Welcome to this brief lecture regarding the associations between type 2 diabetes and NAFLD, from a clinical point of view. It is expected that up to 25% of the world population has NAFLD. Some of these patients may develop NASH with inflammation and fibrosis, and subsequently they may progress to liver cirrhosis. But the relationship with insulin resistance is debated. What is the hen and what is the egg? Some postulate that insulin resistance is the main driver, while others say that NAFLD induces insulin resistance. However, in this academic debate, there is no doubt that insulin resistance is associated with increased risk of type 2 diabetes. There has been an increasing amount of evidence to support a link between NAFLD and type 2 diabetes. In the early cross-sectional studies, elevated alanin transaminase levels were associated with the metabolic syndrome and type 2 diabetes. The metabolic syndrome is a clustering of at least three or five clinical medical conditions. Abdominal obesity, high blood pressure, high blood glucose levels, high serum triglycerides, and low serum high-density lipoprotein. In the US epidemiological study, NHANES, almost 70% of cases were elevated ALT, suggesting the presence of NAFLD could be explained by the metabolic syndrome. Further, elevated ALT levels is a frequent observation in patients with type 2 diabetes. Moving from cross-sectional studies to prospective clinical studies, the relationship between ALT, metabolic syndrome and diabetes has further established and reviewed in this publication from 2006. It was shown that elevated ALT, as a marker of fatty liver disease, was associated with later development of type 2 diabetes. The studies in the green box all show a relative increase between two and four fold for the risk of later development of type 2 diabetes. While the studies in the red boxes are insignificant, but with a risk between 1.2 and 1.4. However, they all point in the same direction for the last study. In this study by Sattar, the investigators follow groups of patients, either healthy controls or patients at high risk of type 2 diabetes. In the controls, ALT and high blood glucose levels were quite stable over time and no one developped diabetes. In contrast, in the at risk group, patients showed an increase in ALT levels over time, and interestingly before the patient started to develop increased blood glucose levels. The authors conclude that the development of diabetes and the rapid increase in fasting glucose levels are preceded by and associated with liver fat accumulation and increase in ALT levels. This suggests that liver fat is a contributing factor for the development of type 2 diabetes. This is also in line with more recent reviews of data. For example, this review by Shulman, that demonstrates that hepatic insulin resistance is a key risk factor for later development of type 2 diabetes. The role of liver fat as a predictor for later type 2 diabetes development has also been confirmed in this last korean cohort study, with 4-7 years follow up. In this study, ultrasound was used to detect fatty liver at inclusion. Knowing that ultrasound is only positive when liver fat exceeds 15-20%, the fatty liver group had significant steatosis. As shown in table 1, the group of patients having fatty liver on ultrasound had an increased risk of later development of all features of the metabolic syndrome with increased risk of obesity, hypertension, elevated triglycerides and cholesterol levels, but also increased risk for the development of impaired fasting glucose and type 2 diabetes development. In table 2, it is shown that both obese and non-obese subjects with fatty liver has increased risk of developing all features of the metabolic syndrome, including impaired fasting glucose and type 2 diabetes compared to patients with obesity alone and without fatty liver. The first study demonstrating a link between insulin resistance and NAFLD was published by Marchesini in 1999. He investigated 46 patients with high body mass index and elevated ALT, but normal oral glucose tolerance test and compared them to 92 healthy controls. He showed that hyperinsulinemia, insulin resistance, and elevated triglycerides were associated with fatty liver disease, even when correcting for body mass index. Marchesini could therefore conclude that NAFLD is associated with insulin resistance and hyperinsulinemia, even in lean subjects. Professor Marchesini further investigated the metabolic aberrations in NAFLD patients. He performed hyperinsulinemic euglycemic clamp studies in NAFLD patients without diabetes and compared them to patients with type 2 diabetes and healthy controls. As shown in figure A, glucose disposal was similar in NAFLD and type 2 diabetic patients and significantly lower than healthy controls. In figure B, free fatty acid levels are shown at baseline as gray scale and end of the clamp here in black. Again, the patients with NAFLD and type 2 diabetes showed exactly the same characteristics and significantly different from the healthy controls. He concluded that NAFLD patients are characterized by the same clinical and biochemical abnormalities as seen in patients with type 2 diabetes. He suggested that NAFLD should be determined as an additional feature of the metabolic syndrome. I will enter my conclusions. NAFLD is associated with type 2 diabetes. NAFLD is determined by elevated ALT levels or by ultrasound, which is associated with later development of the metabolic syndrome and also with a later development of type 2 diabetes. Improving risk factors including the metabolic syndrome and type 2 diabetes, by losing weight, by exercising, improving insulin resistance, may reduce NAFLD severity. Thank you for your attention.
