Treatment of type 2 diabetes by free fatty acid receptor agonists

Dietary free fatty acids (FFAs), such as ω-3 fatty acids, regulate metabolic and anti-inflammatory processes, with many of these effects attributed to FFAs interacting with a family of G protein-coupled receptors. Selective synthetic ligands for Free Fatty Acid receptors (FFA1-4) have consequently been developed as potential treatments for type 2 diabetes (T2D). In particular, clinical studies show that Fasiglifam, an agonist of the long chain FFA receptor, FFA1, improved glycaemic control and reduced HbA1c levels in T2D patients, with a reduced risk of hypoglycemia. However, this ligand was removed from clinical trials due to potential liver toxicity and determining if this is a target or a ligand-specific feature is now of major importance. Pre-clinical studies also show that FFA4 agonism increases insulin sensitivity, induces weight loss and reduces inflammation and the metabolic and anti-inflammatory effects of short chain fatty acids (SCFAs) are linked with FFA2 and FFA3 activation. In this review, we therefore show that FFA receptor agonism is a potential clinical target for T2D treatment and discuss ongoing drug development programmes within industry and academia aimed at improving the safety and effectiveness of these potential treatments

Non-Acidic Free Fatty Acid Receptor 4 Agonists with Antidiabetic Activity

The free fatty acid receptor 4 (FFA4 or GPR120) has appeared as an interesting potential target for the treatment of metabolic disorders. At present, most FFA4 ligands are carboxylic acids that are assumed to mimic the endogenous long-chain fatty acid agonists. Here, we report preliminary structure-activity relationship studies of a previously disclosed nonacidic sulfonamide FFA4 agonist. Mutagenesis studies indicate that the compounds are orthosteric agonists despite the absence of a carboxylate function. The preferred compounds showed full agonist activity on FFA4 and complete selectivity over FFA1, although a significant fraction of these noncarboxylic acids also showed partial antagonistic activity on FFA1. Studies in normal and diet-induced obese (DIO) mice with the preferred compound 34 showed improved glucose tolerance after oral dosing in an oral glucose tolerance test. Chronic dosing of 34 in DIO mice resulted in significantly increased insulin sensitivity and a moderate but significant reduction in bodyweight, effects that were also present in mice lacking FFA1 but absent in mice lacking FFA4

Health Insurance Coverage in the Gulf Coast States after Affordable Care Act by Rural and Urban Area between 2009 and 2017

Background: Although health insurance coverage for adults in each of the Gulf Coast States and the rest of the country increased after implementing the Affordable Care Act, the coverage rates in the Gulf Coast region remained lower to rural residents, compared to those in the rest of the Nation. Purpose: This study aimed to update the changes of health insurance coverage in all states and the Gulf Coast states, confirm the significance of the health policy on insurance coverage by analyzing Louisiana, and examine the relationships between socio-demographic variables and rural/urban area by using interaction variables. Methods: This study used the American Community Survey, which is an annual survey of about three million U.S. households and collected social, demographic, and economic information, including health insurance coverage. Logistic regression was used to estimate the effects of the demographic and economic variables on health insurance coverage. Results: Florida and Texas increased health insurance coverage in the urban areas, while Alabama, Louisiana, and Mississippi present a more considerable increase in the rural area. However, Louisiana showed a significant increase in insurance coverage, rural areas in particular after joining the Medicaid expansion in 2016. A significant decrease in insurance coverage was found among young adults, African American, non-married, not in the labor force, and being poor for rural residents in Florida and Texas. In contrast, minorities in other races and unemployed decreased the likelihood of having insurance for rural residents in Alabama, Louisiana, and Mississippi. Discussion: Our examination of how socio-demographic variables interact with living in a rural area revealed a clear rural disadvantage pattern. The pattern, however, was varied between Florida and Texas and Alabama, Louisiana, and Mississippi. These findings have meaningful implications for the ongoing effort to reduce insurance coverage disparities in the Gulf Coast states and all Americans

The promoter from SlREO, a highly-expressed, root-specific Solanum lycopersicum gene, directs expression to cortex of mature roots

Root-specific promoters are valuable tools for targeting transgene expression, but many of those already described have limitations to their general applicability. We present the expression characteristics of SlREO, a novel gene isolated from tomato (Solanum lycopersicum L.). This gene was highly expressed in roots but had a very low level of expression in aerial plant organs. A 2.4-kb region representing the SlREO promoter sequence was cloned upstream of the uidA GUS reporter gene and shown to direct expression in the root cortex. In mature, glasshouse-grown plants this strict root specificity was maintained. Furthermore, promoter activity was unaffected by dehydration or wounding stress but was somewhat suppressed by exposure to NaCl, salicylic acid and jasmonic acid. The predicted protein sequence of SlREO contains a domain found in enzymes of the 2-oxoglutarate and Fe(II)-dependent dioxygenase superfamily. The novel SlREO promoter has properties ideal for applications requiring strong and specific gene expression in the bulk of tomato root tissue growing in soil, and is also likely to be useful in other Solanaceous crop

A divisibility property of binomial coefficients viewed as an elementary sieve

The triangular array of binomial coefficients 012301111212131331… is said to have undergone a j-shift if the r-th row of the triangle is shifted rj units to the right (r=0,1,2,…). Mann and Shanks have proved that in a 2-shifted array a column number c>1 is prime if and only if every entry in the c-th column is divisible by its row number. Extensions of this result to j-shifted arrays where j>2 are considered in this paper. Moreover, an analog of the criterion of Mann and Shanks [2] is given which is valid for arbitrary arithmetic progressions

The effect of health insurance coverage and the doctor-patient relationship on health care utilization in high poverty neighborhoods

African Americans have higher rates of mortality than whites who are the same age and sex. We hypothesize that in low socioeconomic status neighborhoods, having health insurance coverage and a regular health care provider increases the likelihood of receiving diagnostic tests for cardiovascular disease and diabetes. We use data from a random two-stage cluster sample of 230 adults living in high poverty census tracts to examine the effects of insurance coverage and having a regular doctor on the likelihood receiving diagnostic tests for high cholesterol, high blood sugar, and blood pressure. We find that health insurance coverage increases the odds of having a regular health care provider (p \u3c 0.05) and of receiving the diagnostic tests (p \u3c 0.05). Having a regular doctor mediates the effect of insurance coverage on the likelihood of receiving the tests, especially when the participant can report the physician\u27s name