Association between maternal glucose and large for gestational outcomes: Real-world evidence to support Hyperglycaemia and Adverse Pregnancy Outcomes (HAPO) study findings.

AIMS: To compare large for gestational age (LGA) rates by maternal glucose levels in a real-world setting with those in the Hyperglycaemia and Adverse Pregnancy Outcomes (HAPO) study. To examine the association between fasting plasma glucose (FPG), 1- and 2-h on a 75-g oral glucose tolerance tests (OGTT) and LGA. METHODS: Pregnancies were categorized according to HAPO thresholds. Category-specific LGA rates were compared to those in HAPO. Categories with glucose thresholds below or above the diagnostic criteria for gestational diabetes mellitus (GDM) were labelled as lower and higher/GDM, respectively. GDM pregnancies were further stratified according to FPG or post-load elevations and logistic regression was used to examine their independent association with LGA. FINDINGS: In our cohort of 97,032 pregnancies, rates of LGA increased with increasing maternal glucose in lower categories of FPG, 1- and 2-h glucose (trend p < 0.01). However, LGA rates in higher/GDM categories were significantly lower in our study than those in HAPO for 1- and 2-h glucose, but not for FPG. Elevated FPG alone was associated with an almost twofold increase in risk of LGA, while elevated post-load glucose alone was associated with a 20% reduction in risk of LGA, compared to negative OGTT. CONCLUSIONS: Real-world data confirm the HAPO study findings at lower levels of maternal glycaemia. At higher levels, GDM diagnosis and treatment appear to be effective in reducing rates of LGA in pregnancies with post-load glucose elevations, but not elevated FPG. Elevated FPG is a stronger predictor of LGA than post-load glucose elevations.

Association between maternal diabetes, being large for gestational age and breast-feeding on being overweight or obese in childhood.

AIMS/HYPOTHESIS: This study aimed to examine the association of maternal diabetes, being large for gestational age (LGA) and breast-feeding with being overweight or obese in pre-school-aged children. METHODS: Data on height and weight at the time of their pre-school (age 4-6 years) immunisation visit between January 2009 and August 2017, as well as breast-feeding status in the first 5 months of life, for 81,226 children born between January 2005 and August 2013 were linked with maternal hospitalisation and outpatient records and birth registry data. Children were grouped into six categories based on maternal diabetes status during pregnancy (no diabetes, gestational diabetes or pre-existing diabetes) and birthweight (appropriate for gestational age [AGA] or LGA). WHO criteria were used to identify children who were overweight or obese. RESULTS: There were 69,506 children in the no diabetes/AGA group (control), 5926 in the no diabetes/LGA group, 4563 in the gestational diabetes/AGA group, 573 in the gestational diabetes/LGA group, 480 in the pre-existing diabetes/AGA group and 178 in the pre-existing diabetes/LGA group. The rate of being overweight/obese at pre-school age ranged from 20.5% in the control group to 42.9% in the gestational diabetes/LGA group. The adjusted attributable risk per cent for LGA alone (39.4%) was significantly higher than that for maternal gestational diabetes (16.0%) or pre-existing diabetes alone (15.1%); the risk for the combinations of gestational diabetes/LGA and pre-existing diabetes/LGA were 50.1% and 39.1%, respectively. Further stratification of the pre-existing diabetes groups found the prevalence of being overweight/obese was 21.2% in the type 1/AGA group, 31.4% in the type 1/LGA group (similar to those in the no diabetes groups), 26.7% in the type 2/AGA group and 42.5% in the type 2/LGA group. Breast-feeding was associated with a lower likelihood of being overweight/obese in childhood in all groups except gestational diabetes/LGA and pre-existing diabetes/LGA (both type 1 and type 2). CONCLUSION/INTERPRETATION: LGA is a stronger marker for risk of being overweight/obese in early childhood, compared with maternal diabetes during pregnancy. Rates of being overweight/obese in childhood were highest in LGA children born to mothers with gestational diabetes or pre-existing type 2 diabetes. Breast-feeding was associated with a lower risk of being overweight/obese in childhood in the majority of children; however, this association was not maintained in LGA children of mothers with diabetes.

Metformin in women with type 2 diabetes in pregnancy (MiTy): a multi-center randomized controlled trial.

