MGAT2 deficiency ameliorates high-fat diet-induced obesity and insulin resistance by inhibiting intestinal fat absorption in mice.

Background: Resynthesis of triglycerides in enterocytes of the small intestine plays a critical role in the absorption of dietary fat. Acyl-CoA:monoacylglycerol acyltransferase-2 (MGAT2) is highly expressed in the small intestine and catalyzes the synthesis of diacylglycerol from monoacylglycerol and acyl-CoA. To determine the physiological importance of MGAT2 in metabolic disorders and lipid metabolism in the small intestine, we constructed and analyzed Mgat2-deficient mice.

Reduction of renal transport maximum for glucose by inhibition of NA(+)-glucose cotransporter suppresses blood glucose elevation in dogs.

T-1095, an orally active inhibitor of Na(+)-glucose cotransporter (SGLT), excretes excess plasma glucose into urine, lowers blood glucose levels, and thus has therapeutic potential for treatment of diabetes mellitus. To elucidate the correlation between threshold for renal glucose reabsorption and blood glucose levels, we evaluated the effects of T-1095 on transport maximum for glucose (TmG) in dogs. Intravenous infusion of T-1095A (0.

Long-term treatment with the Na+-glucose cotransporter inhibitor T-1095 causes sustained improvement in hyperglycemia and prevents diabetic neuropathy in Goto-Kakizaki Rats.

We examined the effects of T-1095, an orally active inhibitor of Na(+)-glucose cotransporter (SGLT), on the development and severity of diabetes in Goto-Kakizaki (GK) rat, a spontaneous, non-obese model of type 2 diabetes. T-1095 was administered as dietary admixture (0.1% w/w) beginning at 7 weeks of age for 32 weeks.

LDA-catalyzed cycloisomerization of 2-(2-propynyloxy)ethyl iodides leading to 3-(iodomethylene)tetrahydrofurans.

LDA catalyzes cycloisomerization of 2-(2-propynyloxy)ethyl iodides to give 3-(iodomethylene)tetrahydrofurans. The reaction is proposed to proceed through a mechanism involving exo-cyclization of an alkynyllithium intermediate and protonation of the resulting alkylidene carbenoid by the starting iodide. [reaction: see text]

Carbon-carbon bond-forming reaction of cyclic sulfonium ylides stabilized by a carbonyl group.

Rhodium(II)-catalyzed decomposition of diazoketones 1 and 5 bearing a cyclic dithioacetal, in the presence of aldehyde and ClTi(Oi-Pr)(3), afforded both or one of the C=C-bonded products, i.e., ring-enlarged enone 2 and ring-transformed thiophenone 3, that were formed between aldehyde and intermediate bicyclosulfonium ylide.

[3 + 2] Cycloreversion of bicyclo[m.3.0]alkan-3-on-2-yl-1-oxonium ylides to alkenyloxyketenes. Stereospecific aspect.

Rhodium(II)-catalyzed intramolecular reaction of diazoketones 1 bearing a cyclic ethereal moiety transiently formed bicyclo[m.3.0]octan-3-one-1-oxonium-2-ylides (2), which underwent sigmatropic and stereospecific [3 + 2] cycloreversion reaction to form alkenyloxyketenes 3.

Enantioselective Lewis acid-catalyzed Mukaiyama-Michael reactions of acyclic enones. Catalysis by allo-threonine-derived oxazaborolidinones.

allo-Threonine-derived O-aroyl-B-phenyl-N-tosyl-1,3,2-oxazaborolidin-5-ones 1g,n catalyze the asymmetric Mukaiyama-Michael reaction of acyclic enones with a trimethylsilyl ketene S,O-acetal in high enantioselectivity. A range of alkenyl methyl ketones is successfully employed as Michael acceptors affording ee values of 85-90% by using 10 mol % of the catalyst. The use of 2,6-diisopropylphenol and tert-butyl methyl ether as additives is found to be essential to achieve high enantioselectivity in these reactions.

Carbon-carbon bond formation reaction of ethereal oxonium ylides via metal-enolate intermediates.

