Pathways Targeted by Antidiabetes Drugs Are Enriched for Multiple Genes Associated With Type 2 Diabetes Risk

Genome-wide association studies (GWAS) have uncovered >65 common variants associated with type 2 diabetes (T2D); however, their relevance for drug development is not yet clear. Of note, the first two T2D-associated loci (PPARG and KCNJ11/ABCC8) encode known targets of antidiabetes medications. We therefore tested whether other genes/pathways targeted by antidiabetes drugs are associated with T2D. We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis (MAGENTA [Meta-Analysis Gene-set Enrichment of variaNT Associations]) to this gene set, using available GWAS meta-analyses for T2D and seven quantitative glycemic traits. We detected a strong enrichment of drug target genes associated with T2D (P = 2 × 10⁻⁵; 14 potential new associations), primarily driven by insulin and thiazolidinedione (TZD) targets, which was replicated in an independent meta-analysis (Metabochip). The glycemic traits yielded no enrichment. The T2D enrichment signal was largely due to multiple genes of modest effects (P = 4 × 10⁻⁴, after removing known loci), highlighting new associations for follow-up (ACSL1, NFKB1, SLC2A2, incretin targets). Furthermore, we found that TZD targets were enriched for LDL cholesterol associations, illustrating the utility of this approach in identifying potential side effects. These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design.     

Greater Carboxy-Methyl-Lysine Is Associated With Increased Fracture Risk in Type 2 Diabetes

Accumulation of advanced glycation end-products (AGE) in bone alters collagen structure and function. Fluorescent AGEs are associated with fractures but less is known regarding non-fluorescent AGEs. We examined associations of carboxy-methyl-lysine (CML), with incident clinical and prevalent vertebral fractures by type 2 diabetes (T2D) status, in the Health, Aging, and Body Composition cohort of older adults. Incident clinical fractures and baseline vertebral fractures were assessed. Cox regression was used to analyze the associations between serum CML and clinical fracture incidence, and logistic regression for vertebral fracture prevalence. At baseline, mean ± standard deviation (SD) age was 73.7 ± 2.8 and 73.6 ± 2.9 years in T2D (n = 712) and non-diabetes (n = 2332), respectively. Baseline CML levels were higher in T2D than non-diabetes (893 ± 332 versus 771 ± 270 ng/mL, p < 0.0001). In multivariate models, greater CML was associated with higher risk of incident clinical fracture in T2D (hazard ratio [HR] 1.49; 95% confidence interval [CI], 1.24–1.79 per 1-SD increase in log CML) but not in non-diabetes (HR 1.03; 95% CI, 0.94–1.13; p for interaction = 0.001). This association was independent of bone mineral density (BMD), glycated hemoglobin (hemoglobin A1c), weight, weight loss, smoking, cystatin-C, and medication use. CML was not significantly associated with the odds of prevalent vertebral fractures in either group. In conclusion, higher CML levels are associated with increased risk of incident clinical fractures in T2D, independent of BMD. These results implicate CML in the pathogenesis of bone fragility in diabetes. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Nitrogen-Containing Bisphosphonates Are Associated With Reduced Risk of Pneumonia in Patients With Hip Fracture

The objective of this work was to study the risk of pneumonia and pneumonia mortality among patients receiving nitrogen-containing bisphosphonates (N-BPs), non-N-BP anti-osteoporosis medications, and no anti-osteoporosis medications after hip fracture. We studied a historical cohort using a population-wide database. Patients with first hip fracture during 2005–2015 were identified and matched by time-dependent propensity score. The cohort was followed until December 31, 2016, to capture any pneumonia and pneumonia mortality. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox-proportional hazards regression. Absolute risk difference (ARD) and number needed to treat (NNT) were calculated. We identified 54,047 patients with hip fracture. Of these, 4041 patients who received N-BPs and 11,802 without anti-osteoporosis medication were propensity score–matched. N-BPs were associated with a significantly lower risk of pneumonia compared with no treatment (6.9 versus 9.0 per 100 person-years; HR 0.76; 95% CI, 0.70 to 0.83), resulting in an ARD of 0.02 and NNT of 46. A similar association was observed with pneumonia mortality (HR 0.65; 95% CI, 0.56 to 0.75). When N-BPs were compared with non-N-BP anti-osteoporosis medications, the association remained significant. N-BPs were associated with lower risks of pneumonia and pneumonia mortality. Randomized controlled trials are now required to determine whether N-BPs, non–vaccine-based medications, can reduce pneumonia incidence in high risk groups. © 2020 American Society for Bone and Mineral Research.     

