Incomplete suppression of hepatic glucose production in non-insulin dependent diabetes mellitus measured with [6,6-2H2]glucose enriched glucose infusion during hyperinsulinaemic euglycaemic clamps

We have minimized methodological errors in the isotope dilution technique by using stable isotope, [6,6-2H2]glucose, thus avoiding the problem of contamination of tritiated glucose tracers and, by maintaining a constant plasma tracer enrichment have reduced error due to mixing transients. Using these modifications we have calculated hepatic glucose production in 20 patients with non-insulin-dependent diabetes mellitus during low (1 mU kg-1 min-1) and high (8 mU kg-1 min-1) dose insulin infusions. Mean fasting hepatic glucose production was 14.2 +/- 0.8 mumol kg-1 min-1. This suppressed by only 68% to 4.6 +/- 0.8 mumol kg-1 min-1 during the low-dose insulin infusion (plasma insulin 0.85 +/- 0.05 nmol l-1) and did not suppress further during the high-dose insulin infusion (plasma insulin 14.55 +/- 0.83 nmol l-1). Hepatic glucose production was significantly higher than zero throughout the study. Thus, we have found that minimization of known errors in the isotope dilution technique results in physiologically plausible and significantly positive values for hepatic glucose production indicating that the liver is resistant to insulin in patients with non-insulin-dependent diabetes mellitus.     

Myocardial Lipid and Carbohydrate Metabolism in Healthy, Fasting Men at Rest: Studies During Continuous Infusion of 3H-Palmitate

Abstract Myocardial metabolism of lipid and carbohydrate substrates was studied in 17 healthy men at rest by measuring the arterial-coronary sinus [(a—cs)] concentration differences. A continuous intravenous infusion of albumin-bound ³H-palmitate was given to provide a tracer for the plasma free fatty acids (FFA) and to produce endogenous labelling of plasma triglycerides (TG). A statistically significant positive (a—cs) difference in triglyceride (TG) concentration was detected in 10 of the 17 subjects and averaged 18±4 (SEM) μmol/1 plasma for the 17 subjects. This was 1.0% of the average arterial TG concentration. A significant positive (a—cs) difference in TG radioactivity was found in 12 of the 17 subjects but it was not possible to quantitate myocardial TG extraction from these radioisotope data. Myocardial extraction of FFA based on the radiopalmitate data was on average 39% greater than the extraction of FFA measured chemically. This was interpreted as indicating an efflux of unlabelled fatty acids into the coronary sinus, most probably from a glyceride pool within the myocardium. The finding that this efflux of fatty acids was not accompanied by free glycerol suggested either that the fatty acids were derived from partial hydrolysis of glycerides, or that glycerol was metabolised within the myocardium. Seven of the subjects had significant, positive (a—cs) differences in free glycerol concentration suggesting that the human heart is capable of metabolising glycerol. There were significant, negative linear correlations between arterial FFA concentration and myocardial extraction of glucose, lactate and pyruvate with significant efflux of pyruvate from the heart at higher FFA concentrations. These findings suggested that FFA can decrease glucose extraction by the human heart and that one possible mechanism for this may be the inhibition of pyruvate dehydrogenase. The average (±SEM) oxygen extraction ratios (OERs) for the substrates were: TG 16±4%; FFA 48±3%; glucose 20±3%; lactate 8±2%; pyruvate 1±0.3%. The total OER for these substrates averaged 97% suggesting that in the resting, fasting, state there is little change in the total energy content of endogenous myocardial substrate pools.     

Comparative Absorption of Ferri-Haemoglobin-59Fe/Ferro-Haemoglobin-59Fe and 59Fe3+/59Fe2+ in Humans with Normal and Depleted Iron Stores*

