sign in sign up
<<
Home , Blood sugar level

ISSN: 2277- 7695 CODEN Code: PIHNBQ ZDB-Number: 2663038-2 Received: 21-12-2012 IC Journal No: 7725 Accepted: 26-02-2013 Vol. 2 No. 1 2013 Online Available at www.thepharmajournal.com THE PHARMA INNOVATION - JOURNAL

The Problem of Fatty Disease (FLD ) in Diabetics

Dr Seema Mishra 1*

1. Professor, Department of Clinical Nutrition, Govt Bilasa Girls’s College, Bilaspur Chhattisgarh, India [E-mail: [email protected]]

The diabetics are 50% more likely to develop . Particularly fatty liver disease. Fatty liver disease is incredibly common in overweight people (type II diabetics); nearly everyone with excess weight on their abdomen has some degree of fatty liver. Diabetics, specially Type II are prone to carrying excess weight on their abdomen, but even slim diabetics often have a fatty liver. The liver relevant all biochemical parameters were measured in diabetics and compared with the estimated parameters of non diabetics, a significant differences were noticed among both groups in relation with the enzymatic profile and hepato-proteins etc. It was concluded by this work that diabetics are extremely prone to develop fatty liver disease. Keyword: Steatohepatitis, Syndrome X, Hepatic , , Albumin

Introduction higher, loses its ability to control It is well known that increases the risk of levels. Therefore the kidney disease, nerve damage, blood vessel creeps upwards, eventually getting high enough damage, infections, blindness and heart disease, to qualify as diabetes. The vast majority of but even today it is not realized that diabetes have diabetics have a fatty liver. One do not need to be terrible adverse effects on the liver. Insulin overweight to have a fatty liver; the condition is resistance (syndrome X) is the driving force very common in slim people even. behind the development of fatty liver. usually develops in childhood, although The Hepato-damaging Effect of Diabetes: The by the time they are in their mid 30s, most type 1 liver plays a central and crucial role in the diabetics have developed as regulation of . Its well in India. People with insulin resistance have normal functioning is essential for the high levels of insulin in their bloodstream. Insulin maintenance of blood levels and of a signals to ones liver to manufacture fat, especially continued supply to organs that require a glucose and . This promotes the energy source. This central role for the liver in accumulation of fat inside the liver, inside other glucose offers a clue to the organs, inside and as general body fat pathogenesis of glucose intolerance in liver stores. As insulin levels become higher and

`Vol. 2 No. 1 2013 www.thepharmajournal.com Page | 89 The Pharma Innovation - Journal

