|Year : 2021 | Volume
| Issue : 2 | Page : 135-145
Role of diet and lifestyle modification in the management of nonalcoholic fatty liver disease and type 2 diabetes
Orsu Prabhakar, Mylipilli Bhuvaneswari
Department of Pharmacology, GITAM Institute of Pharmacy, Visakhapatnam, Andhra Pradesh, India
|Date of Submission||23-Apr-2020|
|Date of Acceptance||08-Jun-2020|
|Date of Web Publication||05-Oct-2020|
Dr. Orsu Prabhakar
Department of Pharmacology, GITAM Institute of Pharmacy, Visakhapatnam - 530 045, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Nonalcoholic fatty liver disease (NAFLD) is considered as the hepatic evidence of insulin resistance which is the hallmark of type 2 diabetes. NAFLD is considered as the risk factor for developing type 2 diabetes and has a high frequency of occurrence in those with existing type 2 diabetes. Compared with patients with only NAFLD or type 2 diabetes, these patients show a poor metabolic profile and increase mortality. Hence, effective treatment strategies are necessary. Here, we review the role of diet and lifestyle modification in the management of NAFLD and type 2 diabetes. Based on the available studies, it has been shown that the addition of any kind of physical activity or exercise is beneficial for patients with both NAFLD and type 2 diabetes. Proper dietary management leads to weight loss are also effective in improving metabolic parameters in patients with both NAFLD and type 2 diabetes. In conclusion, it is clear that increasing physical activity or exercise is effective in improving metabolic parameters in patients who are suffering with both NAFLD and type 2 diabetes.
Keywords: Hepatic steatosis, Insulin resistant, Nonalcoholic fatty liver disease, Physical activity, Type 2 diabetes
|How to cite this article:|
Prabhakar O, Bhuvaneswari M. Role of diet and lifestyle modification in the management of nonalcoholic fatty liver disease and type 2 diabetes. Tzu Chi Med J 2021;33:135-45
|How to cite this URL:|
Prabhakar O, Bhuvaneswari M. Role of diet and lifestyle modification in the management of nonalcoholic fatty liver disease and type 2 diabetes. Tzu Chi Med J [serial online] 2021 [cited 2021 Apr 21];33:135-45. Available from: https://www.tcmjmed.com/text.asp?2021/33/2/135/297286
| Introduction|| |
Nonalcoholic fatty liver disease (NAFLD) is now considered as one of the most common liver disorders and its prevalence expecting to increase further in the near future . NAFLD constitutes a spectrum of pathological conditions such as nonalcoholic steatohepatitis (NASH), hepatic steatosis, hepatocellular carcinoma (HCC), terminal liver failure, cell necrosis, perilobular, and cirrhosis . The continuously increasing frequency of obesity in today's generation is linked with many health issues including NAFLD ,. These include diabetes, hyperlipidemia, hypertension, cardiovascular, and fatty liver diseases. These set of conditions exhibit metabolic syndrome . NAFLD is a complex disease that includes the interaction of genetics, diet, and lifestyle. About 50% of patients who are suffering with type 2 diabetes have NAFLD. The interconnection between type 2 diabetes and NAFLD is recently recognized and less well known to physicians. Because patients are usually asymptomatic and routine blood test are usually normal, it may be a diagnosis that is overlooked in type 2 diabetic patients ,.
Patients with NAFLD who have type 2 diabetes are particularly at risk of progressive forms of the disease and that they are at higher risk of developing cirrhosis contrast to those who do not have diabetes ,. Although cardiovascular disease is the major cause of excess morbidity and mortality in type 2 diabetes, liver failure may also be considered to be a threat to patients who are suffering with type 2 diabetes NAFLD ,. As NAFLD and type 2 diabetes are associated with obesity, weight loss constitutes the principle key in NAFLD management. Sudden weight loss achieved through dietary and lifestyle modification may lead to the progression of liver failure in some NAFLD patients. Alternatively, weight loss using surgical methods, even with rapid weight reduction after surgery, has been successful in reducing NAFLD progression ,,. This review highlights the role of diet and lifestyle modification in the management of NAFLD and type 2 diabetes and also focuses on human studies related to physical activity and dietary modifications.
| Diet Management in Nonalcoholic Fatty Liver Disease and Type 2 Diabetes|| |
The central features of NAFLD pathogenesis comprise metabolic dysregulation (increased steatosis, mitochondrial dysfunction, and insulin resistance), inflammation, apoptosis, and fibrosis. Carbohydrates, fatty acids, proteins, amino acids, and Vitamin D can simultaneously either activate or inhibit the critical nodes of NAFLD pathogenesis. [Figure 1] shows mechanisms involved in parthenogenesis of NAFLD and its possible treatment options.
|Figure 1: Pathogenesis and treatment of nonalcoholic fatty liver disease|
Click here to view
| Carbohydrates|| |
Normally, human diet is naturally rich in carbohydrates  and some epidemiological studies have shown a strong relationship between increase in fructose intake and occurrence of NAFLD . Low-level carbohydrate diet <45% per day has shown positive results regarding depletion of intrahepatic triglyceride content, weight loss, and development of metabolic parameters in obese patients. When the consumption of fructose exceeds 25% of the energy requirement, it will show the effects on glucose homeostasis, free fatty acid metabolism, etc. . Fructose slows down the hepatic lipid oxidation by blocking the action of peroxisome proliferator-activated receptor alpha  and increases fibroblast growth factor 21 (FGF21) in a CHO-response element-binding protein-dependent manner even when protein consumption is controlled .
Fructose-driven biochemical alterations lead to steatosis, obesity, insulin resistance, hepatic fibrosis, inflammation, etc. ,,. In contrast, a carbohydrate such as resistant starch that is resistant to digestion, which is found in many food materials, it can helps to maintain the blood glucose levels. Therefore, It can decreases the risk of the type 2 diabetes ,. Gut flora which include Bactericides, Bifidobacterium, etc., are responsible for metabolizing fermentable polysaccharides such as pectin or insulin to produce short-chain fatty acids, which not only improve insulin resistance  but also activate G protein-coupled receptors to induce epigenetic and anti-inflammatory effects to modulate metabolic disease status ,.
Some studies have shown beneficial results of dietary fibers on body composition parameters such as reduced body fat percentage, insulin resistance, and waist circumference. Dietary fibers are composed of plus lignin, nonstarch polysaccharides, resistant starch, and oligosaccharides. These fibers present in food containing hemicellulose, cellulose, hydrocolloids, resistant starch, and resistant oligosaccharides. And also, the fibers are classified into two types: soluble and insoluble dietary fibers. Insoluble dietary fibers are insoluble in gastric fluids and water; whereas, soluble dietary fibers are soluble in water and can withstand GI enzymatic digestion. Soluble fiber passes through small intestinal and reaches the colon where the soluble fiber can be fermented by intestinal microflora (Bactericides, Bifidobacterium, etc.) . Both insoluble and soluble fibers play different roles in maintaining gastrointestinal health . Information regarding the effect of different kinds of fiber remains unclear . Thus, current research is permitted to determine the optimal requirement of dietary fibers for prevention and reduction of NAFLD and type 2 diabetes.
| Fatty Acids|| |
Dietary fatty acids can regulate the action of key cell types such as macrophages and hepatocytes implicated across the NAFLD spectrum . Dietary fatty acids can easier the development, reversal of some NAFLD features depending on fatty acids' composition, the molecular targets they hold, carbon chain length, etc. ,. Over-injection of saturated fatty acids promotes fatty liver, induces hepatic endoplasmic reticulum stress, and impairs insulin signaling and apoptosis ,,,,,. Saturated fatty acids induced oxidative stress which results in the activation of the c-Jun N-terminal kinase (JNK) pathway, which acts as a key mechanism in the pathophysiology of NASH and insulin resistance .