BACKGROUND: The incidence of type 2 diabetes in pregnancy is rising and rates of serious adverse maternal and fetal outcomes remain high. Metformin is a biguanide that is used as first-line treatment for non-pregnant patients with type 2 diabetes. We hypothesize that metformin use in pregnancy, as an adjunct to insulin, will decrease adverse outcomes by reducing maternal hyperglycemia, maternal insulin doses, maternal weight gain and gestational hypertension/pre-eclampsia. In addition, since metformin crosses the placenta, metformin treatment of the fetus may have a direct beneficial effect on neonatal outcomes. Our aim is to compare the effectiveness of the addition of metformin to insulin, to standard care (insulin plus placebo) in women with type 2 diabetes in pregnancy. METHODS: The MiTy trial is a multi-centre randomized trial currently enrolling pregnant women with type 2 diabetes, who are on insulin, between the ages of 18-45, with a gestational age of 6 weeks 0 days to 22 weeks 6 days. In this randomized, double-masked, parallel placebo-controlled trial, after giving informed consent, women are randomized to receive either metformin 1,000 mg twice daily or placebo twice daily. A web-based block randomization system is used to assign women to metformin or placebo in a 1:1 ratio, stratified for site and body mass index. The primary outcome is a composite neonatal outcome of pregnancy loss, preterm birth, birth injury, moderate/severe respiratory distress, neonatal hypoglycemia, or neonatal intensive care unit admission longer than 24 h. Secondary outcomes are large for gestational age, cord blood gas pH < 7.0, congenital anomalies, hyperbilirubinemia, sepsis, hyperinsulinemia, shoulder dystocia, fetal fat mass, as well as maternal outcomes: maternal weight gain, maternal insulin doses, maternal glycemic control, maternal hypoglycemia, gestational hypertension, preeclampsia, cesarean section, number of hospitalizations during pregnancy, and duration of hospital stays. The trial aims to enroll 500 participants. DISCUSSION: The results of this trial will inform endocrinologists, obstetricians, family doctors, and other healthcare professionals caring for women with type 2 diabetes in pregnancy, as to the benefits of adding metformin to insulin in this high risk population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: no. NCT01353391 . Registered February 6, 2009.

Elevated lipogenesis and diminished cholesterol synthesis in patients with hepatitis C viral infection compared to healthy humans.

UNLABELLED: Hepatitis C virus (HCV) exerts a profound influence on host lipid metabolism. It has been suggested that the synthesis of both fatty acids (FA) and cholesterol is dysregulated in HCV but this has not been directly quantified in humans. The purpose of this study was to measure lipogenesis and cholesterol synthesis using stable isotopes in patients with HCV (n = 5) and healthy control (n = 9) subjects recruited from the University of Alberta hospital. Blood samples were taken at fasting (0 and 24 hours) and after meals over the day to mimic typical food consumption and postprandial metabolism. Isolation of free cholesterol (FC), cholesteryl ester (CE), and triglyceride (TG) from plasma and very low-density lipoproteins (VLDL) was used to measure FA and cholesterol synthesis using deuterium uptake and isotope ratio mass spectrometry. FA composition was analyzed by gas chromatography. VLDL-TG levels of polyunsaturated fatty acids (PUFA), including linoleic and linolenic acid, were lower in HCV compared to control (P < 0.05 for both). Fasting hepatic lipogenesis was significantly higher in HCV (2.80 ± 0.55%) compared to control (1.19 ± 0.27%; P = 0.03). Conversely, fasting whole-body synthesis of FC (HCV 1.64 ± 0.28% versus control 8.78 ± 1.59%) and CE (HCV 0.26 ± 0.08% versus control 1.92 ± 0.25%), as well as hepatic FC synthesis (HCV 1.68 ± 0.26% versus control 8.12 ± 0.77%) was lower in HCV (P < 0.001 for all). CONCLUSION: These data provide evidence that lipogenesis is elevated while cholesterol synthesis is impaired in HCV, supporting previous findings from cellular and animal models. Low PUFA levels combined with elevated lipogenesis suggests a role for dietary PUFA supplementation in HCV patients.

Glucose control during labor and delivery.

Neonatal hypoglycemia is an important consequence for the infant of the mother with diabetes. We have reviewed 24 published papers of various protocols for control of glucose in pregnant diabetic women during labor and delivery including our own published work. A relationship of maternal glucose during labor and neonatal hypoglycemia was sought in 19 of these studies. A significant inverse relationship was found in 10 reports with 3 others showing a similar trend. In all but 1 of these 13 studies the participants had pregestational diabetes. Three of the 6 studies not reporting an inverse relationship involved women with GDM. From this review it appears that the maternal glucose should be maintained between 4.0 and 6.0-7.0 mmol/L during labor. Most women with gestational diabetes, especially if they require <1.0 units/kg/d of insulin, can simply be monitored without intravenous insulin. Our own results demonstrate that a target glucose of 4.0-6.0 mmol/L can be used safely and results in a low rate of neonatal hypoglycemia using an iterative glucose insulin infusion protocol for women with pregestational diabetes and when needed for women with gestational diabetes.

