Individuals with insulin resistance and type 2 diabetes have an impaired ability to switch appropriately between carbohydrate and fatty acid oxidation. However, whether this is a cause or consequence of insulin resistance is unclear, and the mechanism(s) involved in this response is not completely elucidated. Whole-body fat oxidation and transcriptional regulation of genes involved in lipid metabolism in skeletal muscle were measured after a prolonged fast and after consumption of either high-fat (76%) or high-carbohydrate (76%) meals in individuals with no family history of type 2 diabetes (control, n ؍ 8) and in ageand fatness-matched individuals with a strong family history of type 2 diabetes (n ؍ 9). Vastus lateralis muscle biopsies were performed before and 3 h after each meal. Insulin sensitivity and fasting measures of fat oxidation were not different between groups. However, subjects with a family history of type 2 diabetes had an impaired ability to increase fatty acid oxidation in response to the high-fat meal (P < 0.05). This was related to impaired activation of genes involved in lipid metabolism, including those for peroxisome proliferator-activated receptor coactivator-1␣ (PGC1␣) and fatty acid translocase (FAT)/CD36 (P < 0.05). Of interest, adiponectin receptor-1 expression decreased 23% after the high-fat meal in both groups, but it was not changed after the high-carbohydrate meal. In conclusion, an impaired ability to increase fatty acid oxidation precedes the development of insulin resistance in genetically susceptible individuals. PGC1␣ and FAT/CD36 are likely candidates in mediating this response. Diabetes 56: [2046][2047][2048][2049][2050][2051][2052][2053] 2007 R elatives of individuals with type 2 diabetes are an ideal human model to test for mechanisms in the early development of insulin resistance because approximately two-thirds eventually develop diabetes, and they can be tested before the development of other confounding factors, including hyperglycemia, dyslipidemia, and changes in insulin secretion (1). Insulin-resistant relatives will also develop impaired lipid metabolism, including increased circulating free fatty acids (FFAs) (2), accumulation of triglycerides and other lipid moieties within skeletal muscle (3), and postprandial hypertriglyceridemia (4). However, the mechanism(s) responsible for these early defects in lipid metabolism is not completely elucidated, although we and others suggest that intramuscular triglyceride accumulation may occur secondary to the development of insulin resistance (3,5).In lean individuals, increasing the proportion of dietary fat switches on fatty acid oxidation, whereas the infusion of glucose and insulin promotes carbohydrate oxidation. The cellular capacity to switch from lipid to carbohydrate and vice versa has been termed "metabolic flexibility," and there is large variation in this parameter between individuals (6). Obese and weight-reduced obese individuals have impaired metabolic flexibility on a whole-body level (7). Fatty acid...
Almost all cystic fibrosis patients develop hyperglycaemia after lung transplantation, but patients with prior diabetes have more complication-related admissions to hospital and a higher mortality rate.
Objective: To examine differences in gene expression between visceral (VF) and subcutaneous fat (SF) to identity genes of potential importance in regulation of VF. Methods and Procedures:We compared gene expression (by DNA array and quantitative PCR (qPCR)) in paired VF and SF adipose biopsies from 36 subjects (age 54 ± 15 years, 15 men/21 women) with varying degrees of adiposity and insulin resistance, in chow and fat fed mice (± rosiglitazone treatment) and in c-Cbl −/− mice. Gene expression was also examined in 3T3-L1 preadipocytes during differentiation. Results: A twofold difference or more was found between VF and SF in 1,343 probe sets, especially for genes related to development, cell differentiation, signal transduction, and receptor activity. Islet-1 (ISL1), a LIM-homeobox gene with important developmental and regulatory function in islet, neural, and cardiac tissue, not previously recognized in adipose tissue was virtually absent in SF but substantially expressed in VF. ISL1 expression correlated negatively with BMI (r = −0.37, P = 0.03), abdominal fat (by dual energy X-ray absorptiometry, r = −0.44, P = 0.02), and positively with circulating adiponectin (r = 0.33, P = 0.04). In diet-induced obese mice, expression was reduced in the presence or absence of rosiglitazone. Correspondingly, expression was increased in the c-Cbl −/− mouse, which is lean and insulin sensitive (IS). ISL1 expression was increased sevenfold in 3T3-L1 preadipocytes during early (day 1) differentiation and was reduced by day 2 differentiation. Discussion: An important developmental and regulatory gene ISL1 is uniquely expressed in VF, probably in the preadipocyte. Our data suggest that ISL1 may be regulated by adiposity and its role in metabolic regulation merits further study.
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