In some studies, it has been shown that monounsaturated and polyunsaturated fatty acids such as oleic acid, arachidonic acid, alpha-linolenic acid were found in dietary foods like avocados, olive oil and nuts. They can reduce intrahepatic triglyceride accumulation and inflammation. Examples: Dietary intake of polyunsaturated fatty acids in a cross-sectional study of patients with NAFLD showed that >80% of patients did not reach daily recommended intake of linolenic acids and linolenic . Well-controlled human clinical trials have shown that n-6 polyunsaturated fatty acids (linoleic acid) compared to saturated fatty acid (butter) prevent intrahepatic triglyceride in the context of 7 weeks of overfeeding .
NASH patients had a significantly higher n-6 fatty acids and a decrease ratio of n-6/n-3 fatty acids . Treatment with glucagon-like peptide-7 analog improves steatohepatitis and modulates the hepatic n-3/n-6 ratio by the regulation of hepatic fatty acid metabolism . Both quantity and quality of dietary fat may alter the glucose tolerance and insulin sensitivity ,,. The presence of high-fat content in the diet may cause a decline of glucose tolerance by several ways which include reduced binding of insulin to its receptors decreased quantity of glycogen synthase, impaired glucose transport, and aggregation of stored triglycerides in skeletal muscle ,,,,.
In animal experiments, saturated, monounsaturated, and polyunsaturated fatty acids have produced insulin resistance when given as high-fat diets ,,,,. According to epidemiological studies, higher intake of saturated fat results in increased risk of impaired glucose tolerance and increased fasting glucose and insulin levels ,. High content of saturated fatty acids in muscles phospholipids or serum lipids is connected with increased fasting insulin levels, reduced insulin sensitivity, and greater chance of developing type 2 diabetes. Whereas, higher intake of vegetable fat (unsaturated fat) is associated with lower risk of developing type 2 diabetes ,. High content of long-chain polyunsaturated fatty acids in skeleton muscle phospholipids leads to increased insulin sensitivity in human ,. The epidemiological data are in consistent regarding monounsaturated fatty acids. Some studies have shown that higher consumption of monounsaturated fatty acids may be harmful regarding increased diabetes risk ,. Adequate amount of fatty acids <30% is necessary to show its beneficial effects in NAFLD and type 2 diabetes patients.
| Proteins and Amino Acids|| |
Liver fat levels can be reduced by high-protein diet. Increasing dietary protein content reduces the level of triglyceride diffusion in the liver . Adequate amount of proteins, 15%–20%, is necessary to show its beneficial effects in NAFLD and type 2 diabetes patients. A prospective study of 37 patients with type-2 diabetes and NAFLD fed a high-protein diet showed a 36% to 48% reduction in intrahepatic triglyceride levels, regardless of even if the protein came from plant or animal source .
In a subset of PREVIEW (Prevention of Diabetes through Lifestyle Intervention and Population Studies in around the world) cohort, 25 patients with NAFLD who were insulin resistant and obese were administered a weight maintaining protein diet containing either 15% or 25% protein for up to 2 years following an initial reduction in weight for a period of 8 weeks. In both groups, visceral adipose tissue levels, intrahepatic triglyceride levels, homeostatic model assessment score for insulin resistance, subcutaneous adipose tissue levels, and insulin sensitivity were reduced independent of body weight . A recent trial combining moderate carbohydrate restriction (30% of calories) with a high-protein diet (30%) decreased the absolute hepatic fat content by 2.4% in adults with type 2 diabetes in contrast to 0.2% increase observed in those on a high carbohydrate (50%) and normal protein diet (17%) ,. Neither protein nor leucine ingestion altered plasma adiponectin or nonesterified fatty acids concentrations. Therefore, 3-hydroxyisobutyrate (HIB) and fibroblast growth factor 21(FGF21) might be involved in protein-mediated insulin resistance .
Further, preclinical studies suggest that high-protein diet may have negative impacts on insulin sensitivity, whereas low-protein diet shows metabolic benefits ,,,,,. Adequate amount of protein consumption (10%–15%) is beneficial and shows positive results regarding weight loss in patients with NAFLD and type 2 diabetes . These studies show the importance of balancing the quantity and quality of dietary protein relative to other nutrients as a key element of metabolic health. Certain amino acids in the diet may preferentially regulate key biological processes. Recent studies reported that when specific dietary amino acids are matched to protein coding genes, growth and reproduction are enhanced without affecting the life span .
In some studies, It has been shown that amino acids may regulate certain aspects of NAFLD pathogenesis such as fibroinflammation and glucose homeostasis. Oral supplementation of amino acids in type 2 diabetic patients which can results in decreasing of postprandal plasma glucose levels without any change in insulin levels in plasma. Animal proteins consist of high amount of homocysteine, cysteine, and methionine on metabolism; they give a rise to sulfate (transsulfuration), which is considered as an important requirement of the daily acid load. The metabolism of these amino acids occurs in the liver, which is known as one carbon metabolism. Accumulation of these amino acids takes place due to dysregulation of the above pathway in the plasma and liver, which acts as a risk factor for NAFLD, facture, and cerebrovascular disease ,,.
Plant proteins consist of high amount of glycine and glutamate that requires high proportion of H2 ions to be metabolized alkalinizing the microenvironment ,. Compared to vegetarian diet, animal protein-based diets consist of the high amount of ornithine and glutamine, which is considered as major precursors for ammoniagenesis . An increase in dietary vegetable protein improves the blood glucose response in persons with type 2 diabetes . One more study has shown that depletion of alanine aminotransferase after high-level protein diet was provided to the NAFLD patients . An increase in renal plasma flow and glomerular filtration rate is associated with consumption of high animal protein diet, which is not seen in case of vegetable protein diet ,.
One more study demonstrated that a vegetable diet with low amounts of methionine and aromatic amino acids, but rich in branched chain amino acids (valine, leucine, and isoleucine), helped to improve the health condition of patients suffering with cirrhosis associated with mild portal-systemic encephalopathy . Branched chained amino acids also stimulate insulin production and glucose uptake from stem cells and liver . When branched chain amino acids are supplied to men who are suffering with obese cirrhosis, It can resultant to decrease in the development of HCC and also upgrades the survival rate leads to decrease in the development of HCC and upgrades the survival rate ,.