Clinical diagnosis of gestational diabetes.

Gestational diabetes mellitus (GDM) diagnosis remains controversial. ACOG criteria are based on the long-term risk of maternal diabetes. ADA recently suggested diagnosing GDM with 1 elevated value on an oral glucose tolerance test based on a 1.75-fold risk of large-for-gestational age infants resulting in a 17.8% rate of GDM. Given the lack of neonatal-based outcomes for the traditional position and problems of reproducibility and benefit/harm balance of the ADA approach, an alternative is presented herein based on a 2-fold risk of a large-for-gestational age baby, requiring 2 separate abnormalities to reduce false positives giving a more balanced benefit/harm ratio (10% GDM rate).

Risks of gestational diabetes and preeclampsia over the last decade in a cohort of Alberta women.

OBJECTIVES: The incidence of gestational diabetes mellitus (GDM) is increasing. However, less is known about the incidence of preeclampsia (PE) and whether it is affected by the presence of GDM. We sought to document the population-level incidence of GDM and PE during the last decade and examine the association between GDM and PE after accounting for established risk factors. METHODS: We selected a population-based cohort retrospectively using data from the Alberta Perinatal Health Program registry. Logistic regression was used to examine the association between GDM and PE after adjusting for baseline characteristics. RESULTS: Of 426 296 deliveries between 2000 and 2009, 422 672 were in women without pre-existing diabetes. Among these women, the incidence of GDM increased from 3.1% in 2000 to 4.6% in 2009 (P < 0.01), while the incidence of PE remained stable at approximately 1.3% per year. The incidence of PE was significantly higher in women with GDM than in those without GDM (2.6% vs. 1.2%; P < 0.01). After adjustment, women with GDM had a 90% higher risk of PE than those without GDM (OR 1.9; 95% CI 1.7 to 2.1). Other significant risk factors for PE were age, obesity, nulliparity, multifetal gestation, pre-existing hypertension, and chronic kidney disease. CONCLUSION: In this contemporary population-based study spanning 10 years, there was a significant increase in the incidence of GDM over time. The higher incidence of PE in women with GDM than in normoglycemic women suggests a need for heightened surveillance and monitoring of women with GDM for the development of PE.

Objectifs : L'incidence du diabète sucré gestationnel (DSG) est en hausse. Toutefois, nous en savons moins pour ce qui est de l'incidence de la prééclampsie (PE) et de la question de savoir si cette dernière est affectée par la présence d'un DSG. Nous avons cherché à documenter l'incidence populationnelle du DSG et de la PE au cours de la dernière décennie, ainsi qu'à examiner l'association entre le DSG et la PE à la suite de la neutralisation de l'effet des facteurs de risque établis. Méthodes : Nous avons, de façon rétrospective, sélectionné une cohorte en population générale au moyen de données issues du registre du Alberta Perinatal Health Program. Une régression logistique a été utilisée pour examiner l'association entre le DSG et la PE, à la suite de la neutralisation de l'effet des caractéristiques de base. Résultats : Des 426 296 accouchements s'étant déroulés entre 2000 et 2009, 422 672 ont été constatés chez des femmes ne présentant pas un diabète préexistant. Chez ces femmes, l'incidence du DSG est passée de 3,1 % en 2000 à 4,6 % en 2009 (P < 0,01), tandis que l'incidence de la PE est demeurée stable à environ 1,3 % par année. L'incidence de la PE était considérablement plus élevée chez les femmes présentant un DSG que chez les femmes qui n'en présentaient pas un (2,6 % vs 1,2 %; P < 0,01). À la suite de la neutralisation, les femmes présentant un DSG connaissaient une hausse du risque de PE de l'ordre de 90 %, par comparaison avec les femmes ne présentant pas un DSG (RC 1,9; IC à 95 %, 1,7 - 2,1). Parmi les autres facteurs de risque significatifs en matière de PE, on trouvait l'âge, l'obésité, la nulliparité, la gestation multifœtale, l'hypertension préexistante et la maladie rénale chronique. Conclusion : Dans le cadre de cette étude contemporaine en population générale couvrant une période de 10 ans, nous avons constaté une hausse considérable de l'incidence du DSG avec le temps. L'incidence accrue de la PE chez les femmes présentant un DSG, par comparaison avec les femmes normoglycémiques, semble indiquer la nécessité d'intensifier la surveillance et le monitorage de l'apparition d'une PE chez les femmes qui présentent un DSG.

