The impairment of normal uptake of glucose by adipocytes and muscle cells and the paradoxical storage of FFA in muscles and release from adipocytes perpetuates peripheral IR. These metabolic perturbations are intimately involved with the concept of hepatocyte IR Fig. Biochemistry of normal insulin sensitivity and insulin resistance. Normal glucose levels are maintained by insulin action which effectively stimulates glucose uptake in adipose tissue and skeletal muscles and inhibits hepatic glucose output.
Type 2 Diabetes and Fatty Liver Disease
Moreover, insulin contributes to normal plasma lipid levels by stimulating lipid storage in the adipose tissue through inhibition of the activity of hormone-sensitive lipoprotein lipase. Hyperglycemia and compensatory hyperinsulinemia result from decreased glucose uptake by peripheral tissues and decreased inhibition of hepatic glucose output.
Moreover, atherogenic hyperlipidemia results from impaired inhibition of lipoprotein lipase, leading to lipotoxicity, namely tissue malfunction and damage from excess lipid depots in non-adipose tissues such as liver, muscles and kidney. In addition, adipocytokines are unbalanced so contribute to perpetuating insulin resistance. The exact mechanisms of hepatocyte IR tend to be more and more precisely elucidated. In addition to the role of WAT, adipocytokines, the microbiome and inflammation most likely contribute to hepatocyte IR. Lifestyle — specifically diet and exercise — is involved.
Although physical exercise, by reversing muscle IR, decreases hepatic de novo lipogenesis and hepatic triglyceride synthesis after a carbohydrate-rich meal in experimental conditions, 45 diet ameliorated central adiposity and liver enzymes and exercise training did not confer significant incremental benefits in a recent study mimicking clinical conditions more closely. These findings, however, do not translate into specific lifestyle suggestions so far. Consumption of dairy products may be associated, via increased Trans-palmitoleate trans Hepatic protein kinase C PKC isoforms promote hepatocyte IR by inhibiting insulin signaling in human liver biopsy samples.
Lipotoxicity remains key to the pathogenesis of T2D. Therefore, morphological evidence of fatty changes in the pancreas could be a better marker of pancreatic lipotoxicity. Recent studies suggest that steatosis of the pancreas is visible through endoscopic ultrasound. Assessment of mediators of IR is of critical importance: Fetuin-A and IL-6 could be such mediators. Fetuin-A, a protein secreted by the liver and associated with the development of IR in animals and with fatty liver in humans, has been proposed as one such mediator.
IL-6 — a major pro-inflammatory cytokine, the expression of which is increased in experimental NAFLD, resulting in systemic IR — could be another mediator. The first reservoir of hepatocyte FFA is from digestion and transfers across the intestinal epithelium to hepatocytes. The second source of FFA is from digestion and transfers across the intestinal epithelium to hepatocytes, as mentioned previously. The concept that triglycerides may serve as a protective reservoir in the pathogenesis of NAFLD was the result of two important studies.
Their findings were striking in that mice administrated ASO for DGAT2 had significantly higher levels of lipid peroxidation products, hepatic fibrosis and FFA, but diminished hepatocyte steatosis. The vast majority of proteins that a cell secretes or displays on its surface first enter the endoplasmic reticulum ER , where they fold and assemble.
Only properly assembled proteins advance from the ER to the cell surface. To ascertain fidelity in protein folding, cells regulate the protein folding capacity in the ER according to need. The ER responds to the burden of unfolded proteins in its lumen ER stress by activating intracellular signal transduction pathways, collectively termed the unfolded protein response. These recent studies implicate the role of ER stress and the ability to discriminate between what is a normal unfolded protein response which the ER can handle without resort to cell death when the stress mechanism is overwhelmed.
Finally, despite a clear pathway of understanding in the development of hepatic IR, the discovery by Czaja and colleagues that the elimination of fat stores by lysosomal degradation pathway, or autophagy, may have profound implications for not just NAFLD but hepatic IR because the storage of FFA may be dangerous and also perpetuate hepatocyte IR.
