Summary Background The evolving epidemic of type 2 diabetes has challenged health-care providers to assess the safety and efficacy of various diabetes prevention strategies. The CANOE (CAnadian ...Normoglycemia Outcomes Evaluation) trial investigated whether low-dose combination therapy would affect development of type 2 diabetes. Methods In this double-blind, randomised controlled trial undertaken in clinics in Canadian centres, 207 patients with impaired glucose tolerance were randomly assigned to receive combination rosiglitazone (2 mg) and metformin (500 mg) twice daily or matching placebo for a median of 3·9 years (IQR 3·0–4·6). Randomisation was computer-generated in blocks of four, with both participants and investigators masked to treatment allocation. The primary outcome was time to development of diabetes, measured by an oral glucose tolerance test or two fasting plasma glucose values of 7·0 mmol/L or greater. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00116932. Findings 103 participants were assigned to rosiglitazone and metformin, and 104 to placebo; all were analysed. Vital status was obtained in 198 (96%) participants, and medication compliance (taking at least 80% of assigned medication) was 78% (n=77) in the metformin and rosiglitazone group and 81% (n=80) in the placebo group. Incident diabetes occurred in significantly fewer individuals in the active treatment group (n=14 14%) than in the placebo group (n=41 39%; p<0·0001). The relative risk reduction was 66% (95% CI 41–80) and the absolute risk reduction was 26% (14–37), yielding a number needed to treat of 4 (2·70–7·14). 70 (80%) patients in the treatment group regressed to normal glucose tolerance compared with 52 (53%) in the placebo group (p=0·0002). Insulin sensitivity decreased by study end in the placebo group (median −1·24, IQR −2·38 to −0·08) and remained unchanged with rosiglitazone and metformin treatment (−0·39, −1·30 to 0·84; p=0·0006 between groups). The change in β-cell function, as measured by the insulin secretion-sensitivity index-2, did not differ between groups (placebo −252·3, −382·2 to −58·0 vs rosiglitazone and metformin −221·8, −330·4 to −87·8; p=0·28). We recorded an increase in diarrhoea in participants in the active treatment group compared with the placebo group (16 16% vs 6 6%; p=0·0253). Interpretation Low-dose combination therapy with rosiglitazone and metformin was highly effective in prevention of type 2 diabetes in patients with impaired glucose tolerance, with little effect on the clinically relevant adverse events of these two drugs. Funding GlaxoSmithKline.
OBJECTIVE:--The purpose of this study was to test the hypothesis that any degree of abnormal glucose homeostasis detected on antepartum screening for gestational diabetes mellitus (GDM) should be ...associated with an increased risk of postpartum pre-diabetes or diabetes. RESEARCH DESIGN AND METHODS--In this prospective cohort study, 487 women underwent 1) antepartum GDM screening by a glucose challenge test (GCT) and a diagnostic oral glucose tolerance test (OGTT) and 2) postpartum metabolic characterization by OGTT at 3 months after delivery. Four baseline glucose tolerance groups were defined on the basis of the antepartum GCT/OGTT: 1) GDM (n = 137); 2) gestational impaired glucose tolerance (GIGT) (n = 91); 3) abnormal GCT with normal glucose tolerance on an OGTT (abnormal GCT NGT) (n = 166); and 4) normal GCT with NGT on an OGTT (normal GCT NGT) (n = 93). RESULTS:--The prevalence of postpartum glucose intolerance (pre-diabetes or diabetes) increased across the groups from normal GCT NGT (3.2%) to abnormal GCT NGT (10.2%) to GIGT (16.5%) to GDM (32.8%) (Ptrend < 0.0001). On logistic regression analysis, all three categories of abnormal glucose homeostasis in pregnancy independently predicted postpartum glucose intolerance: abnormal GCT NGT odds ratio (OR) 3.6 (95% CI 1.01-12.9); GIGT OR 5.7 (1.6-21.1); and GDM OR 14.3 (4.2-49.1). Furthermore, both in pregnancy and at 3 months postpartum, insulin sensitivity (ISOGTT) and pancreatic β-cell function (insulinogenic index/homeostasis model assessment of insulin resistance) progressively decreased across the groups from normal GCT NGT to abnormal GCT NGT to GIGT to GDM (all Ptrend < 0.0001). CONCLUSIONS:--Any degree of abnormal glucose homeostasis in pregnancy independently predicts an increased risk of glucose intolerance postpartum.