Combined Risk Allele Score of Eight Type 2 Diabetes Genes Is Associated With Reduced First-Phase Glucose-Stimulated Insulin Secretion During Hyperglycemic Clamps

OBJECTIVE

At least 20 type 2 diabetes loci have now been identified, and several of these are associated with altered β-cell function. In this study, we have investigated the combined effects of eight known β-cell loci on insulin secretion stimulated by three different secretagogues during hyperglycemic clamps.

RESEARCH DESIGN AND METHODS

A total of 447 subjects originating from four independent studies in the Netherlands and Germany (256 with normal glucose tolerance [NGT]/191 with impaired glucose tolerance [IGT]) underwent a hyperglycemic clamp. A subset had an extended clamp with additional glucagon-like peptide (GLP)-1 and arginine (n = 224). We next genotyped single nucleotide polymorphisms in TCF7L2, KCNJ11, CDKAL1, IGF2BP2, HHEX/IDE, CDKN2A/B, SLC30A8, and MTNR1B and calculated a risk allele score by risk allele counting.

RESULTS

The risk allele score was associated with lower first-phase glucose-stimulated insulin secretion (GSIS) (P = 7.1 × 10⁻⁶). The effect size was equal in subjects with NGT and IGT. We also noted an inverse correlation with the disposition index (P = 1.6 × 10⁻³). When we stratified the study population according to the number of risk alleles into three groups, those with a medium- or high-risk allele score had 9 and 23% lower first-phase GSIS. Second-phase GSIS, insulin sensitivity index and GLP-1, or arginine-stimulated insulin release were not significantly different.

CONCLUSIONS

A combined risk allele score for eight known β-cell genes is associated with the rapid first-phase GSIS and the disposition index. The slower second-phase GSIS, GLP-1, and arginine-stimulated insulin secretion are not associated, suggesting that especially processes involved in rapid granule recruitment and exocytosis are affected in the majority of risk loci.Type 2 diabetes is a polygenic disease in which the contribution of a number of detrimental gene variants in combination with environmental factors is thought to be necessary for the development of disease. In the past 2 years, results of several genome-wide association studies (GWASs) have been published (1–5), leading to a rapidly increasing number of detrimental type 2 diabetes susceptibility loci. More recently, it has indeed been shown that combining information from these diabetes loci into a risk allele score for all loci enhances diabetes risk (6–9). However, the predictive power of this combined risk allele score is yet insufficient to substitute or largely improve predictive power of known clinical risk factors (8,9). At present, little is known about how these gene variants in combination affect insulin secretion or insulin resistance. Based on recent data, mainly obtained from oral glucose tolerance tests (OGTTs), it was shown that a combined risk allele score from gene variants associated with type 2 diabetes is associated with insulin secretion and not with insulin sensitivity (10–13). However, the OGTT is unable to distinguish between first- and second-phase insulin secretion. Furthermore, other secretagogues, like glucagon-like peptide (GLP)-1 and arginine, were not included in these studies.It is thought that the rapid recruitment and release of insulin granules from the readily releasable pool (RRP) is responsible for the first phase of insulin secretion, whereas the slower prolonged second phase involves recruitment to the membrane of more distant granules and de novo insulin synthesis. Although the exact pathways regulating both phases of glucose-stimulated insulin secretion (GSIS) are not completely resolved, it seems logical that they are at least in part different. This is further corroborated by our recent observation that the heritability for both phases of GSIS in twins is derived from partly nonoverlapping sets of genes (13a).Also, other nonglucose, stimuli-like incretins and amino acids can evoke an insulin response. Detailed phenotypic investigations of the response to these different stimuli may help to elucidate which processes are primarily affected by these loci. Previously, we have already shown that type 2 diabetes genes/loci can have different effects on first- and second-phase GSIS, as measured using hyperglycemic clamps. Also, based on the method of stimulation (i.e., oral versus intravenous), the outcome may differ substantially (14–17), which provides further clues about the mechanism by which they affect insulin secretion.In this study, we genotyped gene variants in TCF7L2, KCNJ11, HHEX/IDE, CDKAL1, IGF2BP2, SLC30A8, CDKN2A/CDKN2B, and MTNR1B in 447 hyperglycemic clamped subjects (256 with normal glucose tolerance [NGT] and 191 with impaired glucose tolerance [IGT]) from four independent studies in the Netherlands and Germany. These eight loci were chosen based on the fact that they were reproducibly associated with β-cell function in various studies (rev. in 18,19). A combined risk allele score of all eight gene variants was calculated for each individual and tested against the various detailed measurements of β-cell function using the hyperglycemic clamp, generally considered to be the gold standard for quantification of first- and second-phase GSIS (20). Furthermore, we also assessed the combined effect of these eight genes on two other stimuli, GLP-1 and arginine-stimulated insulin secretion during hyperglycemia, in a subset of the study sample (n = 224). The latter test provides an estimation of the maximal insulin secretion capacity of a subject and may, according to animal studies, serve as a proxy for β-cell mass (21).     