The issue of susceptibility of race or ethnicity to NAFLD progression was recently highlighted by the discovery of a point mutation in the gene encoding for adiponutrin, or PNPLA3, in which Hispanics were far more likely to have more hepatic fat and inflammation if they had an allelic variant. Conversely, non-Hispanics and African-Americans were more likely to have a protective allelic variant, and were less likely to have either excess hepatocyte fat or inflammation.
Although limited by their study design, cross-sectional studies offer some interesting hints. For instance, they indicate that the pathogenesis of NAFLD could be sex-specific; 90 that NAFLD patients display metabolic abnormalities indistinguishable from those observed in diabetic and obese patients; 91 and that it is difficult to dissociate the development of T2D alone from the development of the MS on the grounds that NAFLD is a risk factor for both.
Prospective studies provide the most robust evidence, given that they are based on both surrogate indices, hepatobiliary enzymes 97 — and on the natural history of NAFLD. Moreover, imaging studies have been performed in Asian populations alone. In this regard, a study reported that it is NASH rather than pure fatty liver that is associated with T2D and another study suggested that those with pre-diabetes, elevated glutamyl transpeptidase, triglycerides and insufficient physical activity are the patients more in need of specific interventions to prevent T2D.
They also provide useful clinical clues to identifying subjects who, being particularly prone to developing the disease, may benefit most from strategies of prevention and early treatment. In this connection, two recent meta-analytic reviews provide somewhat conflicting results.
This topic may be schematically divided into two sections: Interestingly, fibrosis in the liver might progress parallel to atherogenesis. White adipose tissue adipokines appear to play a critical role in hepatic fibrosis, particularly in NASH. Inflammatory cytokines are differentially expressed in the adipose tissue of fibrosing NASH, as well in NASH associated with T2D pointing to pathogenic cross-talk of adipose inflammatory cytokines, T2D and liver fibrosis leading to cirrhosis and end-stage liver disease.
A comprehensive review of our understanding of the molecular pathways connecting lipotoxic IR and hepatic fibrogenesis is specifically discussed elsewhere. Hepatocellular carcinoma, the most common primary liver cancer, ranks fourth among the most prevalent malignancies worldwide and third leading cause of cancer-related deaths. However, the etiology of disease remains unclear in up to half of HCC cases suggesting that T2D and obesity, via the development of NASH with or without cirrhosis , might play a role.
Several mechanisms could favor the development of HCC in the setting of NAFLD, including abnormal glucose metabolism, hepatocyte iron deposition, age and advanced fibrosis. The subclinical inflammatory state associated with IR, steatosis, oxidative stress and unbalanced adipocytokine ratio i. Interestingly, recent studies suggest that the type of antidiabetic drug treatment used may modulate the risk of developing HCC, insulin increasing and insulin sensitizers decreasing it. Diabetic patients with elevated body mass index and low fibrosis stage are at risk for higher rates of fibrosis progression.
First, these individuals will tend to have NASH rather than pure fatty liver and therefore should preferentially receive a biopsy as opposed to non-invasive diagnosis. Further, the risk for cirrhosis is also increased and therefore aggressive therapeutic intervention is warranted in these patients. Importantly, they may be prone to developing HCC against a background of non-cirrhotic livers. Therefore, markers identifying those individuals at a high risk of HCC are necessary.
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Fatty liver is a major determinant in the development of T2D in predisposed individuals. However, once T2D is fully developed, not only will it further contribute to steatogenesis, but also contribute to progressive liver damage including NASH, fibrosis, cirrhosis and possibly to HCC in a subset of patients. Molecular mechanisms involved in the vicious circle linking fatty liver to diabetes and diabetes to progressive liver injury. Left, the first part of the journey, leading from initial insulin resistance to fatty liver and eventually to the development of T2D in those predisposed individuals in whom pancreatic lipotoxicity occurs.
On these grounds, diagnostic and early therapeutic interventions are warranted in treating NASH patients at risk for developing T2D, as well as to prevent, or make an early diagnosis of, progressive liver disease in those with T2D. National Center for Biotechnology Information , U. Author manuscript; available in PMC Aug 5. The publisher's final edited version of this article is available at Hepatol Res. See other articles in PMC that cite the published article. Abstract The complex and bi-directional relationship linking the liver and diabetes has recently gained intense new interest.