Low plasma content of branched chain amino acids and glycine in NAFLD and type 2 diabetes patients is inversely connected with insulin resistance. Epidemiological studies show that high-protein consumption for short term does not interfere with calcium homeostasis, but on the long term, it reduces the incidence of bone fracture . High amount of amino acids in the diet promotes increased glomerular filtration rate, serum uric acid, albuminuria, and urinary pH value, which promotes chronic kidney disease progression. Consumption of a high-level protein diet obtained from dairy products contains high amount of proline and glutamic acid and has been connected with high chances to develop diabetes. High consumption of branched chain amino acids with high-fat diet leads to aggregation of succinyl and propionyl-CoA, which might interfere with the tricarboxylic acid cycle, glycolysis, and insulin sensitivity through mitochondrial stress.
Recent evidences have shown that amino acids can cause inhibition of insulin signaling through a mechanistic target of rapamycin activation ,. Effects caused due to high-protein diet in NAFLD patients remain controversial. Therefore, more intense randomized clinical trials are necessary where the effect of single amino acid pool subscription over health must be explored.
| Vitamin D|| |
Vitamin D is considered as a fat-soluble hormone which is acquired from sunlight exposure and dietary supplements. Oily fish and fortified food are dietary supplements which includes cereals, soya milk and shiitake mushrooms. Sunlight is a major source of Vitamin D up to 90%. 7-dehydrocholesterol in the skin gets converted to form pre-Vitamin-D3 upon sunlight exposure (UVB irradiance), which is later converted to Vitamin D3. The term Vitamin D includes ergocalciferol or Vitamin D2 or cholecalciferol or Vitamin D3. The principal metabolites of Vitamin D are calcieliol (25(OH)D) or 25-hydroxy Vitamin D and calcitriol (1,25-(-OH)2D3) OR 1,25-dihydroxy Vitamin D3, which vary in their hydroxylation patterns. In humans, skin is the main source of Vitamin D obtained through the cutaneous synthesis of Vitamin D3 or cholecalciferol and small amount is obtained through the intake of food which are rich in Vitamin D2 or Vitamin D3.
Circulating Vitamin D gets bound to the Vitamin D-binding protein, through which Vitamin D is transported to the liver, their Vitamin D 25-hydroxylase changes it to 25(OH)D, where 25(OH)D is converted to 1, 25-(OH)D in the kidney which is the most biologically active form. 25-hydroxy Vitamin D-1 alpha-hydroxylase (CYP27B1) is the enzyme which is responsible for the above transformation. The presence of Vitamin D receptors demonstrates that Vitamin D also plays a major role beyond bone metabolism. Recently, two quantitative meta-analyses concluded that the amount of 25(OH)D was low in patients with NAFLD compared to those people without fatty liver ,. In cross-sectional studies only, limited evidence is provided against the effectiveness of Vitamin D supply in patients who are suffering with NAFLD ,.
From animal model, information is provided that Vitamin D interferes with the activation of perisinusoidal cells (also known as hepatic stellate cells [HSCs]) and plays an important role in collagen deposits and extracellular matrix remodeling leads to fibrosis (fibrotic scarring) . Vitamin D inhibits proliferation of HSC; clinical trials are required to reveal that Vitamin D supplementation might reduce the advancement from NAFLD to NASH. Vitamin D also plays an important role in bone homeostasis .
Insufficient levels of Vitamin D have been found in patients with osteoporosis, even though the only moderate amount of favorable effects of Vitamin D supplementation has been reported in facture prevention . In last few years, mounting curiosity has been conveyed to Vitamin D action on skeleton muscle. Decrease in Vitamin D levels has been linked with disability, falls in the elderly and sarcopenia. Vitamin D deficiency in adults shows histological changes in muscle fiber composition and width . Serum Vitamin D levels increased through weight loss and enhanced the metabolic parameters in patients with NAFLD .
In this study, it has been found that compared to Vitamin D deficiency supplement weight loss was more effective in increasing serum Vitamin D level in patients with NAFLD. In addition to potential effects of Vitamin D on immune and inflammation processes, other studies are also necessary to look over whether Vitamin D decreases oxidation stress in patients with NAFLD. Some animal studies show that Vitamin D has some beneficial effects, in which one of the studies states that Vitamin D decreases tumor necrosis factor alpha. At the present times, exact convincing data are not there to support that the use of Vitamin D to enhance the results in NAFLD. However, people who are suffering with Vitamin D deficiency should be medicated and given proper musculoskeletal benefits.
Vitamin D controls insulin secretion by regulating voltage gated calcium channels. Calcitriol plays an important role as a chemical messenger by interacting with various receptors, which are regulating calcium flux in B-lymphocytes (beta cells). B-lymphocytes are situated on the phospholipid layers of the plasma membrane.
In case of Vitamin D deficiency normal insulin secretion may be altered through changes in flux in B-lymphocytes. Therefore, appropriate insulin secretion by pancreatic beta cells is essential ,. Preclinical studies demonstrate that Vitamin D can decrease the excitability of the renin angiotensin system and therefore, enhances the function of B-lymphocytes . An adequate amount of Vitamin D level may also enhance insulin resistance pathways connected with diabetes. It is mainly caused due to changes in calcium flux and concentration along the cell membrane of insulin-responsive tissue .
Regulation of intracellular and extracellular calcium concentration stimulates dephosphorylation of glucose transporter-4 operates a decreased insulin-stimulated glucose transport . 1, 25-(OH)2 D accelerates the expression of insulin receptors and thus, accelerates insulin sensitivity. Calcitriol proliferator-activated delta receptor (PPAR-d) is a transcription factor which is responsible for regulating the fatty acid metabolism in skeleton muscle and adipose tissue. Insulin resistance also gets decreased by the specific actions of a calcitriol on hepatic lipid synthesis, glucose output, and on skeleton muscle .
Calcitriol plays an important role in a wide range of metabolic pathways by binding to the VRD and dimension of its substrate 25(OH)D is the principal marker for health issues. The receptor is present in various cells of Langerhans pancreatic B-lymphocytes, adipose, muscle, and liver ,. Fat tissue is the main storage place for Vitamin D. High body mass index is linked to reduce Vitamin D concentration. Vitamin D also plays an important role in reducing chronic inflammation and plays a major role in the probability of deactivating inflammatory cytokines which are linked to insulin resistance and thereby enhancing calbindin expression which involves protection from cellular suicide (apoptosis). Proper dietary management is one of the appropriate ways which can produce sustain reduction in weight, fibrosis, inflammation, etc., in patients who are suffering with both NAFLD and type 2 diabetes.
The summary of sources, uses and abnormalities of diet in the NAFLD were shown in the [Table 1] and Diet management in NAFLD was shown in [Figure 2].
|Table 1: Sources, uses, and abnormalities of diet in the nonalcoholic fatty liver disease|
Click here to view
|Figure 2: Role of diet in the management of nonalcoholic fatty liver disease|
Click here to view
| Lifestyle Modification in Management of Nonalcoholic Fatty Liver Disease and Type 2 Diabetes|| |
At present, weight loss is the cure of choice to reduce hepatic fat accumulation and reduce the advancements of fibrosis and inflammation. Lifestyle modification is one of the possible ways to reduce weight which include programmed diet and physical exercise, which are very effective treatment options for patients who are suffering with NAFLD and type 2 diabetes. Lifestyle modifications are advantageous in patients with NAFLD, improving not only liver disease but also atherogenic dyslipidemia, blood pressure levels, and hyperglycemia ,,. The effectiveness of lifestyle modification on improving various markers of NAFLD (steotosis, presence of NASH, reduction of circulating liver enzymes) was recently explained in a systematic review of 22 randomized clinical trials with 2588 patients with NAFLD . However, much information is not available about the long-term effects of lifestyle modification on liver histology, on the least amount of weight loss required to attain such histological benefit and on best approach to maintain it over long time. In imaging studies, relative depletion in hepatic steatosis achieved through lifestyle modification has been usually in the range of ~40%–50% and absolute changes have often been small on the order of ~5% ,,.
