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Metabolism during Fasting in Humans -studies on regional intermediary metabolism

Jakob Gjedsted

Summary

This thesis is based on one accepted article I(60), one submitted manuscript II (59) and a review of the literature on metabolism during fasting in humans and methods applied. The review will include a presentation of study I and II in context with the literature. The aims of the studies performed were to describe the regional contributions to intermediary metabolism during short term fasting applying methods such as arterio-venous (A-V) balance technique, microdialysis, calorimetry, hyperinsulinemic euglycemic clamp with concomitant amino acid infusion and labelled glucose, lipid and amino acid dilution techniques. Most of the methods used were well established in the laboratory but the A-V balance technique involving percutaneous cannulation of the femoral vessels is new.

Results:
72 hours of fasting in normal weight, healthy male volunteer’s results in a classical shift in the balance between insulin levels and the levels of counter regulatory hormones (e.g. cortisol, glucagon, GH and catecholamines).Glucose metabolism was fundamentally affected by fasting, primarily by the development of insulin resistance. Since 80 % of insulin stimulated glucose uptake is cleared by skeletal muscle, it was not surprising that A-V balance of glucose revealed a significant drop in glucose clearance both in the forearm and in the leg. Both the respiratory quotient (RQ) and endogenous glucose production (EGP) decreased. Free fatty acid (FFA) turnover, estimated by 3H3-palmitate was doubled. FFA levels and oxidation rates of FFA increased significantly. The A-V balances across forearm and leg demonstrated a two to three fold increase in palmitate release and microdialysis in the vastus lateralis and gastrocnemius muscle displayed a significant increase in glycerol. The protein oxidation rate and urea nitrogen synthesis rate (UNSR) did not differ after fasting whereas phenylalanine degradation decreased. Alanine A-V balances both in forearm and leg increased significantly.

Conclusions:
The regional contributions from upper and lower body (forearm and leg) in delivering FFA, glycerol and gluconeogenic amino acids seem to be equally affected. A significant increase in abdominal subcutaneous adipose tissue was detected by microdialysis but leg subcutaneous adipose tissue only plays a minor role in the early phase of starvation. The activation of intramuscular lipolysis after fasting could be due to either lipolysis of intermyocellular adipocytes or
perhaps hydrolysis of circulating lipoproteins.The protein and amino acid degradation had returned to postabsorptive levels as demonstrated by UNSR, phenylalanine degradation and indirect calorimetry. In conclusion young healthy volunteers successfully adapts to short term fasting in mobilising and oxidizing lipids from abdominal subcutaneous adipose tissue. These protein retaining effects of lipid mobilisation is vital in surviving long term starvation.