IR and the fatty liver: Does the hypothalamus play a role in the development of IR? Importance of the intestinal microbiome in IR Recent demonstrations indicate that while germ-free mice consume more calories than their wild-type lean littermates, the latter gain significantly more weight.
Open in a separate window. Skeletal and cardiac muscle Insulin resistance in skeletal and cardiac muscle also impairs their ability to transport glucose for fuel in part by the inhibition of the Glut4 transporter. Danger of fatty acids and the concept of lipotoxicity: In vitro fat loading studies The vast majority of proteins that a cell secretes or displays on its surface first enter the endoplasmic reticulum ER , where they fold and assemble.
Hepatocyte apoptosis and the potential for dysfunctional ER stress response Czaja and colleagues clearly implicated Janus Kinase 1 JNK1 as a principal player in driving the pathogenesis of NASH and hepatocyte apoptosis. Lipoautophagy Finally, despite a clear pathway of understanding in the development of hepatic IR, the discovery by Czaja and colleagues that the elimination of fat stores by lysosomal degradation pathway, or autophagy, may have profound implications for not just NAFLD but hepatic IR because the storage of FFA may be dangerous and also perpetuate hepatocyte IR.
Fibrogenesis Interestingly, fibrosis in the liver might progress parallel to atherogenesis. Hepatic carcinogenesis Hepatocellular carcinoma, the most common primary liver cancer, ranks fourth among the most prevalent malignancies worldwide and third leading cause of cancer-related deaths. Type 2 diabetes across generations: Contribution of reduced insulin sensitivity and secretion to the pathogenesis of hepatogenous diabetes: Nonalcoholic fatty liver in Asia: Risk factors for resistance to ceftriaxone and its impact on mortality in community, healthcare and nosocomial spontaneous bacterial peritonitis.
Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. A novel component of the metabolic syndrome. Arterioscler Thromb Vasc Biol. Diabetes and non-alcoholic Fatty liver disease. Endocrine and liver interaction: Nat Rev Gastroenterol Hepatol.
Hyperinsulinemia and the development of nonalcoholic Fatty liver disease in nondiabetic adults. Wanless IR, Shiota K. The pathogenesis of nonalcoholic steatohepatitis and other fatty liver diseases: Tilg H, Moschen AR. Evolution of inflammation in non-alcoholic fatty liver disease: Effects of identical weight loss on body composition and features of insulin resistance in obese women with high and low liver fat content.
Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Hepatic steatosis and insulin resistance: Dissociation between fatty liver and insulin resistance in humans carrying a variant of the patatin-like phospholipase 3 gene. The DGAT2 gene is a candidate for the dissociation between fatty liver and insulin resistance in humans.
Clin Sci Lond ; Dissociation between intrahepatic triglyceride content and insulin resistance in familial hypobetalipoproteinemia. Dissociation between fatty liver and insulin resistance: Insulin resistance and neurodegeneration: Curr Opin Investig Drugs. Increased brain fatty acid uptake in metabolic syndrome. Hypothalamic lipotoxicity and the metabolic syndrome. The gut microbiota as an environmental factor that regulates fat storage. Interplay between obesity and associated metabolic disorders: Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5.
The microbes made me eat it. Metabolic adaptation to a high-fat diet is associated with a change in the gut microbiota. Leptin and the regulation of body weight in mammals. Weight-reducing effects of the plasma protein encoded by the obese gene. Positional cloning of the mouse obese gene and its human homologue.
Paradoxical decrease of an adiposespecific protein, adiponectin, in obesity. Biochem Biophys Res Commun. The hormone resistin links obesity to diabetes. Tumor necrosis factor-alpha regulates in vivo expression of the rat UCP family differentially. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab.
