Glucose metabolism in Familial Hypobetalipoproteinemia

Subjects with familial hypobetalipoproteinemia (FHBL) are characterized by low plasma total cholesterol, LDL cholesterol and total apolipoprotein B. Moreover, the prevalence of nonalcoholic fatty livers (steatosis) is increased in these subjects. Hepatic steatosis is associated with hepatic and peripheral insulin resistance and has been suggested to play a role in the pathogenesis of diabetes mellitus type 2 and the metabolic syndrome. Due to the hepatic steatosis in subjects with FHBL, hepatic glucose production could be increased. As peripheral insulin sensitivity is correlated to hepatic insulin sensitivity (in part probably by a common mechanism, namely increased availability and intracellular concentrations of longchain fatty acids and their metabolites and in part by a yet largely unknown direct influence from the liver on peripheral glucose uptake), one could expect peripheral insulin resistance as well. However subjects with FHBL have normal glucose and insulin level
s as well as normal oral glucose tolerance tests (OGTT).
Two hypotheses can be formulated to explain these findings:
A] The existence of increased in stead of decreased peripheral insulin sensitivity. This could be explained by a lower concentration of IMCL (probably a surrogate marker for increased fatty acid metabolites intracellularly) in muscle of subjects with FHBL as they have a dysfunctional triglycerides transport system.
B] Increased plasma adiponectin. Adiponectin is produced and secreted by adipose tissue and has an insulin sensitizing effect on glucose metabolism and enhances fatty acid oxidation (which would promote a lower IMCL concentration). In animal experiments, administration of adiponectin stimulated glucose-uptake in muscles and suppressed hepatic glucose output. High levels of adiponectin could counteract the effects of hepatic steatosis on insulin sensitivity in subjects with FHBL.
We, therefore, propose a detailed and controlled study of carbohydrate and lipid metabolism in subjects with FHBL and their matched controls, using stable isotopes, combined with measurements of liver and intramyocellular fat content.

We hypothesize that:

1. Subjects with FHBL have disturbed glucose metabolism, consisting of decreased hepatic insulin sensitivity leading to increased glucose production but increased peripheral insulin sensitivity due to decreased concentrations of IMCL and free fatty acid metabolites.

2. Adiponectin plasma levels are increased due to increased production/ secretion or reduced clearance to compensate for the enhanced glucose production.

Subjects will be studied on 2 occasions:

- after an overnight fast glucose production, disposal and oxidation will be measured using [6,6-2H2]glucose and indirect calorimetry. Lipolysis will be measured using [2H5]glycerol. Muscle metabolites will be measured via muscle biopsy. Subjects will be studied at basal and during a two step hyperinsulinemic euglycemic clamp.

- Hepatic and muscle lipid content will be measured by 1HMRS (magnetic resonance spectroscopy).

Total and regional fat mass will be measured by a DEXA-scan, subcutaneous and visceral fat will be measured by a single slice CT-scan.