Glucose control during labour in diabetic women.

OBJECTIVES: Glucose control during labour is important for mother and neonate, with high rates of neonatal hypoglycemia reported in offspring of women with pre-existing or gestational diabetes (48% and 19%, respectively). How glucose control can be achieved is rarely specified. We conducted a chart review of a standardized approach using an iterative intravenous insulin-glucose infusion. METHODS: We performed a retrospective review of the records of 274 diabetic women during labour. Fifty-five women had type 1 diabetes, 55 had type 2 diabetes, and 164 had gestational diabetes (GDM). The protocol used hourly capillary blood glucose determinations, each prompting changes in insulin-glucose infusion rates as required. Outcomes included maternal blood glucose levels three hours before delivery and neonatal hypoglycemia (blood glucose < 2 mmol/L). RESULTS: The insulin-glucose infusion was used in 47% of women with type 1, type 2, and gestational diabetes requiring ≥ 0.5 units/kg/day of insulin during pregnancy and in 8% of women with GDM treated by diet or < 0.5 units/kg/day of insulin. The overall rate of maternal hypoglycemia was low (6.6% with blood glucose ≤ 3.5 mmol/L and 1.5% ≤ 3.0 mmol/L) pre-delivery; 13.9% of women had a blood glucose level ≥ 7.0 mmol/L. The neonatal hypoglycemia rate was 7.3% (4.9% in the offspring of women with GDM and 10.9% in the offspring of women with pre-existing diabetes). In women with type 1 and type 2 diabetes and high-dose insulin-requiring GDM, the rate of blood glucose values outside the range of 3.6 to 6.9 mmol/L was lower in those using the intravenous protocol (16.7%) than in those not using it (34.8%), but this reduction was not statistically significant. CONCLUSION: Standardized management for diabetic women in labour using an intravenous insulin-glucose protocol was effective in achieving stable maternal blood glucose levels with low rates of neonatal hypoglycemia.

Interorgan Metabolism of Ganglioside Is Altered in Type 2 Diabetes.

GM3 is implicated in cell signaling, inflammation and insulin resistance. The intestinal mucosa metabolizes ganglioside and provides gangliosides for uptake by peripheral tissues. Gangliosides downregulate acute and chronic inflammatory signals. It is likely that transport of intestinal derived gangliosides to other tissues impact the same signals characteristic of inflammatory change in other chronic conditions such as Type 2 Diabetes (T2DM). The postprandial ceramide composition of GM3 and other gangliosides in plasma and chylomicrons has not been examined in T2DM. The present study assessed if diet or T2DM alters ganglioside components in plasma and chylomicrons secreted from the intestinal mucosa after a meal. GD1, GD3, and GM3 content of chylomicrons and plasma was determined by LC/triple quad MS in non-diabetic (control) and T2DM individuals in the fasting and postprandial state after 2 days of consuming a low or high fat diet in a randomized blinded crossover design. Diet fat level did not alter baseline plasma or chylomicron ganglioside levels. Four hours after the test meal, plasma monounsaturated GD3 was 75% higher, plasma saturated GD3 was 140% higher and plasma polyunsaturated GM3 30% lower in diabetic subjects compared to control subjects. At 4 h, chylomicron GD1 was 50% lower in T2DM compared to controls. The proportion of d34:1 in GD3 was more abundant and d36:1 in GD1 less abundant in T2DM compared to control subjects at 4 h. The present study indicates that T2DM alters ceramide composition of ganglioside available for uptake by peripheral tissues.

The challenge of predicting blood glucose concentration changes in patients with type I diabetes.

Patients with Type I Diabetes (T1D) must take insulin injections to prevent the serious long term effects of hyperglycemia. They must also be careful not to inject too much insulin because this could induce (potentially fatal) hypoglycemia. Patients therefore follow a "regimen" that determines how much insulin to inject at each time, based on various measurements. We can produce an effective regimen if we can accurately predict a patient's future blood glucose (BG) values from his/her current features. This study explores the challenges of predicting future BG by applying a number of machine learning algorithms, as well as various data preprocessing variations (corresponding to 312 [learner, preprocessed-dataset] combinations), to a new T1D dataset that contains 29,601 entries from 47 different patients. Our most accurate predictor, a weighted ensemble of two Gaussian Process Regression models, achieved a (cross-validation) errL1 loss of 2.7 mmol/L (48.65 mg/dl). This result was unexpectedly poor given that one can obtain an errL1 of 2.9 mmol/L (52.43 mg/dl) using the naive approach of simply predicting the patient's average BG. These results suggest that the diabetes diary data that is typically collected may be insufficient to produce accurate BG prediction models; additional data may be necessary to build accurate BG prediction models over hours.

