 41.1% in the HAPO 2-2 groups, respectively. Excessive maternal weight (≥91 kg) was associated with a higher risk for all adverse outcomes. CONCLUSIONS: The 2-step approach effectively identifies pregnancies at low risk for adverse outcomes. Labelling influences induction practice. Any glucose intolerance increases risk for adverse outcomes, and pregnancies with highest (2 or higher) abnormal glucose values remain at greatest risk. Further research is needed to determine whether glycemic thresholds for GDM diagnosis should incorporate information about maternal weight.

A single Glu(62)-to-Lys(62) mutation in the Mos residues of the R7Delta447Gag-tMos protein causes the mutant virus to induce brain lesions.

We previously reported that R7Delta447, a 2954-base-pair (bp) laboratory-generated Moloney murine sarcoma virus, induced subcutaneous tumors in about 14% of infected mice but did not induce brain lesions. We now report that R7Delta447K, a spontaneous mutant of R7Delta447, induced brain lesions as well as subcutaneous tumors in all injected mice. The genomes of the two viruses differ in a single base pair: the deduced Glu(62) of the Mos residue of the R7Delta447 Gag-tMos protein is changed to Lys(62). More R7Delta447 than R7Delta447K focus-forming units were detected in both NIH3T3 and mouse cerebral vascular endothelial (MCVE) cells. However, R7Delta447K transformed NIH3T3 and MCVE cells more acutely than did R7Delta447. A distinctive feature that distinguished the morphologic transformation of R7Delta447- and R7Delta447K-infected MCVE cells is the markedly prolonged spindle-shaped phase exhibited by R7Delta447-infected MCVE cells. In addition, R7Delta447K was more efficient in inducing the phosphorylation of ERK1/2 than R7Delta447 in both MCVE and NIH3T3 cells. Moreover morphologic transformation was inhibited, and levels of phosphorylated ERK1/2 were reduced when R7Delta447- or R7Delta447K-infected NIH3T3 or MCVE cells were grown in the presence of the MEK1/2-specific inhibitor PD98095. Thus, we have identified a key residue in the Gag-tMos protein that profoundly affects activation of the Mos/MEK/ERK pathway, virus and cell replication, morphologic transformation in vitro and pathogenicity in vivo.

Insulin action during pregnancy. Studies with the euglycemic clamp technique.

To assess the mechanisms responsible for the insulin resistance associated with both normal human pregnancy and gestational-onset diabetes, we have measured exogenous glucose disposal using sequential insulin infusions with the euglycemic glucose clamp technique and erythrocyte insulin binding. Three groups of women were studied: nonpregnant women with normal glucose tolerance (N = 7, mean age 32.9 +/- 2.1 yr), pregnant women with normal glucose tolerance (N = 5, mean age 24.8 +/- 3.5 yr), and pregnant women with gestational-onset diabetes (N = 5, mean age 34.6 +/- 2.6 yr). Despite normal plasma glucose levels obtained during a 100-g oral glucose tolerance test, plasma insulin levels were significantly elevated in the pregnant women compared with the nonpregnant control subjects, suggesting a state of insulin resistance. Insulin binding to erythrocytes was similar in all three groups (maximum specific binding being 5.0 +/- 0.6%, 5.5 +/- 1.1%, and 6.0 +/- 0.7% in nonpregnant, nondiabetic pregnant, and gestational-onset diabetic women, respectively). In vivo peripheral insulin action was measured using the euglycemic glucose clamp technique during an insulin infusion of 40 mU/m2 X min, with blood glucose clamped at a concentration of 75 mg/dl using a variable glucose infusion. Glucose infusion rates were 213 +/- 11 mg/m2 X min, 143 +/- 23 mg/m2 X min, and 57 +/- 18 mg/m2 X min in nonpregnant, nondiabetic pregnant, and gestational-onset diabetic women, respectively. This demonstrates that pregnant subjects display a state of insulin resistance, and that this appears to be more marked in gestational-onset diabetic subjects. To further define the possible mechanism of insulin resistance during pregnancy, the insulin infusion rate was increased to 240 mU/m2 X min and further euglycemic clamp measurements performed. Glucose infusion rates were 372 +/- 11 mg/m2 X min, 270 +/- 31 mg/m2 X min, and 157 +/- 26 mg/m2 X min, in nonpregnant, nondiabetic pregnant, and gestational-onset diabetic women, respectively. This demonstrates a shift to the right of the dose-response curve of insulin action and suggests that the insulin resistance of pregnancy may include a decrease in presumed "maximum" insulin responsivity. In four subjects, studies were repeated in the postpartum period, and these demonstrated that the insulin resistance of pregnancy is ameliorated shortly after delivery. These studies suggest that the insulin resistance of pregnancy results from a target cell defect in insulin action beyond the initial step of insulin binding to cellular receptors, a postreceptor (or postbinding) defect in insulin action.