Insulin resistance in hepatocytes and sinusoidal liver cells: Reversal of muscle insulin resistance with exercise reduces postprandial hepatic de novo lipogenesis in insulin resistant individuals. The effects of dietary weight loss with or without exercise training on liver enzymes in obese metabolic syndrome subjects. Am J Physiol Endocrinol Metab. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. Nonalcoholic Steatohepatitis Clinical Research Network Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease.
Cigarette smoking exacerbates nonalcoholic fatty liver disease in obese rats. Active smoking and the risk of type 2 diabetes: Further studies are needed to establish the strength of the associations of NAFLD with these long-term diabetes complications and whether it has an actual causal role. The pathogenesis of NAFLD is not yet fully understood, but insulin resistance appears to be a critical contributing factor, with obesity as the most common cause of the insulin resistant state.
As body fat stores expand with calorie excess and progressive obesity, alterations in lipid metabolism together with inflammation in adipose tissue and ectopic sites of fat deposition lead to insulin resistance predominantly secondary to post-receptor abnormalities in insulin signaling pathways Elevated circulating free fatty acid levels, in part related to diminished suppression of adipose tissue lipolysis by insulin, result in increased delivery of free fatty acids to the liver.
The synthesis of excess triglyceride in the liver is driven by this supply of fatty acids and the accumulation of excess liver fat is further exacerbated by impaired hepatic fatty acid oxidation secondary to insulin resistance. When glucose levels are elevated in the context of pre-diabetes or overt diabetes, this provides further substrate for triglyceride synthesis.
Additionally, impaired very low density lipoprotein VLDL secretion, which commonly occurs with insulin resistance, further contributes to hepatic fat accumulation. Insulin resistance is not only a factor in obesity and diabetes, but also may be an underlying mechanism for NAFLD even in non-obese individuals without diabetes, as noted in a euglycemic insulin clamp study However, insulin resistance most commonly is associated with NAFLD in the context of obesity, and the development and progression of NAFLD usually occurs in association with both insulin resistance and a state of ongoing excess calorie intake.
In a study comparing NAFLD patients and control subjects, none of whom had diabetes at baseline, those with NAFLD were more likely to have diabetes and metabolic syndrome when re-evaluated eleven years later When overt diabetes develops in the setting of preceding insulin resistance and obesity, the diabetic state may be an independent additional factor contributing to progression of NAFLD and the ultimate development of cirrhosis.
In a study of over adults with NAFLD, those with moderate to severe fibrosis were more likely to have diabetes T1DM is an autoimmune disorder in which obesity is not believed to have a significant causal pathogenic role. However, with the high prevalence of obesity in the general population, patients with T1DM not uncommonly are overweight or obese. Regarding liver abnormalities in T1DM, it is important to recognize the occurrence of glycogen hepatopathy 21 and distinguish this clinically from NAFLD.
Excess liver glycogen deposition resulting in hepatomegaly was originally described during the early years after introduction of insulin for management of T1DM as a component of the Mauriac syndrome. This syndrome, which likely represents consequences of sustained, very poor metabolic control in diabetes in childhood, includes hyperlipidemia, growth failure, delayed sexual maturation, and Cushingoid appearance, in addition to hepatic glycogen accumulation. Glycogen hepatopathy occurs more commonly today in the absence of the other features of the Mauriac syndrome.
It can develop in adults or children with poorly controlled T1DM and is characterized by overloading of hepatocytes with glycogen, resulting in hepatic enlargement, modestly elevated transaminases, and sometimes abdominal pain, nausea, and vomiting The pathogenic mechanism appears to involve increased glycogen synthesis and decreased glycogenolysis in the liver as a consequence of the simultaneous presence of insulin and sustained high glucose levels Glycogen hepatopathy cannot be distinguished from NAFLD by ultrasound and ultimately requires liver biopsy for a firm diagnosis.
However, it differs clinically from NAFLD, in that liver size, transaminase elevations, and associated symptoms typically resolve rapidly on improvement in diabetes control with glycogen hepatopathy but not with NAFLD Achieving and maintaining appropriate body weight is the single most important means of preventing NAFLD.
