Non-alcoholic fatty liver disease is increasingly being identified in routine clinical practice [
Screening patients with non-alcoholic fatty liver disease for impaired glucose regulation or type 2 diabetes mellitus could help the earlier diagnosis and treatment of these conditions preventing their possible complications, such as cardiovascular diseases. The measurement of fasting plasma glucose is considered as the preferred initial screening test for the identification of hyperglycemia [
We prospectively studied a cohort of patients who presented with elevated levels of serum aminotransferases at the outpatient hepatology clinic of Attikon University Hospital, in Athens, Greece, between June 2006 and September 2009, and was diagnosed with non-alcoholic fatty liver disease. The diagnosis of non-alcoholic fatty liver disease was based on the presence of hypertransaminasemia along with characteristic findings of fatty infiltration in liver ultrasonography (“bright liver” or hyperechoic appearance) and the exclusion of other possible causes of hypertransaminasemia, including alcoholic liver disease, adverse events of drugs, viral hepatitis, autoimmune disorders, and hereditary diseases affecting the liver.
The patients that were diagnosed with non-alcoholic fatty liver disease underwent an oral glucose tolerance test, unless they had a known prior history of diabetes or a fasting serum glucose ≥126 mg/dL. Specifically, 75 g of glucose were administered orally after an overnight fast. Serum glucose and insulin were measured in blood samples obtained through an indwelling peripheral vein cannula at time 0 and 30, 60, 90, and 120 min after the glucose challenge. Patients were classified as having normoglycemia (normal glucose values), impaired fasting glucose (IFG), IGT, or type 2 diabetes, according to the criteria endorsed by the American Diabetes Association [
We grouped the non-alcoholic fatty liver disease patients into normoglycemic and hyperglycemic (IFG, IGT, or type 2 diabetes). We assessed for the presence of differences between the above 2 groups in the patient demographics, body mass index (BMI), and common laboratory tests. We also assessed for differences between the 2 groups in the levels of glucose and insulin obtained at the 5 time points specified above during the 75 g oral glucose tolerance test and the overall insulin response during the test. The overall insulin response was determined on the basis of the area under the curve (AUC) of insulin levels versus time, extracting the area corresponding to the baseline insulin level (net incremental insulin AUC). We used the trapezoid method to calculate the AUC. Finally, we calculated the updated homeostasis model assessment of insulin resistance (HOMA2-IR) index and assessed for differences between the 2 groups [
A total of 152 Caucasian patients (52.0% females and 48% males) with non-alcoholic fatty liver disease, with mean ± standard deviation age of 50.1 ± 11.4 years were included in the study. According to the values of fasting serum glucose or serum glucose 2 hours after the 75 g oral glucose challenge, 78 of the 152 patients (51.3%) were normoglycemic, while 45 patients (29.6%) had IFG or IGT (21 and 41 patients, resp.), and 29 (19.1%) had type 2 diabetes (Figure
Classification of the 152 included patients with non-alcoholic fatty liver disease on the basis of fasting serum glucose and 2-hour post-load serum glucose.
In Table
Baseline characteristics of non-alcoholic fatty liver disease patients with and without hyperglycemia.