A new model for the study of mild diabetes during pregnancy. Syngeneic islet-transplanted STZ-induced diabetic rats.

Diabetes during pregnancy carries short- and long-term consequences for the offspring. Improved obstetrical and diabetic care has resulted in decreased morbidity and mortality in the neonate of the diabetic mother. Mild hyperglycemia is still found in both IDDM pregnant women and women with GDM. The long-term consequences of exposure to mild hyperglycemia in utero remain to be determined. In an effort to develop an appropriate animal model of mild diabetes during pregnancy, we mated female STZ-induced diabetic rats previously transplanted with specific numbers of islets of Langerhans (2500, 1000, 700, or 500 islets). Diabetic and nondiabetic sham-transplanted control groups also were studied. During pregnancy, the plasma glucose levels in the diabetic rats and the group receiving 500 islets (26.5 +/- 1.1 and 10.0 +/- 0.8 mM, respectively) were significantly greater than in control animals (5.4 +/- 0.5 mM, P < 0.0001). The mean glucose levels in rats receiving 700 or 1000 transplanted islets (6.8 +/- 0.2 and 6.5 +/- 0.2 mM) also were significantly greater than in control animals (P < 0.001). No difference was evident between control rats and the group receiving 2500 islets (5.8 +/- 0.2 mM). No gross congenital abnormalities were apparent in the offspring. The pup plasma glucose was significantly greater in the offspring of dams receiving either none (diabetic) or 500 islets (10.6 +/- 0.7 and 11.1 +/- 1.1 mM, respectively) compared with the offspring of nondiabetic control dams (4.4 +/- 0.3 mM, P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Defects in insulin secretion and action in women with a history of gestational diabetes.

Gestational diabetes mellitus (GDM) is associated with defects in insulin secretion and insulin action, and women with a history of GDM carry a high risk for the development of non-insulin-dependent diabetes mellitus (NIDDM). Assessment of subjects with a history of GDM who are currently normoglycemic should help elucidate some of the underlying defects in insulin secretion or action in the evolution of NIDDM. We have studied 14 women with normal oral glucose tolerance who had a history of GDM. They were compared with a group of control subjects who were matched for both body mass index (BMI) and waist-to-hip ratio (WHR). All subjects underwent tests for the determination of oral glucose tolerance, ultradian oscillations in insulin secretion during a 28-h glucose infusion, insulin secretion in response to intravenous glucose, glucose disappearance after intravenous glucose (Kg), and insulin sensitivity (SI) as measured by the Bergman minimal model method. The BMI in the post-GDM women was similar to that in the control subjects (24.9 +/- 1.2 vs. 25.4 +/- 1.4 kg/m2, respectively), as was the WHR ratio (0.80 +/- 0.01 vs. 0.76 +/- 0.01, respectively). The post-GDM women were slightly older (35.2 +/- 0.9 vs. 32.1 +/- 1.4 years, P = 0.04). The fasting plasma glucose levels were significantly higher in the post-GDM group than in the control group (4.9 +/- 0.1 vs. 4.4 +/- 0.1 mmol/l, respectively, P < 0.001) and remained higher at each of the subsequent determinations during the oral glucose tolerance test, although none had a result indicative of either diabetes or impaired glucose tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol.