Additionally, the best approach to reversing the course of established NAFLD in overweight or obese patients is weight loss. Weight reduction by lifestyle modification is a safe and effective means of preventing and treating NAFLD. Diets that include substantial ingestion of sweet beverages or a high content of meats have been associated with an increased risk of NAFLD For patients with NAFLD, weight loss can improve serum insulin levels, liver function, and quality of life It was suggested in a study of 41 patients followed for approximately 8 months that rapid weight loss can result in worsening of the liver disease It is also advisable that individuals at risk for NAFLD reduce or altogether avoid alcohol consumption.
Liver and diabetes. A vicious circle
Three pharmacological agents have been approved by the US Federal Drug Administration in the past two years for weight loss in overweight or obese patients: These agents represent a reasonable therapeutic option to consider for weight reduction in patients who have not been able to achieve adequate weight loss by lifestyle changes. For patients who have been unable to achieve adequate weight reduction by diet and lifestyle modification, bariatric surgery can be considered for the proper candidate with NAFLD.
A majority of these studies were prospective in design and employed Roux-en-Y gastric bypass as the type of bariatric surgery. Gastric bypass can significantly improve hepatic function and overall histology, likely mediated by several molecular factors. The available evidence thus indicates that bariatric surgery, in particular Roux-en-Y gastric bypass, is generally effective in obese patients with NAFLD in association with its established marked effects in reducing body weight. It is well established that good blood glucose control reduces both acute and chronic complications in T2DM.
A study involving 39 T2DM patients with NAFLD in Japan found that a decrease in hemoglobin A1c and the use of insulin were associated with an improvement in hepatic fibrosis over a median 2. The decrease in hepatic fibrosis correlated better with blood glucose control as measured by the change in hemoglobin A1c than use of insulin. Additional studies will be required to firmly establish whether improved blood glucose control in general in T2DM, independent of changes in obesity, can result in prevention or reversal of NAFLD.
Limited data are available on the potential effects on NAFLD of specific non-insulin pharmacological agents used in the management of blood glucose levels in T2DM. Metformin is the most commonly prescribed first line oral agent in T2DM. Its primary actions include decreasing hepatic gluconeogenesis and net hepatic glucose production and increasing glucose uptake in skeletal muscle. Due to the risk of lactic acidosis, there is a relative contraindication to the use of metformin in liver disease.
Small studies have shown that metformin is well tolerated in NAFLD and suggest that it can result in improved liver transaminases. For example, a study of 20 subjects with NAFLD treated with metformin for four months showed improvement in liver transaminase levels when compared to non-compliant individuals within the group In a meta-analysis that combined data from three studies, there was no improvement in hepatic steatosis or fibrosis following metformin treatment This results in augmented insulin sensitivity and leads to increased glucose uptake in peripheral tissues and reduced hepatic glucose production.
Pioglitazone is the most widely used TZD, with much less current use of rosiglitazone because of a history of concerns about its potential cardiovascular side effects. Data from multiple studies have suggested potential beneficial effects of TZDs on NAFLD, presumably as a consequence of their actions to decrease insulin resistance.
In a meta-analysis that included five clinical trials involving subjects both with and without overt diabetes, TZDs were found to improve steatosis but not fibrosis. However, in a subset of subjects without diabetes, the pooled analysis showed significant improvements in fibrosis as well as steatosis Pioglitazone further showed a greater decrease in fibrosis compared to rosiglitazone or placebo in the analysis.
Additional studies will be required to resolve whether there are specific patient groups for whom pioglitazone can effectively decrease the development or progression of NAFLD. GLP-1 analogs are stabilized long-acting agonists that bind receptors for the endogenous, intestinally-secreted hormone, GLP Three members of this drug class are approved in the US, including exenatide, liraglutide, and albiglutide.
They improve blood glucose control by enhancing glucose-dependent insulin secretion, slowing gastric emptying, suppressing postprandial glucagon production, and decreasing food intake through enhanced satiety. They are administered by subcutaneous injection from twice daily to once weekly for different preparations , and they most often are used as second-line agents in conjunction with other glucose-lowering drugs or insulin.
