Postpartum weight retention and the early evolution of cardiovascular risk over the first 5 years after pregnancy.

BACKGROUND: The cumulative effect of postpartum weight retention from each pregnancy in a woman's life may contribute to her risk of ultimately developing type 2 diabetes and cardiovascular disease. However, there is limited direct evidence supporting this hypothesis. Thus, we sought to characterize the impact of postpartum weight retention on the trajectories of cardiovascular risk factors over the first 5-years after pregnancy. METHODS: In this prospective observational cohort study, 330 women (mean age 35.7 ± 4.3 years, mean pre-pregnancy body mass index 25.2 ± 4.8 kg/m2, 50.9% primiparous) underwent serial cardiometabolic characterization (anthropometry, blood pressure, lipids, oral glucose tolerance test, insulin sensitivity/resistance (Matsuda index, HOMA-IR), C-reactive protein (CRP), adiponectin) at 1-year, 3-years, and 5-years postpartum. Based on the magnitude of weight change between pre-pregnancy and 5-years postpartum, they were stratified into the following 3 groups: weight loss (n = 100), weight gain 0-6% (n = 110), and weight gain ≥ 6% (n = 120). RESULTS: At 1-year postpartum, cardiovascular risk factors did not differ between the groups. However, an adverse risk factor profile progressively emerged in the weight retention groups at 3- and 5-years. Indeed, after covariate adjustment, there was stepwise worsening (from the weight loss group to weight gain 0-6% to weight gain ≥ 6% group) of the following cardiovascular risk factors at 5-years: triglycerides (p = 0.001), HDL (p = 0.02), LDL (p = 0.01), apolipoprotein-B (p = 0.003), Matsuda index (p < 0.0001), HOMA-IR (p < 0.0001), fasting glucose (p = 0.07), and CRP (p = 0.01). Moreover, on logistic regression analyses, weight gain ≥ 6% emerged as an independent predictor of pre-diabetes/diabetes at 5-years (adjusted OR = 3.40, 95%CI: 1.63-7.09). CONCLUSION: Postpartum weight retention predicts trajectories of worsening cardiovascular risk factors and glucose intolerance over the first 5-years after delivery, consistent with its postulated contribution to future vascular disease in women.

Deteriorating beta cell function is the dominant determinant of progression from normal glucose tolerance to prediabetes/diabetes in young women following pregnancy.

AIMS/HYPOTHESIS: Excess adiposity, insulin resistance and beta cell dysfunction each contribute to the development of prediabetes (impaired glucose tolerance and/or impaired fasting glucose)/diabetes but their comparative impact in relation to one another remains uncertain. We thus ranked their contributions to incident dysglycaemia over the first 5 years postpartum in women reflecting the full spectrum of gestational glucose tolerance (spanning normoglycaemia to gestational diabetes) and hence a range of future diabetic risk. METHODS: In this study, 302 women with normal glucose tolerance (NGT) on OGTT at 3 months postpartum underwent repeat OGTT at 1 year, 3 years and 5 years, enabling serial assessment of glucose tolerance, insulin sensitivity/resistance (Matsuda index, HOMA-IR) and beta cell function (insulin secretion-sensitivity index-2 [ISSI-2], insulinogenic index [IGI]/HOMA-IR). Determinants of prediabetes/diabetes were ranked by change in concordance index (CCI) of Cox proportional hazard regression models. RESULTS: Over 5 years of follow-up, 89 women progressed from NGT to prediabetes/diabetes (progressors). At 3 months postpartum, though all women were normoglycaemic, future progressors had higher fasting glucose (p=0.03) and 2 h glucose (p<0.0001) than non-progressors, coupled with higher BMI (p=0.001), greater insulin resistance (both Matsuda index and HOMA-IR, p≤0.02) and poorer beta cell function (both ISSI-2 and IGI/HOMA-IR, p≤0.006). Unlike their peers, progressors exhibited deteriorating beta cell function from 1 year to 5 years (both p<0.0001). On regression analyses, the dominant determinants of progression to prediabetes/diabetes were time-varying ISSI-2 (change in CCI 25.2%) and IGI/HOMA-IR (13.0%), in contrast to time-varying Matsuda index (2.9%) and HOMA-IR (0.5%). Neither time-varying BMI nor waist were significant predictors after adjustment for beta cell function and insulin sensitivity/resistance. CONCLUSION/INTERPRETATION: Declining beta cell function is the dominant determinant of incident prediabetes/diabetes in young women following pregnancy.

The impact of urbanisation on the cardiometabolic health of Indigenous Brazilian peoples: a systematic review and meta-analysis, and data from the Brazilian Health registry.

