Antonius Scheurink

Physiology of stress: a behavioral review

Stress is viewed as a general biological and usually functional response to environmental and bodily demands. This paper summarises recent findings on interactions between environment, individual behavioral and physiological characteristics and the properties of stressors, stress states (responses) and organ systems in determining health or disease.

Excessive portal venous supply of long-chain free fatty acids to the liver, leading to hypothalamus-pituitary-adrenal-axis and sympathetic activation as a key to the development of Syndrome X - A proposed concept for the induction of Syndrome X

Insulin resistance and hypertension are two major symptoms of Syndrome X. A distinct relation between these symptoms and weight maintenance has been observed. Weight gain decreases insulin sensitivity and glucose tolerance and increases blood pressure, while loss of excessive weight normalizes these symptoms.1,2 Epidemiological studies show that upper-body obesity is associated with a higher incidence of the symptoms of Syndrome X than is lower-body obesity.3,4 This is primarily related to the amount of visceral fat rather than to the amount of subcutaneous fat.3,5 The causal relationship between visceral obesity and Syndrome X, however, is still unknown. A clue to this relation may be found in the metabolic characteristics and anatomical location of visceral adipose tissue. Visceral adipose tissue, especially the omental and mesenteric fat pads, which are drained by the portal circulation, has metabolic characteristics that are unique in comparison with other adipose tissues. The fat cells from these regions are metabolically more active,6 they have increased 3-adrenoceptor sensitivity,7 and they have a higher lipolytic activity5 than do other adipocytes. Moreover, the inhibitory action of insulin on fatty acid release from visceral adipocytes is lower than in subcutaneous fat cells.8 It has subsequently been demonstrated that visceral obesity is associated with increased fatty acid release and turnover9 and with an elevated fasting plasma fatty acid concentration.10 Normally, the liver will not be exposed to an exuberant supply of long-chain fatty acids, because long-chain fatty acids absorbed from the gut are mainly transported as triglycerides incorporated in chylomicrons by the lymphatic system, thus bypassing the liver. Primary metabolism of chylomicrons takes place in fat and muscle; the chylomicron remnants are subsequently taken up and metabolized by the liver. The increased lipolytic rate in visceral adipocytes in upper-body obesity and the direct drainage to the portal vein create a situation in which the liver directly will be ex-

Effects of GLP-1 and 2,5-Anhydro-D-Mannitol on Insulin Secretion and Plasma Glucose in Mice

The truncated glucagon-like peptide-1 (GLP-1(7-36)amide or GLP-1) stimulates insulin secretion, enhances glucose elimination and is of potential interest in diabetes treatment. We studied the hypoglycemic action of GLP-1 in normal mice when given alone or together with the fructose analogue, 2,5-anhydro-D-mannitol (2,5-AM), which inhibits glycogenolysis and gluconeogenesis. GLP-1 (32 nmol/kg iv) lowered plasma glucose levels after 25 min to 4.6 +/- 0.2 mmol/l compared with 7.3 +/- 0.4 mmol/l in controls (P < 0.001). Also 2,5-AM (0.5 mumol/kg iv) reduced plasma glucose levels, to 5.6 +/- 0.3 mmol/l (P < 0.01). When given together, the glucose lowering action of GLP-1 and 2,5-AM was additive, since the 25 min glucose level was 2.8 +/- 0.2 mmol/l. At 5 min after injection, GLP-1 had increased plasma insulin levels to 693 +/- 68 pmol/l compared with 342 +/- 42 pmol/l in controls (P < 0.01). 2,5-AM abolished this increase. Furthermore, GLP-1 (32 nmol/kg) did not affect the glycogen content, neither in the liver nor in the gastrocnemic muscle in samples taken at 30 min after injection. Moreover, in isolated islets incubated at 3.3 and 8.3 mmol/l glucose, 2,5-AM at 75 mmol/l inhibited glucose-stimulated insulin secretion (P < 0.05) showing that 2,5-AM inhibits insulin secretion both in vivo and in vitro. We conclude that GLP-1 may reduce plasma glucose levels also to levels below the basal levels under normal conditions, and that an insulin- and liver-independent action of the peptide contributes to its hypoglycemic action in normal animals.

Total energy expenditure assessed by salivary doubly labelled water analysis and its relevance for short-term energy balance in humans.

RATIONALE The doubly labelled water (DLW) method is a stable isotopic technique for measuring total energy expenditure (TEE). Saliva is the easiest sampling fluid for assessing isotopic enrichments, but blood is considered superior because of its rapid exchange with body water. Therefore, we compared a large range of isotopic enrichments in saliva and blood, and related TEE in subjects with their ad libitum total energy intake (TEI). The relevance of these parameters to body weight and fat change over an 8-day interval was also assessed. METHODS Thirty subjects underwent DLW analysis over either 8 or 14 days, during which time initial and final blood and saliva enrichments were compared. TEI was assessed by dieticians over the 8-day period only. Isotope ratio mass spectrometry was used for the measurement of δ(2)H and δ(18)O values. RESULTS No discrepancies were observed between sampling fluids over a wide range of enrichments. During the 8-day period, average TEI exceeded TEE by ~5% or less. Using saliva as sampling fluid, TEI and TEI-TEE, but not TEE, were positively correlated to body weight change. TEI-TEE and physical activity EE (AEE), but not TEI, correlated, respectively, positively and negatively to changes in fat mass. CONCLUSIONS The DLW method in humans can be reliably applied using saliva as sampling fluid. TEI-TEE as well as AEE contributes significantly to changes in fat mass over an 8-day period.

The metabolic effects of olanzapine and topiramate in rats and humans

In humans the anti-psychotic Olanzapine (OLZ) has negative side effects on metabolism: it causes weight gain and increases the risk of developing type 2 Diabetes. The anti-convulsant Topiramate (TPM) has the opposite effects: it reduces body weight and improves insulin sensitivity. Because of this, it has been proposed to use TPM to counteract OLZs side effects. The underlying mechanisms by which OLZ and TPM influence metabolism are unknown. To study this, we performed a series of studies in both rats and humans. In rats we administered OLZ and TPM via a permanent intragastric cannula, to mimic oral drug administration, and found that chronic OLZ treatment stimulates weight gain and causes insulin resistance reflected by increased insulin responses during an intravenous-glucose tolerance test OLZ also decreased locomotor activity and core temperature, pointing to a reduction in energy expenditure. OLZ also increased weight gain in humans, accompanied with decreased daily physical activity, reduced body temperature and increased baseline and glucosestimulated insulin levels during an oral glucose tolerance test. TPM reduced the OLZ-induced overeating and weight gain in both rats and humans combined with an increased postprandial satiety rating (in humans). We conclude that, in both rats and humans, a reduction in energy expenditure may explain, at least in part, the OLZ effects on weight gain and that the OLZ-induced effects on insulin resistance has a peripheral side of action. We also conclude that TPM may prevent the negative metabolic side effects induced by OLZ. Supported by: Top Institute Pharma.