Islet transplantation offers the prospect of good glycemic control without major surgical risks. After our initial report of successful islet transplantation, we now provide further data on 12 type 1 diabetic patients with brittle diabetes or problems with hypoglycemia previous to 1 November 2000. Details of metabolic control, acute complications associated with islet transplantation, and long-term complications related to immunosuppression therapy and diabetes were noted. Insulin secretion, both acute and over 30 min, was determined after intravenous glucose tolerance tests (IVGTTs). The median follow-up was 10.2 months (CI 6.5-17.4), and the longest was 20 months. Glucose control was stable, with pretransplant fasting and meal tolerance-stimulated glucose levels of 12.5+/-1.9 and 20.0+/-2.7 mmol/l, respectively, but decreased significantly, with posttransplant levels of 6.3+/-0.3 and 7.5+/-0.6 mmol/l, respectively (P < 0.006). All patients have sustained insulin production, as evidenced by the most current baseline C-peptide levels 0.66+/-0.06 nmol/l, increasing to 1.29+/-0.25 nmol/l 90 min after the meal-tolerance test. The mean HbA1c level decreased from 8.3+/-0.5% to the current level of 5.8+/-0.1% (P < 0.001). Presently, four patients have normal glucose tolerance, five have impaired glucose tolerance, and three have post-islet transplant diabetes (two of whom need oral hypoglycemic agents and low-dose insulin (<10 U/day). Three patients had a temporary increase in their liver-function tests. One patient had a thrombosis of a peripheral branch of the right portal vein, and two of the early patients had bleeding from the hepatic needle puncture site; but these technical problems were resolved. Two patients had transient vitreous hemorrhages. The two patients with elevated creatinine levels pretransplant had a significant increase in serum creatinine in the long term, although the mean serum creatinine of the group was unchanged. The cholesterol increased in five patients, and lipid-lowering therapy was required for three patients. No patient has developed cytomegalovirus infection or disease, posttransplant lymphoproliferative disorder, malignancies, or serious infection to date. None of the patients have been sensitized to donor antigen. In 11 of the 12 patients, insulin independence was achieved after 9,000 islet equivalents (IEs) per kilogram were transplanted. The acute insulin response and the insulin area under the curve (AUC) after IVGTT were consistently maintained over time. The insulin AUC from the IVGTT correlated to the number of islets transplanted, but more closely correlated when the cold ischemia time was taken into consideration (r = 0.83, P < 0.001). Islet transplantation has successfully corrected labile type 1 diabetes and problems with hypoglycemia, and our results show persistent insulin secretion. After a minimum of 9,000 IEs per kilogram are provided, insulin independence is usually attained. An elevation of creatinine appears to be a contraindication to this immunosuppressive regimen. For the subjects who had labile type 1 diabetes that was difficult to control, the risk-to-benefit ratio is in favor of islet transplantation.

Insulin requirements in insulin-dependent and insulin-requiring GDM women during final month of pregnancy.

OBJECTIVE: To determine the significance of falling insulin requirements after the 36th wk of gestation in insulin-requiring pregnant women. RESEARCH DESIGN AND METHODS: Insulin requirements of women with IDDM and IRGDM were assessed from the 36th wk of pregnancy, with evaluation of maternal characteristics and fetal outcomes. RESULTS: In 32 pregnancies of women with IDDM, there was a 5 +/- 2% decrease in insulin requirements, and in 19 pregnancies of women with IRGDM, there was a 28 +/- 10% increase. Of the 62% of women whose insulin requirements declined, the decrement was 12 +/- 2% and was associated with longer duration of diabetes (12 +/- 2 vs. 6 +/- 1 yr, P less than 0.05) but not with age, prepregnancy BMI, weight gain, or maternal or fetal complications. Only 3 pregnancies in IRGDM women were associated with a decrease in insulin requirements. Although maternal parameters were no different from those with IDDM, infants born to women with IRGDM were smaller (3531 +/- 123 vs. 3874 +/- 94 g, P less than 0.005). CONCLUSIONS: Insulin requirements from the 36th wk of gestation commonly decreased in women with IDDM, associated with longer duration of diabetes but did not carry any adverse prognostic indication for the infants. Women with IRGDM experienced a continual increase in insulin requirements over the final weeks of pregnancy.

Assessment of value of glycosylated albumin and protein in detection of gestational diabetes.

There is a recognized need for the early detection of gestational diabetes, and a single blood test, if reliable, would be advantageous. Because serum albumin and total protein are glycosylated and have short life spans, we investigated the usefulness of glycosylated albumin and glycosylated protein in the detection of gestational diabetes. We studied five groups, each with 20 subjects: nonpregnant and pregnant controls, nonpregnant and pregnant insulin-dependent diabetic (IDDM) patients, and gestational diabetic patients. All patients with no history of diabetes had an oral glucose tolerance test to define their carbohydrate status. Our results showed that percent glycosylated albumin and percent glycosylated protein were significantly elevated in both groups of IDDM patients compared with the other groups. However, gestational diabetic patients had glycosylated albumin and glycosylated protein values similar to those of both control groups. Both glycosylated albumin and glycosylated protein correlated well with HbA1c determinations. Thus, glycosylated albumin and glycosylated protein may be a good index of glycemic control, but they are of little value in the diagnosis of gestational diabetes because of a lack of sensitivity: 8 and 3% for glycosylated albumin and glycosylated protein, respectively.

A comparison of the effects of n-3 fatty acids from linseed oil and fish oil in well-controlled type II diabetes.