BACKGROUND: Indigenous Brazilian peoples have faced an unparalleled increase in the rate of cardiovascular diseases following rapid nutritional transition to more urban diets. We aimed to conduct a systematic review and meta-analysis to evaluate the association between urbanisation (including data from Amazon rainforest deforestation) and cardiometabolic risk factors and outcomes. METHODS: In this systematic review and meta-analysis, we searched Pubmed, Embase, Web of Science, and Scopus for articles published in any language between the year 1950 and March 10, 2022. Studies conducted in Indigenous Brazilian adults that evaluated metabolic health were included. Data for deforestation was obtained by the Amazon Deforestation Monitoring Project. Cardiovascular mortality was obtained from the Brazilian Health registry. Two independent reviewers evaluated studies for risk of bias, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations. The main outcomes assessed were the prevalence of obesity and related cardiometabolic risk factors among Indigenous Brazilian peoples and its association with urbanisation. Summary data were extracted from published reports for the meta-analyses. We calculated pooled estimates of the prevalence of each cardiometabolic outcome by using a random-effects model (DerSimonian-Laird method). This study is registered with the International Prospective Register of Systematic Reviews, CRD42021285480. FINDINGS: 46 studies were identified, including a total of 20 574 adults from at least 33 Indigenous Brazilian ethnicities. Meta-analyses of the prevalence of obesity showed that there were higher rates of obesity (midwest region: 23% [95% CI 17-29]; and south region 23% [13-34]) and hypertension (south region: 30% [10-50]) in Indigenous peoples living in urban regions of Brazil, while the lowest rates of obesity (11% [95% CI 8-15]) and hypertension (1% [1-2]) were observed in those in the less urbanised (north) regions of Brazil. The prevalence of obesity was 3·5 times higher in participants living in urbanised Indigenous territories (28%) than in those living in lands with >80% native Amazon rainforest (8%). In meta-analyses that evaluated blood pressure level, there was no incremental change in blood pressure with ageing in Indigenous peoples who lived according to traditional lifestyle, in contrast to those living in urbanised regions. For Indigenous men with traditional lifestyles, systolic blood pressure changed from 109·8 mm Hg to 104·4 mm Hg between the youngest (<30 years) and the oldest (>60 years) age groups, and diastolic blood pressure changed from 69·8 mm Hg to 66·1 mm Hg. For Indigenous women with traditional lifestyles, systolic blood pressure was 100·0 mm Hg for the youngest age group with no changes for older age groups, and diastolic blood pressure was 62 mm Hg for the youngest age group with no changes for older age groups. For Indigenous men with urbanised lifestyles, systolic blood pressure changed from 117·3 mm Hg to 124·9 mm Hg between the youngest and the oldest age groups, and diastolic blood pressure changed from 72·7 mm Hg to 76·4 mm Hg. For Indigenous women with urbanised lifestyles, systolic blood pressure changed from 110·0 mm Hg to 116·0 mm Hg between the youngest and the oldest age groups, and diastolic blood pressure changed from 68·3 mm Hg to 74·0 mm Hg. For the years 1997 and 2019, the cardiovascular mortality rate in individuals living in the southeast region (the most urbanised) was 2·5 times greater than that observed in the north. Conversely, the incremental rise in cardiovascular mortality in the past two decades among Indigenous Brazilians living in the north or northeast (2·7 times increase) stands in stark contrast to the stable rates in those living in already urbanised regions. INTERPRETATION: The macrosocial changes of Indigenous peoples' traditional ways of living consequent to urbanisation are associated with an increased prevalence of adverse cardiometabolic outcomes. These data highlight the urgent need for environmental policies to ensure the conservation of the natural ecosystem within Indigenous territories, as well as the development of socio-health policies to improve the cardiovascular health of Indigenous Brazilians peoples living in urban areas. FUNDING: None.

The vascular function effects of adding exenatide or meal insulin to basal insulin therapy in early type 2 diabetes.