Metformin in women with type 2 diabetes in pregnancy (MiTy): a multicentre, international, randomised, placebo-controlled trial.

BACKGROUND: Although metformin is increasingly being used in women with type 2 diabetes during pregnancy, little data exist on the benefits and harms of metformin use on pregnancy outcomes in these women. We aimed to investigate the effects of the addition of metformin to a standard regimen of insulin on neonatal morbidity and mortality in pregnant women with type 2 diabetes. METHODS: In this prospective, multicentre, international, randomised, parallel, double-masked, placebo-controlled trial, women with type 2 diabetes during pregnancy were randomly assigned from 25 centres in Canada and four in Australia to receive either metformin 1000 mg twice daily or placebo, added to insulin. Randomisation was done via a web-based computerised randomisation service and stratified by centre and pre-pregnancy BMI (<30 kg/m2 or ≥30 kg/m2) in a ratio of 1:1 using random block sizes of 4 and 6. Women were eligible if they had type 2 diabetes, were on insulin, had a singleton viable pregnancy, and were between 6 and 22 weeks plus 6 days' gestation. Participants were asked to check their fasting blood glucose level before the first meal of the day, before the last meal of the day, and 2 h after each meal. Insulin doses were adjusted aiming for identical glucose targets (fasting glucose <5·3 mmol/L [95 mg/dL], 2-h postprandial glucose <6·7 mmol/L [120 mg/dL]). Study visits were done monthly and patients were seen every 1-4 weeks as was needed for standard clinical care. At study visits blood pressure and bodyweight were measured; patients were asked about tolerance to their pills, any hospitalisations, insulin doses, and severe hypoglycaemia events; and glucometer readings were downloaded to the central coordinating centre. Participants, caregivers, and outcome assessors were masked to the intervention. The primary outcome was a composite of fetal and neonatal outcomes, for which we calculated the relative risk and 95% CI between groups, stratifying by site and BMI using a log-binomial regression model with an intention-to-treat analysis. Secondary outcomes included several relevant maternal and neonatal outcomes. The trial was registered with ClinicalTrials.gov, NCT01353391. FINDINGS: Between May 25, 2011, and Oct 11, 2018, we randomly assigned 502 women, 253 (50%) to metformin and 249 (50%) to placebo. Complete data were available for 233 (92%) participants in the metformin group and 240 (96%) in the placebo group for the primary outcome. We found no significant difference in the primary composite neonatal outcome between the two groups (40% vs 40%; p=0·86; relative risk [RR] 1·02 [0·83 to 1·26]). Compared with women in the placebo group, metformin-treated women achieved better glycaemic control (HbA1c at 34 weeks' gestation 41·0 mmol/mol [SD 8·5] vs 43·2 mmol/mol [-10]; 5·90% vs 6·10%; p=0·015; mean glucose 6·05 [0·93] vs 6·27 [0·90]; difference -0·2 [-0·4 to 0·0]), required less insulin (1·1 units per kg per day vs 1·5 units per kg per day; difference -0·4 [95% CI -0·5 to -0·2]; p<0·0001), gained less weight (7·2 kg vs 9·0 kg; difference -1·8 [-2·7 to -0·9]; p<0·0001) and had fewer caesarean births (125 [53%] of 234 in the metformin group vs 148 [63%] of 236 in the placebo group; relative risk [RR] 0·85 [95% CI 0·73 to 0·99]; p=0·031). We found no significant difference between the groups in hypertensive disorders (55 [23%] in the metformin group vs 56 [23%] in the placebo group; p=0·93; RR 0·99 [0·72 to 1·35]). Compared with those in the placebo group, metformin-exposed infants weighed less (mean birthweight 3156 g [SD 742] vs 3375 g [742]; difference -218 [-353 to -82]; p=0·002), fewer were above the 97th centile for birthweight (20 [9%] in the metformin group vs 34 [15%] in the placebo group; RR 0·58 [0·34 to 0·97]; p=0·041), fewer weighed 4000 g or more at birth (28 [12%] in the metformin group vs 44 [19%] in the placebo group; RR 0·65 [0·43 to 0·99]; p=0·046), and metformin-exposed infants had reduced adiposity measures (mean sum of skinfolds 16·0 mm [SD 5·0] vs 17·4 [6·2] mm; difference -1·41 [-2·6 to -0·2]; p=0·024; mean neonatal fat mass 13·2 [SD 6·2] vs 14·6 [5·0]; p=0·017). 30 (13%) infants in the metformin group and 15 (7%) in the placebo group were small for gestational age (RR 1·96 [1·10 to 3·64]; p=0·026). We found no significant difference in the cord c-peptide between groups (673 pmol/L [435] in the metformin group vs 758 pmol/L [595] in the placebo group; p=0·10; ratio of means 0·88 [0·72 to 1·02]). The most common adverse event reported was gastrointestinal (38 events in the metformin group and 38 events in the placebo group). INTERPRETATION: We found several maternal glycaemic and neonatal adiposity benefits in the metformin group. Along with reduced maternal weight gain and insulin dosage and improved glycaemic control, the lower adiposity and infant size measurements resulted in fewer large infants but a higher proportion of small-for-gestational-age infants. Understanding the implications of these effects on infants will be important to properly advise patients who are contemplating the use of metformin during pregnancy. FUNDING: Canadian Institutes of Health Research, Lunenfeld-Tanenbaum Research Institute, University of Toronto.

