Pleistocene range dynamics in the eastern Greater Cape Floristic Region: A case study of the Little Karoo endemic Berkheya cuneata (Asteraceae)

AbstractThe glacial–interglacial climate cycles of the Pleistocene played a significant role in dramatically altering species distributions across the globe. However, the climate of the Greater Cape Floristic Region is thought to have been decoupled from global fluctuations and the current Mediterranean climate remained relatively buffered during this period. Here we explore the roles of climate stability and the topographic complexity of the region on the range history of an endemic Little Karoo plant, Berkheya cuneata, using ensemble species distribution modelling and multi-locus phylogeography. The species distribution models projected onto downscaled climate simulation of the Last Glacial Maximum demonstrated a considerable range contraction and fragmentation into the western and eastern Little Karoo, separated by the Rooiberg inselberg. This population fragmentation is mirrored in the phylogeographic structuring of both chloroplast and nuclear DNA. These results suggest that sufficient climatic buffering coupled with regionally complex topography ensured the localised population persistence during Pleistocene climate cycles but these features have also promoted population vicariance in this, and likely other, Little Karoo lowland species

Liver Enzymes in Early to Mid-pregnancy, Insulin Resistance, and Gestational Diabetes Risk: A Longitudinal Analysis

Background: Liver enzymes may be implicated in glucose homeostasis; liver enzymes progressively change during pregnancy but longitudinal data during pregnancy in relation to insulin resistance and gestational diabetes (GDM) risk are lacking. We investigated longitudinal associations of γ-glutamyl transferase (GGT) and alanine aminotransferase (ALT) with insulin secretion and resistance markers across early to mid-pregnancy and subsequent GDM risk.Methods: Within the prospective Pregnancy Environment and Lifestyle Study cohort, 117 GDM cases were ascertained and matched to 232 non-GDM controls in a nested case-control study. Fasting blood samples were collected at two clinic visits (CV1, gestational weeks 10–13; CV2, gestational weeks 16–19). Linear mixed model and conditional logistic regression were used, adjusting for major risk factors for GDM.Results: In repeated measure analysis, after adjusting for confounders including body mass index and waist-to-hip ratio, GGT per standard deviation increment was associated with elevated fasting glucose and HOMA-IR (% change = 1.51%, 95% CI 0.56–2.46% and 7.43%, 95% CI 1.76–13.11%, respectively) and decreased adiponectin (% change = −2.86%, 95% CI−5.53 to −0.20%) from CV1 to CV2. At CV1 and CV2, GGT levels comparing the highest versus lowest quartile were associated with 3.01-fold (95% CI 1.32–6.85) and 3.51-fold (95% CI 1.37–8.97) increased risk of GDM, respectively. Progressively increased (<median at CV1, ≥median at CV2) and stably high (≥median at both CV1 and CV2) GGT levels were associated with 3.89- and 2.39-fold increased risk of GDM, compared to stably low levels (<median at both CV1 and CV2), respectively (both P < 0.05). Similar but non-significant trends were observed for ALT.Conclusion: Elevated levels of GGT in early and mid-pregnancy, even within the conventional normal range, and its progressive increase from early to mid-pregnancy may be implicated in the pathogenesis of GDM, highlighting its potential to inform early screening or preventive strategies to mitigate subsequent risk of GDM

High Blood Pressure Before and During Early Pregnancy Is Associated With an Increased Risk of Gestational Diabetes Mellitus

OBJECTIVE—While women with prior gestational diabetes mellitus (GDM) are more likely to display features of the metabolic syndrome, including hypertension, in the years after delivery, it is unclear whether these components are also present before pregnancy. We examined the relationship between blood pressure (BP) measured before and during early pregnancy (<20 weeks) and the risk of GDM in a nested case-control study

Genetic Variants in <i>CPA6</i> and <i>PRPF31</i> are Associated with Variation in Response to Metformin in Individuals with Type 2 Diabetes

Metformin is the first-line treatment for type 2 diabetes (T2D). Although widely prescribed, the glucose-lowering mechanism for metformin is incompletely understood. Here, we used a genome-wide association approach in a diverse group of individuals with T2D from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial to identify common and rare variants associated with HbA1c response to metformin treatment and followed up these findings in four replication cohorts. Common variants in PRPF31 and CPA6 were associated with worse and better metformin response, respectively (P &lt; 5 × 10-6), and meta-analysis in independent cohorts displayed similar associations with metformin response (P = 1.2 × 10-8 and P = 0.005, respectively). Previous studies have shown that PRPF31(+/-) knockout mice have increased total body fat (P = 1.78 × 10-6) and increased fasted circulating glucose (P = 5.73 × 10-6). Furthermore, rare variants in STAT3 associated with worse metformin response (q &lt;0.1). STAT3 is a ubiquitously expressed pleiotropic transcriptional activator that participates in the regulation of metabolism and feeding behavior. Here, we provide novel evidence for associations of common and rare variants in PRPF31, CPA6, and STAT3 with metformin response that may provide insight into mechanisms important for metformin efficacy in T2D