OBJECTIVE: Basal insulin glargine has a neutral effect on cardiovascular risk in type 2 diabetes (T2DM). In practice, basal insulin is often paired with a glucagon-like peptide-1 receptor agonist (GLP1-RA) or meal insulin; however, the cardiovascular implications of these combinations have not been fully elucidated. In this context, we sought to evaluate the vascular function effects of adding the GLP1-RA exenatide or meal insulin lispro to basal glargine therapy in early T2DM. METHODS: In this 20-week trial, adults with T2DM of < 7-years duration were randomized to 8-weeks treatment with (i) insulin glargine (Glar), (ii) glargine + thrice-daily lispro (Glar/Lispro), or (iii) glargine + twice-daily exenatide (Glar/Exenatide), followed by 12-weeks washout. At baseline, 8-weeks, and washout, fasting endothelial function was assessed with reactive hyperemia index (RHI) measurement by peripheral arterial tonometry. RESULTS: At baseline, there were no differences in blood pressure (BP), heart rate (HR) or RHI between participants randomized to Glar (n = 24), Glar/Lispro (n = 24), and Glar/Exenatide (n = 25). At 8-weeks, Glar/Exenatide decreased systolic BP (mean - 8.1 mmHg [95%CI - 13.9 to - 2.4], p = 0.008) and diastolic BP (mean - 5.1 mmHg [- 9.0 to - 1.3], p = 0.012) compared to baseline, with no significant changes in HR or RHI. Notably, baseline-adjusted RHI (mean ± SE) did not differ between the groups at 8-weeks (Glar 2.07 ± 0.10; Glar/Lispro 2.00 ± 0.10; Glar/Exenatide 1.81 ± 0.10; p = 0.19), nor did baseline-adjusted BP or HR. There were no differences between the groups in baseline-adjusted RHI, BP or HR after 12-weeks washout. CONCLUSION: Adding either exenatide or lispro to basal insulin therapy does not appear to affect fasting endothelial function in early T2DM. TRIAL REGISTRATION: ClinicalTrials.Gov NCT02194595.

Lifestyle intervention for the prevention of type 2 diabetes in women with prior gestational diabetes: A systematic review and meta-analysis.

AIM: To determine whether current evidence supports lifestyle intervention for type 2 diabetes (T2D) prevention in women with previous gestational diabetes (GD). METHODS: We systematically searched MEDLINE/PubMed, Web of Science, EMBASE, The Cochrane Library, International Pharmaceutical Abstracts, Global Health, Sinomed and Clinicaltrials.gov for randomized controlled trials (published from 1 January 1950 to 14 December 2022) comparing lifestyle intervention with standard care in women with previous GD. Our primary outcome was incident T2D, with pooled estimates calculated by a fixed-effects model. RESULTS: Of 1652 studies identified, 13 were eligible and were included in our analysis (N = 3745 women). Compared with standard care, lifestyle intervention yielded a reduction of 24% in the incidence of T2D (relative risk 0.76 [95% CI 0.63-0.93]). Meta-regression analyses revealed no impact of the duration of lifestyle intervention (P = .81) or baseline body mass index (P = .90) on the observed reduction in incident T2D. Importantly, this published literature shows evidence of publication bias on funnel plot and Egger test (P = .048). CONCLUSIONS: Current published evidence suggests that lifestyle intervention can reduce the risk of T2D in women with prior GD. However, this finding should be interpreted with caution in the presence of documented publication bias.

Baseline determinants of remission of type 2 diabetes in response to short-term insulin-based therapy: The pivotal role of beta-cell function.

AIM: To identify baseline determinants of diabetes remission in response to short-term insulin-based therapy. METHODS: In this study, adult patients with type 2 diabetes (T2D) of less than 7 years duration were randomized to 8 weeks of treatment with (a) insulin glargine, (b) glargine + thrice-daily lispro, or (c) glargine + twice-daily exenatide, followed by 12 weeks of washout that enabled assessment of remission (defined as HbA1c < 6.5% after ≥ 3 months without glucose-lowering therapy). At baseline, 8 weeks and washout, beta-cell function was assessed with four measures: Insulin Secretion-Sensitivity Index-2 (ISSI-2), insulinogenic index/Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), ΔC-peptide0-120 /Δglucose0-120 × Matsuda and Δinsulin secretion rate (ISR)0-120 /Δgluc0-120 × Matsuda. RESULTS: Diabetes remission was achieved in 31 of 90 participants (34.4%). Compared with their peers, those who went on to remission had lower HbA1c (P < .001) and better beta-cell function at baseline (all four measures P ≤ .01). The non-remission and remission groups did not otherwise differ in baseline insulin sensitivity/resistance (Matsuda, HOMA-IR), body mass index, duration of diabetes, pretrial diabetes medications or allocated insulin-based therapy during the trial. On logistic regression analyses, each baseline measure of beta-cell function emerged as a significant predictor of remission (log ISSI-2: adjusted OR 4.41 [95% CI: 1.71-11.34]; log insulinogenic index/HOMA-IR: 2.21 [1.26-3.89]; log ΔC-peptide0-120 /Δglucose0-120 × Matsuda: 1.62 [1.00-2.64]; log ΔISR0-120 /Δgluc0-120 × Matsuda: 1.87 [1.09-3.23]). Similarly, higher baseline ISSI-2 tertile predicted longer time to glycaemic relapse after cessation of the insulin-based therapy (log-rank P = .029). CONCLUSION: Beta-cell function is the dominant baseline pathophysiological determinant of the likelihood of achieving remission of diabetes in response to short-term insulin-based therapy.

Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors and the Treatment of Type 2 Diabetes.

Clinical studies evaluating the cardiovascular safety/impact of sodium-glucose cotransporter-2 (SGLT-2) inhibitors demonstrated a reduction in major adverse cardiovascular events driven primarily by a reduced cardiovascular mortality in individuals with type 2 diabetes and previous cardiovascular disease. These somewhat unexpected results are coupled with SGLT-2 inhibitors' known acute effect of improvement in glycemia, reduction in blood pressure, and weight loss. In this review, we summarize the mechanism of action of SGLT-2 inhibitors, the metabolic effects of this class of medication, and the remarkable results of cardiovascular safety trials. In addition, we discuss adverse effects associated with these medications and the current recommendations for the use of these agents in the management of diabetes.

Short-term intensive insulin as induction and maintenance therapy for the preservation of beta-cell function in early type 2 diabetes (RESET-IT Main): A 2-year randomized controlled trial.

AIM: To test the hypothesis that the addition of periodic courses of short-term intensive insulin therapy (IIT) could enhance the effect of metformin (MET) maintenance therapy on preservation of beta-cell function following induction IIT. METHODS: In this multicentre, randomized controlled trial, 108 adults with type 2 diabetes (median 1.3 years' duration; HbA1c 6.6% ± 0.6%) were randomized to 3 weeks of induction IIT (glargine, lispro) followed by MET maintenance, either with or without periodic 2-week courses of IIT every 3 months for 2 years. Beta-cell function was assessed by the Insulin Secretion Sensitivity Index-2 (ISSI-2) at an oral glucose tolerance test every 3 months. RESULTS: In both arms, induction IIT increased ISSI-2, improved whole-body insulin sensitivity and reduced hepatic insulin resistance (all P ≤ .0004). The primary outcome of baseline-adjusted ISSI-2 at 2 years was not improved by the addition of intermittent IIT (MET + IIT) and was slightly higher in the MET arm (baseline-adjusted difference -35 [95% CI: -66, -3]), with three additional beta-cell measures showing no significant differences. Baseline-adjusted HbA1c at 2 years did not differ between MET and MET + IIT (6.3% ± 0.1% vs. 6.4% ± 0.1%, P = .46), with 32.6% of participants in each arm maintaining HbA1c of 6.0% or less at 2 years. CONCLUSION: Although initial induction IIT induces metabolic improvement, subsequent repeat courses of IIT every 3 months do not further enhance the effect of MET maintenance therapy on beta-cell function.

Gestational diabetes and the risk of cardiovascular disease in women: a systematic review and meta-analysis.

AIMS/HYPOTHESIS: Women who develop gestational diabetes mellitus (GDM) have an elevated lifetime risk of type 2 diabetes mellitus. Recently, a series of studies has suggested that women with GDM also have an increased risk of cardiovascular disease (CVD). However, it is unclear if this risk is dependent upon the intercurrent development of type 2 diabetes. Thus, we conducted a systematic review and meta-analysis to evaluate the impact of GDM on future risk of incident CVD and to ascertain the role of type 2 diabetes in this regard. METHODS: We systematically searched the PubMed and EMBASE databases for observational studies that evaluated the association of GDM with subsequent CVD, with publication between 1 January 1950 and 30 August 2018. Two independent reviewers extracted data and the analysis was performed in accordance with Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. RRs were calculated using a random-effects model to assess the predictive value of GDM for future cardiovascular events. To evaluate whether incident type 2 diabetes in the GDM population influenced the association with CVD, we used meta-regression models followed by sensitivity analyses restricted to women who did not develop type 2 diabetes during follow-up. RESULTS: A pooled analysis of nine studies yielded data from 5,390,591 women (101,424 cardiovascular events). Compared with those who did not have GDM, women with GDM had a twofold higher risk of future cardiovascular events (RR 1.98 [95% CI 1.57, 2.50]). Meta-regression analysis showed that the rates of incident type 2 diabetes across the studies did not affect this risk (p = 0.34). Moreover, when restricted to women who did not develop type 2 diabetes, GDM remained associated with a 56% higher risk of future cardiovascular events (RR 1.56 [95% CI 1.04, 2.32]). GDM conferred a 2.3-fold increased risk of cardiovascular events in the first decade postpartum (RR 2.31 [95% CI 1.57, 3.39]). CONCLUSIONS/INTERPRETATION: The diagnosis of GDM identifies young women who have a twofold higher risk of cardiovascular events postpartum compared with their peers. This risk is not dependent upon intercurrent type 2 diabetes and is apparent within the first decade after pregnancy. Thus, even without progressing to type 2 diabetes, women with GDM comprise an at-risk population for CVD and hence a potential opportunity for early risk factor surveillance and risk modification.

