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

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

Lactation intensity and postpartum maternal glucose tolerance and insulin resistance

OBJECTIVEdTo examine the association between breastfeeding intensity in relation to maternal blood glucose and insulin and glucose intolerance based on the postpartum 2-h 75-g oral glucose tolerance test (OGTT) results at 6-9 weeks after a pregnancy with gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODSdWe selected 522 participants enrolled into the Study of Women, Infant Feeding, and Type 2 Diabetes (SWIFT), a prospective observational cohort study of Kaiser Permanente Northern California members diagnosed with GDM using the 3-h 100-g OGTT by the Carpenter and Coustan criteria. Women were classified as normal, prediabetes, or diabetes according to American Diabetes Association criteria based on the postpartum 2-h 75-g OGTT results. RESULTSdCompared with exclusive or mostly formula feeding (.17 oz formula per 24 h), exclusive breastfeeding and mostly breastfeeding (#6 oz formula per 24 h) groups, respectively, had lower adjusted mean (95% CI) group differences in fasting plasma glucose (mg/dL) of 24.3 (27.4 to 21.3) and 25.0 (28.5 to 21.4), in fasting insulin (mU/mL) of 26.3 (210.1 to 22.4) and 27.5 (211.9 to 23.0), and in 2-h insulin of 221.4 (241.0 to 21.7) and 236.5 (259.3 to 213.7) (all P , 0.05). Exclusive or mostly breastfeeding groups had lower prevalence of diabetes or prediabetes (P = 0.02). CONCLUSIONSdHigher intensity of lactation was associated with improved fasting glucose and lower insulin levels at 6-9 weeks&apos; postpartum. Lactation may have favorable effects on glucose metabolism and insulin sensitivity that may reduce diabetes risk after GDM pregnancy. 35:50-56, 2012 Diabetes Car

Variation in the Glucose Transporter gene <i>SLC2A2 </i>is associated with glycaemic response to metformin

Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear1. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10−14) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine

Diagnostic thresholds for pregnancy hyperglycemia, maternal weight status and the risk of childhood obesity in a diverse Northern California cohort using health care delivery system data.

ObjectiveTo estimate the risk of childhood obesity associated with the various criteria proposed for diagnosis of gestational diabetes (GDM), and the joint effects with maternal BMI.MethodsCohort study of 46,396 women delivering at the Kaiser Permanente Northern California health care delivery system in 1995-2004 and their offspring, followed through 5-7 years of age. Pregnancy hyperglycemia was categorized according to the screening and oral glucose tolerance test values proposed for the diagnosis of GDM by the International Association of the Diabetes and Pregnancy Study Group (IADPSG), Carpenter Coustan (CC), and the National Diabetes Data Group (NDDG). Childhood obesity was defined by the International Obesity Task Force's age and sex-specific BMI cut-offs. Poisson regression models estimated the risks of childhood obesity associated with each category of pregnancy glycemia compared to normal screening, and the joint effects of maternal BMI category and GDM by the CC and the IADPSG criteria.ResultsCompared with normal screening, increased risks of childhood obesity were observed for abnormal screening [RR (95% CI): 1.30 (1.22, 1.38)], 1+ abnormal values by the IADPSG or CC [1.47 (1.36, 1.59) and 1.48 (1.37, 1.59), respectively], and 2+ values by CC or NDDG [1.52 (1.39, 1.67) and 1.60 (1.43, 1.78), respectively]. Compared to obese women without GDM, obese women with GDM defined by the CC criteria had significantly increased risk of childhood obesity [1.20 (1.07, 1.34)], which was also observed for GDM by the IADSPG [1.18 (1.07, 1.30)], though GDM did not significantly increase the risk of childhood obesity among normal weight or overweight women.ConclusionsThe risk of childhood obesity starts to increase at levels of pregnancy glycemia below those used to diagnose GDM and the effect of GDM on childhood obesity risk appears more pronounced in women with obesity. Interventions to reduce obesity and pregnancy hyperglycemia are warranted