HLA DPA1, DPB1 Alleles and Haplotypes Contribute to the Risk Associated With Type 1 Diabetes: Analysis of the Type 1 Diabetes Genetics Consortium Families

OBJECTIVE

To determine the relative risk associated with DPA1 and DPB1 alleles and haplotypes in type 1 diabetes.

RESEARCH DESIGN AND METHODS

The frequency of DPA1 and DPB1 alleles and haplotypes in type 1 diabetic patients was compared to the family based control frequency in 1,771 families directly and conditional on HLA (B)-DRB1-DQA1-DQB1 linkage disequilibrium. A relative predispositional analysis (RPA) was performed in the presence or absence of the primary HLA DR-DQ associations and the contribution of DP haplotype to individual DR-DQ haplotype risks examined.

RESULTS

Eight DPA1 and thirty-eight DPB1 alleles forming seventy-four DPA1-DPB1 haplotypes were observed; nineteen DPB1 alleles were associated with multiple DPA1 alleles. Following both analyses, type 1 diabetes susceptibility was significantly associated with DPB1*0301 (DPA1*0103-DPB1*0301) and protection with DPB1*0402 (DPA1*0103-DPB1*0402) and DPA1*0103-DPB1*0101 but not DPA1*0201-DPB1*0101. In addition, DPB1*0202 (DPA1*0103-DPB1*0202) and DPB1*0201 (DPA1*0103-DPB1*0201) were significantly associated with susceptibility in the presence of the high risk and protective DR-DQ haplotypes. Three associations (DPB1*0301, *0402, and *0202) remained statistically significant when only the extended HLA-A1-B8-DR3 haplotype was considered, suggesting that DPB1 alone may delineate the risk associated with this otherwise conserved haplotype.

CONCLUSIONS

HLA DP allelic and haplotypic diversity contributes significantly to the risk for type 1 diabetes; DPB1*0301 (DPA1*0103-DPB1*0301) is associated with susceptibility and DPB1*0402 (DPA1*0103-DPB1*0402) and DPA1*0103-DPB1*0101 with protection. Additional evidence is presented for the susceptibility association of DPB1*0202 (DPA1*0103-DPB1*0202) and for a contributory role of individual amino acids and DPA1 or a gene in linkage disequilibrium in DR3-DPB1*0101 positive haplotypes.Insulin-dependent autoimmune or type 1 diabetes is a common autoimmune disorder of unknown etiology which results in the destruction of the insulin-secreting pancreatic β-cells. The concordance rate in monozygotic twins is estimated to be 30 to 50% with an average risk to sibs of 6% (1) and an overall genetic risk ratio (λ-s) of about 15 (2). The increasing incidence of type 1 diabetes in a genetically homogeneous population, however, clearly indicates that environmental factors also play a key role (3,4).Multiple association studies and genome linkage and association scans have confirmed that the greatest genetic risk is associated with variation within the HLA region located on chromosome six with evidence for modest associations at other regions in addition to HLA (5,6). In particular allelic, haplotypic or genotypic differences at the HLA class II DRB1, DQA1 or DQB1 loci have been shown in many studies, including a subset of this dataset (7), to have the greatest association.The most plausible mechanism explaining the association with genes of the HLA class II region is their role in presentation of peptides derived from exogenous protein to CD4+ T-helper cells which, in the case of type 1 diabetes, may result in an inappropriate T cell immune response against self-antigens on the pancreatic β-cells. Allelic differences at the DRB1, DQA1 and DQB1 loci have been shown to influence the peptide binding and T cell stimulatory capacities of the individual HLA molecules (8), suggesting that such differences contribute to the association of individual or groups of alleles with autoimmune diseases. Genetic polymorphisms at other loci, both within and outside the HLA region may, in addition, contribute to and influence the magnitude of the immune response.The HLA DPA1 and DPB1 genes are the third set of classical HLA class II loci which code for the DP antigen and have been associated with a lower immunostimulatory capacity and level of expression (9,10) although differences at individual DPB amino acids have been associated with an increased proliferative response in the mixed lymphocyte reaction (11,12). Similarly, a single DPB amino acid, glutamic acid at position 69, has been shown to contribute to graft versus host disease in otherwise HLA identical sibling bone marrow transplantation (13) and susceptibility to Beryllium disease (14).Association studies of HLA-DPB1 and type 1 diabetes have shown multiple associations with conflicting results. The following have been reported as susceptibility alleles in populations of different ethnic backgrounds: DPB1*0201, *0202, *0301, *0401, *0402, *1701 and the following as protective alleles; DPB1*0101, *0202, *0401, *0402, *1701 (15–23). Other studies have reported weak or no association with HLA DPB1 alleles (24,25). The conflicting nature of these association studies may be a reflection of population specific differences, inconsistent typing approaches, differences in study design or inadequately powered studies.The HLA DPA1 and DPB1 loci are highly polymorphic with 28 DPA1 and 136 DPB1 alleles defined as of October, 2009 (http://www.ebi.ac.uk/imgt/hla/). Association analyses in the HLA region are complicated by the occurrence of extensive linkage disequilibrium between loci such that the classical HLA loci, A, B, C, DR, DQ and DP, as well as other genes in this region, are often inherited as a “block”. The DR/DQ recombination frequency per meiosis between DR-DQ and DP has been estimated to range between 1–3% (13,26). Estimates of the relative contribution of HLA DP to susceptibility or protection against type 1 diabetes must therefore consider the potential influence of co-inherited loci, some of which are strongly associated with type 1 diabetes.The Type 1 Diabetes Genetic Consortium (T1DGC) is a large worldwide collaborative study of type 1 diabetes families that have been collected in a highly standardized fashion from various populations (27). High resolution HLA typing has been performed at eight loci at four genotyping centers using standardized typing protocols and reagents (28). The large sample size and addition of DPA1 typing permits, for the first time, an association analysis of the DPA1 locus in addition to DPB1 and DPA1-DPB1 haplotypes, which encode the antigen presenting alpha and beta chain heterodimer with type 1 diabetes.     