Abstract Background Although exclusive breastfeeding is recommended for the first six months of life, research suggests that breastfeeding initiation rates and duration among Indigenous communities ...differ from this recommendation. Qualitative studies point to a variety of factors influencing infant feeding decisions; however, there has been no collective review of this literature published to date. Therefore, the objective of this scoping review was to identify and summarize the qualitative literature regarding Indigenous infant feeding experiences within Canada, the United States, Australia, and Aotearoa. Methods Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses- Scoping Reviews and the Joanna Briggs Institute Guidelines, in October 2020, Medline, Embase, CINAHL, PsycINFO, and Scopus were searched for relevant papers focusing on Indigenous infant feeding experiences. Screening and full-text review was completed by two independent reviewers. A grey literature search was also conducted using country-specific Google searches and targeted website searching. The protocol is registered with the Open Science Framework and published in BMJ Open. Results Forty-six papers from the five databases and grey literature searches were included in the final review and extraction. There were 18 papers from Canada, 11 papers in the US, 9 studies in Australia and 8 studies conducted in Aotearoa. We identified the following themes describing infant feeding experiences through qualitative analysis: colonization, culture and traditionality, social perceptions, family, professional influences, environment, cultural safety, survivance, establishing breastfeeding, autonomy, infant feeding knowledge , and milk substitutes , with family and culture having the most influence on infant feeding experiences based on frequency of themes. Conclusions This review highlights key influencers of Indigenous caregivers’ infant feeding experiences, which are often situated within complex social and environmental contexts with the role of family and culture as essential in supporting caregivers. There is a need for long-term follow-up studies that partner with communities to support sustainable policy and program changes that support infant and maternal health.
Obesity prevention efforts in Aboriginal (First Nations, Métis, or Inuit) communities in Canada should focus predominantly on children given their demographic significance and the accelerated time ...course of occurrence of type 2 diabetes mellitus in the Aboriginal population. A socioecological model to address childhood obesity in Aboriginal populations would focus on the numerous environments at different times in childhood that influence weight status, including prenatal, sociocultural, family, and community environments. Importantly, for Aboriginal children, obesity interventions need to also be situated within the context of a history of colonization and inequities in the social determinants of health. This review therefore advocates for the inclusion of a historical perspective and a life-course approach to obesity prevention in Aboriginal children in addition to developing interventions around the socioecological framework. We emphasize that childhood obesity prevention efforts should focus on promoting maternal health behaviours before and during pregnancy, and on breastfeeding and good infant and child nutrition in the postpartum and early childhood development periods. Ameliorating food insecurity by focusing on improving the sociodemographic risk factors for it, such as increasing income and educational attainment, are essential. More research is required to understand and measure obesogenic Aboriginal environments, to examine how altering specific environments modifies the foods that children eat and the activities that they do, and to examine how restoring and rebuilding cultural continuity in Aboriginal communities modifies the many determinants of obesity. This research needs to be done with the full participation of Aboriginal communities as partners in the research.
Disposition index (DI) and glucose effectiveness (S(G)) are risk factors for diabetes. However, the effect of DI and S(G) on future diabetes has not been examined in large epidemiological studies ...using direct measures.
Insulin sensitivity index (S(I)), acute insulin response (AIR), and S(G) were measured in 826 participants (aged 40-69 years) in the Insulin Resistance Atherosclerosis Study (IRAS) by the frequently sampled intravenous glucose tolerance test. DI was expressed as S(I) x AIR. At the 5-year follow-up examination, 128 individuals (15.5%) had developed diabetes.
The area under the receiver operating characteristic curve of a model with S(I) and AIR was similar to that of DI (0.767 vs. 0.774, P = 0.543). In a multivariate logistic regression model that included both DI and S(G), conversion to diabetes was predicted by both S(G) (odds ratio x 1 SD, 0.61 0.47-0.80) and DI (0.68 0.54-0.85) after adjusting for demographic variables, fasting and 2-h glucose concentrations, family history of diabetes, and measures of obesity. Age, sex, race/ethnicity, glucose tolerance status, obesity, and family history of diabetes did not have a significant modifying impact on the relation of S(G) and DI to incident diabetes.
The predictive power of DI is comparable to that of its components, S(I) and AIR. S(G) and DI independently predict conversion to diabetes similarly across race/ethnic groups, varying states of glucose tolerance, family history of diabetes, and obesity.
Recent studies using untargeted metabolomics approaches have suggested that plasma branched-chain amino acids (BCAAs) are associated with incident diabetes. However, little is known about the role of ...plasma BCAAs in metabolic abnormalities underlying diabetes and whether these relationships are consistent across ethnic populations at high risk for diabetes. We investigated the associations of BCAAs with insulin sensitivity (SI), acute insulin response (AIR), and metabolic clearance of insulin (MCRI) in a multiethnic cohort.
