OBJECTIVEHuman blood glucose levels have likely evolved toward their current point of stability over hundreds of thousands of years. The robust population stability of this trait is called canalization. It has been represented by a hyperbolic function of two variables: insulin sensitivity and insulin response. Environmental changes due to global migration may have pushed some human subpopulations to different points of stability. We hypothesized that there may be ethnic differences in the optimal states in the relationship between insulin sensitivity and insulin response.RESEARCH DESIGN AND METHODSWe identified studies that measured the insulin sensitivity index (SI) and acute insulin response to glucose (AIRg) in three major ethnic groups: Africans, Caucasians, and East Asians. We identified 74 study cohorts comprising 3,813 individuals (19 African cohorts, 31 Caucasian, and 24 East Asian). We calculated the hyperbolic relationship using the mean values of SI and AIRg in the healthy cohorts with normal glucose tolerance.RESULTSWe found that Caucasian subpopulations were located around the middle point of the hyperbola, while African and East Asian subpopulations are located around unstable extreme points, where a small change in one variable is associated with a large nonlinear change in the other variable.CONCLUSIONSOur findings suggest that the genetic background of Africans and East Asians makes them more and differentially susceptible to diabetes than Caucasians. This ethnic stratification could be implicated in the different natural courses of diabetes onset.

Various size-consistent approaches to the calculation of molecular hyperpolarizabilities are analyzed based on the double perturbation theory. General equations for the nth-order response property with respect to an external time-independent field are derived on the basis of the Rayleigh-Schrödinger perturbation theory ͑RSPT͒ and the coupled-cluster ͑CC͒ theory. The corresponding equations for the time-dependent case are also derived by the CC formalism, which is referred to as the time-dependent CC ͑TDCC͒ method. In order to clarify the spatial characteristics of polarizability and hyperpolarizability, we present an analysis method using a new concept ''the polarizability and hyperpolarizability densities.'' As an application of the size-consistent methods, the static second hyperpolarizabilities ͑␥͒ of -conjugated polymeric systems are calculated by the use of the uncoupled ͑UCHF͒, and coupled-Hartree-Fock ͑CHF͒ methods combined with the semiempirical INDO approximation. Characteristics of ␥ values calculated for regular polyenes, solitonlike polyenes and donor(D) -acceptor(A) disubstituted polyenes are investigated, particularly in relation to the chain-length effect. Further, we employ ␥ density analysis method, in which the third derivatives of the Mulliken charge densities against applied electric fields are plotted for exploring the local contributions of the constituent atoms to ␥ values. Results for the finite polyenes are also extrapolated to an infinity of the chain length to predict the intrinsic ␥ values per unit carbon-carbon ͑CC͒ bond of polymeric chains. Furthermore, the CHFϩMo "ller-Plesset second-order perturbation ͑MP2͒ method in the PPP approximation is applied to polymeric systems with larger chain length in order to elucidate the electron correlation effects on the chain-length dependencies of ␥ values.