Type 2 Diabetes Is Causally Associated With Reduced Serum Osteocalcin: A Genomewide Association and Mendelian Randomization Study

Recent advances indicate that bone and energy metabolism are closely related. However, little direct evidence on causality has been provided in humans. We aimed to assess the association of three bone-related biomarkers—25 hydroxyvitamin D (25OHD), parathyroid hormone (PTH), and osteocalcin (OCN)—with several metabolic phenotypes and investigate any causal relevance to the associations using a Mendelian randomization (MR) study. Serum 25OHD, PTH, and total OCN were measured at baseline in 5169 eligible Chinese participants in Changfeng study. Partial correlation and bivariate GREML analysis were used to estimate phenotypic and genetic correlations, respectively. Multiple linear regression and logistic regression were used to assess linear associations. Genomewide association analysis (GWAS) was performed. Bidirectional two-sample MR analyses were conducted to examine causal relationships between OCN and body mass index (BMI), diastolic blood pressure (DBP), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), glycated hemoglobin A1c (HbA1c), and type 2 diabetes (T2DM), using our GWAS result of OCN and GWAS statistics from Biobank Japan project (BBJ) and the largest meta-analysis of T2DM GWAS in East Asian population. Circulating OCN was significantly associated with higher DBP and HDL-C and decreased TG, blood glucose level, insulin resistance, liver fat content, bone mineral density, BMI, and a favorable body fat distribution pattern. GWAS identified one novel serum PTH locus and two novel serum OCN loci, explaining 0.81% and 1.98% of variances of PTH and OCN levels, respectively. MR analysis suggested a causal effect of T2DM on lower circulating OCN concentration (causal effect: −0.03; −0.05 to −0.01; p = 0.006 for T2DM_BBJ and −0.03; −0.05 to −0.01; p = 0.001 for T2DM_EAS). These findings indicate that T2DM might impact bone remodeling and provide a resource for understanding complex relationships between osteocalcin and metabolic (and related) traits in humans. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Nitric Oxide Synthesis Is Reduced in Subjects With Type 2 Diabetes and Nephropathy

OBJECTIVE

Nitric oxide (NO) is a key metabolic and vascular regulator. Its production is stimulated by insulin. A reduced urinary excretion of NO products (NOx) is frequently found in type 2 diabetes, particularly in association with nephropathy. However, whether the decreased NOx excretion in type 2 diabetes is caused by a defective NOx production from arginine in response to hyperinsulinemia has never been studied.

RESEARCH DESIGN AND METHODS

We measured NOx fractional (FSR) and absolute (ASR) synthesis rates in type 2 diabetic patients with diabetic nephropathy and in control subjects, after l-[¹⁵N₂-guanidino]-arginine infusion, and use of precursor–product relationships. The study was conducted both before and after an euglycemic hyperinsulinemic (∼1,000–1,200 pmol/l) clamp.

