Although patients with DM-NAFLD or T2DM only showed no difference in age, BMI, FPG, and glucose intolerance, they exhibited significantly different degrees of impairment in insulin secretion and insulin resistance as determined by a 75-g standard OGTT. This study showed that patients with DM-NAFLD had higher plasma C-peptide concentrations than those with T2DM only most likely to suppress EGP and also in response to variation in plasma glucose during the OGTT.
Proposed mechanisms of hyperinsulinemia have been reported by several authors, including increased insulin secretion by the pancreas, diminished hepatic insulin extraction, or a combination of the two. In advanced liver disease, insulin clearance is decreased and is considered one of the main causes of hyperinsulinemia in patients with liver cirrhosis [6–8]. Because fat accumulation in the liver may affect insulin clearance , it has long been debated whether impaired insulin clearance in patients with NAFLD is one of the causes of hyperinsulinemia . To investigate true pancreatic insulin secretion, which excludes the effects of insulin extraction by the liver with exogenously administered insulin and insulin sensitizing, we used C-peptide to monitor the average β-cell insulin secretion. C-peptide is secreted by pancreatic β-cells in equal amounts with insulin; however, unlike insulin, C-peptide is not extracted by the liver and has a constant peripheral clearance [11–13]. Thus, plasma C-peptide concentrations may reflect true pancreatic insulin secretion more accurately than the level of plasma insulin itself. Significant β-cell hypersecretion appeared in patients with DM-NAFLD after glucose loading during fasting, early, and late phases based on the total AUC of plasma C-peptide concentrations after the OGTT, compared with non-NAFLD patients who were well matched for baseline glycemic parameters. The β-cell hypersecretion, however, was no longer obvious when the fasting C-peptide was normalized to the FPG. By contrast, following the glucose load, the ratio of incremental C-peptide to incremental plasma glucose levels was still significantly higher in patients with DM-NAFLD than in those with T2DM only. This could be explained by significant additional β-cell insulin secretion in patients with DM-NAFLD following oral glucose administration.
Insulin sensitivity and insulin secretion are reciprocally related. Reduced insulin sensitivity and compensatory hyperinsulinemia play key etiologic roles in the development of NAFLD [14–16]. In our study, hepatic insulin resistance, as calculated by HOMA-IR (derived from FPG and fasting plasma insulin concentrations), was not significantly different between patients with DM-NAFLD and those with T2DM only. The muscle insulin sensitivity index was measured by the rate of decline in plasma glucose concentration divided by the plasma insulin concentration. The decline from the peak plasma glucose concentration during the OGTT primarily reflects glucose uptake by peripheral tissues such as skeletal muscle. This index showed a good correlation with the muscle insulin sensitivity measurement by the euglycemic-hyperinsulinemic clamp in obese patients with normal glucose tolerance (r = 0.78, P < 0.0001) . The patients with DM-NAFLD and those with T2DM only had similar muscle insulin sensitivities at 120–180 min following the glucose load as plasma glucose levels began to decline.
The present study also examined the difference in the relative contributions of both insulin secretion and insulin sensitivity to the suppression of EGP and variations in oral glucose tolerance in patients with DM-NAFLD and those with T2DM only. A predominantly positive association between HOMA-IR and FPG and a negative association between HOMA-B and FPG were observed in both groups. Patients with DM-NAFLD and those with T2DM only manifested similarly severe defects in late-phase insulin in responses to oral glucose intake. In addition, hepatic insulin sensitivity independently contributed to the early phase (0–30 min) of the OGTT in patients with T2DM and NAFLD, whereas a significant deficit in late-phase insulin secretion independently contributed to glucose disposal into peripheral tissues at 30–120 min during the OGTT in the T2DM-only group. This could be explained by the different postreceptor defects leading to insulin resistance and the different patterns of impaired insulin secretion between patients with DM-NAFLD and those with T2DM only.
Our data suggest that relative hyperinsulinemia is characteristic of patients with DM-NAFLD compared with those with T2DM only. Hyperinsulinemia in patients with DM-NAFLD is caused primarily by β-cell hypersecretion in response to a similar degree of insulin resistance and the equivalent level of hyperglycemia in patients with T2DM only during the OGTT. This distinct difference in the underlying pathophysiology of patients with DM-NAFLD and those with T2DM only may have consequences for clinical outcomes. Clearly, there are limitations that hinder adjusting the insulin dose by measuring the plasma glucose value alone. Exogenously administered insulin does not mimic endogenous insulin secretion . Thus, therapeutically increasing insulin doses may result in increased peripheral hyperinsulinemia in patients with DM-NAFLD, further increasing the risk of hypoglycemia. Additionally, studies have shown that insulin directly promotes fat accumulation in liver cells, further contributing to nonalcoholic steatohepatitis, which is an increasingly frequent cause of cirrhosis, hepatocellular carcinoma, and liver failure [19, 20]. Increasing exogenously administered insulin doses results in further peripheral hyperinsulinemia, which may worsen NAFLD.