Novel aspects of the role of the liver in carbohydrate metabolism

Abstract

Malfunction of the liver is a central factor in metabolic disease. Glucose production by liver is complex and controlled via indirect mechanisms; insulin regulates adipose tissue lipolysis, and free fatty acids in turn regulate liver glucose output. This latter concept is confirmed by studies in L-Akt-Foxo1 knockout mice. The adipocyte is a likely locus of hepatic insulin resistance. Also, kidneys play a role in regulating glucose production; denervated kidneys abrogate the effect of fat feeding to cause insulin resistance. Glucose itself is an important regulator of liver metabolism ("glucose effectiveness"); after entering liver, glucose is phosphorylated and can be exported as lactate. Using the dynamic glucose/lactate relationship, we have been able to estimate glucose effectiveness in intact animals and human subjects. Families have been identified with a glucokinase regulatory protein defect; modeling demonstrates elevated glucokinase activity. Insulin clearance by liver is highly variable among normal individuals, and is under environmental control: high fat diet reduces clearance by 30%. Liver insulin clearance is significantly lower in African American (AA) adults and children compared to European American participants, accounting for fasting hyperinsulinemia in AA. We hypothesize that reduced hepatic insulin clearance causes peripheral insulin resistance and increased Type 2 diabetes in AA.

Figure 1.

Renal denervation by surgical ablation in the canine model. (A) Validation of denervation; (B) Demonstration that hepatic resistance induced by fat feeding is reversed by renal denervation (bottom), but not sham procedure (top). Adapted from (15).

Figure 2.

Phases of glucose normalization during the intravenous glucose tolerance test. Glucose was injected at t=0. Somatostatin was infused from −1 to 30 minutes to delay insulin response. Phase 1: glucose mixing; Phase 2: insulin-independent glucose disappearance (i.e. glucose effectiveness); Phase 3: insulin-dependent glucose disappearance; Phase 4: glucose renormalization. Adapted from (18).

Figure 3.

Time course of plasma glucose and lactate during the intravenous glucose tolerance test.

Figure 4.

Two-compartment mathematical model of lactate kinetics. From the time course of plasma glucose and lactate from the intravenous glucose tolerance test, the model output includes parameter K_GK represents glucokinase activity. Adapted from (19).

Figure 5.

Plasma insulin time courses during euglycemic clamps with either intraportal or peripheral insulin infusions. Insulin is infused at 3 sequential rates shown in the table. Note that intraportal infusion rates are twice the rates infused peripherally to account for ~50% first-pass hepatic extraction. As a result, insulin levels in the peripheral circulation were well-matched. Adapted from (22).

Figure 6.

Steady state plasma insulin versus insulin infusion rate from clamps in which insulin is infused at 3 sequential rates either intraportally or peripherally. First pass hepatic insulin extraction is calculated from the ratio of slopes from this dose response (see text). Adapted from (22).

Figure 7.

Mathematical model to estimate hepatic insulin extraction and extra-hepatic insulin clearance. Model input includes time course of insulin secretion, calculated by C-peptide deconvolution, and exogenous insulin administered during the IVGTT. Adapted from (28).

Figure 8.

Distribution of hepatic extraction and extra-hepatic clearance in subjects of European American or African American ethnicity. Gray shaded area represents median values. Horizontal dashed lines depict median value for European American cohort, and bracket demonstrates differences in median values between ethnic groups. Adapted from (29).