RESULTS

In type 2 diabetes, NOx FSR was reduced both under basal (19.3 ± 3.9% per day, vs. 22.9 ± 4.5% per day in control subjects) and hyperinsulinemic states (24.0 ± 5.6% per day, vs. 37.9 ± 6.4% per day in control subjects; P < 0.03 by ANOVA). Similarly, in type 2 diabetes, NOx ASR was lower than in control subjects under both conditions (basal, 0.32 ± 0.06 vs. 0.89 ± 0.34 mol per day; hyperinsulinemia, 0.35 ± 0.07 vs. 1.15 ± 0.38 mol per day; P = 0.01 by ANOVA). In type 2 diabetes, the ability of insulin to stimulate both the FSR (4.7 ± 3.2% per day) and the ASR (0.03 ± 0.04 mol per day) of NOx was several-fold lower than that in control subjects (15.0 ± 2.9% per day and 0.25 ± 0.07 mol per day, P < 0.03 and P < 0.02, respectively). Also the fraction of arginine flux converted to NOx (basal, 0.22 ± 0.05% vs. 0.65 ± 0.25%; hyperinsulinemia, 0.32 ± 0.06% vs. 1.03 ± 0.33%) was sharply reduced in the patients (P < 0.01 by ANOVA).

CONCLUSIONS

In type 2 diabetic patients with nephropathy, intravascular NOx synthesis from arginine is decreased under both basal and hyperinsulinemic states. This defect extends the concept of insulin resistance to NO metabolism.Nitric oxide (NO) is a key regulatory molecule with extensive metabolic, vascular, and cellular effects (1–6). The regulation of NO metabolism is particularly important in type 2 diabetes, because activation of NO synthase (NOS) is under insulin control through the Akt pathway (3,5). Thus, disturbances of NO generation may be a consequence of insulin resistance affecting also the vascular response (3). An impaired NO metabolism is found in type 2 diabetes (7–10), in particular in the presence of nephropathy (11). A reduced urinary excretion of nitric oxide–related products, such as nitrites and nitrates, collectively termed as [NOx], has been reported in type 2 diabetic patients with nephropathy (12,13). Conversely, microalbuminuria is associated with impaired endothelial function in type 2 diabetic subjects (14). Hyperglycemia may also play a role in the decreased NO production in type 2 diabetes, because high glucose per se inhibited endothelial NOS activity in the glomeruli, through a protein kinase C–associated mechanism (15). Moreover, high glucose and/or the associated advanced glycosylation end products decreased NOS expression (11). Urinary NOx production is reduced in nondiabetic renal disease (16), although also increased plasma nitrate concentrations have been reported in type 2 diabetes, as well as in the Metabolic Syndrome (17,18), thus questioning the validity of urinary methods to assess whole-body NOx production.Because the stimulation of NOS activity by insulin is impaired in muscle of type 2 diabetic patients (19), investigations on the response to the hormone of whole-body NO production in type 2 diabetes is of key relevance. An impaired NO generation in type 2 diabetes may be another feature of insulin resistance (3).We recently developed a precursor–product, stable isotope method to measure whole-body synthesis of NO-related compounds in vivo (20). Therefore, the aim of this study was twofold: 1) to measure NOx production rate (both fractional and absolute), as well as the rate of arginine conversion to NOx, in type 2 diabetic patients with diabetic nephropathy and 2) to study the effects of acute hyperinsulinemia on these parameters.     

Risk of Newly Diagnosed Type 2 Diabetes Is Reduced in Users of Alendronate

To study the risk of developing type 1 (T1D) or type 2 (T2D) diabetes among users of drugs against osteoporosis compared to nonusers. Nationwide cohort study in Denmark with all users of drugs against osteoporosis (n = 103,562) as exposed and three age- and sex-matched nondiabetic control subjects (n = 310,683) randomly selected from the background population. The main outcome variable was an incident diagnosis of diabetes after the baseline date. Among users of alendronate, etidronate, and raloxifene, no change in the risk of T1D was observed. However, the risk of developing T2D was reduced with all three drugs (alendronate: hazard ratio [HR] = 0.71, 95% confidence interval [CI] 0.59–0.85, etidronate: HR = 0.77, 95% CI 0.69–0.86, raloxifene: HR = 0.46, 95% CI 0.25–0.87). For alendronate, a dose-dependent risk reduction was observed (≥1 defined daily dose (DDD) per day: HR = 0.22, 95% CI 0.12–0.41, P for trend <0.01), while this was not the case for etidronate and raloxifene. Antiresorptive drugs do not seem associated with an increased risk of diabetes, but they may perhaps provide a protective effect related to the suppression of bone turnover. However, further studies are needed.     