Type 2 diabetes algorithm “Lifestyle development is necessary for all patients with diabetes. In obese patients who are suffering with prediabetes and type 2 diabetes weight loss should be considered to reduce their weight. The need for medical therapy should not be elucidated as a failure of lifestyle modification, but as a complement to it”. A type 2 diabetes patient with NAFLD tends to consume more calories and takes part less in physical activities. In fact, data from the Nutrition Examination and National health survey demonstrated that when patient with NAFLD have concomitant diabetes, they participate less in physical activities . Similar to diabetes, the 1st tool which is used in the management of NAFLD should be sustained reduce in weight through lifestyle modification by proper diet and exercise. Moderate weight loss of 3%–5% of total body weight helps to reduce hepatic steatosis, weight loss of 7%–9% is necessary to reduce inflammation, and weight loss of 10% or more is required to reduce regression of liver fibrosis .
In some studies, it is mentioned that orlistat (tetrahydrolipstatin) which is a drug used to treat obesity has reported better histological improvement corresponding to the amount of weight reduced ,. Thus, pharmacological agents which cause weight loss should always be considered especially when lifestyle intervention is failed. Pharmacological agents which cause weight loss should always be considered, especially when lifestyle modification is failed. Thus, it indicates that there may not be a lifestyle modification strategy which is better than the rest, and weight loss should be the primary aim. For example, physical training and aerobic exercise intervention achieving similar weight loss were equally essential in decreasing liver triglyceride content by ~30% among patients who are suffering with type 2 diabetes and NAFLD . The following methods are included in performing physical training and aerobic exercise: 60 min of aerobic exercise per session by participants at 60%–65% of heart rate reserve, according to Karvonen formula (Target heart rate = [(max HR − resting HR) × % intensity] + resting HR) . Aerobic exercise is performed on cycle, elliptical machines, treadmill and the participants can change their cardiovascular equipment from one session to the next session as they wish. Participants perform physical training which includes 9 different exercises like major muscle groups of weighing machines (vertical traction, chest press, shoulder press, leg extension, abdominal crunch, leg press, leg curls) and free weight (abdominal, biceps). Participants perform 3 sets of 10 repetitions after a learning phase at 70%–80% one-repetition maximum; with 1-minute rest period between each set.
However, some studies show that even with minimal weight loss steatosis reduction can be achieved, specifying that other determinants may play minor role in NASH improvement ,. For example, several small (n = 18–45) and short-term studies (4–24 weeks) reported a moderate decrease in intrahepatic triglyceride accumulation by 1H-magnetic resonance spectroscopy (~15%) after physical exercise without any significant reduce in weight . Dietary supplements, such as Vitamin D, have also been recommended for treating patients with NAFLD, but unsuccessful to show any consistent associations with liver triglyceride accumulation or NASH ,. Clearly, more studies are required to completely understand the role of lifestyle management in treating patients with NAFLD and type 2 diabetes.
| Bariatric Surgery and Nonalcoholic Fatty Liver Disease|| |
Bariatric surgery means a gastrointestinal surgery which helps to reduce weight in obese patients. A meta-analysis of 136 studies was performed by Buchwald et al. that estimated the effect of bariatric surgery on metabolic results and announced a complete resolution regarding type 2 diabetes which is seen in >75% patients who are suffering with diabetes and reduction in weight up to 60%.
NAFLD is linked with obesity and type 2 diabetes and the procedure used in improving obesity and type 2 diabetes by following bariatric surgery plays a key role in the resolution of NAFLD. Bariatric surgery not only plays an important role in the substantial weight reduction in NAFLD patients, but also through contemporaneous effects on important inflammatory and lipid metabolic pathways which are involved in the NAFLD pathophysiology ,,. Bariatric surgery enhances some changes in 3 main metabolic areas controlling NAFLD: improved lipid metabolism, reduced inflammatory activity and improved glucose homeostasis.
Long term-studies have stated that the metabolic benefits of bariatric surgery continue for a wide period. 5 years fallow up of obese patients who are allocated to bariatric surgery which resultant to enhanced diabetic control and wight loss. Retrospective surveys of a larger unit of patients who have undergone sleeve gastrectomy have been found to regain weight at 3 and 5 years after the surgery and endurance of diabetes is some patients. RYGB (Roux-en-Y gastric bypass) has been recently surpassed as one of the most common bariatric surgeries performed and can reduce inflammation, fibrosis and steatosis. RYGB and SG procedures involve in the glycemic control which is following three primary mechanisms such as early enhanced hepatic insulin sensitivity because of postsurgery caloric restriction, late enhanced peripheral insulin sensitivity because of reduction in weight and enhanced postprandial insulin secretion because of increase in glucagon-like peptide 1 secretion.
In line with these findings, large amount of weight loss is obtained after bariatric surgery, which is showed in most of patients and they experienced inhibition of fibrosis (~65%), steatohepatitis (~80%) and steatosis (~90%) , Therefore, these results were recently confirmed in a study where ~50% patients showed better results in fibrosis scores. The magnitude of fibrosis depletion depends on the baseline severity of liver disease, with no development in fibrosis observed 5 years after bariatric surgery in a large unit of patients (n = 381) with mild liver disease ,.
Most of the bariatric surgery studies have some limitations. These studies lack standardization of the preoperative very low caloric diet management and postoperative dietary management about how the intraoperative liver biopsy sample is obtained. Moreover, the repeat post bypass liver biopsies are usually carried at varying intervals over time. Finally, most of the studies have not been controlled, and therefore they were potentially at risk for patient selection bias. It is also not clear that whether changes in liver disease are simply the result of weight reduction or whether bariatric surgery has an intrinsic metabolic effect on the liver. Well-designed prospective studies are required to govern the ideal patient, long-term efficacy, type of surgery and safety of bariatric surgery in NAFLD ,. Different therapeutic approaches for the management of NAFLD were shown in the [Figure 3].
|Figure 3: Different therapeutic approaches of nonalcoholic fatty liver disease|
Click here to view
| Conclusion|| |
From the above studies, it is clear that increasing physical activity or exercise is effective in improving metabolic parameters in patients who are suffering with both NAFLD and type 2 diabetes. Proper dietary management leads to weight loss are also effective in improving metabolic parameters in patient with both NAFLD and type 2 diabetes. Comparing treatment approaches in patients with both NAFLD and type 2 diabetes is required to develop future cost-effective treatment strategies. Future studies should employ accurate methods to establish the most effective means of producing a sustained reduction in liver fat, fibrosis, inflammation etc., and report their interventions. Such interventions play an important role in deciding upon future treatment approaches for patients with both NAFLD and type 2 diabetes.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: Impact of ethnicity. Hepatology 2004;40:1387-95.