OBJECTIVE: Supplementation of type II diabetic diets with n-3 fatty acids (FAs) from fish oil (FO) has been associated with lowered triglyceride and VLDL levels, although reports of impaired glycemic control have limited their use. Effects of n-3FAs from nonmarine sources are less well documented. Therefore, an investigation comparing the effects of linseed oil (LO) with FO supplementation was undertaken in subjects with type II diabetes. RESEARCH DESIGN AND METHODS: Eleven subjects with type II diabetes were given supplements with LO and FO for 3 months each in a randomized double-blind crossover fashion after 3 months of olive oil placebo. Oils were given as 35 mg FA.kg body wt-1.day-1. After each 3-month period, fasting glucose and insulin levels, HbA1c, lipid profiles, insulin sensitivity (SI), glucose effectiveness (SG), and acute insulin response to glucose (AIRG) were evaluated. RESULTS: HbA1c and lipid values were within the normal range at randomization. Repeated measures analysis of variance testing found no significant differences in weight; fasting glucose and insulin levels; HbA1c; total, LDL, and HDL cholesterol levels; SI; SG; or AIRG with either active oil. FO was associated with significant reductions in triglycerides and a trend toward decreased SI. CONCLUSIONS: In a population with well-controlled type II diabetes, 3 months of FO but not LO resulted in lowered triglyceride levels. Neither LO nor FO significantly affected glycemic control, cholesterol values, SG, or insulin secretion, while a nonsignificant trend toward decreased insulin sensitivity was found with FO.

Variation of postprandial plasma glucose, palatability, and symptoms associated with a standardized mixed test meal versus 75 g oral glucose.

OBJECTIVE: To compare within-subject variability of plasma glucose measured 2 h after a glucose tolerance test (GTT) with that of plasma glucose measured 2 h after administration of a standardized test meal (diabetes screening product [DSP], Ceapro, Edmonton, Alberta, Canada) and to determine the relationship between the two sets of plasma glucose measurements. RESEARCH DESIGN AND METHODS: Plasma glucose and insulin responses of 36 overnight-fasted subjects (10 lean normal, 9 obese normal, 9 with impaired glucose tolerance [IGT], and 8 with mild diabetes) were studied on eight different mornings after they consumed 75 g oral glucose or 50 g carbohydrate from the DSP. Each test meal was repeated four times by each subject. Within-subject coefficients of variation (CVs) (CV = 100 x SD/mean) of plasma glucose concentrations 2 h after administration of the GTT and DSP were compared by repeated measures ANOVA and linear regression analysis. RESULTS: Mean plasma glucose 2 h after administration of the DSP (D) was linearly related to that 2 h after the GTT (G): G = 1.5 x D - 1.6 (r = 0.97, P < 0.0001). The CV of 2-h plasma glucose was significantly lower after administration of the DSP, 10.5 +/- 1.0%, than after the GTT, 12.7 +/- 1.18% (P = 0.025). The effect of test meal on CV differed in different groups of subjects (P = 0.018), with the largest difference found in IGT subjects, in whom the CV after DSP administration was 47% less than after the GTT (P = 0.0005). The DSP was significantly more palatable and produced fewer adverse symptoms than the GTT. CONCLUSIONS: Plasma glucose concentrations measured 2 h after DSP administration are closely related to those measured 2 h after the GTT but are more consistent than the 2-h post-GTT concentrations within the critical IGT range. This finding suggests that measurement of plasma glucose 2 h after administration of the DSP may allow more precise discrimination among normal glucose levels, IGT, and diabetes than measurement of plasma glucose 2 h after the GTT.

No relationship between carbohydrate intake and effect of acarbose on HbA1c or gastrointestinal symptoms in type 2 diabetic subjects consuming 30-60% of energy from carbohydrate.