In 685 participants without diabetes of the Insulin Resistance Atherosclerosis Study (IRAS) (290 Caucasians, 165 African Americans, and 230 Hispanics), we measured plasma BCAAs (sum of valine, leucine, and isoleucine) by mass spectrometry and SI, AIR, and MCRI by frequently sampled intravenous glucose tolerance tests.
Elevated plasma BCAAs were inversely associated with SI and MCRI and positively associated with fasting insulin in regression models adjusted for potential confounders (β = -0.0012 95% CI -0.0018, -0.00059, P < 0.001 for SI; β = -0.0013 95% CI -0.0018, -0.00082, P < 0.001 for MCRI; and β = 0.0015 95% CI 0.0008, 0.0023, P < 0.001 for fasting insulin). The association of BCAA with SI was significantly modified by ethnicity, with the association only being significant in Caucasians and Hispanics. Elevated plasma BCAAs were associated with incident diabetes in Caucasians and Hispanics (multivariable-adjusted odds ratio per 1-SD increase in plasma BCAAs: 1.67 95% CI 1.21, 2.29, P = 0.002) but not in African Americans. Plasma BCAAs were not associated with SI-adjusted AIR.
Plasma BCAAs are associated with incident diabetes and underlying metabolic abnormalities, although the associations were generally stronger in Caucasians and Hispanics.
The Developmental Origins of Health and Disease (DOHaD) paradigm emphasizes the significance of early life factors for the prevention of chronic health conditions, like type 2 diabetes (T2DM) and ...obesity, which disproportionately affect First Nations communities in Canada. Despite increasing DOHaD research related to maternal health during pregnancy, early childhood growth patterns, and infant feeding practices with many populations, data from First Nations communities in Canada are limited. In partnership with Sandy Lake First Nation, the aims of this project were to characterize birthweights and growth patterns of First Nations infants/children over the first 6 years of life and to study the impact of maternal and infant social and behavioral factors on birthweight and growth trajectories.
We recruited 194 families through community announcements and clinic visits. Infant/child length/height and weight were measured at 1 and 2 weeks; 1, 2, 6, 12, and 18 months; and 2, 3, 4, 5 and 6 years. Maternal and infant/child questionnaires captured data about health, nutrition, and social support. Weight-for-Age z-score (WAZ), Height-for-Age z-score (HAZ), and BMI-for-Age z-score (BAZ) were calculated using WHO reference standards and trajectories were analyzed using generalized additive models. Generalized estimating equations and logistic regression were used to determine associations between exposures and outcomes.
WAZ and BAZ were above the WHO mean and increased with age until age 6 years. Generalized estimating equations indicated that WAZ was positively associated with age (0.152; 95% CI 0.014, 0.29), HAZ was positively associated with birthweight (0.155; 95% CI 0.035, 0.275), and BAZ was positively associated with caregiver's BMI (0.049; 95% CI 0.004, 0.090). There was an increased odds of rapid weight gain (RWG) with exposure to gestational diabetes (OR: 7.47, 95% CI 1.68, 46.22). Almost 70% of parents initiated breastfeeding, and breastfeeding initiation was modestly associated with lower WAZ (-0.18; 95% CI -0.64, 0.28) and BAZ (-0.23; 95% CI -0.79, 0.34).
This work highlights early life factors that may contribute to T2DM etiology and can be used to support community and Indigenous-led prevention strategies.
Context/Objective: Gestational diabetes mellitus (GDM) and even mild glucose intolerance in pregnancy are both associated with increased risks of developing type 2 diabetes and cardiovascular disease ...in the future. Because the metabolic syndrome also identifies patients at risk of type 2 diabetes and cardiovascular disease, we hypothesized that gestational dysglycemia may be associated with an unrecognized latent metabolic syndrome. Thus, we sought to evaluate the relationship between gestational glucose tolerance status and postpartum risk of metabolic syndrome.
Design/Setting/Participants: In this prospective cohort study, 487 women underwent oral glucose tolerance testing in pregnancy and cardiometabolic characterization at 3 months postpartum. The antepartum testing defined three gestational glucose tolerance groups: GDM (n = 137); gestational impaired glucose tolerance (GIGT) (n = 91); and normal glucose tolerance (NGT) (n = 259).
Main Outcome Measure: The primary outcome was the presence of the metabolic syndrome at 3 months postpartum, as defined by International Diabetes Federation (IDF) and American Heart Association/National Heart Lung and Blood Institute (AHA/NHLBI) criteria, respectively.