Hazlehurst JM, Woods C, Marjot T, Cobbold JF, Tomlinson JW. Non-alcoholic fatty liver disease and diabetes. Metabolism 2016;65:1096-108.
Pi-Sunyer FX. The obesity epidemic: Pathophysiology and consequences of obesity. Obes Res 2002;10 Suppl 2:97S-104S.
Haynes P, Liangpunsakul S, Chalasani N. Nonalcoholic fatty liver disease in individuals with severe obesity. Clin Liver Dis 2004;8:535-47, viii.
Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: A joint interim statement of the international diabetes federation task force on epidemiology and prevention; National Heart, Lung, And Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120:1640-5.
Targher G, Bertolini L, Padovani R, Rodella S, Tessari R, Zenari L, et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 2007;30:1212-8.
Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999;30:1356-62.
Younossi ZM, Gramlich T, Matteoni CA, Boparai N, Mccullough AJ. Nonalcoholic fatty liver disease in patients with type 2 diabetes. Clin Gastroenterol Hepatol 2004;2:262-5.
Bugianesi E, Vanni E, Marchesini G. Nash and the risk of cirrhosis and hepatocellular carcinoma in type 2 diabetes. Curr Diab Rep 2007;7:175-80.
Weiner RA. Surgical treatment of non-alcoholic steatohepatitis and non-alcoholic fatty liver disease. Dig Dis 2010;28:274-9.
Mathurin P, Hollebecque A, Arnalsteen L, Buob D, Leteurtre E, Caiazzo R, et al. Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology 2009;137:532-40.
Furuya CK Jr., De Oliveira CP, De Mello ES, Faintuch J, Raskovski A, Matsuda M, et al. Effects of bariatric surgery on nonalcoholic fatty liver disease: Preliminary findings after 2 years. J Gastroenterol Hepatol 2007;22:510-4.
Sevastianova K, Santos A, Kotronen A, Hakkarainen A, Makkonen J, Silander K, et al. Effect of short-term carbohydrate overfeeding and long-term weight loss on liver fat in overweight humans. Am J Clin Nutr 2012;96:727-34.
Stanhope KL, Schwarz JM, Havel PJ. Adverse metabolic effects of dietary fructose: Results from the recent epidemiological, clinical, and mechanistic studies. Curr Opin Lipidol 2013;24:198-206.
Stanhope KL, Schwarz JM, Keim NL, Griffen SC, Bremer AA, Graham JL, et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J Clin Invest 2009;119:1322-34.
Roglans N, Vilà L, Farré M, Alegret M, Sánchez RM, Vázquez-Carrera M, et al. Impairment of hepatic stat-3 activation and reduction of pparalpha activity in fructose-fed rats. Hepatology 2007;45:778-88.
Lundsgaard AM, Fritzen AM, Sjøberg KA, Myrmel LS, Madsen L, Wojtaszewski JF, et al. Circulating FGF21 in humans is potently induced by short term overfeeding of carbohydrates. Mol Metab 2017;6:22-9.
Weltman MD, Farrell GC, Hall P, Ingelman-Sundberg M, Liddle C. Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis. Hepatology 1998;27:128-33.
Sellmann C, Priebs J, Landmann M, Degen C, Engstler AJ, Jin CJ, et al. Diets rich in fructose, fat or fructose and fat alter intestinal barrier function and lead to the development of nonalcoholic fatty liver disease over time. J Nutr Biochem 2015;26:1183-92.
Mann J, Cummings JH, Englyst HN, Key T, Liu S, Riccardi G, et al. FAO/WHO scientific update on carbohydrates in human nutrition: Conclusions. Eur J Clin Nutr 2007;61 Suppl 1:S132-7.
Ahmadi S, Mainali R, Nagpal R, Sheikh-Zeinoddin M, Soleimanian-Zad S, Wang S, et al. Dietary polysaccharides in the amelioration of gut microbiome dysbiosis and metabolic diseases. Obes Control Ther 2017;4:10.15226/2374-8354/4/2/00140.
Canfora EE, Jocken JW, Blaak EE. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat Rev Endocrinol 2015;11:577-91.
Li M, van Esch BC, Henricks PA, Folkerts G, Garssen J. The anti-inflammatory effects of short chain fatty acids on lipopolysaccharide- or tumor necrosis factor α-stimulated endothelial cells via activation of gpr41/43 and inhibition of HDACS. Front Pharmacol 2018;9:533.
Tan J, Mckenzie C, Potamitis M, Thorburn AN, Mackay CR, Macia L. The role of short-chain fatty acids in health and disease. Adv Immunol 2014;121:91-119.
Sawicki CM, Livingston KA, Obin M, Roberts SB, Chung M, Mckeown NM. Dietary fiber and the human gut microbiota: Application of evidence mapping methodology. Nutrients 2017;9:125.
Holscher HD. Dietary fiber and prebiotics and the gastrointestinal microbiota. Gut Microbes 2017;8:172-84.
Mello VD, Laaksonen DE. Dietary fibers: Current trends and health benefits in the metabolic syndrome and type 2 diabetes. Arq Bras Endocrinol Metabol 2009;53:509-18.
Juárez-Hernández E, Chávez-Tapia NC, Uribe M, Barbero-Becerra VJ. Role of bioactive fatty acids in nonalcoholic fatty liver disease. Nutr J 2016;15:72.
Errazuriz I, Dube S, Slama M, Visentin R, Nayar S, O'connor H, et al. Randomized controlled trial of a mufa or fiber-rich diet on hepatic fat in prediabetes. J Clin Endocrinol Metab 2017;102:1765-74.
Masterton GS, Plevris JN, Hayes PC. Review article: Omega-3 fatty acids – a promising novel therapy for non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2010;31:679-92.
Pfaffenbach KT, Gentile CL, Nivala AM, Wang D, Wei Y, Pagliassotti MJ. Linking endoplasmic reticulum stress to cell death in hepatocytes: Roles of c/ebp homologous protein and chemical chaperones in palmitate-mediated cell death. Am J Physiol Endocrinol Metab 2010;298:E1027-35.
Wang D, Wei Y, Pagliassotti MJ. Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis. Endocrinology 2006;147:943-51.
Rosqvist F, Kullberg J, Ståhlman M, Cedernaes J, Heurling K, Johansson HE, et al. Overeating saturated fat promotes fatty liver and ceramides compared with polyunsaturated fat: A randomized trial. J Clin Endocrinol Metab 2019;104:6207-19.
Seki E, Brenner DA, Karin M. A liver full of JNK: Signaling in regulation of cell function and disease pathogenesis, and clinical approaches. Gastroenterology 2012;143:307-20.
Da Silva HE, Arendt BM, Noureldin SA, Therapondos G, Guindi M, Allard JP. A cross-sectional study assessing dietary intake and physical activity in Canadian patients with nonalcoholic fatty liver disease vs. healthy controls. J Acad Nutr Diet 2014;114:1181-94.
Rosqvist F, Iggman D, Kullberg J, Cedernaes J, Johansson HE, Larsson A, et al. Overfeeding polyunsaturated and saturated fat cause distinct effects on liver and visceral fat accumulation in humans. Diabetes 2014;63:2356-68.
