Section 10 Section Editor: Rajesh Upadhyay Gastroenterology 124. Type 2 Diabetes Mellitus Originates 135. Proton Pump Inhibitors—Long-term Use: from Fatty Liver Boon or Bane? Rajesh Upadhyay, Ankit Gupta Manish Manrai, Rohit Upreti 125. Non-Pharmacological Management of 136. Eosinophilic Esophagitis— NAFLD/NASH (Diet, Exercise, and Role of An Underdiagnosed Entity Intermittent Fasting) Goundappa Loganathan, H Leena Shree Sundeep Kumar Goyal 137. Non-Cirrhotic Portal Hypertension in India 126. Medical Management of Acute Pancreatitis Srikant Mohta, Anoop Saraya D Nageshwar Reddy, Hardik Rughwani 138. Drug-induced Liver Injury 127. Functional Gastrointestinal Disorders Harshad Devarbhavi Uday C Ghoshal 139. Achalasia Cardia—Diagnosis and 128. Variceal Bleed Management Endoscopic Treatment Srikanth Gopi, Deepak Gunjan Mohan Ramchandani, Partha Pal 129. Hepatorenal Syndrome: Current 140. Non-Variceal Upper GI Bleed—Clinical Approach Diagnosis and Management Bhabadev Goswami, Preeti Sarma Shri Krishna Gautam 141. Recent Updates in Management of IBS 130. Hepatic Encephalopathy: Management Nikhil Gupta, Manisha Dwivedi, SP Misra Sudhir Maharshi, Barjesh Chander Sharma 142. Evaluation of Occult GI Bleed 131. The Healthy Indian Gut Microbiota Sanjay Bandyopadhyay Rupjyoti Talukdar 143. Endoscopic Ultrasound for the Internist 132. Celiac Disease: Who to Screen and How to Screen? Surinder S Rana Ashish Agarwal, Archita Makharia, Govind K Makharia 144. Gastroesophageal Reflux Disease—What’s New! 133. Differentiating Crohn’s Disease from Intestinal Piyush Dadhich, Shraddha Sharma, Shreyans Singhvi, Tuberculosis: A Diagnostic Challenge Gautam Bhandari, Sunil Kumar Dadhich Pabitra Sahu, Saurabh Kedia, Vineet Ahuja 145. Post-Infectious Irritable Bowel Syndrome 134. Acute Liver Failure and Acute-on-Chronic-Liver BK Tripathi Failure in India: How They Are Different from West? Subrat Kumar Acharya Section-10.indb 785 28-01-2021 12:10:33 Section-10.indb 786 28-01-2021 12:10:33 CHAPTER Type 2 Diabetes Mellitus 124 Originates from Fatty Liver Rajesh Upadhyay, Ankit Gupta Abstract The relationship between diabetes mellitus and liver disease is bidirectional, both supporting and accelerating the development of each other. The key pathogenic mechanism is insulin resistance (IR). The main factor leading to IR is accumulation of fat in the liver. The hepatic fat predominately comes from three sources • Dietary fat, • De-novo lipogenesis due to high insulin level and • Fatty acid generation from adipose tissue lipolysis. Fat in the liver impairs insulin signaling, leading to IR. Liver is the largest metabolic organ leading to IR. The resultant IR worsens hyperinsulinemia, which affects various metabolic processes in the liver. The IR prevents glucose transport from blood to liver, thus leading to poor trapping in liver and consequent rise in blood sugar. In addition increased free fatty acids inhibit the insulin action on liver, and insulin-induced suppression of glucagon is impaired, thus leading to increased production of hepatic glucose which has a major contribution in fasting hyperglycemia. Evidence suggests that improvement in fatty liver reduces IR and prevents development and/or improvement of diabetes mellitus. There are numerous observational studies suggesting that fatty liver is an independent risk factor for development of diabetes. Chronic liver disease is associated with development of diabetes (secondary diabetes). Glucose intolerance can be seen in about 80% of patients, and diabetes in about 30% of patients with chronic liver disease. Thus, fatty liver may be considered the main organ responsible for IR and T2DM. Diabetes should be considered a reversible metabolic state due to excess intra-organ fat, especially fatty liver. Introduction T2DM and NAFLD. The relationship between diabetes mellitus and liver disease is bidirectional, both supporting The interest in relationship between chronic liver disease and diabetes mellitus has increased since last decade. and accelerating the development of each other. What Chronic liver disease particularly NAFLD is associated remains unclear is the chicken-egg conundrum—which with diabetes mellitus. In the United States, NAFLD is the comes first? In other words, does diabetes lead to fatty liver most common cause of chronic liver disease and affects or fatty liver causes diabetes? An understanding of this between 80–100 million individuals.1 According to an requires a deep study of the physiology and pathogenesis estimate in India, approximate 30% of the population is of both conditions and developing clear concepts. having NAFLD and its prevalence approaches to 64% in Although IR is the common pathogenetic mechanism for diabetics.2 The association is based on insulin resistance