Context Use of insulin in patients with diabetes and advanced chronic kidney disease (CKD; stages 4 to 5) is challenging and shows great variability among individuals. We explored the mechanisms underlying this variability. Evidence Acquisition PubMed was searched for articles in English from 1960 to 2018 for advanced CKD and diabetes, glucose and insulin metabolism, insulin clearance, secretion and resistance, plasma insulin concentration, glycemic control, hypoglycemia, insulin dosage, and continuous glucose monitoring (CGM) in CKD. Evidence Synthesis The evidence shows that in most patients the daily dose of insulin needs to be significantly reduced with a high degree of variability; in some the dose remains unchanged, and rarely it is increased. The premise that the marked reduction in insulin requirement is essentially attributable to decreased insulin clearance by kidneys leading to prolongation of its plasma half-life, elevated blood insulin concentration, and hypoglycemia is not entirely correct. Other factors including decreases in food intake, insulin secretion, insulin clearance by peripheral tissues, and renal gluconeogenesis play important roles. There is also heightened resistance to insulin due to metabolic acidosis, uremic toxins, inflammatory state, and vitamin D deficiency. Importantly, the magnitude of changes in each of these factors varies between individuals with the same degree of CKD. Conclusions In the presence of diabetes with advanced CKD, the insulin regimen should be individualized based on knowledge of the daily glucose patterns. The use of CGM is promising for safer glycemic control in patients with advanced CKD and diabetes and helps prevent extremes of hypoglycemia and hyperglycemia.

Nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as a major expanding national and international health problem. Despite numerous investigations using a variety of therapeutic agents, the positive result on any single medication has not been established enough to gain widespread approval. This is in part related to concerns regarding side effects of agents, but is also related to the complex etiology of NAFLD. An often discussed question has been whether insulin resistance that is frequently present in those with NAFLD is a cause of NAFLD or is merely associated with the condition. Nevertheless, it is clear that a very high proportion of patients with NAFLD are obese, have elements of metabolic syndrome, or have type 2 diabetes (T2DM). Also, much progress has been made toward a better understanding of the pathophysiology of NAFLD. Life-style interventions resulting in weight loss remain the foundation for the prevention and treatment of NAFLD. In addition, agents such as Vitamin E and pioglitazone as well as other glycemia-lowering agents including Glucagon Like Peptide-1 (GLP-1) receptor agonists and Sodium Glucose Contransporter-2 inhibitors (SGLT-2i(s)) exhibit positive effects on the clinical course of NAFLD. This narrative review summarizes the current understanding of the diagnosis, epidemiology, and pathophysiology of NAFLD and specifically focuses on the efficacy of SGLT2i (s) as a potentially promising group of agents for the management of patients with NAFLD. Plain language summaryNonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are major growing national and international health problems. NAFLD is commonly associated with obesity, metabolic syndrome, type 2 diabetes. There is high insulin resistance that is irrespective of presence of diabetes. Hepatic lipid content is a function of food intake and fatty acid delivery from adipose tissue, de novo synthesis in liver (a process stimulated by elevated glucose and insulin levels), βoxidation of fatty acids (a process stimulated by glucagon), and export of triglycerides from the liver by VLDL particles. Use of SGLT2 inhibitors has been shown to reduce insulin resistance, glucose and insulin concentrations while increasing glucagon levels and glucagon/insulin ratios, all changes that decrease liver fat content. Recent evidence suggests that use of SGLT2 inhibitors represents a promising new approach for the management of patients with NAFLD and NASH.

Background: Hepatic dysfunction in the setting of hyperthyroidism is difficult to diagnose and poses a challenge in therapy, since the classic medications used are potentially hepatotoxic. Clinical case: A 51-year-old female patient presented with fatigue, palpitations and tremors. BP 146/65 mmHg, HR 111 bpm and Temp 97.8 F. She was severely thyrotoxic with 3 + DTRs, tremors, enlarged thyroid gland with bruit on auscultation, clear lungs and no lower extremities edema. Blood tests showed TSH <0.003 IU/ml (0.450-5.330 IU/ml), Free T4 5.33 ng/dL (0.45-1.80 ng/dL), Free T3 > 30.0 pg/mL (2.3-4.2 pg/mL). Liver enzymes showed elevation in transaminases with ALT 319 IU/L (7-40 IU/L), AST 330 IU/L (7-40 IU/L) normal total Bilirubin 0.7 mg/dL (0.1-1.5 mg/dL) and Alkaline phosphatase 65 IU/L (40-200 IU/L). Transaminases were also elevated 3 weeks prior to presentation and this was extensively worked up with no identifiable etiology to explain the liver dysfunction. She was started on beta blocker therapy and admitted to the ICU. She had no clinical or echocardiographic evidence of cardiac dysfunction and remained hemodynamically stable. She was started on Methimazole 45 mg daily. The patient improved clinically and a pronounced decline in transaminase levels was documented in the first 72 hours. She was discharged home on day 3 of admission. On follow up visit her transaminases were found to have completely normalized within 14 days. Discussion: The diagnosis of elevated transaminases in hyperthyroidism is a challenge. This is due to the possibility of multiple etiologies including decreased cardiac output and/or liver congestion, concomitant primary liver disease or more specifically autoimmune hepatic disease such as primary biliary cirrhosis. (1-2). Incidentally Methimazole has been associated with transient asymptomatic transaminitis typically during the first three months of therapy (3). Our case indicates, that methimazole can be used in patients with a presumed diagnosis of hyperthyroidism induced hepatotoxicity after all possible etiologies are ruled out. Hyperthyroidism as the cause of liver dysfunction can only be entertained after all those etiologies are ruled out and upon resolution of transaminase elevation in conjunction with improvement in the hyperthyroid state itself, as was demonstrated in this case. Conclusion: Methimazole can be safely used in patients with severe hyperthyroidism and elevated liver enzymes when all other etiologies of liver dysfunction have been ruled out. References: 1. Khemichian S, Fong TL. Hepatic dysfunction in hyperthyroidism. Gastroenterol Hepatol (N Y). 2. Elias RM, Dean DS, Barsness GW. Hepatic dysfunction in hospitalized patients with acute thyrotoxicosis: a decade of experience. 3. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD): Methimazole