الفهرس 
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Abstract
It has long been known that, hypoglycemia almost invariably manifest serious breakdown in lipid dynamics, reflected by elevated levels of free fatty acids and triglycerides. Alterations in metabolic function that occur in response to overnutrition that inturn because insulin resistance was suggested to be derived from impairment of fatty acid oxidation. Inefficient LCFA-β-oxidation generates chain shortened acylcarnitines reflective of muscle fat catabolism that trigger insulin resistance. Acylcarnitines have been viewed as a detoxifying system that permits efflux of excess acyl groups. Thus accumulation of acylcarnitine intermediates could reflect mitochondrial overload that occur in response to overnutrition. Mitochondrial fuel selection has been rekindled by studies showing that obese and/or diabetic human fail to shift from fatty acid to glucose oxidation during the transition from fasting to feeding. Identification of metabolic signature reflective of muscle LCFA combustion capacity (acylcarnitine) yields the connection between fat metabolism and insulin sensitivity.
Present work aimed to study the interactions between series of fatty acid acylcarnitines of various chain-length and glucose metabolism in obese insulin- resistant women before and after 3 months of treatment with liraglutide for weight loss.
Present results demonstrating comprehensive blood acylcarnitine profile revealed elevated markers of incomplete LCFAs catabolism. The concept of increased acylcarnitines through incomplete FAO by disproportional regulation of FAO,TCA and ETC was attractive to explain IR in the circulating parameters of our obese women compared to control.
The study was carried out on fifty female subjects aged between 20-60 years, they were divided into the following groups:
Control group: comprised 25 non-obese (BMI<25 Kg/m2) apparently healthy women.
Obese group: comprised 25 obese women (BMI>30 Kg/m2) treated with liraglutide for 3 months for weight loss.
All subjects were free of any liver, renal or other endocrinal disorder; they also were free from any significant cardiovascular or respiratory disease.
Laboratory investigations included plasma acylcarnitine profile analysis, measurement of fasting serum levels of glucose and insulin and calculation of insulin resistance by using HOMA equation. Also, estimation of glycosylated hemoglobin (HbA1c) %, plasma lactate, plasma pyruvate and plasma lactate-pyruvate ratio.
The results of the current study revealed a significant increase in palmitoylcarnitine (C16). Palmitoylcarnitine inhibits glycogen synthase activity. Also its known effects on insulin signaling (S1) which is known to be associated with IR. This support biochemical pathway linking myocellular lipid metabolism and insulin actions.
Also, we detected the inability of insulin to reverse the inhibitory effects of increased MCFAs (C6, C8, C10, C12) on glucose metabolism. Person to person difference in acylcarnitines (C12, C14) were positively correlated with HbA1c, this indicates that lipid metabolism can have devastating consequences on glucose homeostasis and chain length dependency of interaction between MCFAs and glucose metabolism.
Additionally, it was detected a significant increase in acetylcarntine C2. Fasting plasma C2 level has been shown to positively associate with HbA1c and it was suggested that C2 as a marker of prediabetes.
Moreover, our results demonstrated a significant decreased propionylcarnitine (C3) with obesity. It was suggested that therapeutic benefit of propionylcarnitine means increase proportion of glucose converted into 14CO2 and its decrease support replenishment of TCA cycle intermediates. This support compromised TCA Cycle with obesity.
Furthermore, the present study evaluated a significant decline in free carnitine of our obese women compared to control. Dietary L-carnitine is known to enhance body glucose tolerance.
Present results concerning lactate and pyruvate metabolism, we obtained a significant increased plasma lactate and lactate-pyruvate ratio in our obese insulin- resistant women which positively correlated with IR. This was agree with several studies which stated that intracellular lactate-pyruvate interconversion rate are greatly enhanced due to complemantary nutritional alterations in obese subjects. This support the idea of compromized TCA cycle, fat metabolism and their consequences on glucose homeostasis.
Liraglutide treatment was used in the current study to examine the effect of weight loss on the circulating parameters of obese insulin- resistant women. The data of this study demonstrated that systemic administration of liraglutide for 3 months have the potential benifit for weight management, long-term control of hyperglycaemia (HbA1c), lactate and pyruvate metabolism, while having no significant effect on plasma insulin levels and no significant effect on renal function. With respect to muscle fatty acid metabolism in the present results the effect of liraglutide was relatively modest.