both these conditions; however, it is the liver which is the (IR), which is the common underlying mechanism for both key player for IR. Section-10.indb 787 28-01-2021 12:10:33 788 SECTION 10 Gastroenterology Liver is the Main Organ Producing IR to the fatty pool. Fatty acid accumulation occurs in the liver cells which would normally be oxidized to produce Being the largest metabolic organ of human body, it plays energy. However, the oxidative stress and mitochondrial an important role in glucose metabolism. It is the site for dysfunction in fatty liver prevents oxidation. The fatty acid glycogenesis, glycogenolysis, and gluconeogenesis. It has is therefore esterified into triglycerides and stored in the an immense capacity to store sugar in times of excess and liver cells. Fat in the liver impairs insulin signaling, leading push out glucose into circulation in deficient condition. to IR. The resultant IR worsens hyperinsulinemia, which Therefore, in states of fasting or hypoglycemia, liver affects various metabolic processes in the liver. First, it releases glucose into the circulation by glycogenolysis stimulates the enzyme hexokinase, which phosphorylates and/or gluconeogenesis. On the other hand, it is also the glucose. In addition, it also activates the enzymes main organ which prevents rapid rise of blood glucose phosphofructokinase and glycogen synthase, which are after food ingestion. Whatever glucose is absorbed from involved in glycogen synthesis. When glycogen stores are the intestines it goes through the portal vein to the liver saturated, the excess glucose is then shunted to fatty acid where, almost all of it is retained. The rise in prandial synthesis, which further adds to liver fat. plasma glucose reflects only a minor component of The liver mediated IR is a manifestation of the inherent the absorbed glucose. It is pertinent to note that the ability of liver to protect itself from ongoing onslaught of first glycemic abnormality in T2DM is postprandial further sugar/fat accumulation in liver cells, which is likely hyperglycemia, which may actually indicate insufficient to cause cell disintegration. The stored fat is therefore trapping of glucose by the liver. The insufficient trapping transported out from the cell in the form of free fatty of glucose in the liver is due to the liver mediated IR. The acid and VLDL, which causes tissue IR in various organs main factor leading to IR is accumulation of fat in the liver. (Fig. 1). The IR prevents glucose transport from blood to This brings us to the basic question as to what causes liver, thus leading to poor trapping in liver and consequent fatty liver (Flowchart 1). High carbohydrate/high fat diet rise in blood sugar. increases insulin production, which pushes sugar from blood into liver. The liver cells are filled up with stored glycogen. The hepatic fat predominately comes from three Increased Hepatic Glucose Output in sources: Diabetes Dietary fat, It is also well known that hepatic glucose output is De-novo lipogenesis due to high insulin level, and increased in T2DM, and it has a major contribution Fatty acid generation from adipose tissue lipolysis. in fasting hyperglycemia. Increased free fatty acids In addition the role of absorbed fructose is also inhibit the insulin action on liver, and insulin-induced important. Fructose unlike glucose can only be suppression of glucagon is impaired, thus leading to metabolized by the liver and not by other tissues. In fatty increased production of hepatic glucose excessive release liver, there is already high hepatic glucose/glycogen; of glucose from liver further increases blood sugar levels hence, fructose can only be converted into fat which adds although the levels may still be maintained within the normal range due to compensatory high pancreatic beta Flowchart 1: What causes fatty liver? cell production of insulin. Phases of T2DM and the Role of Pancreatic Fat It is well known that in diabetics, there is a prolonged period of 12–14 years of IR with compensatory hyperinsulinemia keeping the blood sugar within the normal range with gradually increasing HbA1c to prediabetic levels. Then comes the pancreatic beta cell failure resulting in reduced Section-10.indb 788 28-01-2021 12:10:34 Type 2 Diabetes Mellitus Originates from Fatty Liver CHAPTER 124 789 Fig. 1: Sources and fate of free fatty acids in liver insulin production causing overt diabetes (Fig. 2). The question is what causes beta cell failure? Various theories in literature have been suggested especially the burnout theory due to persistent insulin overproduction by the pancreatic beta cells leading to cell death causing reduced insulin production. If this was so then T2DM would clearly be an irreversible condition. On the contrary, there is