Stability of insulin and C-peptide measurement with long-term frozen storage of serum: Implications for diabetes research studies.

The current era of large-scale clinical trials in diabetes has generated thousands of biological samples from study participants that are being stored long-term under frozen conditions for the future measurement of analytes of interest. Insulin and C-peptide are two such analytes that can provide insight into underlying pathophysiological processes (insulin sensitivity and ß-cell function). However, the validity of the inferences that may be drawn from such future measurements is contingent on the stability of these analytes after long-term frozen storage. We conducted the present study to determine the stability of insulin and C-peptide concentrations that were first measured on fresh serum at the time of collection, followed by frozen storage at -80°C for >5 years and then repeat measurement. Bland-Altman analyses revealed good agreement between the repeated insulin measurements and between the repeated C-peptide measurements. The concordance correlation coefficient (CCC) confirmed reproducibility for both insulin (CCC 0.98, 95% confidence interval [CI] 0.96-0.99) and C-peptide (CCC 0.91, 95% CI 0.84-0.95); thus, insulin and C-peptide measurements are both stable and reproducible after long-term frozen storage of serum samples.

INTERMITTENT INTENSIVE INSULIN THERAPY FOR TYPE 2 DIABETES: EFFECTS ON HYPOGLYCEMIA, WEIGHT GAIN, AND QUALITY OF LIFE OVER 2 YEARS.

Objective: In early type 2 diabetes (T2DM), the administration of short-term intensive insulin therapy (IIT) can induce glycemic remission for a year thereafter, but this effect ultimately wanes. In this context, intermittently repeating short-term IIT could provide a strategy for maintaining the otherwise transient benefits of this intervention. However, the viability of this strategy would be contingent upon not inducing undesirable effects of insulin therapy such as excessive hypoglycemia and fat deposition. We thus sought to evaluate the effect of administering short-term IIT every 3 months on hypoglycemia, weight gain, and quality of life in early T2DM. Methods: In this 2-year pilot trial, 24 adults with T2DM of 2.0 ± 1.7 years duration and hemoglobin A1c of 6.4 (46 mmol/mol) ± 0.1% were randomized to 3 weeks of IIT (glargine, lispro) followed by either (1), repeat IIT for up to 2 weeks every 3 months or (2), daily metformin. IIT was titrated to target near-normoglycemia (premeal glucose 4 to 6 mmol/L; 2-hour postmeal <8 mmol/L). Participants were assessed every 3 months, with quality of life (QOL) evaluated annually. Results: The rate of hypoglycemia (<3.5 mmol/L) was low in the metformin and intermittent IIT arms (0.37 versus 0.95 events per patient-year; P = .28). There were no differences between the groups in changes over time in overall, central, or hepatic fat deposition (as reflected by weight [P = .10], waist-to-hip ratio [P = .58], and alanine aminotransferase [P = .64], respectively). Moreover, there were no differences between the groups in QOL at 1- and 2-years. Conclusion: Intermittent short-term IIT may be safely administered in early T2DM without excessive adverse impact on hypoglycemic risk, anthropometry, or QOL. Abbreviations: ALT = alanine aminotransferase; HbA1c = hemoglobin A1c; IIT = intensive insulin therapy; ISSI-2 = insulin secretion-sensitivity index-2; OGTT = oral glucose tolerance test; QOL = quality of life; SF-36 = medical outcomes study 36-item short-form health survey; T2DM = type 2 diabetes.

Impact of daily incremental change in environmental temperature on beta cell function and the risk of gestational diabetes in pregnant women.