OBJECTIVE: To determine the relationship between carbohydrate intake and the effect of acarbose on HbA1c in subjects with type 2 diabetes treated with acarbose alone, acarbose plus sulfonylurea, acarbose plus metformin, or acarbose plus insulin. RESEARCH DESIGN AND METHODS: We conducted a double-blind randomized placebo-controlled study in which subjects with diabetes in four treatment strata (77 on diet alone, 83 treated with metformin, 103 treated with sulfonylurea, and 91 treated with insulin) were randomized to treatment with placebo or acarbose for 12 months. Before randomization, and 3, 6, 9, and 12 months after randomization, fasting blood was obtained for HbA1c, and 3-day diet records were collected. Subjects who completed at least 6 months of acarbose therapy and provided at least three 3-day diet records were included. RESULTS: In the 114 subjects included in this analysis, carbohydrate intake varied from approximately 30-60% of energy There was no significant relationship between carbohydrate intake and change in HbA1c in any of the four treatment strata (diet: n=26, r=0.35, P=0.076; metformin: n=27, r=0.26, P=0.19; sulfonylurea: n=35, r=0.24, P=0.16; insulin: n=25, r=-0.27, P=0.19). In the 80 subjects consuming <50% of energy from carbohydrate, the fall in HbA1c (7.83 +/-0.17% at baseline to 6.72+/-0.13% on acarbose, P < 0.001) was no different from that of the 34 subjects consuming >50% of energy from carbohydrate (7.55+/-0.25% at baseline to 6.66+/-0.23% on acarbose, P < 0.001). There was no difference in carbohydrate intake between those who dropped out of the study because of gastrointestinal side effects and those who did not, and there was no relationship between severity of symptoms and the composition of the diet. CONCLUSIONS: In subjects with type 2 diabetes consuming 30-60% of energy from carbohydrate, the effect of acarbose on HbA1c and gastrointestinal symptoms was not related to carbohydrate intake. Because most people consume at least 30% of energy from carbohydrate, we conclude that no special diet is needed for acarbose to be effective in improving blood glucose control in the treatment of type 2 diabetes.

Effect of acarbose on insulin sensitivity in elderly patients with diabetes.

OBJECTIVE: To study the effect of acarbose, an alpha-glucosidase inhibitor, on insulin release and insulin sensitivity in elderly patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Elderly patients with type 2 diabetes were randomly treated in a double-blind fashion with placebo (n = 23) or acarbose (n = 22) for 12 months. Before and after randomization, subjects underwent a meal tolerance test and a hyperglycemic glucose clamp study designed to measure insulin release and sensitivity. RESULTS: After 12 months of therapy there was a significant difference in the change in fasting plasma glucose levels (0.2 +/- 0.3 vs. -0.5 +/- 0.2 mmol/l, placebo vs. acarbose group, respectively; P < 0.05) and in incremental postprandial glucose values (-0.4 +/- 0.6 vs. -3.5 +/- 0.6 mmol/l, placebo vs. acarbose group, P < 0.001) between groups. There was a significant difference in the change in HbA(1c) values in response to treatment (0.4 +/- 0.2 vs. -0.4 +/- 0.1%, placebo vs. acarbose group, P < 0.01). The change in fasting insulin in response to treatment (-2 +/- 2 vs. -13 +/- 4 pmol/l, placebo vs. acarbose group, P < 0.05) and incremental postprandial insulin responses (-89 +/- 26 vs. -271 +/- 59 pmol/l, placebo vs. acarbose group, P < 0.01) was also significantly different between groups. During the hyperglycemic clamps, glucose and insulin values were similar in both groups before and after therapy However, there was a significant difference in the change in insulin sensitivity in response to treatment between the placebo and the acarbose groups (0.001 +/- 0.001 vs. 0.004 +/- 0.001 mg/kg x min(-1) [pmol/l](-1), respectively, P < 0.05) CONCLUSIONS: Acarbose increases insulin sensitivity but not insulin release in elderly patients with diabetes.

Influence of a natural and a synthetic inhibitor of factor XIIIa on fibrin clot rheology.

We investigated the origins of greater clot rigidity associated with FXIIIa-dependent cross-linking. Fibrin clots were examined in which cross-linking was controlled through the use of two inhibitors: a highly specific active-center-directed synthetic inhibitor of FXIIIa, 1,3-dimethyl-4,5-diphenyl-2[2(oxopropyl)thio]imidazolium trifluoromethylsulfonate, and a patient-derived immunoglobulin directed mainly against the thrombin-activated catalytic A subunits of thrombin-activated FXIII. Cross-linked fibrin chains were identified and quantified by one- and two-dimensional gel electrophoresis and immunostaining with antibodies specific for the alpha- and gamma-chains of fibrin. Gamma-dimers, gamma-multimers, alpha(n)-polymers, and alpha(p)gamma(q)-hybrids were detected. The synthetic inhibitor was highly effective in preventing the production of all cross-linked species. In contrast, the autoimmune antibody of the patient caused primarily an inhibition of alpha-chain cross-linking. Clot rigidities (storage moduli, G') were measured with a cone and plate rheometer and correlated with the distributions of the various cross-linked species found in the clots. Our findings indicate that the FXIIIa-induced dimeric cross-linking of gamma-chains by itself is not sufficient to stiffen the fibrin networks. Instead, the augmentation of clot rigidity was more strongly correlated with the formation of gamma-multimers, alpha(n)-polymers, and alpha(p)gamma(q)-hybrid cross-links. A mechanism is proposed to explain how these cross-linked species may enhance clot rigidity.