Genome-wide meta-analysis identifies genetic variants associated with glycemic response to sulfonylureas

OBJECTIVE: Sulfonylureas, the first available drugs for the management of type 2 diabetes, remain widely prescribed today. However, there exists significant variability in glycemic response to treatment. We aimed to establish heritability of sulfonylurea response and identify genetic variants and interacting treatments associated with HbA(1c) reduction. RESEARCH DESIGN AND METHODS: As an initiative of the Metformin Genetics Plus Consortium (MetGen Plus) and the DIabetes REsearCh on patient straTification (DIRECT) consortium, 5,485 White Europeans with type 2 diabetes treated with sulfonylureas were recruited from six referral centers in Europe and North America. We first estimated heritability using the generalized restricted maximum likelihood approach and then undertook genome-wide association studies of glycemic response to sulfonylureas measured as HbA(1c) reduction after 12 months of therapy followed by meta-analysis. These results were supported by acute glipizide challenge in humans who were naïve to type 2 diabetes medications, cis expression quantitative trait loci (eQTL), and functional validation in cellular models. Finally, we examined for possible drug-drug-gene interactions. RESULTS: After establishing that sulfonylurea response is heritable (mean ± SEM 37 ± 11%), we identified two independent loci near the GXYLT1 and SLCO1B1 genes associated with HbA(1c) reduction at a genome-wide scale (P < 5 × 10(−8)). The C allele at rs1234032, near GXYLT1, was associated with 0.14% (1.5 mmol/mol), P = 2.39 × 10(−8)), lower reduction in HbA(1c). Similarly, the C allele was associated with higher glucose trough levels (β = 1.61, P = 0.005) in healthy volunteers in the SUGAR-MGH given glipizide (N = 857). In 3,029 human whole blood samples, the C allele is a cis eQTL for increased expression of GXYLT1 (β = 0.21, P = 2.04 × 10(−58)). The C allele of rs10770791, in an intronic region of SLCO1B1, was associated with 0.11% (1.2 mmol/mol) greater reduction in HbA(1c) (P = 4.80 × 10(−8)). In 1,183 human liver samples, the C allele at rs10770791 is a cis eQTL for reduced SLCO1B1 expression (P = 1.61 × 10(−7)), which, together with functional studies in cells expressing SLCO1B1, supports a key role for hepatic SLCO1B1 (encoding OATP1B1) in regulation of sulfonylurea transport. Further, a significant interaction between statin use and SLCO1B1 genotype was observed (P = 0.001). In statin nonusers, C allele homozygotes at rs10770791 had a large absolute reduction in HbA(1c) (0.48 ± 0.12% [5.2 ± 1.26 mmol/mol]), equivalent to that associated with initiation of a dipeptidyl peptidase 4 inhibitor. CONCLUSIONS: We have identified clinically important genetic effects at genome-wide levels of significance, and important drug-drug-gene interactions, which include commonly prescribed statins. With increasing availability of genetic data embedded in clinical records these findings will be important in prescribing glucose-lowering drugs

Opportunities for primary and secondary prevention of excess gestational weight gain: General Practitioners' perspectives

BackgroundThe impact of excess gestational weight gain (GWG) on maternal and child health outcomes is well documented. Understanding how health care providers view and manage GWG may assist with influencing healthy gestational weight outcomes. This study aimed to assess General Practitioner\u27s (GPs) perspectives regarding the management and assessment of GWG and to understand how GPs can be best supported to provide healthy GWG advice to pregnant women.MethodsDescriptive qualitative research methods utilising semi - structured interview questions to assess GPs perspectives and management of GWG. GPs participating in shared antenatal care in Geelong, Victoria and Sydney, New South Wales were invited to participate in semi - structured, individual interviews via telephone or in person. Interviews were digitally recorded and transcribed verbatim. Data was analysed utilising thematic analysis for common emerging themes.ResultsTwenty eight GPs participated, 14 from each state. Common themes emerged relating to awareness of the implications of excess GWG, advice regarding weight gain, regularity of gestational weighing by GPs, options for GPs to seek support to provide healthy lifestyle behaviour advice and barriers to engaging pregnant women about their weight. GPs perspectives concerning excess GWG were varied. They frequently acknowledged maternal and child health complications resulting from excess GWG yet weighing practices and GWG advice appeared to be inconsistent. The preferred support option to promote healthy weight was referral to allied health practitioners yet GPs noted that cost and limited access were barriers to achieving this.ConclusionsGPs were aware of the importance of healthy GWG yet routine weighing was not standard practice for diverse reasons. Management of GWG and perspectives of the issue varied widely. Time efficient and cost effective interventions may assist GPs in ensuring women are supported in achieving healthy GWG to provide optimal maternal and infant health outcomes.<br /

Primary Prevention of Gestational Diabetes Mellitus and Large-for-Gestational-Age Newborns by Lifestyle Counseling: A Cluster-Randomized Controlled Trial

In a cluster-randomized trial, Riitta Luoto and colleagues find that counseling on diet and activity can reduce the birthweight of babies born to women at risk of developing gestational diabetes mellitus (GDM), but fail to find an effect on GDM