diseases but little insight into the mechanisms of by first-pass extraction in the liver. Insulin liver disease in diabetes mellitus. promotes synthesis ()  The liver uses glucose as a fuel and also has in the liver and inhibits its breakdown the ability to store it as glycogen and (glycogenolysis). It promotes protein, synthesize it from non carbohydrate cholesterol, and synthesis and precursors (). stimulates formation of very-low-density  Glucose absorbed from the intestinal tract is cholesterol. It also inhibits hepatic transported via the portal vein to the liver. gluconeogenesis, stimulates glycolysis, and Although the absolute fate of this glucose is inhibits ketogenesis. The liver is the primary still controversial, some authors suggest that target organ for action, where it most of the absorbed glucose is retained by promotes glycogenolysis, gluconeogenesis, the liver so that the rise in peripheral glucose and ketogenesis. concentration reflects only a minor  Glucose that is taken up by a cell may be component of postprandial absorbed glucose. oxidized to form energy (glycolysis). It is Therefore, it is possible that the liver plays a oxidized to pyruvate in the cytosol, and more significant role than does peripheral electrons generated from this process are tissue in the regulation of systemic blood transferred to the mitochondria. Pyruvate glucose levels following a meal. generated by this Emden-Meyerhof pathway  Many cells in the body, including fat, liver, is oxidized to acetyl CoA in the mitochondria, and muscle cells, have specific cell membrane which in turn undergoes further oxidation by insulin receptors, and insulin facilitates the the Krebs tricarboxylic acid cycle. Nearly 36 uptake and utilization of glucose by these moles of high energy phosphate are generated cells. Glucose rapidly equilibrates between from each molecule of glucose by aerobic the liver cytosol and the . glycolysis. Transport into certain cells, such as resting  If oxygen not be available, pyruvate is muscle, is tightly regulated by insulin, converted to lactate by the action of lactate whereas uptake into the nervous system is not dehydrogenase. Lactate is a potential fuel, or insulin-dependent. it may be converted back to glucose. The  Glucose can be used as a fuel or stored in a formation of glucose from lactate and various macromolecular form as polymers: in non carbohydrate precursors is known as plants and glycogen in animals. Glycogen gluconeogenesis and occurs mainly in the storage is promoted by insulin, but the liver and kidneys. capacity within tissues is physically limited  The liver, kidney, intestine, and platelets because it is a bulky molecule. contain the glucose-6-phosphatase,  Insulin is formed from a precursor molecule, which produces glucose from glucose-6- pre-insulin, which is then cleaved to pro- phosphate and is the final step in the insulin. Further maturation results in the production of glucose via gluconeogenesis. conversion of proinsulin into insulin and a This enzyme is absent in other tissues. smaller peptide called C-peptide. Glucose that is metabolized peripherally may  A small amount of pro-insulin enters the therefore be converted back to glucose or to circulation. It has a half-life 3–4 times longer hepatic glycogen via gluconeogenesis with than that of insulin because it is not lactate as the primary substrate. This is known metabolized by the liver. However, pro- as the Cori cycle. insulin has <10% of the biological activity of  In type 2 diabetes, excessive hepatic glucose insulin. output contributes to the  Insulin is metabolized by insulinase in the . Increased gluconeogenesis is liver, kidney, and placenta. About 50% of the predominant mechanism responsible for insulin secreted by the is removed this increased glucose output, while

Vol. 2 No. 1 2013 www.thepharmajournal.com Page | 90

The Pharma Innovation - Journal

glycogenolysis has not been shown to be have reported the combination also in obese increased in patients with type 2 patients. diabetes. Hyperglucagonemia has been shown  Patients showing solely excessive glycogen to augment increased rates of hepatic glucose deposition may exhibit hepatomegaly and output, probably through enhanced liver enzyme abnormalities and may have gluconeogenesis. abdominal pain and even nausea and vomiting and rarely ascites. All these abnormalities Liver Disease Occurring as a Consequence of may improve with sustained glucose control. Diabetes Mellitus  Fatty Liver, Steatohepatitis-Hepatic fat Glycogen-Deposition -Excess glycogen accumulation is a well-recognized accumulation in the liver is seen in 80% of of diabetes with a reported diabetic patients. Glycogen synthesis in the liver frequency of 40–70%. Unfortunately, is impaired in diabetes due to defective activation associated is a frequently occurring of glycogen synthase. However, studies attesting confounding variable. Type 1 diabetes is not to this were usually performed on animals with associated with fat accumulation if glycemia recently induced diabetes. In patients with is well controlled, but may chronic diabetes, glycogen accumulation is seen, have a 70% correlation regardless of blood and it is postulated that long-standing insulin glucose control. deficiency may actually facilitate synthase  Fat is stored in the form of triglyceride and activity. This and enhanced gluconeogenesis may may be a manifestation of increased fat account for the net accumulation of glycogen in transport to the liver, enhanced hepatic fat diabetes. synthesis, and decreased oxidation or removal  The mechanism of cytoplasmic glycogen of fat from the liver. The steatosis may be deposition is uncertain but is perhaps related micro-vesicular or macro-vesicular and may to the large variations in glucose progress to fibrosis and cirrhosis. The degree concentration and frequent insulin dosing. No of glycaemic control does not correlate with correlation between hepatic glycogen content the presence or absence of fat. The most and fasting blood glucose levels has been common clinical presentation is demonstrated. There is also no demonstrable hepatomegaly, and most patients have normal association between the type of diabetes or or only mildly abnormal and the fat content of the hepatocytes and the normal . presence of glycogen.  The mechanism for nuclear glycogen Complications of Diabetes Therapy: Insulin deposition is also unclear, with the stored therapy may increase patientsí risk of acquiring glycogen resembling muscle glycogen more viral hepatitis because of the exposure to needles. than hepatocyte cytoplasmic glycogen. It is Adhering to good infection-control practices postulated that glycogen is actually should significantly reduce this risk. synthesized in the nucleus and has been found  The biguanide (Glucophage) does in 60–75% of diabetic patients. Nuclear not undergo hepatic metabolism and, like glycogen deposition is also seen in , chlorpropamide (Diabinese), is excreted tuberculosis, some patients with hepatitis unchanged in the urine. In contrast, the (particularly autoimmune chronic hepatitis), sulfonylurea glyburide (Micronase, Glynase, Wilson's disease, and cirrhosis. Diabeta) is excreted in bile and urine in a  The finding of glycogen nuclei in a patient 50/50 ratio. The sulfonylurea glipizide with fatty liver is useful confirmatory (Glucotrol, Glucotrol XL) is metabolized evidence that the fatty liver is secondary to mainly by the liver, and, in theory, hepatic diabetes even if the is disease may result in increased blood levels. normal. However, some previous experiments