International trial of the Edmonton protocol for islet transplantation.

BACKGROUND: Islet transplantation offers the potential to improve glycemic control in a subgroup of patients with type 1 diabetes mellitus who are disabled by refractory hypoglycemia. We conducted an international, multicenter trial to explore the feasibility and reproducibility of islet transplantation with the use of a single common protocol (the Edmonton protocol). METHODS: We enrolled 36 subjects with type 1 diabetes mellitus, who underwent islet transplantation at nine international sites. Islets were prepared from pancreases of deceased donors and were transplanted within 2 hours after purification, without culture. The primary end point was defined as insulin independence with adequate glycemic control 1 year after the final transplantation. RESULTS: Of the 36 subjects, 16 (44%) met the primary end point, 10 (28%) had partial function, and 10 (28%) had complete graft loss 1 year after the final transplantation. A total of 21 subjects (58%) attained insulin independence with good glycemic control at any point throughout the trial. Of these subjects, 16 (76%) required insulin again at 2 years; 5 of the 16 subjects who reached the primary end point (31%) remained insulin-independent at 2 years. CONCLUSIONS: Islet transplantation with the use of the Edmonton protocol can successfully restore long-term endogenous insulin production and glycemic stability in subjects with type 1 diabetes mellitus and unstable control, but insulin independence is usually not sustainable. Persistent islet function even without insulin independence provides both protection from severe hypoglycemia and improved levels of glycated hemoglobin. (ClinicalTrials.gov number, NCT00014911 [ClinicalTrials.gov].).

The Canadian Trial of Carbohydrates in Diabetes (CCD), a 1-y controlled trial of low-glycemic-index dietary carbohydrate in type 2 diabetes: no effect on glycated hemoglobin but reduction in C-reactive protein.

BACKGROUND: The optimal source and amount of dietary carbohydrate for managing type 2 diabetes (T2DM) are unknown. OBJECTIVE: We aimed to compare the effects of altering the glycemic index or the amount of carbohydrate on glycated hemoglobin (HbA1c), plasma glucose, lipids, and C-reactive protein (CRP) in T2DM patients. DESIGN: Subjects with T2DM managed by diet alone (n=162) were randomly assigned to receive high-carbohydrate, high-glycemic-index (high-GI), high-carbohydrate, low-glycemic-index (low-GI), or low-carbohydrate, high-monounsaturated-fat (low-CHO) diets for 1 y. RESULTS: The high-GI, low-GI, and low-CHO diets contained, respectively, 47%, 52%, and 39% of energy as carbohydrate and 31%, 27%, and 40% of energy as fat; they had GIs of 63, 55, and 59, respectively. Body weight and HbA1c did not differ significantly between diets. Fasting glucose was higher (P=0.041), but 2-h postload glucose was lower (P=0.010) after 12 mo of the low-GI diet. With the low-GI diet, overall mean triacylglycerol was 12% higher and HDL cholesterol 4% lower than with the low-CHO diet (P<0.05), but the difference in the ratio of total to HDL cholesterol disappeared by 6 mo (time x diet interaction, P=0.044). Overall mean CRP with the low-GI diet, 1.95 mg/L, was 30% less than that with the high-GI diet, 2.75 mg/L (P=0.0078); the concentration with the low-CHO diet, 2.35 mg/L, was intermediate. CONCLUSIONS: In subjects with T2DM managed by diet alone with optimal glycemic control, long-term HbA1c was not affected by altering the GI or the amount of dietary carbohydrate. Differences in total:HDL cholesterol among diets had disappeared by 6 mo. However, because of sustained reductions in postprandial glucose and CRP, a low-GI diet may be preferred for the dietary management of T2DM.