Objective To determine the efficacy and safety of low carbohydrate diets (LCDs) and very low carbohydrate diets (VLCDs) for people with type 2 diabetes. Design Systematic review and meta-analysis. Data sources Searches of CENTRAL, Medline, Embase, CINAHL, CAB, and grey literature sources from inception to 25 August 2020. Study selection Randomized clinical trials evaluating LCDs (<130 g/day or <26% of a 2000 kcal/day diet) and VLCDs (<10% calories from carbohydrates) for at least 12 weeks in adults with type 2 diabetes were eligible. Data extraction Primary outcomes were remission of diabetes (HbA 1c <6.5% or fasting glucose <7.0 mmol/L, with or without the use of diabetes medication), weight loss, HbA 1c , fasting glucose, and adverse events. Secondary outcomes included health related quality of life and biochemical laboratory data. All articles and outcomes were independently screened, extracted, and assessed for risk of bias and GRADE certainty of evidence at six and 12 month follow-up. Risk estimates and 95% confidence intervals were calculated using random effects meta-analysis. Outcomes were assessed according to a priori determined minimal important differences to determine clinical importance, and heterogeneity was investigated on the basis of risk of bias and seven a priori subgroups. Any subgroup effects with a statistically significant test of interaction were subjected to a five point credibility checklist. Results Searches identified 14 759 citations yielding 23 trials (1357 participants), and 40.6% of outcomes were judged to be at low risk of bias. At six months, compared with control diets, LCDs achieved higher rates of diabetes remission (defined as HbA 1c <6.5%) (76/133 (57%) v 41/131 (31%); risk difference 0.32, 95% confidence interval 0.17 to 0.47; 8 studies, n=264, I 2 =58%). Conversely, smaller, non-significant effect sizes occurred when a remission definition of HbA 1c <6.5% without medication was used. Subgroup assessments determined as meeting credibility criteria indicated that remission with LCDs markedly decreased in studies that included patients using insulin. At 12 months, data on remission were sparse, ranging from a small effect to a trivial increased risk of diabetes. Large clinically important improvements were seen in weight loss, triglycerides, and insulin sensitivity at six months, which diminished at 12 months. On the basis of subgroup assessments deemed credible, VLCDs were less effective than less restrictive LCDs for weight loss at six months. However, this effect was explained by diet adherence. That is, among highly adherent patients on VLCDs, a clinically important reduction in weight was seen compared with studies with less adherent patients on VLCDs. Participants experienced no significant difference in quality of life at six months but did experience clinically important, but not statistically significant, worsening of quality of life and low density lipoprotein cholesterol at 12 months. Otherwise, no significant or clinically important between group differences were found in terms of adverse events or blood lipids at six and 12 months. Conclusions On the basis of moderate to low certainty evidence, patients adhering to an LCD for six months may experience remission of diabetes without adverse consequences. Limitations include continued debate around what constitutes remission of diabetes, as well as the efficacy, safety, and dietary satisfaction of longer term LCDs. Systematic review registration PROSPERO CRD42020161795.

Periodontal ligament-associated protein-1 (PLAP-1)/asporin is a recently identified novel member of the small leucine-rich repeat proteoglycan family. PLAP-1/asporin is involved in chondrogenesis, and its involvement in the pathogenesis of osteoarthritis has been suggested. We report that PLAP-1/asporin is also expressed specifically and predominantly in the periodontal ligament (PDL) and that it negatively regulates the mineralization of PDL cells. In situ hybridization analysis revealed that PLAP-1/asporin was expressed specifically not only in the PDL of an erupted tooth but also in the dental follicle, which is the progenitor tissue of the PDL during tooth development. Overexpression of PLAP-1/asporin in mouse PDL-derived clone cells interfered with both naturally and bone morphogenetic protein 2 (BMP-2)-induced mineralization of the PDL cells. On the other hand, knockdown of PLAP-1/asporin transcript levels by RNA interference enhanced BMP-2-induced differentiation of PDL cells. Furthermore co-immunoprecipitation assays showed a direct interaction between PLAP-1/asporin and BMP-2 in vitro, and immunohistochemistry staining revealed the co-localization of PLAP-1/asporin and BMP-2 at the cellular level. These results suggest that PLAP-1/ asporin plays a specific role(s) in the periodontal ligament as a negative regulator of cytodifferentiation and mineralization probably by regulating BMP-2 activity to prevent the periodontal ligament from developing non-physiological mineralization such as ankylosis.