Vol. 2 No. 1 2013 www.thepharmajournal.com Page | 91

The Pharma Innovation - Journal

 There is a rare association between the use of Hepatic Steatosis in Diabetics and non diabetics. I oral hypoglycemics and hepatic injury, but have selected Diabetic patients who have been sulfonylureas can cause chronic hepatitis with diagnosed as diabetic at least 2-3 years age, by necroinflammatory changes. Granulomatous contacting personally and also by contacting in changes can also be seen. They are described various diabetic clinics in Bilaspur. The controls as having a well-circumscribed cellular were selected randomly from the societies, who infiltrate comprised of acidophilic histiocytes were demographically matched with the subjects. and eosinophils surrounding necrotic Study Area- Bilaspur city and outskirt area hepatocytes. The mechanism of liver injury is Study duration-November 2015-June 2016 not known. Sample Size-30 Subjects, 30 controls. I have not  Chlorpropamide appears to be the most included the persons who are having High Blood hepatotoxic of these drugs, with cholestatic Pressure or of non-diabetic hepatitis occurring in 0.5% of people on the origin, women having PCOs were also dropped drug. Jaundice develops over 2–5 weeks and from the study. The patients having Hepatitis resolves in virtually all patients when the drug were also not included in the study. is stopped. Hepatic disease is very rare with Objectives-The following objects were set to tolbutamide (Orinase and generics), and conduct this research- (Tolinase and generics). Although  The demographic data of all the subjects and very uncommon, acetohexamide and controls were collected. glyburide can cause acute hepatocellular  The blood sugar of all the related persons necrosis, and fatalities have been reported. At were analyzed by using NYCOCARD. least two cases of granulomatous hepatitis  The Blood tests were done to assess the thought secondary to glyburide have been level of the following enzymes- reported in the literature.  Aspartate aminotransferase (AST or SGOT)  The biguanides, such as metformin  Alanine aminotransferase (ALT or SGPT) hydrochloride, have not been associated with  , 5' nucleotidase, liver injury. Lactic acidosis can be associated  Gamma-glutamyl transpeptidase (GGT) with the use of metformin to treat diabetes,  LDH () but it is reported to occur occasionally and usually in patients with major Biochemical Auto-analyzer Star 21 was used for contraindications to the drug. "Chronic liver the serum level analysis of these enzymes. The disease" is one of the conditions that may estimation kits of Span Diagnostics were used for predispose patients taking metformin to the quantative analysis. developing lactic acidosis, probably due to a  Estimation of Coagulation panel (prothrombin reduced ability of the liver to clear lactate. It time or PT), it was done by using Ink Spot is therefore listed as a contraindication. method.  Troglitazone (Rezulin) is an oral  Estimation of Albumin level by using antihyperglycemic agent that acts primarily Autoanalyser –Star 21 model. by decreasing insulin resistance. Its package  Estimation of serum Bilirubin level was done insert carries a warning that severe by using Autoanalyser –Star 21 model. idiosyncratic hepatocellular injury, usually  Platelet count was done, by using Total reversible but possibly leading to death or Hematology chamber, DT 5000 of Mindrey liver transplantation, has been reported in company. patients using the medication, usually during

the early months of therapy. Imaging procedures: Imaging procedures used to diagnose fatty liver disease include ultrasound, Hypothesis: Based on these finding I designed a computerized tomography (CT) scan and research to assess the presence and severity of

Vol. 2 No. 1 2013 www.thepharmajournal.com Page | 92

The Pharma Innovation - Journal

magnetic resonance imaging (MRI).Out of 30 liver (liver biopsy). The tissue sample is patients only 5 were followed CT Procedure, one examined in a laboratory to look for signs of patient followed MRI and 11 were followed and scarring. Only 3 patients scanning procedure on my request. followed this procedure on my request.