Functional Variants in MBL2 Are Associated With Type 2 Diabetes and Pre-Diabetes Traits in Pima Indians and the Old Order Amish

OBJECTIVE

MBL2 encodes the mannose-binding lectin, which is a key player in the innate immune system and has recently been found to play a role in insulin resistance and development of type 1 diabetes and gestational diabetes mellitus. To assess the role of MBL2 in diabetes susceptibility, this gene was analyzed in the Pima Indian population, which has a high prevalence of type 2 diabetes.

RESEARCH DESIGN AND METHODS

Nineteen tag single nucleotide polymorphisms (SNPs) were genotyped in a population-based sample of 3,501 full-heritage Pima Indians, and selected SNPs were further genotyped in independent samples of Native American (n = 3,723) and Old Order Amish (n = 486) subjects.

RESULTS

Two variants, a promoter SNP (rs11003125) at −550 bp with a risk allele frequency of 0.77 and a Gly54Asp (rs1800450) with a risk allele frequency of 0.83, were associated with type 2 diabetes in the full-heritage Pima Indians (odds ratio 1.30 per copy of the G allele for rs1103125, P = 0.0007, and 1.30 per copy of the glycine allele for rs1800450, P = 0.002, adjusted for age, sex, birth year, and family membership). These associations replicated in an independent Native American sample (1.19, P = 0.04, for rs11003125) and a Caucasian sample, the Old Order Amish (1.51, P = 0.004, for rs1103125 and 2.38, P = 0.003, for rs1800450). Among Pima Indians with normal glucose tolerance, the diabetes risk allele glycine of Gly54Asp was associated with a decreased acute insulin response to an intravenous glucose bolus infusion (P = 0.004, adjusted for age, sex, percent body fat, glucose disposal under physiological insulin stimulation, and family membership).

CONCLUSIONS

Our data suggest that the functional variants in MBL2 contribute to type 2 diabetes susceptibility in both Native Americans and the Old Order Amish.Mannose-binding lectin (MBL) is a liver-derived serum lectin involved in the innate immune defense. Upon binding to specific carbohydrate structures on various microorganisms, MBL may utilize MBL serine protease (MASP)-2 to activate the third pathway of complement (lectin pathway) and thereby opsonophagocytosis (1).Serum MBL levels have been shown to be strongly correlated with the presence of variants within the MBL2 gene. Missense polymorphisms at codon 54 (resulting in a glycine to aspartic acid), codon 57 (resulting in a glycine to glutamic acid), and codon 52 (resulting in an arginine to cysteine) impair oligomer formation, leading to reduced serum levels of functional MBL. In addition, three promoter polymorphisms at position −550 bp G > C (H/l), −221 bp G > C (Y/X) and +4 bp C > T (P/Q) influence the expression of MBL2 (1–3).Deficiency of MBL has been associated with immunodeficiency, autoimmune disorders such as systemic lupus erythematosus, and rheumatoid arthritis (4,5). Recent studies have further implicated MBL deficiency in the development of type 1 diabetes (6), gestational diabetes mellitus (7), diabetic nephropathy (8), and insulin resistance and obesity (9). Based on the biological role of MBL2, this gene was investigated as a potential susceptibility gene for type 2 diabetes in Pima Indians.     

A Polygenic Score for Type 2 Diabetes Risk Is Associated With Both the Acute and Sustained Response to Sulfonylureas

There is a limited understanding of how genetic loci associated with glycemic traits and type 2 diabetes (T2D) influence the response to antidiabetic medications. Polygenic scores provide increasing power to detect patterns of disease predisposition that might benefit from a targeted pharmacologic intervention. In the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH), we constructed weighted polygenic scores using known genome-wide significant associations for T2D, fasting glucose, and fasting insulin, comprising 65, 43, and 13 single nucleotide polymorphisms, respectively. Multiple linear regression tested for associations between scores and glycemic traits as well as pharmacodynamic end points, adjusting for age, sex, race, and BMI. A higher T2D score was nominally associated with a shorter time to insulin peak, greater glucose area over the curve, shorter time to glucose trough, and steeper slope to glucose trough after glipizide. In replication, a higher T2D score was associated with a greater 1-year hemoglobin A_1c reduction to sulfonylureas in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) study (P = 0.02). Our findings suggest that individuals with a higher genetic burden for T2D experience a greater acute and sustained response to sulfonylureas.     