Patient characteristics | IFG/IGT, | DM, | Hyperglycemia (IFG/IGT or DM), | Normoglycemia, | |
n/N (%) OR mean ± standard deviation | |||||
Sex, Female | 21/45 (46.7%) | 14/29 (48.3%) | 35/74 (47.3%) | 44/78 (56.4%) | 0.26 |
Age, years | 51.2 ± 10.2 | 55.9 ± 11.0 | 53.0 ± 10.7 | 47.3 ± 11.4 | |
Body mass index, kg/m2 | 30.0 ± 4.2 | 31.1 ± 4.9 | 30.5 ± 4.5 | 28.5 ± 4.8 | |
AST, U/L | 43.7 ± 46.6 | 38.8 ± 23.5 | 41.7 ± 38.8 | 40.2 ± 33.4 | 0.81 |
ALT, U/L | 64.6 ± 45.9 | 59.8 ± 39.1 | 62.7 ± 38.8 | 67.7 ± 55.6 | 0.55 |
AST/ALT ratio | 0.68 ± 0.22 | 0.72 ± 0.30 | 0.70 ± 0.25 | 0.71 ± 0.39 | 0.85 |
GGT, U/L | 86.7 ± 70.8 | 89.6 ± 87.1 | 87.9 ± 77.2 | 86.6 ± 88.7 | 0.92 |
Cholesterol, mg/dL | 209.4 ± 40.7 | 209.2 ± 50.8 | 209.3 ± 44.6 | 211.9 ± 42.3 | 0.74 |
Triglycerides, mg/dL | 135.1 ± 64.5 | 146.4 ± 76.2 | 139.7 ± 69.1 | 123.1 ± 72.3 | 0.18 |
HDL-C, mg/dL | 47.6 ± 14.3 | 45.0 ± 12.7 | 46.5 ± 13.6 | 53.7 ± 18.8 | |
LDL-C, mg/dL | 128.3 ± 32.1 | 131.2 ± 40.3 | 129.6 ± 35.8 | 133.9 ± 34.1 | 0.51 |
Triglycerides/HDL-C ratio | 3.6 ± 3.4 | 3.6 ± 2.2 | 3.6 ± 2.9 | 2.7 ± 2.2 | 0.05 |
Total Protein, g/dL | 7.0 ± 1.5 | 7.0 ± 1.6 | 7.0 ± 1.5 | 7.1 ± 1.7 | 0.83 |
Albumin, g/dL | 4.2 ± 0.4 | 4.0 ± 0.5 | 4.1 ± 0.5 | 4.4 ± 0.4 | |
Albumin/globulin ratio | 3.1 ± 7.9 | 1.8 ± 1.7 | 2.5 ± 6.1 | 2.3 ± 3.1 | 0.83 |
Hemoglobin, g/dL | 14.4 ± 1.5 | 13.6 ± 1.7 | 14.0 ± 1.6 | 14.1 ± 1.4 | 0.93 |
Hematocrit, % | 43.4 ± 4.6 | 41.8 ± 4.2 | 42.7 ± 4.5 | 42.2 ± 3.8 | 0.45 |
ALT: alanine aminotransferase, AST: aspartate aminotransferase, DM: type 2 diabetes mellitus, IFG: impaired fasting glucose, IGT: impaired glucose tolerance, GGT: gamma-glutamyl transpeptidase, HDL-C: high-density lipoprotein cholesterol, IFG: impaired fasting glucose, and IGT: impaired glucose tolerance.
Table
Glucose and insulin regulation in response to a 75 g oral glucose tolerance test in non-alcoholic fatty liver disease patients with and without hyperglycemia.
Patient characteristics | IFG/IGT, | DM, | Hyperglycemia (IFG/IGT or DM), | Normoglycemia, | |
Mean ± standard deviation | |||||
Glucose 0 min, mg/dL | 89.9 ± 14.1 | 104.0 ± 21.9 | 95.4 ± 18.7 | 80.9 ± 10.5 | |
Insulin 0 min, | 15.4 ± 8.3 | 19.5 ± 10.2 | 17.0 ± 9.3 | 13.8 ± 7.2 | |
Glucose 30 min, mg/dL | 160.4 ± 27.0 | 179.9 ± 42.1 | 167.7 ± 34.6 | 147.8 ± 32.5 | |
Insulin 30 min, | 79.5 ± 53.4 | 65.3 ± 42.3 | 74.2 ± 49.7 | 94.5 ± 53.9 | |
Glucose 60 min, mg/dL | 204.5 ± 34.9 | 241.7 ± 40.3 | 219.1 ± 41.1 | 152.9 ± 39.0 | |
Insulin 60 min, | 133.1 ± 72.0 | 112.4 ± 70.7 | 125.0 ± 71.7 | 136.7 ± 88.8 | 0.38 |
Glucose 90 min, mg/dL | 196.9 ± 37.4 | 264.1 ± 38.9 | 219.8 ± 49.4 | 126.9 ± 32.9 | |
Insulin 90 min, | 163.6 ± 80.0 | 183.0 ± 95.1 | 170.1 ± 84.6 | 122.9 ± 97.7 | |
Glucose 120 min, mg/dL | 163.2 ± 24.2 | 243.6 ± 38.3 | 194.7 ± 49.8 | 105.4 ± 21.7 | |
Insulin 120 min, | 160.9 ± 96.3 | 168.8 ± 110.1 | 164.0 ± 101.2 | 85.3 ± 61.9 | |
Net incremental insulin AUC, | 11872.9 ± 6608.2 | 10545.7 ± 6688.5 | 11352.8 ± 6626.1 | 10285.4 ± 6690.6 | 0.33 |
HOMA2-IR index | 1.9 ± 1.0 | 2.5 ± 1.3 | 2.2 ± 1.2 | 1.7 ± 0.9 |
AUC: area under the curve, HOMA2-IR: homeostasis model assessment of insulin resistance, DM: type 2 diabetes mellitus, IFG: impaired fasting glucose, IGT: impaired glucose tolerance, and LDL-C: low-density lipoprotein cholesterol.
