4-Hydroxyisoleucine from Fenugreek (Trigonella foenum-graecum): Effects on Insulin Resistance Associated with Obesity.

Obesity and insulin resistance (IR) are interdependent multifactorial processes that cannot be understood separately. Obesity leads to systemic inflammation and increased levels of free fatty acids that provoke IR and lipotoxicity. At the same time, IR exacerbates adipose cell dysfunction, resulting in chronic inflammation and major lipotoxic effects on nonadipose tissues. 4-Hydroxyisoleucine (4-OHIle), a peculiar nonprotein amino acid isolated from fenugreek (Trigonella foenum-graecum) seeds, exhibits interesting effects on IR related to obesity. 4-OHIle increases glucose-induced insulin release, and the insulin response mediated by 4-OHIle depends on glucose concentration. The beneficial effects observed are related to the regulation of blood glucose, plasma triglycerides, total cholesterol, free fatty acid levels, and the improvement of liver function. The mechanism of action is related to increased Akt phosphorylation and reduced activation of Jun N-terminal kinase (JNK)1/2, extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK), and nuclear factor (NF)-κB. Here, we present a review of the research regarding the insulinotropic and insulin-sensitising activity of 4-OHIle in in vitro and in vivo models.

Effect of a ß-Hydroxyphosphonate Analogue of ʟ-Carnitine on Insulin-Sensitive and Insulin-Resistant 3T3-L1 Adipocytes.

This study investigated the effect of a ß-x200B;hydroxyphosphonate analog of ʟ-carnitine (L-CA) (CAS number: 1220955-x200B;20-3, Component: 1221068-91-2, C12H29NO4PI), (3-Hexanaminium, 1-(dimethoxyphosphinyl)-2-hydroxy-N,N,N,5-x200B;tetramethy-iodide (1:1), (2R, 3S)) on parameters related with type-2 diabetes in an in vitro model. Nontoxic concentrations of L-CA were assayed and compared to commercial ʟ-carnitine effects. L-CA did not affect adipogenesis in normal cells, but an increment of TG accumulation was observed on insulin-resistant adipocytes (80%) when compared with resistant control. L-CA also stimulated glucose analog 2-NBDG uptakes on insulin-resistant adipocytes in a similar way as insulin when compared to insulin-resistant cells. Our results show that the L-CA promoted insulin-like responses on insulin-resistant adipocytes without appreciable pro-adipogenic effect in sensitive adipocytes.

Pharmacokinetic and pharmacological effects of ß-hydroxyphosphocarnitine in animal models.

The purpose of this research was to describe the pharmacokinetic parameters of ß-hydroxyphosphocarnitine (ß-HPC; CAS No. 1220955-20-3) after a single oral dose in rats and rabbits as well as to assess the impact of 14 weeks of ß-HPC (100 mg/kg) treatment on the serum metabolites and liver enzymes, body weight, and hepatic steatosis of lean and obese Zucker fa/fa rats. In the case of the rat and rabbit study, the ß-HPC area under the curve, biological half-life, and clearance were 2,174.4 versus 3,128 µg ∙ h/ml, 23.7 versus 8.87 h, and 13.9 versus 151.1 ml/h in the rats versus the rabbits, respectively. The values for the time of maximal concentration were 0.58 versus 1.53 h, for the maximal concentration, they were 62.4 versus 221.4 µg/ml, and for the absorption rate constant 0.02 versus 2.40 h(-1), respectively. In the case of the Zucker fa/fa rat study, ß-HPC administered orally once a day reduced insulin, triglyceride, and cholesterol levels in the liver and serum; it also reduced weight gain and decreased liver steatosis in obese rats after 14 weeks. ß-HPC could therefore potentially be used in the treatment of metabolic syndrome.

Pharmacological evaluation of a ß-hydroxyphosphonate analogue of l-carnitine in obese Zucker fa/fa rats.

In this study, we evaluated the effect of an analogue of l-carnitine on parameters involved with Metabolic Syndrome in obese Zucker rats. Twenty-four rats were treated for 5 weeks with l-carnitine (300 mg/kg) and its analogue at two concentrations (100 and 250 mg/kg) to assess their impact on glucose, triglycerides and cholesterol in liver and blood samples, as well as the amount of liver glycogen. Liver slices were also analysed. The analogue reduced the levels of glucose, triglycerides and cholesterol in liver and the level of triglycerides in serum. At 100 mg/kg, the analogue proved more effective than l-carnitine in improving the biochemical alterations present in liver. The amount of liver glycogen content was higher in obese animals treated with both l-carnitine and the analogue. No changes on insulin and leptin were observed in animals treated. l-carnitine and its analogue reduced the microvesicular fatty infiltration in liver. This study demonstrated that the analogue tested is more potent and efficient than l-carnitine and improves the pharmacological profile of l-carnitine.

Efficacy and safety of two analogs of L-carnitine on rats made insulin resistant by a high-fructose diet.

AIM: To evaluate the efficacy and safety of 2 analogs of L-carnitine on rats made insulin resistant by a high-fructose diet. METHODS: Using rats made insulin resistant by a high-fructose diet, we investigated the impact of 2 analogs of L-carnitine (25 mg/kg) and L-carnitine (250 mg/kg) on glucose, triglycerides and cholesterol blood levels, and liver glycogen. We also evaluated the safety of both analogs by the assessment of some biochemical and hematological parameters, a histological analysis and a study of embryotoxicity. RESULTS: Both analogs reduced the levels of triglycerides in the liver and plasma, but only analog 2 reduced the cholesterol levels in insulin-resistant rats. No changes were observed in glycogen content. Safety evaluations revealed alterations in blood lymphocytes and embryotoxicity data. CONCLUSION: This study demonstrated that the 2 analogs maintain the pharmacological properties of L-carnitine but have a different efficacy, potency and toxicity.

Highly diastereoselective synthesis of anti-gamma-N-benzylamino-beta-hydroxyphosphonates.

The reduction of gamma-N-benzylamino-beta-ketophosphonates derived from readily available amino acids can be carried out stereoselectively with Zn(BH(4))(2) at -78 degrees C to produce the anti-gamma-amino-beta-hydroxyphosphonates.