Cortez-Pinto H, Jesus L, Barros H, Lopes C, Moura MC, Camilo ME. How different is the dietary pattern in non-alcoholic steatohepatitis patients? Clin Nutr 2006;25:816-23.
Kawaguchi T, Itou M, Taniguchi E, Sata M. Exendin-4, a glucagon-like peptide-1 receptor agonist, modulates hepatic fatty acid composition and δ-5-desaturase index in a murine model of non-alcoholic steatohepatitis. Int J Mol Med 2014;34:782-7.
Storlien LH, Baur LA, Kriketos AD, Pan DA, Cooney GJ, Jenkins AB, et al. Dietary fats and insulin action. Diabetologia 1996;39:621-31.
Lichtenstein AH, Schwab US. Relationship of dietary fat to glucose metabolism. Atherosclerosis 2000;150:227-43.
Hu FB, Van Dam RM, Liu S. Diet and risk of type ii diabetes: The role of types of fat and carbohydrate. Diabetologia 2001;44:805-17.
Nagy K, Levy J, Grunberger G. High-fat feeding induces tissue-specific alteration in proportion of activated insulin receptors in rats. Acta Endocrinol Copenhagen 1990;122:361-8.
Grundleger ML, Thenen SW. Decreased insulin binding, glucose transport, and glucose metabolism in soleus muscle of rats fed a high fat diet. Diabetes 1982;31:232-7.
Hedeskov CJ, Capito K, Islin H, Hansen SE, Thams P. Longterm fat-feeding-induced insulin resistance in normal NMRI mice: Postreceptor changes of liver, muscle and adipose tissue metabolism resembling those of type 2 diabetes. Acta Diabetol 1992;29:14-9.
Storlien LH, Jenkins AB, Chisholm DJ, Pascoe WS, Khouri S, Kraegen EW. Influence of dietary fat composition on development of insulin resistance in rats. Relationship to muscle triglyceride and omega-3 fatty acids in muscle phospholipid. Diabetes 1991;40:280-9.
Pan DA, Lillioja S, Kriketos AD, Milner MR, Baur LA, Bogardus C, et al. Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes 1997;46:983-8.
Storlien LH, James DE, Burleigh KM, Chisholm DJ, Kraegen EW. Fat feeding causes widespread in vivo
insulin resistance, decreased energy expenditure, and obesity in rats. Am J Physiol 1986;251:E576-83.
Storlien LH, Kraegen EW, Chisholm DJ, Ford GL, Bruce DG, Pascoe WS. Fish oil prevents insulin resistance induced by high-fat feeding in rats. Science 1987;237:885-8.
Marshall JA, Bessesen DH, Hamman RF. High saturated fat and low starch and fibre are associated with hyperinsulinemia in a non-diabetic population: The San Luis Valley Diabetes Study. Diabetologia 1997;409:430-8.
Parker DR, Weiss ST, Troisi R, Cassano PA, Vokonas PS, Landsberg L. Relationship of dietary saturated fatty acids and body habitus to serum insulin concentrations: The normative aging study. Am J Clin Nutr 1993;58:129-36.
Colditz GA, Manson JE, Stampfer MJ, Rosner B, Willett WC, Speizer FE. Diet and risk of clinical diabetes in women. Am J Clin Nutr 1992;55:1018-23.
Salmerón J, Hu FB, Manson JE, Stampfer MJ, Colditz GA, Rimm EB, et al. Dietary fat intake and risk of type 2 diabetes in women. Am J Clin Nutr 2001;73:1019-26.
Meyer KA, Kushi LH, Jacobs DR Jr., Folsom AR. Dietary fat and incidence of type 2 diabetes in older Iowa women. Diabetes Care 2001;24:1528-35.
Borkman M, Storlien LH, Pan DA, Jenkins AB, Chisholm DJ, Campbell LV. The relation between insulin sensitivity and the fatty-acid composition of skeletal-muscle phospholipids. N Engl J Med 1993;328:238-44.
Pan DA, Lillioja S, Milner MR, Kriketos AD, Baur LA, Bogardus C, et al. Skeletal muscle membrane lipid composition is related to adiposity and insulin action. J Clin Invest 1995;96:2802-8.
Feskens EJ, Virtanen SM, Räsänen L, Tuomilehto J, Stengård J, Pekkanen J, et al. Dietary factors determining diabetes and impaired glucose tolerance. A 20-year follow-up of the Finnish and Dutch cohorts of the seven countries study. Diabetes Care 1995;18:1104-12.
Maron DJ, Fair JM, Haskell WL. Saturated fat intake and insulin resistance in men with coronary artery disease. The stanford coronary risk intervention project investigators and staff. Circulation 1991;84:2020-7.
Bortolotti M, Kreis R, Debard C, Cariou B, Faeh D, Chetiveaux M, et al. High protein intake reduces intrahepatocellular lipid deposition in humans. Am J Clin Nutr 2009;90:1002-10.
Markova M, Pivovarova O, Hornemann S, Sucher S, Frahnow T, Wegner K, et al. Isocaloric diets high in animal or plant protein reduce liver fat and inflammation in individuals with type 2 diabetes. Gastroenterology 2017;152:571-85.e8.
Drummen M, Dorenbos E, Vreugdenhil AC, Raben A, Fogelholm M, Westerterp-Plantenga MS, et al. Long-term effects of increased protein intake after weight loss on intrahepatic lipid content and implications for insulin sensitivity: A preview study. Am J Physiol Endocrinol Metab 2018;315:E885-91.
Skytte MJ, Samkani A, Petersen AD, Thomsen MN, Astrup A, Chabanova E, et al. A carbohydrate-reduced high-protein diet improves HbA1c and liver fat content in weight stable participants with type 2 diabetes: A randomised controlled trial. Diabetologia 2019;62:2066-78.
Jang C, Oh SF, Wada S, Rowe GC, Liu L, Chan MC, et al. A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Nat Med 2016;22:421-6.
Harris LL, Smith GI, Patterson BW, Ramaswamy RS, Okunade AL, Kelly SC, et al. Alterations in 3-hydroxyisobutyrate and FGF21 metabolism are associated with protein ingestion-induced insulin resistance. Diabetes 2017;66:1871-8.
Grandison RC, Piper MD, Partridge L. Amino-acid imbalance explains extension of lifespan by dietary restriction in drosophila. Nature 2009;462:1061-4.
Piper MD, Partridge L, Raubenheimer D, Simpson SJ. Dietary restriction and aging: A unifying perspective. Cell Metab 2011;14:154-60.
Levine ME, Suarez JA, Brandhorst S, Balasubramanian P, Cheng C, Madia F, et al. Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population. Cell Metab 2014;19:407-17.
Solon-Biet SM, Mitchell SJ, Coogan SC, Cogger VC, Gokarn R, Mcmahon AC, et al. Dietary protein to carbohydrate ratio and caloric restriction: Comparing metabolic outcomes in mice. Cell Rep 2015;11:1529-34.
Fontana L, Cummings NE, Arriola Apelo SI, Neuman JC, Kasza I, Schmidt BA, et al. decreased consumption of branched-chain amino acids improves metabolic health. Cell Rep 2016;16:520-30.