Genetic polymorphisms of tumor necrosis factor-alpha modify the association between dietary polyunsaturated fatty acids and fasting HDL-cholesterol and apo A-I concentrations.

BACKGROUND: Heterogeneity in circulating lipid concentrations in response to dietary polyunsaturated fatty acids (PUFAs) may be due, in part, to genetic variations. Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that can induce hyperlipidemia and is known to be modulated by dietary PUFAs. OBJECTIVE: The objective was to determine whether TNF-alpha genotypes modify the association between dietary PUFA intake and serum lipid concentrations. DESIGN: The study involved 53 men and 56 women aged 42-75 y with type 2 diabetes. Dietary intakes were assessed with the use of a 3-d food record, and blood samples were collected to determine fasting serum lipids. DNA was isolated from blood for genotyping by polymerase chain reaction-restriction fragment length polymorphism for the TNF-alpha -238G-->A and -308G-->A polymorphisms. RESULTS: PUFA intake was positively associated with serum HDL cholesterol in carriers of the -238A allele (beta = 0.06 +/- 0.03 mmol/L per 1% of energy from PUFAs; P = 0.03), but negatively associated in those with the -238GG genotype (beta = -0.03 +/- 0.01, P = 0.03) (P = 0.004 for interaction). PUFA intake was inversely associated with HDL cholesterol in carriers of the -308A allele (beta = -0.07 +/- 0.02, P = 0.002), but not in those with the -308GG genotype (beta = 0.02 +/- 0.02, P = 0.13) (P = 0.001 for interaction). A stronger gene x diet interaction was observed when the polymorphisms at the 2 positions (-238/-308) were combined (P = 0.0003). Similar effects were observed for apolipoprotein A-I, but not with other dietary fatty acids and serum lipids. CONCLUSION: TNF-alpha genotypes modify the relation between dietary PUFA intake and HDL-cholesterol concentrations. These findings suggest that genetic variations affecting inflammation may explain some of the inconsistencies between previous studies relating PUFA intake and circulating HDL.

Quality of life after islet transplant: impact of the number of islet infusions and metabolic outcome.

The health-related quality of life (HRQL; Health Utilities Index Mark 2) and the fear of hypoglycemia (Hypoglycemia Fear Survey) were assessed after islet transplant; the impact of a single islet infusion and of the metabolic outcome were determined. A control group included 166 patients with type 1 diabetes. Islet transplant had no impact on overall HRQL. Prior to transplant, islet recipients had more fear of hypoglycemia than controls (P<0.000001), but this improved up to 36 months after transplant (P<0.00001, pretransplant vs. each time point). With a single islet infusion, this fear improved substantially (P<0.00001), but improved further with subsequent islet infusions (P

Tumor necrosis factor alpha -238G>A genotype alters postprandial plasma levels of free fatty acids in obese individuals with type 2 diabetes mellitus.

Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine that impairs insulin action and alters lipid metabolism. We investigated the effects of genetic polymorphisms of TNF-alpha on circulating biomarkers of insulin resistance and lipid metabolism during an 8-hour metabolic profile test and a 2-hour oral glucose tolerance test in subjects with type 2 diabetes mellitus. Subjects (N = 123) recruited were type 2 diabetic men (n = 56) and women (n = 67) aged 36 to 75 years with a body mass index of at least 25 kg/m(2). Blood samples were collected to determine postprandial changes in circulating lipid levels and biomarkers of insulin resistance. Subjects were genotyped by polymerase chain reaction-restriction fragment length polymorphism for the TNF-alpha -238G>A, -308G>A, and -863C>A polymorphisms. Compared with subjects who were homozygous for the -238G allele, carriers of the -238A allele had an altered ability to suppress postprandial free fatty acids as shown by an increased net incremental area under the curve (0.26 +/- 2.44 vs -1.33 +/- 2.71 mEq h(-1) L(-1), P = .002) during the 8-hour metabolic profile test. This effect was observed in obese (1.04 +/- 2.42 vs -1.68 +/- 2.70 mEq h(-1) L(-1), P = .0004) but not in non-obese (-0.63 +/- 2.20 vs -0.95 +/- 2.71 mEq h(-1) L(-1), P = .6) individuals. Among obese subjects, carriers of the -308A allele had greater insulin resistance as estimated by the homeostasis model assessment of insulin resistance index (4.36 +/- 2.83 vs 2.85 +/- 1.75, P = .01), but no differences were observed among non-obese subjects (2.19 +/- 1.24 vs 1.97 +/- 0.90, P = .6). Our findings suggest that the -238G>A and -308G>A polymorphisms of TNF-alpha alter circulating free fatty acids and insulin resistance in obese subjects with type 2 diabetes mellitus.

