Leptin Gene Polymorphism and Insulin Resistance in Obese Diabetic Patients: Pilot Study

Abstract

Obesity is a disease of excess body fat which accumulates in adipose tissue to the extent that may have an adverse effect on health. Obesity is a worldwide epidemic that continues to grow at an alarming rate. In 2013, the American Medical Association classified obesity as a disease, with at least 2.8 million people dying each year as a result of being obese. Obesity is a pro-inflammatory condition in which hypertrophied adipocytes and adipose tissue resident immune cells (primarily lymphocytes and macrophages) both contribute to increased circulating levels of pro-inflammatory cytokines. The obesity associated state of chronic low grade systemic inflammation, termed “metabolic inflammation,” is considered a focal point in the pathogenesis of insulin resistance and T2DM in humans. Insulin resistance in which there is an impaired biological response to high level of insulin either exogenously administered or endogenously secreted in peripheral tissues particularly skeletal muscles, adipocytes and liver, is a cardinal feature in the development of glucose intolerance and type 2 diabetes mellitus. It presents in individuals predisposed to T2DM even before the onset of hyperglycemia. Diabetes mellitus is a multifactorial disease associated with high levels of blood glucose resulting from problems in how insulin is produced, how insulin works, or both”. The CDC links T2DM to a variety of risk factors; including obesity, family history, age, and ethnicity. Leptin is a metabolic and neuroendocrine hormone produced and released mainly by adipocytes, and plasma leptin concentration is proportional to body adiposity and markedly increased in obese. It is an important signal in the regulation of appetite, metabolism, body fat mass and stimulating energy expenditure by the action on satiety through hypothalamic receptors. Important peripheral actions of leptin involve inhibition of insulin biosynthesis and secretion in pancreatic β-cells. Leptin also increases peripheral insulin sensitivity, and decreases hepatic glucose production and glucagon levels. In turn, insulin stimulates leptin secretion from adipose tissue, establishing a hormonal regulatory feedback loop the so called “adipo-insular axis”. The detection of high leptin levels in obese subjects suggests that leptin resistance; impaired leptin signaling and action, is common in obesity .This state could interfere with the physiological relationship between leptin, lipid oxidation in insulin sensitive organs and β-cell function, promoting the development of IR and T2DM. Leptin gene polymorphism is found widely distributed in the promoter, exons, and introns of the leptin gene. LEP G2548A is an LEP gene single nucleotide polymorphism (SNP) consisting of G to A substitution at nucleotide (nt)-2548 upstream of the ATG start site in the LEP gene promoter. Currently, studies on the human LEP gene polymorphisms suggested that these polymorphisms were mainly correlated with obesity, IR and T2DM. Our study aimed to determine LEP –2548G>A polymorphism for the leptin gene in obese diabetic patients and its correlation to obese non diabetic patients and normal-weight individuals, and to assess their influence on insulin resistance. This study was conducted on ninety subjects, chosen from the attendants of outpatient clinics of Ain Shams University hospitals. Fifty subjects were obese diabetic patients, twenty were obese non diabetic, and twenty were non obese non diabetic individuals. From all subjects, anthropometric data was collected, and glycemic indicators (FBG and 2hpp blood glucose) were tested. Fasting serum insulin level was measured using a commercially available ELISA kit and HOMA-IR was calculated. Also, all subjects were genotyped by real-time PCR to identify expression of the G and A alleles of the G2548A polymorphism of the leptin gene.