AIMS/HYPOTHESIS: The prevalence of gestational diabetes (GDM) is higher in summer months, possibly reflecting an association between ambient temperature and blood glucose levels. However, the specific exposure and mechanism by which temperature may affect glucose metabolism in pregnancy remains unclear. We systematically evaluated the relationships of environmental temperature and changes therein over varying durations of exposure time with beta cell function, insulin sensitivity and glucose tolerance in women undergoing antepartum screening for GDM. METHODS: At a mean gestation of 29 weeks, 1464 women in Toronto (ON, Canada) underwent an OGTT, from which 318 were diagnosed with GDM. Blood glucose, beta cell function and insulin sensitivity were evaluated in relation to 18 temperature variables: mean temperature and change in temperature on the day of the OGTT and over the preceding 7, 14, 21, 28, 35, 42, 49 and 56 days, respectively. RESULTS: Temperature changes in the preceding 14, 21, 28, 35, 42, 49 and 56 days (rather than mean temperatures) emerged as independent predictors of blood glucose. These relationships were evident in months where mean daily temperature was rising (February - July), but not in those where it was falling (August - January). Indeed, in February - July, the temperature changes in the preceding 21, 28 and 35 days emerged as predictors of both poorer beta cell function and higher blood glucose. Moreover, in February - July, the changes in temperature in the preceding 21 days (OR 1.16, 95% CI 1.01, 1.33) and 28 days (OR 1.20, 95% CI 1.03, 1.39) were independent predictors of GDM, while mean temperatures were not. CONCLUSIONS/INTERPRETATION: In pregnant women, rising environmental temperature in the 3-4 weeks prior to glucose tolerance testing may be associated with beta cell dysfunction and an increased risk of GDM.

Effect of chronic liraglutide therapy and its withdrawal on time to postchallenge peak glucose in type 2 diabetes.

Delayed timing of peak serum glucose following an oral glucose challenge can predict declining ß-cell function and worsening glucose tolerance over time. Accordingly, postchallenge peak glucose is typically delayed in patients with type 2 diabetes (T2DM). However, little is known about the capacity of antidiabetic medications to reverse this delay. Thus, we sought to evaluate the effect of the glucagon-like peptide-1 agonist liraglutide on time to peak glucose in early T2DM. In this secondary analysis of a double-blind placebo-controlled trial, 51 patients with T2DM of 2.6 ± 1.9 yr duration were randomized to daily subcutaneous liraglutide or placebo injection for 48 wk, with oral glucose tolerance test (OGTT) performed every 12 wk while on therapy and after a 2-wk washout. On each OGTT, time to peak glucose was determined from venous glucose measurements at 0, 10, 20, 30, 60, 90, and 120 min. At randomization, most patients in both arms exhibited peak glucose at 90 min postchallenge. By 12 wk, 65.4% of the liraglutide arm had shifted to an earlier peak (vs. 36% on placebo; P = 0.19), with little change thereafter at 24, 36, and 48 wk. After the 2-wk washout, however, 57.7% of those who had been on liraglutide reverted to a later peak (vs. 4.5% on placebo; P < 0.001). This shift was associated with declining ß-cell function ( P = 0.001), resulting in higher 2-h blood glucose at washout in the liraglutide arm compared with placebo ( P = 0.001). Thus, although liraglutide possibly might improve the delay in peak glucose, its cessation yielded a worsening thereof and higher glycemia. The mechanisms underlying these observations and their clinical implications warrant further investigation.

Two-year trial of intermittent insulin therapy vs metformin for the preservation of ß-cell function after initial short-term intensive insulin induction in early type 2 diabetes.

AIMS: To test the hypothesis that "induction" intensive insulin therapy (IIT) needs to be followed by "maintenance therapy" to preserve ß-cell function, and to evaluate the impact on ß-cell function over 2 years of two approaches to maintenance therapy: intermittent short-term IIT every 3 months vs daily metformin. MATERIALS AND METHODS: In this trial, 24 adults with a mean type 2 diabetes mellitus (T2DM) duration of 2.0 ± 1.7 years and glycated haemoglobin (HbA1c) levels 6.4 ± 0.1% (46 ± 1.1mmol/mol) were randomized to 3 weeks of induction IIT (glargine, lispro) followed by either repeat IIT for up to 2 weeks every 3 months or daily metformin. Participants underwent serial assessment of ß-cell function using the Insulin Secretion-Sensitivity Index-2 (ISSI-2) on an oral glucose tolerance test every 3 months. RESULTS: The primary outcome of baseline-adjusted ISSI-2 at 2 years was higher in the metformin arm compared with intermittent IIT (245.0 ± 31.7 vs 142.2 ± 18.4; P = .008). Baseline-adjusted HbA1c at 2 years (secondary outcome) was lower in the metformin arm (6.0 ± 0.2% vs 7.3 ± 0.2%; P = .0006) (42 ± 2.2 vs 56 ± 2.2mmol/mol). At study completion, 66.7% of participants randomized to metformin had an HbA1c concentration ≤ 6.0% (≤42mmol/mol), compared with 8.3% of those on intermittent IIT (P = .009). There were no differences in insulin sensitivity. CONCLUSION: After induction IIT, metformin was superior to intermittent IIT for maintaining ß-cell function and glycaemic control over 2 years. The strategy of induction and maintenance therapy to preserve ß-cell function warrants exploration in early T2DM.