Long-term graft function after allogeneic islet transplantation.

Islet transplants are emerging as a viable option for the treatment of type 1 diabetes mellitus. From 1989 to 1995 we conducted a series of simultaneous islet-kidney transplants in six uremic type 1 diabetic patients. We report two of these patients who have shown persistent islet graft function over many years. Two female patients with duration of diabetes of 27 and 37 years underwent simultaneous islet-kidney transplant under steroid- and cyclosporine-based immunosuppression. Freshly isolated islets were supplemented with cryopreserved islets from our low-temperature bank of frozen islets. A total islet mass of 9,866 and 15,061 islet equivalents/kg body weight, respectively, was transplanted into the liver through portal vein. Reasonable blood glucose control has been achieved for up to 6 years posttransplant in one patient, but there was minimum clinical benefit from the islet graft at 10 years. In contrast, sustained insulin secretion with nearly normal HbA1c at 13 years follow-up was observed in another patient, providing hope for improving long-term graft outcomes for islet transplant recipient.

Improved A1C Levels in Type 1 Diabetes with Smartphone App Use.

OBJECTIVES: Smartphones are a potentially useful tool in diabetes care. We have developed an application (app) linked to a website, Intelligent Diabetes Management (IDM), which serves as both an insulin bolus calculator and an electronic diabetes diary. We have prospectively studied whether patients using this app improved control of their glucose levels. METHODS: Patients with type 1 diabetes were recruited. There was a 4-week observation period, midway during which we offered to review the participants' records. The app was then downloaded and participants' diabetes regimens entered on the synchronized IDM website. At 2, 4, 8, 12 and 16 weeks of the active phase, their records were reviewed online, and feedback was provided electronically. The primary endpoint was change in levels of glycated hemoglobin (A1C). RESULTS: Of the 31 patients recruited, 18 completed the study. These 18 made 572±98 entries per person on the IDM system over the course of the study (≈5.1/day). Their ages were 40.0±13.9 years, the durations of their diabetes were 27.3±14.9 years and 44% used insulin pumps. The median A1C level fell from 8.1% (7.5 to 9.0, IQ range) to 7.8% (6.9 to 8.3; p<0.001). During the observation period, glucose records were reviewed for 50% of the participants. In the active phase, review of the glucose diaries took less time on the IDM website than using personal glucose records in the observation period, median 6 minutes (5 to 7.5 IQ range) vs. 10 minutes (7.5 to 10.5 IQ range; p<0.05). CONCLUSIONS: Our smartphone app enables online review of glucose records, requires less time for clinical staff and is associated with improved glucose control.

Prevalence of gestational diabetes among Chinese and South Asians: A Canadian population-based analysis.

BACKGROUND: There is considerable geographic variation in gestational diabetes mellitus (GDM) rates. We used data from two Canadian provinces, British Columbia (BC) and Alberta (AB), to determine the impact of ethnicity on GDM prevalence and neonatal outcomes. RESEARCH DESIGN AND METHODS: All deliveries between 04/01/2004 and 03/31/2010 in AB (n=249,796) and BC (n=248,217) were analyzed. We calculated GDM prevalence among Chinese, South-Asian, and the general population (predominantly Caucasian) women. RESULTS: Overall GDM prevalence was 4.8% (n=12,036) in AB and 7.2% (n=17,912) in BC. In both provinces, the prevalence of GDM was significantly higher in Chinese (AB:11%; BC:13.5%) and South Asian women (AB:8.4%;BC:13.9%) compared to the general population (AB:4.2%; BC: 5.8%). Chinese women were significantly older (AB:32.7; BC:33.0years) compared to the general population (AB:29.1; BC:30.1years). The odds of GDM relative to the general-population were 2-fold higher for South Asians in both provinces and almost 3-fold higher for Chinese in BC. Among GDM cases, compared to the general population, Chinese and South Asian infants were less likely to be LGA, more likely to be SGA, and had similar neonatal mortality rates. CONCLUSIONS: Compared to the general population, GDM prevalence is higher in Chinese and South Asian Canadians. Increased maternal age is a major contributor to higher prevalence of GDM in Chinese women. GDM rates were higher in both ethnic and general population women in BC compared to AB, suggesting that in addition to differences in ethnic distribution, differences in diagnostic practices are likely contributing to observed geographic differences in GDM prevalence.