Almost half (48.7%) of the patients with non-alcoholic fatty liver disease who were evaluated in our study and had IFG, IGT, or type 2 diabetes. This group was of older age had higher BMI, lower levels of HDL-C, and lower serum albumin compared with the group of patients without hyperglycemia. Age, BMI, and HDL-C were independent predictors of the presence of IFG, IGT, or type 2 diabetes in our cohort of patients with non-alcoholic fatty liver disease. The patients with hyperglycemia seemed to be more insulin resistant compared with those without hyperglycemia. The acute phase of insulin response to the 75 g oral glucose load was less pronounced in the hyperglycemic group, as evidenced by insulin at 30 min. This was followed by more pronounced hyperinsulinemia at 90 and 120 min after the glucose challenge.
Our study findings agree with those of other studies that have showed variability in the glucose regulation of patients with non-alcoholic fatty liver disease [
In our study, older age was associated with a greater likelihood for impaired glucose regulation in patients with non-alcoholic fatty liver disease. Type 2 diabetes mellitus is known to be associated with older age, a fact that reflects the long process for clinical onset of diabetes mellitus [
Higher BMI is also a known risk factor for type 2 diabetes mellitus [
Serum levels of HDL-C were also lower in the subgroup of patients with hyperglycemia of the non-alcoholic fatty liver disease patients evaluated in our study. Low HDL-C is a characteristic finding in diabetic dyslipidemia and is also associated with prediabetes, insulin resistance, metabolic syndrome, and non-alcoholic fatty liver disease [
Additionally, in our study, the non-alcoholic fatty liver disease patients with hyperglycemia had lower levels of serum albumin compared with those without hyperglycemia, although this difference was not independent of age, BMI, and HDL-C. Presumably, lower serum albumin in patients with non-alcoholic fatty liver disease could also be related to more advanced liver disease, higher degree of systemic inflammation, or albuminuria due to diabetic nephropathy [
Screening for hyperglycemia could be considered in patients with non-alcoholic fatty liver disease given the strong association of this disorder with IGT, including diabetes mellitus. There are known risk factors for type 2 diabetes to guide the selection of patients to screen [
If our patients had undergone assessment of fasting serum glucose alone, 25 of the 74 (33.8%) patients with diabetic or non-diabetic hyperglycemia and 4 of the 29 (13.8%) patients with, specifically, diabetic hyperglycemia would have been identified. In contrast, 70 of the 74 (94.6%) patients with diabetic or non-diabetic hyperglycemia and all of the 29 patients with, specifically, diabetic hyperglycemia were identified on the basis of the 2-hour serum glucose value obtained after an oral glucose tolerance test (Figure
The oral glucose tolerance test is thought to be rather cumbersome to perform in everyday clinical practice [
According to our findings, the value of an oral glucose tolerance test, if performed in patients with non-alcoholic fatty liver disease with appropriate risk factors, would be first to identify those with diabetic hyperglycemia. This group should be managed as for type 2 diabetes, if the diagnosis is confirmed with a second positive relevant test. An oral glucose tolerance test in selected patients with non-alcoholic fatty liver disease can also identify those with impaired glucose tolerance, which indicates an increased risk for developing type 2 diabetes. Although the risk for developing type 2 diabetes can also be determined by considering patient characteristics that are more readily available [
Some of the patients with impaired glucose tolerance and additional risk factors for type 2 diabetes could also be candidates to receive pharmacologic therapy, particularly with metformin [
In conclusion, in our study of patients with non-alcoholic fatty liver disease, older age, higher BMI, and lower serum levels of HDL-C independently predicted the presence of hyperglycemia (defined as IFG, IGT, or type 2 diabetes) that was primarily identified through an oral glucose tolerance test. Conclusively, we suggest that oral glucose tolerance testing should be considered for patients with non-alcoholic fatty liver disease with one or more of the above-mentioned predictor factors for hyperglycemia to readily diagnose and manage disorders of glucose metabolism.
The authors declare that they have no conflict of interests.