Liver tissue testing: If it's suspected that you Observations: As serum analysis and imaging have a more serious form of nonalcoholic fatty procedures were, the following observations were liver disease, your doctor may recommend a found- procedure to remove a sample of tissue from your

Table 1

Significant Sr Parameters Patients Participated Controls Participated Difference 1. Serum Glucose 206mg % 30 96 mg % 30 1.98 Aspartate 15 units 2. aminotransferase 126 Units /L 30 30 1.322 /L (AST or SGOT) Alanine 3. aminotransferase 243 Units/L 30 29 /L 30 8.066 (ALT or SGPT) 0.84 ± 2.09 4. ALT/AST Ratio 1.73 ± 1.31 30 30 0.17 Alkaline 209 U/L 30 56 U/L. 30 1.81 5. phosphatase gamma-glutamyl 6. transpeptidase 81 U/L 30 29 U/L. 30 4.41 (GGT) LDH (Lactate 7. 218 U/L 30 122 U/L 30 1.005 dehydrogenase) Prothrombin 9.8 8. 31 Seconds 30 30 6.93 time seconds. 9. Total Albumin 2.1 g / dL 30 3.9 g/dL 30 4.56 30 0.18 10. serum Bilirubin 3.4 mg/dL 30 1.90 mg/dL Total Platelet 267,000 11. 128,000 /µL 30 30 2.09 Count /µL computed tomography Not 12. CT 5 5 -- showed Fatty Liver shown Grade -3 to 4 Normal 13. Ultra sound 11 9 -- Fatty Liver Liver On in-phase GRE images or T1- or T2-weighted echo- train spin-echo images, Normal 14. MRI 1 2 -- Higher than normal liver MRI suggests fat deposition in liver 15. Biopsy steatohepatitis 3 Not seen 1 --

Vol. 2 No. 1 2013 www.thepharmajournal.com Page | 93

The Pharma Innovation - Journal

serum of patients had higher level of it. Also the Table 2: Correlation among serum Glucose Level and prothrombin time and the platelet count were different factors related to Fatty Liver Disease critically lower in patients, because of lesser