Acetylcholinesterase Inhibitors Are Associated with Reduced Fracture Risk among Older Veterans with Dementia

Acetylcholinesterase inhibitors (AChEIs) have been noted to increase bone density and quality in mice. Human studies are limited but suggest an association with improved bone healing after hip fracture. We examined the relationship between AChEI use and fracture risk in a national cohort of 360,015 male veterans aged 65 to 99 years with dementia but without prior fracture using Veterans Affairs (VA) hospital, Medicare, and pharmacy records from 2000 to 2010. Diagnosis of dementia, any clinical fracture (excluding facial and digital), comorbidities, and medications were identified using ICD-9 and drug class codes. Cox proportional hazard models considering AChEI use as a time-varying covariate and adjusting for fall and fracture risk factors compared the time-to-fracture in AChEI users versus non-AChEI users. Potential confounders included demographics (age, race, body mass index), comorbidities associated with fracture or falls (diabetes, lung disease, stroke, Parkinson's, seizures, etc.) and medications associated with fracture or falls (bisphosphonates, glucocorticoids, androgen deprivation therapy [ADT], proton pump inhibitors [PPIs], selective serotonin receptor inhibitors [SSRIs], etc.). Competing mortality risk was considered using the methods of Fine and Gray. To account for persistent effects on bone density or quality that might confer protection after stopping the medication, we completed a secondary analysis using the medication possession ratio (MPR) as a continuous variable in logistic regression models and also compared MPR increments of 10% to minimal/no use (MPR 0 to <0.10). Among older veterans with diagnosis of dementia, 20.1% suffered a fracture over an average of 4.6 years of follow-up. Overall, 42.3% of the cohort were prescribed AChEIs during the study period. The hazard of any fracture among AChEI users compared with those on other/no dementia medications was significantly lower in fully adjusted models (hazard ratio [HR] = 0.81; 95% confidence interval [CI] 0.75–0.88). After considering competing mortality risk, fracture risk remained 18% lower in veterans using AChEIs (HR = 0.82; 95% CI 0.76–0.89). © 2019 American Society for Bone and Mineral Research. Published 2019. This article is a U.S. Government work and is in the public domain in the USA.     

Previously Associated Type 2 Diabetes Variants May Interact With Physical Activity to Modify the Risk of Impaired Glucose Regulation and Type 2 Diabetes: A Study of 16,003 Swedish Adults

OBJECTIVE

Recent advances in type 2 diabetes genetics have culminated in the discovery and confirmation of multiple risk variants. Two important and largely unanswered questions are whether this information can be used to identify individuals most susceptible to the adverse consequences of sedentary behavior and to predict their response to lifestyle intervention; such evidence would be mechanistically informative and provide a rationale for targeting genetically susceptible subgroups of the population.

RESEARCH DESIGN AND METHODS

Gene × physical activity interactions were assessed for 17 polymorphisms in a prospective population-based cohort of initially nondiabetic middle-aged adults. Outcomes were 1) impaired glucose regulation (IGR) versus normal glucose regulation determined with either fasting or 2-h plasma glucose concentrations (n = 16,003), 2) glucose intolerance (in mmol/l, n = 8,860), or 3) incident type 2 diabetes (n = 2,063 events).

RESULTS

Tests of gene × physical activity interactions on IGR risk for 3 of the 17 polymorphisms were nominally statistically significant:CDKN2A/B rs10811661 (P_interaction = 0.015), HNF1B rs4430796 (P_interaction = 0.026), and PPARG rs1801282 (P_interaction = 0.04). Consistent interactions were observed for the CDKN2A/B (P_interaction = 0.013) and HNF1B (P_interaction = 0.0009) variants on 2-h glucose concentrations. Where type 2 diabetes was the outcome, only one statistically significant interaction effect was observed, and this was for the HNF1B rs4430796 variant (P_interaction = 0.0004). The interaction effects for HNF1B on IGR risk and incident diabetes remained significant after correction for multiple testing (P_interaction = 0.015 and 0.0068, respectively).