A recent small study from Japan showed improved steatosis and NASH histology lower NAS score following liraglutide treatment in overweight or obese subjects with prediabetes This was associated with improved glucose tolerance and a small decrease in BMI. While these initial data are intriguing, further studies will be needed to establish whether or not liraglutide or other GLP-1 analogs can be useful in preventing or treating NAFLD.
DPP-4 inhibitors, currently sitagliptin, saxagliptin, linagliptin, and alogliptin in the US, influence glucose homeostasis by blocking the deactivation of endogenous GLP-1 and a second incretin hormone, glucose-dependent insulinotropic peptide GIP. Some of the effects of DPP-4 inhibitors may overlap with those of administered GLP-1 analogues as noted above , but these drugs likely have additional actions by increasing levels of hormones other than GLP DPP-4 inhibitors have the advantage of being taken orally.
Several clinical studies with sitagliptin in subjects with T2DM and NASH have shown decreases in alanine aminotransferase levels 38 - 40 and, in two studies, improved liver histology 38 , In addition to the usefulness of the multiple members of the statin drug class in treating dyslipidemia, in particular for lowering LDL cholesterol by inhibiting HMG CoA reductase, there is some evidence that statins also can reduce hepatic steatosis in NAFLD Atorvastatin along with another agent, ursodeoxycholic acid, was studied in a clinical trial of over 40 adults with NAFLD 30 non-diabetics and 10 diabetics.
Normolipidemic subjects received ursodeoxycholic, acid, and hyperlipidemic patients received atorvastatin for six months. Liver transaminases decreased in both groups, but a decrease in steatosis was noted only in the statin patients. Statins do have the rare side effect of hepatoxicity; however, this has not been observed in statin treated patients with NAFLD In a follow-up study, the decrease in steatosis in response to statins appeared to be sustained for more than 10 years There is ample clinical evidence that statins decrease both primary and secondary cardiovascular disease risk, and they are widely used for this indication in diabetes.
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Statins are not specifically approved for the prevention or treatment of NAFLD, but there is a need for further studies on the magnitude and duration of their potential effects on NAFLD both in the presence and absence of diabetes. Routine screening for NAFLD is not currently recommended for patients with diabetes or otherwise increased risk in the absence of elevated liver transaminases or other evidence for liver disease. As more data emerge on the effects of specific anti-diabetes drugs, weight loss drugs, and other agents such as statins on NAFLD, it will be important to continuously re-evaluate the cost-effectiveness of screening.
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Since the rate of progression from simple steatosis NAFL to steatosis with associated inflammation and fibrosis NASH appears to be quite low, screening for NAFL is likely to be appropriate only if effective pharmacological agents are identified that have low cost and highly favorable adverse event profiles. Given the much more frequent progression of patients with NASH to serious liver disease, including hepatocellular carcinoma or liver failure, screening targeted to NASH may be cost-effective even for medications that are more costly and have less favorable side effect profiles.
For this reason, it will be important to focus future research on improved non-invasive strategies of screening for NASH, as well as new approaches to treating NASH once it has been diagnosed. Early data suggest that some of the pharmacological agents commonly used in the management of blood glucose and dyslipidemia in T2DM may also be efficacious in treating NAFLD. T2DM patients thus represent a population that should be a focus for further study as new screening methods and treatment options for NAFLD become available.
National Center for Biotechnology Information , U. Journal List Hepatobiliary Surg Nutr v. Bhatt and Robert J. Received Oct 24; Accepted Dec 9. Copyright Hepatobiliary Surgery and Nutrition. This article has been cited by other articles in PMC. Pathophysiological links between NAFLD and type 2 diabetes T2DM The pathogenesis of NAFLD is not yet fully understood, but insulin resistance appears to be a critical contributing factor, with obesity as the most common cause of the insulin resistant state.
Liver disease in type 1 diabetes T1DM T1DM is an autoimmune disorder in which obesity is not believed to have a significant causal pathogenic role. Prevention and treatment of fatty liver disease in diabetes Management of body weight and obesity The strategies used to prevent and treat NAFLD in general also apply to this disease in the setting of T2DM.