Degree of production of prothrombin protein and platelet Serial Factors correlation factors by liver. 1. Serum Level of SGPT 0.8039  ALT (SGPT) is, by contrast, normally found 2. GGT 0.1057 largely in the liver. This is not to say that it is 3. Serum Albumin Level -0.70951 exclusively located in the liver, but that is 4. Serum Bilirubin 0.9012 where it is most concentrated. It is released 5. Platelet count -0.1033 into the bloodstream as the result of liver 6. Prothrombin time -0.863 injury. Thus, it serves as a fairly specific indicator of liver status. Coagulation panel Discussion (prothrombin time or PT, and international AST (SGOT) and ALT (SGPT) are reasonably normalized ratio or INR): These tests measure sensitive indicators of liver damage or injury blood's ability for normal clotting and from different types of diseases or conditions, and prevention of bleeding and bruising. This is collectively they are termed liver tests. However, the function of certain proteins called clotting it must be emphasized that higher-than-normal factors that normally are produced in the levels of these liver enzymes should not be liver. Normal values are about 9.5 to 13.8 automatically equated with liver disease. The seconds. interpretation of elevated AST and ALT results  Albumin level (): Albumin depends upon the entire clinical evaluation of an is a very common protein found in the blood individual, and so it is best done by physicians with a variety of functions. It also is produced experienced in evaluating liver disease and only in the liver, and if its levels are lower muscle disease. The serum levels of both hepatic than normal it can be suggestive of chronic enzymes were significantly higher in diabetics in liver disease or liver cirrhosis. Of note, many comparison to demographically matched controls, conditions other than liver disease also may thus this showed a strong positive correlation cause low albumin levels. Normal values are between elevated blood sugar level and liver about 3.5 to 5 g/dL. damage. Other related enzymes as GGT, LDH  Bilirubin: This molecule is a byproduct of the and Alkaline Phosphatase showed many fold routine destruction of red blood cells increase in the serum of patients, as due to occurring in the liver. It is normally released uncontrolled diabetes the hepatic cells are as bile in the feces. Elevation of the bilirubin damaged and the stored enzymes are released in can suggest liver dysfunction. However, other extracellular cells and hence the serum level of conditions with increased destruction of red these enzymes is increased indicating the damage blood cells also can cause elevated bilirubin of hepatic cells. A very strong correlation was levels despite normal liver function. Normal observed among serum Glucose level and values are about 0.1 to 1.0 mg/dL. elevated serum levels of these enzymes. The damaged liver produce little or even no Albumin, A strong positive correlation was observed thus a very significantly reduced serum Albumin among increasing level of serum Glucose and level was observed in patients, but in controls the serum level of SGPT, Serum level of Bilirubin level was near normal. A negative correlation was and also serum level of GGT, Thus it can be observed between these two parameters- serum concluded that uncontrolled Diabetes with high glucose level and serum Albumin level. The liver blood Glucose level has hepato-damaging effect. with reduced functioning capacity can not handle There is significant negative correlation between the bilirubin produced in the body, thus the un- Serum Glucose level and total Albumin levels. excreted bilirubin remained in blood, so the also with serum glucose level and total platelet

Vol. 2 No. 1 2013 www.thepharmajournal.com Page | 94

The Pharma Innovation - Journal

count, thus this showed the reduced functioning 8. Page WF, Mahan CM, Kang HK. Vital status capacity of liver due to uncontrolled diabetes, ascertainment through the files of the also a prominent negative correlation was department of Veterans Affairs and the social observed among glucose level and prothrombin security administration. Ann Epidemiol. time, which may precipitate hemophilic picture. 1996; 6:102-109. Thus a single univariate association is found 9. Pessayre D, Berson A, Fromenty B, Mansouri between Chronic Diabetes and occurrence of A. Mitochondria in steatohepatitis. Sem Liver Fatty liver disease. Dis. 2001; 21:57-69. 10. Tazawa J, Maeda M, Nakagawa M, Suggestions: Diabetics, specially type –II Ohbayashi H, Kusano F, Yamane M et al. diabetics should regularly monitored their hepatic Diabetes mellitus may be associated with health as they are prone to develop Fatty Liver hepatocarcinogenesis in patients with chronic Disease and further other hepatic diseases. hepatitis.

References 1. Amarapurkar D, Das H. Chronic liver disease in diabetes mellitus. Trop Gastroenterol. 2002; 23:33. 2. Boyko EJ, Koepsell TD, Gaziano JM, Horner RD, Feussner JR. US Department of Veterans Affairs medical care system as a resource to epidemiologists. Am J Epidemiol. 2000; 151:307-314. 3. Department of Health and Human Services. in: The international classification of diseases, 9th rev., clinical modification: ICD-9-CM.Diseases: tabular list. 3rd ed. Government Printing Office,Washington, DC; (March. (DHHS publication no. (PHS) 89–1260. 1989, 1. 4. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use of the ICD- 9-CM in administrative databases. J Clin Epidemiol. 1992; 45:613-619. 5. Fong D, Nehra V, Lindor K, Buchman AL. Metabolic and nutritional considerations in nonalcoholic fatty liver. Hepatology. 2000; 32:39. 6. Hassan M, Hwang L, Hatten C, Swaim M, Li D, Abbruzzese J et al. Risk factors for hepatocellular carcinoma(synergism of with viral hepatitis and diabetes mellitus). Hepatology. 2002; 36:1206-2013. 7. Lagiou P, Kuper H, Stuver S, Tzonou A, Trichopoulos D, Adami HO. Role of diabetes mellitus in the etiology of hepatocellular carcinoma. J Natl Cancer Inst. 2000; 92:1096- 1099.

Vol. 2 No. 1 2013 www.thepharmajournal.com Page | 95