FFA and Hepatic Insulin Resistance

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Insulin tightly regulates the rate of endogenous glucose production (EGP). Hepatic glucose production accounts for the majority (>90%) of glucose output in the fasting state, except for a small proportion arising from renal gluconeogenesis (254). The rate of EGP is important under fasting conditions to provide glucose for the metabolic needs of glucose-dependent tissues such as the brain and red blood cells. In lean insulin-sensitive healthy subjects, modest increases in the plasma insulin concentration (i.e., from 5 ^U/mL to 40 ^U/mL) rapidly inhibit EGP by 70-80% and nearly completely suppress EGP when they reach 50-100 ^U/mL (199, 255, 256). In contrast, in nondiabetic insulin-resistant subjects, such as obese individuals or lean subjects with a strong FH of T2DM, to maintain the rate of EGP within normal limits the fasting plasma insulin concentration needs to be two to threefold higher than in lean insulin-sensitive individuals. Fasting hyperglycemia has been shown in many studies to be closely correlated to the rate of EGP in T2DM, as insulin secretion cannot compensate adequately for hepatic insulin resistance and there is a progressive increase in the rate of EGP, particularly when the plasma glucose rises above 140-180 mg/dL (199, 255-257). Glucogenolysis is particularly sensitive to small increases in the plasma insulin concentration, while inhibition of glu-coneogenic flux requires higher levels of insulin (258-261). In T2DM, overproduction of glucose by the liver is primarily due to resistance of hepatic gluconeogenesis to insulin action, while glyco-geonlysis appears to preserve better its response to the inhibitory action of insulin (258-260).

Insulin acts directly by binding to hepatic insulin receptors and thereby activating insulin signaling pathways in the liver. Insulin's indirect effects to regulate hepatic glucose production include reduction of pancreatic glucagon secretion (262, 263). possible effects at the level of the hypothalamus (264), and decreased substrate availability in the form of amino acids and FFA for gluceogenesis by inhibiting muscle protein catabolism and adipose tissue lipolysis, respectively (265). Some have advocated that the indirect effects of insulin on peripheral tissues (mainly on adipose tissue) are keys to controlling hepatic glucose production (266) . However, recent evidence suggests that while FFA is important to glucose production by the liver, the direct effects of insulin on hepatocytes have primacy in the regulation of EGP (267).

Plasma FFA levels play an important role in the relation to hepatic insulin sensitivity and glucose production in humans. In rodents, an increase in FFA supply causes insulin resistance and activates the proinflammatory nuclear factor-KB pathway (268, 269), while perfusion of isolated rat livers with palmitate or oleate decreases insulin-receptor, IRS-1, PI 3-kinase, and Akt phosphorylation (270). In dogs, elevated plasma FFA also stimulates hepatic glucose production and activates proinflammatory pathways that inhibit insulin signaling (271) . In lean healthy subjects, FFA have been reported to induce insulin resistance by stimulating both gluconeogenesis (272) and glycogenolysis (261). In insulin-resistant states such as obesity and T2DM, adipose tissue is the primary source of fatty acids in insulin-resistant states (273, 274). and elevated plasma FFA provide the liver with energy (ATP) and carbons to drive gluconeogenic pathways and de novo lipogenesis (275). Increased plasma FFA also causes the dyslipidemia typically seen in insulin-resistant states, with increased rates of VLDL secretion, which in turn lower plasma HDL and lead to the formation of small dense LDL. Thus, adipose tissue insulin resistance with increased flux of FFA to the liver can lead to the full spectrum

Insulin-resistant adipose tissue insulir resistan

Hepati insulir resistan

Hepati

T Hepatic Glucose Î Production (T fasting plasma glucose)

T VLDL Production (T plasma TG) i HDL-C T smLDL-C

Fig. 7. Multiple abnormalities drive hepatic lipogenesis in insulin-resistant states. Excessive rates of lipolysis from adipose tissue increase plasma free fatty acids (FFA) and provide abundant substrate to the liver for triglyceride synthesis. Hyperinsulinemia activates SREBPlc and hyperglycemia ChREBP to stimulate hepatic steatosis. The clinical manifestations are common to patients with metabolic syndrome and type 2 diabetes mellitus (T2DM), increased fasting plasma glucose and atherogenic dyslipidemia.

T Hepatic Glucose Î Production (T fasting plasma glucose)

t Insulin t Glucose

T VLDL Production (T plasma TG) i HDL-C T smLDL-C

Fig. 7. Multiple abnormalities drive hepatic lipogenesis in insulin-resistant states. Excessive rates of lipolysis from adipose tissue increase plasma free fatty acids (FFA) and provide abundant substrate to the liver for triglyceride synthesis. Hyperinsulinemia activates SREBPlc and hyperglycemia ChREBP to stimulate hepatic steatosis. The clinical manifestations are common to patients with metabolic syndrome and type 2 diabetes mellitus (T2DM), increased fasting plasma glucose and atherogenic dyslipidemia.

of metabolic abnormalities that are so common clinically today, as summarized in Fig. 7. In our hands, a combined low-dose lipid and glucose infusion for 2 days can reproduce all the abnormalities seen in the MS in nondiabetic subjects genetically predisposed to T2DM: an increase in blood pressure, elevated triglycerides, and low HDL-C and systemic inflammation evidenced by an increase in hsCRP, ICAM (inter cell adhesion molecule)/VCAM (vascular cell adhesion molecule) , etc. (245). Moreover, 2-3 days of elevated plasma FFA in lean FH+ reduces insulin clearance and promotes chronic peripheral hyperinsulinemia, as has been reported in insulin-resistant states such as in obesity, PCOS, women with a history of gestational diabetes mellitus (GDM) and T2DM (141). An acute (2-6 h) pharmacological (five to tenfold) elevation of plasma FFA levels (82, 129, 132, 276), as well as low-dose chronic (48 h) lipid infusions (141) , induce hepatic insulin resistance, while reduction of plasma FFA by acipimox partially restore hepatic insulin sensitivity (225). Taken together, these studies highlight the close relationship between increased FFA supply and hepatic insulin sensitivity. But perhaps where this interplay is best exemplified from a clinical standpoint is in the metabolic abnormalities observed in NAFLD.

NAFLD is a chronic liver condition frequently associated with T2DM and characterized by insulin resistance and hepatic fat accumulation. Liver fat may range from simple steatosis to severe steato-hepatitis with necroinflammation and variable degrees of fibrosis (nonalcoholic steatohepatitis or NASH). About 40% of patients with NAFLD develop NASH (277-279), with an early study reporting progression to fibrosis and/or cirrhosis in 15-20% of NASH (280) , although it is believed to be as high as 40% from data of more recent series (281-284). Moreover, recent evidence suggests that the

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Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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