Results: The postpartum prevalence of IDF metabolic syndrome progressively increased from NGT (10.0%) to GIGT (17.6%) to GDM (20.0%) (overall P = 0.016). The same progression was observed for AHA/NHLBI metabolic syndrome (NGT, 8.9%; GIGT, 15.4%; and GDM, 16.8%; overall P = 0.046). On logistic regression analysis, both GDM (odds ratio, 2.05; 95% confidence interval, 1.07–3.94) and GIGT (odds ratio, 2.16; 95% confidence interval, 1.05–4.42) independently predicted postpartum metabolic syndrome.
Conclusions: Both GDM and mild glucose intolerance in pregnancy predict an increased likelihood of metabolic syndrome at 3 months postpartum, supporting the concept that women with gestational dysglycemia may have an underlying latent metabolic syndrome.
Both gestational diabetes and mild glucose intolerance predict an increased likelihood of postpartum metabolic syndrome, suggesting that early cardiovascular risk factor surveillance may be warranted in women with gestational dysglycemia.
Emerging evidence suggests that peripheral neuropathy begins in the early stages of diabetes pathogenesis. Our objective was to describe the prevalence of peripheral neuropathy and nerve dysfunction ...according to glucose tolerance and metabolic syndrome status and examine how these conditions are associated with neurological changes in individuals at risk for type 2 diabetes.
We studied 467 individuals in the longitudinal PROMISE (Prospective Metabolism and Islet Cell Evaluation) cohort. Peripheral neuropathy was defined by Michigan Neuropathy Screening Instrument (MNSI) scores (>2), and the severity of nerve dysfunction was measured objectively by vibration perception thresholds (VPTs) using a neurothesiometer. Metabolic syndrome was defined using the International Diabetes Federation/American Heart Association harmonized criteria.
The prevalence of peripheral neuropathy was 29%, 49%, and 50% for normal glycemia, prediabetes, and new-onset diabetes, respectively (P < 0.001 for trend). The mean VPT was 6.5 V for normal glycemia, 7.9 V for prediabetes, and 7.6 V for new-onset diabetes (P = 0.024 for trend). Prediabetes was associated with higher MNSI scores (P = 0.01) and VPTs (P = 0.004) versus normal glycemia, independent of known risk factors. Additionally, progression of glucose intolerance over 3 years predicted a higher risk of peripheral neuropathy (P = 0.007) and nerve dysfunction (P = 0.002). Metabolic syndrome was not independently associated with MNSI scores or VPTs.
In individuals with multiple risk factors for diabetes, prediabetes was associated with similar risks of peripheral neuropathy and severity of nerve dysfunction as new-onset diabetes. Prediabetes, but not metabolic syndrome, was independently associated with both the presence of peripheral neuropathy and the severity of nerve dysfunction.
A1C is an optional method for diagnosing diabetes and also for detecting individuals at increased risk of the disease. However, how A1C compares with fasting (FPG) and 2-h plasma glucose for ...detecting at-risk individuals is not well known.
A 2-h glucose tolerance test, frequently sampled intravenous glucose tolerance test, and A1C were obtained at the follow-up examination in 855 participants in the Insulin Resistance Atherosclerosis Study (IRAS). For this report, 385 individuals were at increased risk of diabetes as defined by A1C between 5.7 and 6.4%, impaired glucose tolerance (IGT), and/or impaired fasting glucose (IFG).
IFG and IGT identified 69.1 and 59.5% of all individuals at increased risk of diabetes, respectively. A1C 5.7-6.4% detected 23.6% of all at-risk individuals, although more African Americans (31.4%) and Hispanics (35.2%) than non-Hispanic whites (9.9%). Relative to A1C, FPG was more strongly related to fasting insulin (r = 0.38 vs. 0.26; P < 0.01), acute insulin response (r = - 0.20 vs. - 0.09; P < 0.01), and waist circumference (r = 0.43 vs. 0.25; P < 0.001) by the Spearman correlation test. Similarly, 2-h plasma glucose was more strongly related to Si (r = - 0.40 vs. - 0.27; P < 0.01) and triglycerides (r = 0.30 vs. 0.08; P < 0.001).
A1C 5.7-6.4% is less sensitive for detecting at-risk individuals than IFG and IGT, particularly among non-Hispanic whites. Single determinations of FPG and 2-h plasma glucose seem to be more precise correlates of insulin resistance and secretion than A1C and, in general, better for other metabolic disorders.
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