Veldhuis, Johannes D.

Humans cannot live at very high altitude for reasons, which are not completely understood. Since these reasons are not restricted to cardiorespiratory changes alone, changes in the endocrine system might also be involved. Therefore, hormonal changes during prolonged hypobaric hypoxia were comprehensively assessed to determine effects of altitude and hypoxia on stress, thyroid and gonadal hypothalamus–pituitary hormone axes. Twenty-one male and 19 female participants were examined repetitively during a high-altitude expedition. Cortisol, prolactin, thyroid-stimulating hormone (TSH), fT4 and fT3 and in males follicle-stimulating hormone (FSH), luteinizing hormone (LH) and total testosterone were analysed as well as parameters of hypoxemia, such as SaO 2 and paO 2 at 550 m (baseline) ( n = 40), during ascent at 4844 m ( n = 38), 6022 m ( n = 31) and 7050 m ( n = 13), at 4844 m ( n = 29) after acclimatization and after the expedition ( n = 38). Correlation analysis of hormone concentrations with oxygen parameters and with altitude revealed statistical association in most cases only with altitude. Adrenal, thyroid and gonadal axes were affected by increasing altitude. Adrenal axis and prolactin were first supressed at 4844 m and then activated with increasing altitude; thyroid and gonadal axes were directly activated or suppressed respectively with increasing altitude. Acclimatisation at 4844 m led to normalization of adrenal and gonadal but not of thyroid axes. In conclusion, acclimatization partly leads to a normalization of the adrenal, thyroid and gonadal axes at around 5000 m. However, at higher altitude, endocrine dysregulation is pronounced and might contribute to the physical degradation found at high altitude.

We examined the relationship between energy expenditure (in kcal) and epinephrine (Epi), norepinephrine (NE), and growth hormone (GH) release. Ten men [age, 26 yr; height, 178 cm; weight, 81 kg; O2uptake at lactate threshold (LT), 36.3 ml · kg−1 · min−1; peak O2uptake, 49.5 ml · kg−1 · min−1] were tested on six randomly ordered occasions [control, 5 exercise: at 25 and 75% of the difference between LT and rest (0.25LT, 0.75LT), at LT, and at 25 and 75% of the difference between LT and peak (1.25LT, 1.75LT) (0900–0930)]. From 0700 to 1300, blood was sampled and assayed for GH, Epi, and NE. Carbohydrate (CHO) expenditure during exercise and fat expenditure during recovery rose proportionately to increasing exercise intensity ( P = 0.002). Fat expenditure during exercise and CHO expenditure during recovery were not affected by exercise intensity. The relationship between exercise intensity and CHO expenditure during exercise could not be explained by either Epi ( P = 1.00) or NE ( P = 0.922), whereas fat expenditure during recovery increased with Epi and GH independently of exercise intensity ( P = 0.028). When Epi and GH were regressed against fat expenditure during recovery, only GH remained statistically significant ( P < 0.05). We conclude that a positive relationship exists between exercise intensity and both CHO expenditure during exercise and fat expenditure during recovery and that the increase in fat expenditure during recovery with higher exercise intensities is related to GH release.

The purpose of the present study was to determine the contributions of discrete insulin secretory bursts vs. basal insulin release to total insulin secretion in vivo. Quantification of the partitioning of pulsatile and basal insulin secretion is complicated by physiological delivery of these pulses into the portal vein and the absence of validated methods of measuring the rates of pulsatile and basal insulin secretion in vivo. We therefore 1) developed a canine model with chronically implanted portal vein catheters, 2) validated an established deconvolution technique as well as a novel direct catheterization technique (Clustcath) for measurement of pulsatile and nonpulsatile insulin secretion rates in this model, and 3) applied these methods to study insulin secretion in the overnight-fasted dog in vivo to determine the contribution of pulsatile vs. basal insulin secretion to total rates of endogenous insulin secretion. Rates of total, pulsatile, and nonpulsatile endogenous insulin secretion measured by Cluscath closely parallel those measured by deconvolution analysis (54 +/- 15 vs. 51 +/- 11, 38 +/- 12 vs. 36 +/- 11, and 16 +/- 4 vs. 14 +/- 4 pmol/min, respectively). Clustcath and deconvolution indicated that the majority of insulin was secreted as pulses (70 +/- 6 and 66 +/- 7%, respectively). These data infer that any process that selectively decreases the pulsatile component of insulin secretion (e.g., diabetes mellitus) will likely have a major impact on total insulin secretion.

Impaired insulin secretion in type 2 diabetes is characterized by decreased first-phase insulin secretion, an increased proinsulin-to-insulin molar ratio in plasma, abnormal pulsatile insulin release, and heightened disorderliness of insulin concentration profiles. In the present study, we tested the hypothesis that these abnormalities are at least partly reversed by a period of overnight suspension of β-cell secretory activity achieved by somatostatin infusion. Eleven patients with type 2 diabetes were studied twice after a randomly ordered overnight infusion of either somatostatin or saline with the plasma glucose concentration clamped at ∼8 mmol/l. Controls were studied twice after overnight saline infusions and then at a plasma glucose concentration of either 4 or 8 mmol/l. We report that in patients with type 2 diabetes, 1) as in nondiabetic humans, insulin is secreted in discrete insulin secretory bursts; 2) the frequency of pulsatile insulin secretion is normal; 3) the insulin pulse mass is diminished, leading to decreased insulin secretion, but this defect can be overcome acutely by β-cell rest with somatostatin; 4) the reported loss of orderliness of insulin secretion, attenuated first-phase insulin secretion, and elevated proinsulin-to-insulin molar ratio also respond favorably to overnight inhibition by somatostatin. The results of these clinical experiments suggest the conclusion that multiple parameters of abnormal insulin secretion in patients with type 2 diabetes mechanistically reflect cellular depletion of immediately secretable insulin that can be overcome by β-cell rest.

Little is known about the optimal experimental conditions for assessing pulsatile insulin secretion in vivo. To address this, we employed a recently validated canine model (n = 12) to determine the consequences of 1) sampling from the systemic circulation (SC) vs. the portal vein (PV), 2) sampling intensity and duration, and 3) deconvolution vs. cluster analysis on assessing pulsatile insulin secretion. PV vs. SC sampling resulted in a approximately 40% higher pulse frequency by deconvolution (9.0 +/- 0.5 vs. 6.6 +/- 0.9 pulses/h, P < 0.02) and cluster analysis (7.5 +/- 0.3 vs. 5.6 +/- 0.6 pulses/h, P < 0.01) due to a higher signal-to-noise ratio (19 +/- 4.8 PV vs. 12 +/- 1.8 SC). PV sampling also disclosed a higher calculated contribution of the pulsatile vs. nonpulsatile mode of delivery to total insulin secretion (57 +/- 4 vs. 28 +/- 5%, P < 0.001). Analysis of the relevance of sampling intensity revealed that 1-min data yielded a markedly higher estimate of pulse frequency with PV sampling than 2-min data (9.0 +/- 0.5 vs. 5.4 +/- 0.5, P < 0.02, deconvolution; 7.5 +/- 0.3 vs. 4.3 +/- 0.6 pulses/h, P < 0.001, cluster). Optimal sampling duration was shown to be 40 min or more. We conclude that the resolving power of the analytical tool, the anatomic site of blood withdrawal, the frequency of blood sampling, and the duration of the total observation interval all significantly influence estimated insulin secretory pulse frequency and the fraction of insulin secreted in pulses. With the assumption that PV 1-min insulin data constitute the "gold standard," our in vivo inferences of 7.5-9.0 insulin pulses/h closely recapitulate in vitro islet secretory activity.