Glucose Metabolism in Pregnancy at High Altitude

Krampl, Elisabeth; Kametas, Nikos A.; Nowotny, Peter; Roden, Michael; Nicolaides, Kypros H.

doi:10.2337/diacare.24.5.817

Cited by 35 publications

(21 citation statements)

References 34 publications

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“…For example, inhalation of insulin might affect pulmonary neurogenic pathways and associated metabolic regulatory circuits. In our study, we saw no direct evidence for this occurring, although glucose utilization and peripheral insulin sensitivity have been shown to increase at high altitudes as a result of differences in oxygen sensing (23,24). Although this effect may result from a direct action on target tissues due to lower oxygen tension in the blood, it could also be the result of changes in oxygen sensing in the lungs.…”

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confidence: 49%

Inhalation of Insulin (Exubera) Is Associated With Augmented Disposal of Portally Infused Glucose in Dogs

et al. 2005

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The results of the present study, using the conscious beagle dog, demonstrate that inhaled insulin (INH; Exubera) provides better glycemic control during an intraportal glucose load than identical insulin levels induced by insulin (Humulin) infusion into the inferior vena cava (IVC). In the INH group (n ‫؍‬ 13), portal glucose infusion caused arterial plasma glucose to rise transiently (152 ؎ 9 mg/dl), before it returned to baseline (65 min) for the next 2 h. Net hepatic glucose uptake was minimal, whereas nonhepatic uptake rose to 12.5 ؎ 0.5 mg ⅐ kg ؊1 ⅐ min ؊1 (65 min). In the IVC group (n ‫؍‬ 9), arterial glucose rose rapidly (172 ؎ 6 mg/dl) and transiently fell to 135 ؎ 13 mg/dl (65 min) before returning to 165 ؎ 15 mg/dl (125 min). Plasma glucose excursions and hepatic glucose uptake were much greater in the IVC group, whereas nonhepatic uptake was markedly less (8.6 ؎ 0.9 mg ⅐ kg ؊1 ⅐ min ؊1 ; 65 min). Insulin kinetics and areas under the curve were identical in both groups. These data suggest that inhalation of Exubera results in a unique action on nonhepatic glucose clearance. Diabetes 54:1164 -1170, 2005 I nsulin delivered by inhalation is an alternative to injected insulin for patients with diabetes. Clinical studies comparing subcutaneous administration of insulin (Humulin) with insulin inhalation (Exubera) suggest that there is a unique glucose-lowering effect associated with inhaled insulin (1). Previous studies in dogs have shown that inhaled insulin has a higher and earlier peak of arterial insulin that clears more rapidly than subcutaneous insulin. Despite the similar arterial and hepatic insulin areas under the curve (AUCs) in the two groups, a 20% greater glucose infusion rate was required to maintain euglycemia in the inhaled insulin group relative to the subcutaneous insulin group (2). This finding was consistent with the unique glucose-lowering effect of inhaled insulin seen in human studies.The difference in glycemic control resulting from inhalation verses subcutaneous administration of insulin could be explained by the different pharmacokinetic insulin profiles resulting from the two routes of administration, or by some unique aspect of insulin delivery by inhalation. To distinguish between these possibilities, we delivered insulin by inhalation (Exubera) or through infusion (Humulin) into the inferior vena cava (IVC) to create an identical pharmacokinetic profile to that resulting from insulin inhalation. We then examined the effects of both routes of insulin delivery on glucose disposal during a simulated oral glucose load. To further clarify the mechanism by which glucose disposal might be enhanced, we compared the role of the liver and nonhepatic tissues in glucose uptake. RESEARCH DESIGN AND METHODSExperiments were conducted on 22 healthy, conscious, 18-h-fasted, male beagle dogs (weight 8 -10 kg). Before the study, they were fed a standard diet once a day, and water was provided ad libitum. The surgical facility met the standards published by the American Association for the Accredi...

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confidence: 49%

Inhalation of Insulin (Exubera) Is Associated With Augmented Disposal of Portally Infused Glucose in Dogs

et al. 2005

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“…Some of these factors are altered at high altitude, e.g. maternal venous glucose and insulin concentrations are lower [35]. It is probable therefore that the syncytial expression of GLUT1 is the net result of multiple factors, many of which, such as insulin and the insulin-like growth factors, are intimately connected to the regulation of fetal growth, and that these signals can override hypoxia-induced upregulation of the GLUT1 glucose transporter.…”

Section: Discussionmentioning

confidence: 99%

Effects of chronic hypoxia in vivo on the expression of human placental glucose transporters