Efficacy of glucagon-like peptide-1 receptor agonists compared to dipeptidyl peptidase-4 inhibitors for the management of type 2 diabetes: A meta-analysis of randomized clinical trials.

AIMS: Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are both incretin-based therapies for type 2 diabetes (T2DM) but have distinct efficacy and side effect profiles. We thus performed a systematic review and meta-analysis to compare the effects of GLP-1 agonists to DPP-4 inhibitors on glycaemic control, weight and incidence of adverse events in adults with T2DM. We also sought to determine whether there was any additional effect in switching from DPP-4 inhibitor to GLP-1 agonist. MATERIALS AND METHODS: We systematically searched PubMed, Embase and ClinicalTrials.gov for (1) randomized controlled trials (RCTs) comparing any GLP-1 agonist to any DPP-4 inhibitor and (2) interventional studies where a DPP-4 inhibitor was switched to a GLP-1 agonist. We assessed pooled data using random-effects model (CRD42017057115). RESULTS: The pooled analysis of 13 RCTs (n = 4330) showed that, compared to DPP-4 inhibitors, GLP-1 agonists yielded a greater mean reduction in glycated haemoglobin (HbA1c) of -0.41% (95% CI -0.53 to -0.30) and in weight of -2.15 kg (-3.04 to -1.27). GLP-1 agonists were associated with greater likelihood of gastrointestinal side effects with no increased risk of hypoglycaemia. In 5 interventional studies (n = 433), switching from DPP-4 inhibitor to GLP-1 agonist yielded further mean reduction in HbA1c of -0.69% (-1.03 to -0.35) and in weight of -2.25 kg (-3.12 to -1.38). CONCLUSIONS: GLP-1 agonists yield greater reduction in HbA1c and weight as compared to DPP-4 inhibitors, with increased incidence of gastrointestinal symptoms but not hypoglycaemia. Replacing a DPP-4 inhibitor with GLP-1 agonist provides additional benefits in glycaemic control and weight loss.

Chronic liraglutide therapy induces an enhanced endogenous glucagon-like peptide-1 secretory response in early type 2 diabetes.

Sustained exogenous stimulation of a hormone-specific receptor can affect endogenous hormonal regulation. In this context, little is known about the impact of chronic treatment with glucagon-like peptide-1 (GLP-1) agonists on the endogenous GLP-1 response. We therefore evaluated the impact of chronic liraglutide therapy on endogenous GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) response to an oral glucose challenge. A total of 51 people with type 2 diabetes of 2.6 ± 1.9 years' duration were randomized to daily subcutaneous liraglutide or placebo injection and followed for 48 weeks, with an oral glucose tolerance test (OGTT) every 12 weeks. GLP-1 and GIP responses were assessed according to their respective area under the curve (AUC) from measurements taken at 0, 30, 60, 90 and 120 minutes during each OGTT. There were no differences in AUCGIP between the groups. By contrast, although fasting GLP-1 was unaffected, the liraglutide arm had ~2-fold higher AUCGLP-1 at 12 weeks ( P < .001), 24 weeks ( P < .001), 36 weeks ( P = .03) and 48 weeks ( P = .03), as compared with placebo. Thus, chronic liraglutide therapy induces a previously unrecognized, robust and durable enhancement of the endogenous GLP-1 response, highlighting the need for further study of the long-term effects of incretin mimetics on L-cell physiology.

The persistence of maternal vitamin D deficiency and insufficiency during pregnancy and lactation irrespective of season and supplementation.