Piper MD, Soultoukis GA, Blanc E, Mesaros A, Herbert SL, Juricic P, et al. Matching dietary amino acid balance to the in silico
-translated exome optimizes growth and reproduction without cost to lifespan. Cell Metab 2017;25:610-21.
Kargulewicz A, Stankowiak-Kulpa H, Grzymisławski M. dietary recommendations for patients with nonalcoholic fatty liver disease. Prz Gastroenterol 2014;9:18-23.
Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 2012;142:1592-609.
Dai Y, Zhu J, Meng D, Yu C, Li Y. Association of homocysteine level with biopsy-proven non-alcoholic fatty liver disease: A meta-analysis. J Clin Biochem Nutr 2016;58:76-83.
Ji Y, Tan S, Xu Y, Chandra A, Shi C, Song B, et al. Vitamin B supplementation, homocysteine levels, and the risk of cerebrovascular disease: A meta-analysis. Neurology 2013;81:1298-307.
Yang J, Hu X, Zhang Q, Cao H, Wang J, Liu B. Homocysteine level and risk of fracture: A meta-analysis and systematic review. Bone 2012;51:376-82.
Adeva MM, Souto G. Diet-induced metabolic acidosis. Clin Nutr 2011;30:416-21.
Altorf-van der Kuil W, Brink EJ, Boetje M, Siebelink E, Bijlsma S, Engberink MF, et al. Identification of biomarkers for intake of protein from meat, dairy products and grains: A controlled dietary intervention study. Br J Nutr 2013;110:810-22.
Remer T. Influence of nutrition on acid-base balance–metabolic aspects. Eur J Nutr 2001;40:214-20.
Bianchi GP, Marchesini G, Fabbri A, Rondelli A, Bugianesi E, Zoli M, et al. Vegetable versus animal protein diet in cirrhotic patients with chronic encephalopathy. A randomized cross-over comparison. J Intern Med 1993;233:385-92.
Kani AH, Alavian SM, Esmaillzadeh A, Adibi P, Azadbakht L. Effects of a novel therapeutic diet on liver enzymes and coagulating factors in patients with non-alcoholic fatty liver disease: A parallel randomized trial. Nutrition 2014;30:814-21.
Kontessis P, Jones S, Dodds R, Trevisan R, Nosadini R, Fioretto P, et al. Renal, metabolic and hormonal responses to ingestion of animal and vegetable proteins. Kidney Int 1990;38:136-44.
Bosch JP, Saccaggi A, Lauer A, Ronco C, Belledonne M, Glabman S. Renal functional reserve in humans. Effect of protein intake on glomerular filtration rate. Am J Med 1983;75:943-50.
Uribe M, Márquez MA, Ramos GG, Ramos-Uribe MH, Vargas F, et al. Treatment of chronic portal – Systemic encephalopathy with vegetable and animal protein diets. Dig Dis Sci 1982;27:1109-16.
Kawaguchi T, Nagao Y, Matsuoka H, Ide T, Sata M. Branched-chain amino acid-enriched supplementation improves insulin resistance in patients with chronic liver disease. Int J Mol Med 2008;22:105-12.
Kikuchi Y, Hiroshima Y, Matsuo K, Kawaguchi D, Murakami T, Yabushita Y, et al. A randomized clinical trial of preoperative administration of branched-chain amino acids to prevent postoperative ascites in patients with liver resection for hepatocellular carcinoma. Ann Surg Oncol 2016;23:3727-35.
Hayaishi S, Chung H, Kudo M, Ishikawa E, Takita M, Ueda T, et al. Oral branched-chain amino acid granules reduce the incidence of hepatocellular carcinoma and improve event-free survival in patients with liver cirrhosis. Dig Dis 2011;29:326-32.
Cao JJ. High dietary protein intake and protein-related acid load on bone health. Curr Osteoporos Rep 2017;15:571-6.
White PJ, Lapworth AL, An J, Wang L, McGarrah RW, Stevens RD, et al. Branched-chain amino acid restriction in Zucker-fatty rats improves muscle insulin sensitivity by enhancing effciency of fattyacid oxidation and acyl-glycine export. Mol Metab 2016;5:538-51.
Um SH, D'alessio D, Thomas G. Nutrient overload, insulin resistance, and ribosomal protein s6 kinase 1, S6K1. Cell Metab 2006;3:393-402.
Wang X, Li W, Zhang Y, Yang Y, Qin G. Association between Vitamin D and non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: Results from a meta-analysis. Int J Clin Exp Med 2015;8:17221-34.
Eliades M, Spyrou E, Agrawal N, Lazo M, Brancati FL, Potter JJ, et al. Meta-analysis: Vitamin D and non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2013;38:246-54.
Foroughi M, Maghsoudi Z, Askari G. The effect of Vitamin D supplementation on blood sugar and different indices of insulin resistance in patients with non-alcoholic fatty liver disease (NAFLD). Iran J Nurs Midwifery Res 2016;21:100-4.
Barchetta I, Del Ben M, Angelico F, Di Martino M, Fraioli A, La Torre G, et al. No effects of oral Vitamin D supplementation on non-alcoholic fatty liver disease in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled trial. BMC Med 2016;14:92.
Abramovitch S, Sharvit E, Weisman Y, Bentov A, Brazowski E, Cohen G, et al. Vitamin D inhibits development of liver fibrosis in an animal model but cannot ameliorate established cirrhosis. Am J Physiol Gastrointest Liver Physiol 2015;308:G112-20.
Anderson PH, Sawyer RK, Moore AJ, May BK, O'loughlin PD, Morris HA. Vitamin D depletion induces rankl-mediated osteoclastogenesis and bone loss in a rodent model. J Bone Miner Res 2008;23:1789-97.
Reid IR, Bolland MJ, Grey A. Effects of Vitamin D supplements on bone mineral density: A systematic review and meta-analysis. Lancet 2014;383:146-55.
Ceglia L. Vitamin D and its role in skeletal muscle. Curr Opin Clin Nutr Metab Care 2009;12:628-33.
Du J, Zhang M, Lu J, Zhang X, Xiong Q, Xu Y, et al. Osteocalcin improves nonalcoholic fatty liver disease in mice through activation of Nrf2 and inhibition of JNK. Endocrine 2016;53:701-9.
Bland R, Markovic D, Hills CE, Hughes SV, Chan SL, Squires PE, et al. Expression of 25-hydroxyvitamin d3-1alpha-hydroxylase in pancreatic islets. J Steroid Biochem Mol Biol 2004;89-90:121-5.
Reusch JE, Begum N, Sussman KE, Draznin B. Regulation of glut-4 phosphorylation by intracellular calcium in adipocytes. Endocrinology 1991;129:3269-73.
Leung PS. The potential protective action of Vitamin D in hepatic insulin resistance and pancreatic islet dysfunction in type 2 diabetes mellitus. Nutrients 2016;8:147.
Wright DC, Hucker KA, Holloszy JO, Han DH. Ca2+ and ampk both mediate stimulation of glucose transport by muscle contractions. Diabetes 2004;53:330-5.
Draznin B. Cytosolic calcium and insulin resistance. Am J Kidney Dis 1993;21:32-8.