First, the carbon-carbon (C-C) bond-forming reaction of aldehydes with bicyclo[m.n.0]-1-oxonium ylides was studied as the ylide was transiently formed in the Rh(II)-catalyzed reaction of a nonenolizable diazoketone, namely, 2-(3-diazo-1,1-dimethyl-2-oxopropyl)-2-methyldioxolane (1).

Practical asymmetric Mukaiyama-Michael reaction of benzalacetone derivatives catalyzed by allo-threonine-derived oxazaborolidinone.

In the presence of 2,6-diisopropylphenol and t-BuOMe (1 equiv. each), asymmetric Mukaiyama-Michael reaction of a variety of benzalacetone derivatives 2 with silyl ketene acetal 3 is efficiently catalyzed by O-(2-naphthoyl)-N-tosyl-(L)-allo-threonine-derived B-phenyloxazaborolidinone 1 (10 mol%) to give the corresponding adducts 5 in 60-90% ee.

Inter- and intramolecular differentiation of enantiotopic dioxane acetals through oxazaborolidinone-mediated enantioselective ring-cleavage reaction: kinetic resolution of racemic 1,3-alkanediols and asymmetric desymmetrization of meso-1,3-polyols.

Acetals derived from racemic 1,3-alkanediols undergo kinetic resolution in chiral oxazaborolidinone-mediated ring-cleavage reaction with nucleophiles such as enol silanes and allylic silanes. Enantioselectivity of the reaction is affected by nucleophiles, the N-sulfonyl groups of oxazaborolidinones, and the substituents attached to the acetal carbon. For disubstituted acetals rac-1 and for trisubstituted acetal rac-2, derived from syn-2,4-dimethyl-1,3-pentanediol, satisfactory enantioselectivity is obtained by using methallylsilane 7b,c as a nucleophile in combination with N-mesyloxazaborolidinone 4a.

Inhibition of gastric inhibitory polypeptide signaling prevents obesity.

Secretion of gastric inhibitory polypeptide (GIP), a duodenal hormone, is primarily induced by absorption of ingested fat. Here we describe a novel pathway of obesity promotion via GIP. Wild-type mice fed a high-fat diet exhibited both hypersecretion of GIP and extreme visceral and subcutaneous fat deposition with insulin resistance.

Beneficial effect of T-1095, a selective inhibitor of renal Na+-glucose cotransporters, on metabolic index and insulin secretion in spontaneously diabetic GK rats.

1. To investigate the pharmacological effects of T-1095, this novel derivative of phlorizin was administered to GK rats for 8 weeks. T-1095 treatment significantly lowered plasma glucose and glycosylated haemoglobin (HbA1c) levels, but did not significantly affect bodyweight.

Novel Homologation Reaction of Arylzincates Bearing a Leaving Group at the Ortho and Meta Positions.

Arylzincates bearing a leaving group at the ortho, meta, and para positions were generated by iodine/zinc exchange reaction of the corresponding iodoaryl sulfonates with Bu(3)ZnLi, and their reactivity was investigated via product analysis after hydrolysis and treatment with iodine. Zincates derived from o-iodophenyl triflates and tosylate underwent homologation reaction to give o-butylphenylzinc species. o-Benzyne as an intermediate of the reaction was demonstrated by the lack of regioselectivity for trisubstituted zincates.

Three- and Four-Carbon Elongating Ring Expansion of Cyclic Acetals to Medium-Sized Dioxacycloalkenones. Use of the Intramolecular Formation of Oxonium Ylides.

The Rh(II)-catalyzed reaction of 2-(3'-diazo-2'-oxopropyl)-2-methyldioxolane (1) in the presence of a protic nucleophile (NuH) such as AcOH resulted in effective ring enlargement to give the 8-membered 3-acetoxydioxocanone 4a (41%) and dioxocan-2-en-1-one 3 (46%). Similar treatment of 2-(4'-diazo-3'-oxobutyl)-2-methyldioxolane (9) with AcOH gave 4-acetoxydioxonanone 10 (67%), which was readily hydrolyzed on silica gel to a tautomeric mixture of hydrolysis products 16a and 16b (total yield 46%). In contrast, similar treatment of 2-(5'-diazo-4'-oxopentyl)-2-methyldioxolane (19) gave 2,5-dioxa-1-methyldecalin-7-one (20, 24%), and the yield increased to 61% in the absence of AcOH, by Stevens rearrangement.