BACKGROUND: Pregnancy and lactation comprise a critical window spanning all seasons during which maternal vitamin D status potentially may influence the long-term health of the newborn. Women typically receive calcium/vitamin D supplementation through antenatal vitamins, but there has been limited serial evaluation of maternal vitamin D status across this critical window. DESIGN/PATIENTS/MEASUREMENTS: In this prospective observational cohort study, 467 women in Toronto, Canada, underwent measurement of serum 25-hydroxy vitamin D (25-OH-D) at mean 29·7 ± 2·9 weeks' gestation, 3 months postpartum and 12 months postpartum, enabling serial assessment across 3 seasons. At each assessment, vitamin D status was classified as deficiency (25-OH-D<50 nmol/l), insufficiency (25-OH-D≥50 nmol/l and <75 nmol/l) or sufficiency (25-OH-D≥75 nmol/l). RESULTS: The prevalence rates of vitamin D deficiency and insufficiency were 31·5% and 35·1% in pregnancy, 33·4% and 35·3% at 3 months, and 35·6% and 33·8% at 12 months postpartum, respectively. These high rates remained stable over time (P = 0·49) despite declining usage of antenatal calcium/vitamin D supplementation from pregnancy to 3 months to 12 months postpartum (P < 0·001). Indeed, on mixed model analyses, vitamin D deficiency and insufficiency in pregnancy were independently associated with decrements in average 25-OH-D over time of 49·6 nmol/l and 26·4 nmol/l, respectively (both P < 0·001). In contrast, season of baseline assessment and use of calcium/vitamin D supplements were independently associated with changes in 25-OH-D in the range of 3-5 nmol/l (both P < 0·008). CONCLUSIONS: The persistence of vitamin D deficiency/insufficiency during pregnancy and lactation, irrespective of season and supplementation, supports the emerging concept that current vitamin D supplementation in antenatal care is likely inadequate.

Sex of the baby and risk of gestational diabetes mellitus in the mother: a systematic review and meta-analysis.

AIMS/HYPOTHESIS: It has recently emerged that carrying a male fetus may be associated with poorer maternal beta cell function and an increased risk of gestational diabetes mellitus (GDM). Recognising that the overall impact of fetal sex on maternal glucose metabolism is likely to be subtle, we sought to perform a systematic review and meta-analysis of observational studies to obtain a robust estimate of the incremental maternal risk of GDM associated with the sex of the baby. METHODS: We searched PubMed and EMBASE to identify observational studies published between 1 January 1950 and 4 April 2015 that reported data on fetal sex and the prevalence of GDM. Two independent reviewers extracted the data and pooled estimates of the RR were calculated by a random-effects model. We considered male fetus as the exposure and prevalence of GDM as the outcome of interest. RESULTS: We identified 320 studies through electronic searches and nine studies through manual searches. Twenty studies met the inclusion criteria, yielding data on 2,402,643 women. Pooled analysis of these studies demonstrated an increased risk of GDM in women carrying a male fetus compared with women carrying a female fetus (RR 1.04; 95% CI 1.02, 1.06). This result was confirmed in a sensitivity analysis including only studies that applied a stringent definition of GDM (RR 1.03; 95% CI 1.01, 1.06) (I(2) = 0%, p = 0.66). CONCLUSIONS/INTERPRETATION: Pregnant women carrying a boy have a 4% higher relative risk of GDM than those carrying a girl. The fetus thus may have previously unsuspected effects on maternal glucose metabolism in pregnancy.

Delayed timing of post-challenge peak blood glucose predicts declining beta cell function and worsening glucose tolerance over time: insight from the first year postpartum.

AIMS/HYPOTHESIS: On cross-sectional assessment, a delayed timing of the peak blood glucose level at ≥60 min post-challenge on an OGTT is associated with beta cell dysfunction. In this context, we hypothesised that longitudinal changes in the timing of this peak might predict changes in glucose metabolism. We thus sought to evaluate the longitudinal associations of changes in the timing of the peak glucose level with changes over time in insulin sensitivity, beta cell function and glucose tolerance. METHODS: A total of 532 women underwent an OGTT at both 3 months and 12 months postpartum. The participants were stratified into four groups according to the change in timing of their glucose peak between the two visits: women with no change in timing of the glucose peak at 30 min (n = 217), those whose glucose peak shifted to an earlier time point (n = 120), those whose peak shifted to a later time point (n = 87) and women with an unchanged glucose peak at ≥60 min (n = 108). Beta cell function was measured using the Insulin Secretion-Sensitivity Index-2 (ISSI-2). RESULTS: Compared with an unchanged glucose peak at 30 min, both the shift of the glucose peak to a later time point and a peak that was unchanged at ≥60 min were independently associated with declining ISSI-2 scores (ß = -127.5, p < 0.001 and ß = -98.8, p = 0.006, respectively) and increased 2 h post-challenge glucose levels (ß = 1.28, p < 0.001 and ß = 0.91, p < 0.001, respectively) between the two visits. Furthermore, both these patterns of change in peak were independently associated with worsening glucose tolerance (from normal to prediabetes [defined as impaired fasting glucose or impaired glucose tolerance]/diabetes or from prediabetes to diabetes) (OR 8.1, 95% CI 3.0, 22.1 and OR 3.7, 95% CI 1.2, 11.7, respectively). CONCLUSIONS/INTERPRETATION: A delayed timing of the post-challenge peak glucose level is associated with declining beta cell function and worsening glucose tolerance over time.