2006

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Birth weight is reduced and the risk of preeclampsia is increased in human high altitude pregnancies. There has been little work to determine whether hypoxia acts directly to reduce fetal growth (e.g. reduced blood flow and oxygen delivery), or via changes in functional capacities such as nutrient transport. We therefore investigated the expression of a primary nutrient transporter, the GLUT1 glucose transporter and two in vitro markers of hypoxia (erythropoietin receptor, EPO-R, and transferrin receptor, TfR) in the syncytial microvillous (MVM) and basal membrane fractions (BMF) of 13 high (3100 m) and 12 low (1600 m) altitude placentas from normal term pregnancies. Birth weight was lower at 3100 m than at 1600 m despite similar gestational age, but none of the infants were clinically designated as fetal growth restriction. EPO-R, TfR and GLUT1 were examined by immunoblotting and maternal circulating erythropoietin and transferrin by ELISA. EPO-R was greater on the MVM (C75%) and BMF (C25%) at 3100 m. TfR was 32% lower on the MVM at 3100 m. GLUT1 was 40% lower in the BMF at 3100 m. Circulating EPO was greater at high altitude, while transferrin was similar, and neither correlated with their membrane receptors. BMF GLUT1 was positively correlated with birth weight at high, but not low altitude. In this in vivo model of chronic placental hypoxia, syncytial EPO-R increased as expected, while nutrient transporters decreased, opposite to what has been observed in vitro. Therefore, hypoxia acts to reduce fetal growth not simply by reducing oxygen delivery, but also by decreasing the density of nutrient transporters.

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“…However, the mild decrements lung function, as noted in the current analyses, are not likely to be associated with significant hypoxemia, thus making it a less plausible intermediate in the putative causal pathway linking low FVC with incident type 2 diabetes. Moreover, several lines of conflicting evidence suggest that hypoxemia may have no harmful effects in insulin sensitivity (32)(33)(34)(35)(36).…”

Section: Subsidiary Analysesmentioning

confidence: 99%

Vital Capacity as a Predictor of Incident Type 2 Diabetes

et al. 2005

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OBJECTIVE -To test the hypothesis that lower vital capacity is cross-sectionally associated with features of insulin resistance and is an independent predictor of incident type 2 diabetes.RESEARCH DESIGN AND METHODS -We conducted a prospective cohort study of vital capacity as a predictor of incident type 2 diabetes using 9-year follow-up data on 11,479 middle-aged adults without diabetes at baseline from the Atherosclerosis Risk in Communities (ARIC) Study.RESULTS -Forced vital capacity (FVC) and forced expiratory volume in 1 s were measured at baseline using standard spirometry. Incident type 2 diabetes cases were ascertained during follow-up. At baseline, low FVC (% predicted) was independently associated with indicators of the insulin resistance syndrome, including higher fasting levels of glucose, insulin, and triglycerides; lower fasting HDL cholesterol; and higher systolic blood pressure. In prospective analyses, there were graded associations between low FVC (% predicted) and incidence of type 2 diabetes in men and women. These associations persisted in multivariable analyses that adjusted for age, race, adiposity, smoking, physical activity, and ARIC center. Compared with individuals in the highest quartile of FVC (% predicted), the fully adjusted hazard ratio (95% CI) of diabetes in individuals in the lowest quartile was 1.6 (1.3-2.0) in men and 1.7 (1.3-2.1) in women. These relationships were stronger in those who have never smoked.CONCLUSIONS -Lower vital capacity is an independent predictor of incident type 2 diabetes. Pulmonary factors related to vital capacity deserve attention as possible risk factors for insulin resistance and diabetes. Diabetes Care 28:1472-1479, 2005I mpaired lung function has attracted growing interest as a potentially novel risk factor for glucose intolerance (1,2), insulin resistance (3), and type 2 diabetes (4,5,25). Possible mechanisms for the hypothesized link include direct effects of hypoxemia on glucose and insulin regulation (2,6), lung-related inflammatory mediators and their effects on insulin signaling (1,7,8), and adverse early-life exposures and their effects on organ development (9,10). Cross-sectional studies (11-14) have consistently shown that adults with diabetes have lower vital capacity than their nondiabetic counterparts, but such studies cannot establish temporal sequence. Prospective studies have tentatively identified lower vital capacity as a predictor of hyperinsulinemia (3) and type 2 diabetes (4,5,25) but have had limitations related to sample size and availability of diabetes-related data. We therefore analyzed longitudinal data from the Atherosclerosis Risk in Communities (ARIC) study, a biracial communitybased study of 15,792 middle-aged adults, to test the hypothesis that lower lung function, as indicated by lower vital capacity, is cross-sectionally associated with features of insulin resistance and is an independent predictor of incident type 2 diabetes. RESEARCH DESIGN AND METHODS -The ARIC study is an on-going, prospective cohort study des...

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Glucose Metabolism in Pregnancy at High Altitude

Cited by 35 publications

References 34 publications

Inhalation of Insulin (Exubera) Is Associated With Augmented Disposal of Portally Infused Glucose in Dogs

Inhalation of Insulin (Exubera) Is Associated With Augmented Disposal of Portally Infused Glucose in Dogs

Effects of chronic hypoxia in vivo on the expression of human placental glucose transporters

Vital Capacity as a Predictor of Incident Type 2 Diabetes

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