Blum M, Dolnikowski G, Seyoum E, Harris SS, Booth SL, Peterson J, et al. Vitamin D (3) in fat tissue. Endocrine 2008;33:90-4.
Karvonen MJ, Kentala E, Mustala O. The effects of training on heart rate; a longitudinal study. Ann Med Exp Biol Fenn 1957;35:307-15.
European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (Easd), European Association for the Study of Obesity (EASO). Easl-easd-easo clinical practice guidelines for the management of non-alcoholic fatty liver disease. Diabetologia 2016;59:1121-40.
Hannah WN Jr., Harrison SA. Lifestyle and dietary interventions in the management of nonalcoholic fatty liver disease. Dig Dis Sci 2016;61:1365-74.
Koutoukidis DA, Astbury NM, Tudor KE, Morris E, Henry JA, Noreik M, et al. Association of weight loss interventions with changes in biomarkers of nonalcoholic fatty liver disease: a systematic review and meta-analysis. JAMA Intern Med 2019;179:1262-71.
Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: Pathophysiology and clinical implications. Gastroenterology 2012;142:711-25.
Gerber L, Otgonsuren M, Mishra A, Escheik C, Birerdinc A, Stepanova M, et al. Non-alcoholic fatty liver disease (NAFLD) is associated with low level of physical activity: A populationbased study. Aliment Pharmacol Ther 2012;36:772-81.
Lassailly G, Caiazzo R, Pattou F, Mathurin P. Perspectives on treatment for nonalcoholic steatohepatitis. Gastroenterology 2016;150:1835-48.
Mummadi RR, Kasturi KS, Chennareddygari S, Sood GK. Effect of bariatric surgery on nonalcoholic fatty liver disease: Systematic review and meta-analysis. Clin Gastroenterol Hepatol 2008;6:1396-402.
Bacchi E, Negri C, Targher G, Faccioli N, Lanza M, Zoppini G, et al. Both resistance training and aerobic training reduce hepatic fat content in type 2 diabetic subjects with nonalcoholic fatty liver disease (the raed2 randomized trial). Hepatology 2013;58:1287-95.
Prabhakar O, Sravani CH. A review on obesity complications and its management. IJPSR 2020;11:1066-74.
Defronzo RA, Inzucchi S, Abdul-Ghani M, Nissen SE. Pioglitazone: The forgotten, cost-effective cardioprotective drug for type 2 diabetes. Diab Vasc Dis Res 2019;16:133-43.
Bril F, Maximos M, Portillo-Sanchez P, Biernacki D, Lomonaco R, Subbarayan S, et al. Relationship of Vitamin D with insulin resistance and disease severity in non-alcoholic steatohepatitis. J Hepatol 2015;62:405-11.
Argo CK, Patrie JT, Lackner C, Henry TD, de Lange EE, Weltman AL, et al. Effects of n-3 fish oil on metabolic and histological parameters in Nash: A double-blind, randomized, placebo-controlled trial. J Hepatol 2015;62:190-7.
Turner-Mcgrievy GM, Barnard ND, Cohen J, Jenkins DJ, Gloede L, Green AA. Changes in nutrient intake and dietary quality among participants with type 2 diabetes following a low-fat vegan diet or a conventional diabetes diet for 22 weeks. J Am Diet Assoc 2008;108:1636-45.
Klein S, Mittendorfer B, Eagon JC, Patterson B, Grant L, Feirt N, et al. Gastric bypass surgery improves metabolic and hepatic abnormalities associated with nonalcoholic fatty liver disease. Gastroenterology 2006;130:1564-72.
Prabhakar O. Cerebroprotective effect of resveratrol through antioxidant and anti-inflammatory effects in diabetic rats. Naunyn Schmiedebergs Arch Pharmacol 2013;386:705-10.
Viana EC, Araujo-Dasilio KL, Miguel GP, Bressan J, Lemos EM, Moyses MR, et al. Gastric bypass and sleeve gastrectomy: The same impact on il-6 and tnf-α. Prospective clinical trial. Obes Surg 2013;23:1252-61.
Lassailly G, Caiazzo R, Buob D, Pigeyre M, Verkindt H, Labreuche J, et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology 2015;149:379-88.
Chavez-Tapia NC, Tellez-Avila FI, Barrientos-Gutierrez T, Mendez-Sanchez N, Lizardi-Cervera J, Uribe M. Bariatric surgery for non-alcoholic steatohepatitis in obese patients. Cochrane Database Syst Rev 2010;2010:CD007340.
Huang HH, Lee WJ, Chen SC, Chen TF, Lee SD, Chen CY. Bile acid and fibroblast growth factor 19 regulation in obese diabetics, and non-alcoholic fatty liver disease after sleeve gastrectomy. J Clin Med 2019;8:815.
Harrison SA, Fecht W, Brunt EM, Neuschwander-Tetri BA. Orlistat for overweight subjects with nonalcoholic steatohepatitis: A randomized, prospective trial. Hepatology 2009;49:80-6.
Wang W, Fann CS, Yang SH, Chen HH, Chen CY. Weight loss and metabolic improvements in obese patients undergoing gastric banding and gastric banded plication: A comparison. Nutrition 2019;57:290-9.
European Association for Cardiovascular Prevention & Rehabilitation; Reiner Z, Catapano AL, Backer GD, Graham I, Taskinen MR, Wiklund O, et al. ESC/EAS guidelines for the management of dyslipidaemias: The task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769-818.
López-Miranda J, Pérez-Jiménez F, Ros E, De Caterina R, Badimón L, Covas MI, et al. Olive oil and health: Summary of the ii international conference on olive oil and health consensus report, Jaén and Córdoba (Spain) 2008. Nutr Metab Cardiovasc Dis 2010;20:284-94.
Zelber-Sagi S, Salomone F, Mlynarsky L. The mediterranean dietary pattern as the diet of choice for non-alcoholic fatty liver disease: Evidence and plausible mechanisms. Liver Int 2017;37:936-49.
Schwingshackl L, Strasser B, Hoffmann G. Effects of monounsaturated fatty acids on glycaemic control in patients with abnormal glucose metabolism: A systematic review and meta-analysis. Ann Nutr Metab 2011;58:290-6.
Rietman A, Sluik D, Feskens EJ, Kok FJ, Mensink M. Associations between dietary factors and markers of NAFLD in a general Dutch adult population. Eur J Clin Nutr 2018;72:117-23.
Wit NJ, Afman LA, Mensink M, Müller M. Clinical Application of Basic Science Phenotyping the effect of diet on non-alcoholic fatty liver disease. J Hepatol 2012;57:1370-3.
Forouhi NG, Luan J, Cooper A, Boucher BJ, Wareham NJ. Baseline serum 25-hydroxy Vitamin D is predictive of future glycemic status and insulin resistance: The medical research council Ely prospective study 1990-2000. Diabetes 2008;57:2619-25.
Cheng Q, Boucher BJ, Leung PS. Modulation of hypovitaminosis d-induced islet dysfunction and insulin resistance through direct suppression of the pancreatic islet renin-angiotensin system in mice. Diabetologia 2013;56:553-62.
[Figure 1], [Figure 2], [Figure 3]