Characterisation of fatty acid metabolism in different insulin-resistant phenotypes by means of stable isotopes

Abstract

The obese insulin resistant and/or prediabetic state is characterised by systemic lipid overflow, mainly driven by an impaired lipid buffering capacity of adipose tissue, and an impaired capacity of skeletal muscle to increase fat oxidation upon increased supply. This leads to the accumulation of bioactive lipid metabolites in skeletal muscle interfering with insulin sensitivity via various mechanisms. In this review, the contribution of dietary v. endogenous fatty acids to lipid overflow, their extraction or uptake by skeletal muscle as well as the fractional synthetic rate, content and composition of the muscle lipid pools is discussed in relation to the development or presence of insulin resistance and/or an impaired glucose metabolism. These parameters are studied in vivo in man by combining a dual stable isotope methodology with [ 2 H 2 ]-and [U-13 C]-palmitate tracers with the arterio-venous balance technique across forearm muscle and biochemical analyses in muscle biopsies. The insulin-resistant state is characterised by an elevated muscle TAG extraction, despite similar supply, and a reduced skeletal muscle lipid turnover, in particular after intake of a high fat, SFA fat meal, but not after a high fat, PUFA meal. Data are placed in the context of current literature, and underlying mechanisms and implications for long-term nutritional interventions are discussed. The prevalence of overweight and overweight-related metabolic disturbances is increasing at an alarming rate. Worldwide more than 50 % of the adults is overweight (>one billion individuals) and a further 12 % (475 million) can be classified as clinically obese. Every year at least 2·8 million adults die as a result of being overweight/obese (http://www.who.int/gho/ncd/risk_fac-tors/overweight/en). Obesity is an important risk factor for chronic metabolic diseases such as type 2 diabetes mellitus (T2DM) and CVD. A disturbed lipid metabolism in multiple tissues, including adipose tissue, liver, skeletal muscle, gut and pancreas may play an important role in the development of insulin resistance (IR), an impaired glucose metabolism and T2DM. These disturbances, in particular an impaired adipose tissue lipid handling, may lead to systemic lipid overflow, increased circulating concentrations of NEFA and TAG and accumulation of lipids in non-adipose tissues (1)(2)(3)(4) . This lipid overflow together with an impaired capacity to adjust fatty acid (FA) oxidation to FA supply in skeletal muscle (metabolic inflexibility (3) ) may cause excess fat storage in skeletal muscle, which is related to the development or worsening of IR. IR in concert with progressive β-cell failure leads to an increased blood glucose concentration in the non-diabetic range, classified as impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). IFG (fasting glucose >5·6 mM/l) and IGT (2 h oral glucose tolerance testderived glucose concentration >7·8 mM) are intermediate states in the transition from a normal glucose tolerance towards T2DM. IFG and IGT may represent dis...

Current metabolic perspective on malnutrition in obesity: towards more subgroup-based nutritional approaches?

“…Indeed, in the different prediabetic phenotypes the state of impaired glucose tolerance may be characterised by more pronounced peripheral or muscle IR, whilst the state of impaired fasting glucose by more pronounced hepatic IR (12) . Consistent with this, we previously showed that skeletal muscle lipid handling was disturbed in the impaired glucose tolerance state, characterised by an impaired postprandial insulin sensitivity, an increased postprandial TAG extraction and a reduced muscle lipid turnover, compared with individuals with impaired fasting glucose (13,14) .…”

“…From the above it is evident the muscle and liver insulin resistant phenotypes are distinct which subsequently leads to the question whether these phenotypes respond differentially to dietary intervention. The above reported and previously shown disturbances in muscle lipid turnover in individuals with impaired glucose tolerance as compared to individuals with impaired fasting glucose were shown after ingestion of a high fat, high SFA mixed meal (13,14) . There are indications that dietary fat quality may impact muscle lipid handling.…”

Ectopic Fat Accumulation in Distinct Insulin Resistant Phenotypes; Targets for Personalized Nutritional Interventions

“…As mentioned earlier, IR can occur in multiple key metabolic organs such as the liver and skeletal muscle. Nevertheless, insulin sensitivity and lipid metabolism may substantially differ between organs within an individual ( 59 ). Moreover, the extent to which IR is present in these distinct organs may vary among individuals.…”

Evaluation of the antidiabetic activity of hydrolyzed peptides derived fromJuglans mandshuricaMaxim. fruits in insulin-resistant HepG2 cells and type 2 diabetic mice

“…The in vitro hypoglycemic effect of WHPs was investigated by analyzing extracellular glucose consumption in insulin‐resistant HepG2 cells, a human hepatocellular carcinoma cell line with morphology and function similar to those of liver cells. Insulin resistance is a pathological condition highly linked to the consumption of extracellular glucose as a result of reduced insulin receptor sensitivity (Blaak, ; Drouin‐Chartier et al, ). Met was chosen as the positive control for the test as it is widely used in the treatment of diabetes.…”