All of the type 2 diabetic patients manifested severe hepatic and peripheral insulin resistance associated with hepatic steatosis and increased IMCL. A moderate weight loss of ~8 kg, or ~8% of their body weight, normalized fasting plasma glucose concentrations and was associated with an ~10% decrease in plasma cholesterol concentrations. This improved glycemic control could be attributed to a marked improvement in their insulin responsiveness, as reflected by an approximately fourfold increase in the glucose infusion rate required to maintain euglycemia during the hyperinsulinemic-euglycemic clamp. To ascertain the mechanism for the improved insulin responsiveness, we also assessed rates of hepatic and peripheral glucose metabolism using deuterated glucose and found that the weight reduction normalized insulin suppression of hepatic glucose production but had no effects on peripheral insulin sensitivity. This improvement in hepatic insulin sensitivity was associated with an ~80% reduction of hepatic triglyceride content. In contrast, there was no change in IMCL content with weight reduction. Previous studies by our group (3
) and others (11
) have demonstrated a strong relationship between hepatic triglyceride content and hepatic insulin resistance. The mechanism by which hepatic steatosis causes hepatic insulin resistance is unknown but may be related to activation of a serine kinase cascade by accumulation of intracellular fatty acid metabolites that in turn inhibit insulin signaling at the level of the insulin receptor and insulin receptor substrates (IRS) 1 and 2 (IRS-1 and IRS-2) (14
). Studies in transgenic mice with hepatic steatosis as a result of liver-specific overexpression of lipoprotein lipase (9
) or mice with lipodystrophy and hepatic steatosis (15
) have shown that intracellular accumulation of fatty acid–derived metabolites, such as long-chain fatty acyl CoAs, results in reduced insulin activation of IRS-2–associated phosphatidylinositol 3-kinase activity (9
). More recent studies that have examined this question have shown that 3 days of high-fat feeding in rats resulted in hepatic steatosis–associated and liver-specific insulin resistance. These changes were associated with increases in hepatic fatty acyl CoAs, reduced insulin activation of IRS-1– and IRS-2–associated phosphatidylinositol 3-kinase, activation of protein kinase Cε, and increased gluconeogenesis (10
). Furthermore, all of these changes, including the hepatic steatosis, were reversed by treating the rats with a low dose of the mitochondrial uncoupling agent 2,4 dinitrophenol (10
Rates of gluconeogenesis were assessed in a subgroup of type 2 diabetic patients before and after weight loss. Before weight loss, these patients manifested increased rates of glucose production, and, consistent with previous studies (17
), this increased glucose production could be attributed to increased rates of gluconeogenesis. After weight reduction, the normalization of rates of glucose production could be attributed entirely to a reduction in gluconeogenesis.
Recent studies have demonstrated a potentially important role for circulating concentrations of fatty acids (20
) and adipocyte-derived cytokines (23
) in altering insulin responsiveness in liver and muscle. Plasma concentrations of fatty acids, triglycerides, resistin, IL-6, adiponectin, and cortisol were not altered by the weight loss, suggesting that they do not play a major role in causing the reversal of hepatic insulin resistance in these individuals. In contrast, plasma concentrations of glucagon decreased by ~25% after weight reduction, suggesting a potentially important role of chronic hyperglucagonemia in promoting increased gluconeogenesis and hepatic insulin resistance in these patients with moderately to poorly controlled type 2 diabetes (17
). Plasma concentrations of tumor necrosis factor-α also decreased by ~10% in these patients after weight loss and may also have played a minor contributing role in this process given its known ability to activate JNK1, which in turn will result in increased IRS-1 Ser307
). In contrast, plasma levels of leptin decreased with weight reduction, which is consistent with its well-established relationship with body fat mass (34
These results have important clinical implications for treatment of patients with poorly controlled type 2 diabetes, demonstrating that a relatively modest weight reduction of <10% of their body weight leads to a marked reduction of IHL content, improved hepatic insulin sensitivity, and normalization of fasting plasma glucose concentrations. This modest weight reduction of ~8 kg (on a low fat [3%], moderately hypocaloric diet, defined as a diet that contains >800 kcal for adults) can be achieved by ~3 months of aggressive nutrition counseling, and it is psychologically an easier goal than the daunting task of achieving normal body weight. Furthermore, these data suggest that a relatively small pool of IHL, estimated by the 1
H MRS results to be <200 g (35
), may be a major factor responsible for the hepatic insulin resistance and increased gluconeogenesis.
In summary, these studies demonstrate that moderate weight reduction (~8 kg) reverses hepatic steatosis and hepatic insulin resistance and normalizes basal rates of hepatic glucose production by decreasing gluconeogenesis. In contrast, there was no effect on peripheral insulin resistance, IMCL content, or circulating levels of resistin, IL-6, or adiponectin. These data support the hypothesis that a relatively small pool of IHL may be responsible for dysregulated hepatic glucose metabolism in patients with type 2 diabetes.