CONCLUSIONS

Our observations suggest that the genetic predisposition to hyperglycemia is partially dependent on a person''s lifestyle.Recent advances in high-throughput genotyping methods have facilitated the discovery and confirmation (1–7) of multiple common genetic risk factors for type 2 diabetes. The notion of using genetic information for disease prevention is predicated on the assumption that genetic risk can be offset with drug or lifestyle intervention. Thus, studies that explore this possibility are integral to the process of translating the results of genetic association studies into preventive practice. Furthermore, because interaction effects modify the extent to which genetic risk is conveyed, with the risk varying in magnitude across the spectrum of environmental exposure, information on gene × environment interactions may help improve the sensitivity and specificity of genetic prediction models (8).In a recent report from the Diabetes Prevention Program, 10 of the previously associated type 2 diabetes risk polymorphisms were assessed in the context of a clinical trial of drug or lifestyle intervention for diabetes risk reduction (9). In that study, a single nucleotide polymorphism (SNP) at the cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) locus (rs10811661) was shown to modify the effects of lifestyle intervention on diabetes risk reduction, such that the lifestyle intervention slowed the progression to type 2 diabetes to a greater extent in those carrying the previously reported high-risk genotype at rs10811661 compared with those with the lower-risk genotypes.In the current study, we aimed to determine whether the effects of 17 previously associated type 2 diabetes gene variants on the risk of impaired glucose regulation (IGR) or incident type 2 diabetes are modified by physical activity. The study was undertaken in an ethnically homogeneous prospective population-based cohort study of ∼16,000 initially nondiabetic middle-aged adults from Sweden.     

Fetal Exposure to Maternal Type 1 Diabetes Is Associated With Renal Dysfunction at Adult Age

OBJECTIVE

In animal studies, hyperglycemia during fetal development reduces nephron numbers. We tested whether this observation translates into renal dysfunction in humans by studying renal functional reserve in adult offspring exposed in utero to maternal type 1 diabetes.

RESEARCH DESIGN AND METHODS

We compared 19 nondiabetic offspring of type 1 diabetic mothers with 18 offspring of type 1 diabetic fathers (control subjects). Glomerular filtration rate (⁵¹Cr-EDTA clearance), effective renal plasma flow (¹²³I-hippurate clearance), mean arterial pressure, and renal vascular resistances were measured at baseline and during amino acid infusion, which mobilizes renal functional reserve.

RESULTS

Offspring of type 1 diabetic mothers were similar to control subjects for age (median 27, range 18–41, years), sex, BMI (23.1 ± 3.7 kg/m²), and birth weight (3,288 ± 550 vs. 3,440 ± 489 g). During amino acid infusion, glomerular filtration rate and effective renal plasma flow increased less in offspring of type 1 diabetic mothers than in control subjects: from 103 ± 14 to 111 ± 17 ml/min (8 ± 13%) vs. from 108 ± 17 to 128 ± 23 ml/min (19 ± 7%, P = 0.009) and from 509 ± 58 to 536 ± 80 ml/min (5 ± 9%) vs. from 536 ± 114 to 620 ± 140 ml/min (16 ± 11%, P = 0.0035). Mean arterial pressure and renal vascular resistances declined less than in control subjects: 2 ± 5 vs. −2 ± 3% (P = 0.019) and 3 ± 9 vs. −14 ± 8% (P = 0.001).

CONCLUSIONS

Reduced functional reserve may reflect a reduced number of nephrons undergoing individual hyperfiltration. If so, offspring of type 1 diabetic mothers may be predisposed to glomerular and vascular diseases.A reduced number of nephrons may cause hypertension and favor renal and cardiovascular risks in humans (1). Autopsy findings support this assumption (2). In addition, birth weight is a determinant of nephron numbers in humans (3). In animal models, moderate hyperglycemia during pregnancy affects birth weight and nephron numbers in offspring (4), and favors the development of hypertension in adulthood (5). In addition, angiogenesis affects kidney development (6,7). In this respect, moderate hyperglycemia induces a defect in angiogenesis as reported in experimental conditions (8).We hypothesized that the effects of moderate hyperglycemia on kidney development reported in animal studies might have clinical relevance in humans. Thus, we studied kidney function in subjects who had been exposed to hyperglycemia during their fetal development. For this purpose, we investigated, as previously (9), adults whose mothers had type 1 diabetes at the time of their conception and used the offspring of type 1 diabetic fathers as control subjects to minimize potential genetic heterogenicity between groups. Type 1 diabetes as a source of hyperglycemia during fetal development also minimizes confounding factors associated with type 2 diabetes such as hypertension. Counting nephron numbers and/or visualizing glomerular size by noninvasive methods is not currently feasible in humans. Thus, we measured global kidney function at baseline and during vasodilatation produced by amino acid infusion, i.e., renal functional reserve. Reduction in renal functional reserve can be interpreted as reflecting a reduced surface available for filtration, suggesting that the number of functional nephrons is reduced. As a result, the global hemodynamic load provokes hyperfiltration at the single nephron level (1). This disturbance in renal hemodynamics was associated with renal and vascular diseases, both in experimental models (1,4,5) and clinical settings (10–13). We report here that renal functional reserve is reduced in offspring of type 1 diabetic mothers.