The temporomandibular joint (TMJ) is essential for jaw function, but the mechanisms regulating its development remain poorly understood. Because Indian hedgehog (Ihh) regulates trunk and limb skeletogenesis, we studied its possible roles in TMJ development. In wild-type mouse embryos, Ihh expression was already strong in condylar cartilage by embryonic day (E) 15.5, and expression of Ihh receptors and effector genes (Gli1, Gli2, Gli3, and PTHrP) indicated that Ihh range of action normally reached apical condylar tissue layers, including polymorphic chondroprogenitor layer and articular disc primordia. In Ihh ؊/؊ embryos, TMJ development was severely compromised. Condylar cartilage growth, polymorphic cell proliferation, and PTHrP expression were all inhibited, and growth plate organization and chondrocyte gene expression patterns were abnormal. These severe defects were partially corrected in double Ihh ؊/؊ /Gli3؊/؊ mutants, signifying that Ihh action is normally modulated and delimited by Gli3 and Gli3 R in particular. Both single and double mutants, however, failed to form an articular disc primordium, normally appreciable as an independent condensation between condylar apex and neighboring developing temporal bone in wild-type. This failure persisted at later stages, leading to complete absence of a normal functional disc and lubricin-expressing joint cavities. In summary, Ihh is very important for TMJ development, where it appears to regulate growth and elongation events, condylar cartilage phenotype, and chondroprogenitor cell function. Absence of articular disc and joint cavities in single and double mutants points to irreplaceable Ihh roles in formation of those critical TMJ components. Developmental Dynamics 236:426 -434, 2007.

TLR2 participates, at least partly, in the signaling pathway to induce chemokine production in gingival epithelium as a reaction against Pg component(s), probably other than lipopolysaccharide and fimbriae.

Objective Although caloric restriction is a widely used intervention to reduce body weight and insulin resistance, many patients are unable to comply with such dietary therapy for long periods. The clinical effectiveness of low-carbohydrate diets was recently described in a position statement of Diabetes UK and a scientific review conducted by the American Diabetes Association. However, randomised trials of dietary interventions in Japanese patients with type 2 diabetes are scarce. Therefore, the aim of this study was to examine the effects of a non-calorie-restricted, low-carbohydrate diet in Japanese patients unable to adhere to a calorie-restricted diet. Methods The enrolled patients were randomly allocated to receive a conventional calorie-restricted diet or low-carbohydrate diet. The patients received consultations every two months from a registered dietician for six months. We compared the effects of the two dietary interventions on glycaemic control and metabolic profiles. Results The HbA1c levels decreased significantly from baseline to six months in the low-carbohydrate diet group (baseline 7.6±0.4%, six months 7.0±0.7%, p=0.03) but not in the calorie-restricted group (baseline 7.7±0.6%, six months 7.5±1.0%, n.s.), (between-group comparison, p=0.03). The patients in the former group also experienced improvements in their triglyceride levels, without experiencing any major adverse effects or a decline in the quality of life. Conclusion Our findings suggest that a low-carbohydrate diet is effective in lowering the HbA1c and triglyceride levels in patients with type 2 diabetes who are unable to adhere to a calorie-restricted diet.

Type 2 diabetes (T2D) is a complex, polygenic disease affecting nearly 300 million people worldwide. T2D is primarily characterized by insulin resistance, and growing evidence has indicated the causative link between adipose tissue inflammation and the development of insulin resistance. Genetic association studies have successfully revealed a number of important genes consistently associated with T2D to date. However, these robust T2D-associated genes do not fully elucidate the mechanisms underlying the development and progression of the disease. Here, we report an alternative approach, gene expression-based genome-wide association study (eGWAS): searching for genes repeatedly implicated in functional microarray experiments (often publicly available). We performed an eGWAS across 130 independent experiments (totally 1,175 T2D case-control microarrays) to find additional genes implicated in the molecular pathogenesis of T2D and identified the immune-cell receptor CD44 as our top candidate (P = 8.5 × 10 −20 ). We found CD44 deficiency in a diabetic mouse model ameliorates insulin resistance and adipose tissue inflammation and also found that anti-CD44 antibody treatment decreases blood glucose levels and adipose tissue macrophage accumulation in a high-fat, diet-fed mouse model. Further, in humans, we observed CD44 is expressed in inflammatory cells in obese adipose tissue and discovered serum CD44 levels were positively correlated with insulin resistance and glycemic control. CD44 likely plays a causative role in the development of adipose tissue inflammation and insulin resistance in rodents and humans. Genes repeatedly implicated in publicly available experimental data may have unique functionally important roles in T2D and other complex diseases.bioinformatics | meta-analysis | integration | obesity | hyperglycemia