Plasma levels of mannan-binding lectin-associated serine proteases are increased in type 1 diabetes patients with insulin resistance.

Activation of the lectin pathway of the complement system, as demonstrated by elevated levels of mannan-binding lectin proteins (MBL), contributes to vascular pathology in type 1 diabetes (T1D). Vascular complications are greatest in T1D individuals with concomitant insulin resistance (IR), however, whether IR amplifies activiation of the lectin pathway in T1D is unknown. We pooled pretreatment data from two RCTs and performed a cross-sectional analysis on 46 T1D individuals. We employed estimated glucose disposal rate (eGDR), a validated IR surrogate with cut-points of: <5.1, 5.1-8.7, and > 8.7 mg/kg/min to determine IR status, with lower eGDR values conferring higher degrees of IR. Plasma levels of MBL-associated proteases (MASP-1, MASP-2, and MASP-3) and their regulatory protein MAp44 were compared among eGDR classifications. In a subset of 14 individuals, we assessed change in MASPs and MAp44 following improvement in IR. We found that MASP-1, MASP-2, MASP-3, and MAp44 levels increased in a stepwise fashion across eGDR thresholds with elevated MASPs and MAp44 levels conferring greater degrees of IR. In a subset of 14 patients, improvement in IR was associated with significant reductions in MASPs, but not MAp44, levels. In conclusion, IR in T1D amplifies levels of MASP-1/2/3 and their regulator MAp44, and improvement of IR normalizes MASP-1/2/3 levels. Given that elevated levels of these proteins contribute to vascular pathology, amplification of the lectin pathway of the complement system may offer mechanistic insight into the relationship between IR and vascular complications in T1D.

Photochemically Mediated Nickel-Catalyzed Synthesis of N-(Hetero)aryl Sulfamides.

A general method for the N-arylation of sulfamides with aryl bromides is described. The protocol leverages a dual-catalytic system, with [Ir(ppy)2(dtbbpy)]PF6 as a photosensitizer, NiBr2·glyme as a precatalyst, and 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) as a base, and proceeds at room temperature under visible light irradiation. Using these tactics, aryl boronic esters and aryl chlorides can be carried through the reaction untouched. The developed reactions efficiently engage simple bromoarenes and primary sulfamides in between 66% and quantitative yields. For more challenging substrates, such as secondary sulfamides, the reaction efficiency is documented. Thereby, these methods complement the known Buchwald-Hartwig coupling methods for N-arylation of sulfamides.

Photochemically-Mediated, Nickel-Catalyzed Synthesis of N-(Hetero)aryl Sulfamate Esters.

A general method is described for the coupling of (hetero)aryl bromides with O-alkyl sulfamate esters. The protocol relies on catalytic amounts of nickel and photoexcitable iridium complexes and proceeds under visible light irradiation at ambient temperature. This technology engages a broad range of simple and complex O-alkyl sulfamate ester substrates under mild conditions. Furthermore, it is possible to avoid undesirable N-alkylation, which was found to plague palladium-based protocols for N-arylation of O-alkyl sulfamate esters. These investigations represent the first use of sulfamate esters as nucleophiles in transition metal-catalyzed C-N coupling processes.