Abstract. The intestinal ⁵⁹Fe absorption from ferri- and ferro-haemogIobin-⁵⁹Fe and ⁵⁹Fe³⁺ and ⁵⁹Fe⁺ was calculated from whole body-⁵⁹Fe-retention measurements in subjects with normal and depleted iron stores. A ferri-haemoglobin-⁵⁹Fe/ferro-haemoglobin-⁵⁹Fe absorption ratio of 1.03 ±0.11 was observed for the absorption of ferri-haemoglobin-⁵⁹Fe (8.6± 0.77%) and ferro-haemogIobin-⁵⁹Fe (8.7±0.94%) in persons with normal iron stores. Depletion of iron stores caused a slight but significant higher rise of ferri-haemoglobin-⁵⁹Fe absorption (22 ± 1.7%) than the increase of ferro-haemoglobin-⁵⁹Fe absorption (18 ±0.9%) so that the absorption ratio was 1.24±0.073.—This remarkable iron valence independence of haemoglobin iron absorption is in considerable contrast to the well-established valence dependence of inorganic iron absorption which favours ferrous iron absorption especially with rising iron doses. The ⁵⁹Fe³⁺/⁵⁹Fe²⁺ absorption ratio for a diagnostic 0.56 mg Fe dose increased from 0.43 in subjects with normal iron stores to 0.74 in persons with depleted iron stores, whereas this absorption ratio was augmented only from 0.21 to 0.28 for the therapeutic 50 mg Fe-dose.—The different influence of iron valence on iron absorption from inorganic and haemoglobin iron supports other evidence for the existence of two separate mechanisms for ferrous iron and haem iron absorption in humans.     

Effects of four orally administered analogues of prostaglandin E1 and E2 on glucose tolerance and on the secretion of pancreatic and gastrointestinal hormones in man

Oral glucose tolerance tests (75 g, 300 ml) were performed in 12 healthy volunteers, with prior administration of placebo, misoprostol (400 micrograms), rioprostil (300 micrograms), enprostil (70 micrograms), or nocloprost (200 micrograms), in a double-blind, randomized manner. None of the drugs significantly affected glucose tolerance, although with misoprostal some volunteers displayed an impaired glucose tolerance. Nocloprost was without effect on gastric inhibitory polypeptide (GIP) and did not influence insulin or C-peptide concentrations. Misoprostol and rioprostil reduced integrated incremental responses of GIP by 57% (P less than or equal to 0.001) and 45% (P less than or equal to 0.01), respectively, and both gave rise to an initial (approximately 10 min) delay of insulin and C-peptide responses, without a significant overall reduction in integrated incremental responses. Enprostil almost totally inhibited the GIP response (by 94%; P less than or equal to 0.001), delayed initial insulin and C-peptide responses, but reduced the integrated incremental C-peptide response (which corresponds to the overall release of insulin) by only 14% (P less than or equal to 0.05). Enprostil more substantially reduced the integrated incremental response of insulin by 36% (P less than or equal to 0.01), and also reduced the ratio of insulin and C-peptide incremental responses (P less than or equal to 0.001). In conclusion, prostaglandin E analogues which caused a reduction in GIP responses, and thereby disrupting the enteroinsular axis to varying degrees, delayed the time-course of insulin secretion without a significant impact on glucose tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Na+/H+ antiporter activity in peripheral blood lymphocytes of obese and type 2 diabetic patients is increased only in the presence of arterial hypertension

Abstract. The aim of this work is to evaluate whether type 2 diabetes mellitus, obesity and arterial hypertension, three conditions characterized by the presence of insulin resistance, share some common genetic markers. A potential candidate is the Na⁺/H⁺ anti-porter, the increased activity of which is considered a marker of essential hypertension. This ion exchanger seems to be related to the Na⁺/Li⁺ countertransport, that is considered a marker of insulin resistance in essential hypertension and in type 1 diabetes mellitus. In this study we wished to clarify whether the activity of the Na⁺/H⁺ antiporter is increased not only in hypertensive subjects, but also in obese and type 2 diabetic patients, both in the presence and in the absence of arterial hypertension. The activity of the ion exchanger was measured in peripheral blood lymphocytes (PBL) by clamping intracellular pH (pH_i) at 5·8–6·2 and then detecting the rate of the proton efflux after sodium addition. In the absence of arterial hypertension, no significant difference in this parameter was observed in obese and type 2 diabetic patients in comparison with normal subjects. In the presence of arterial hypertension, there was a significant increase in the Na⁺-induced H⁺ efflux at the internal pH (pHi) values of 5·8 and 6·2 both in hypertensive controls and in hypertensive obese and type 2 diabetic patients (P= 0·05–0·0001 vs. normotensive subjects and patients). In particular, H⁺ efflux at pH 5·8 (mmol l^-1 min^-1) was 35·36 ± 2·48 in normotensive and 42·77 ± 1·63 in hypertensive control subjects (P= 0·045), 33·06 ± 1·88 in normotensive and 50·40 ± 5·21 in hypertensive obese patients (P= 0·009), 31·16 ± 1·84 in normotensive and 55·54 ± 5·83 in hypertensive type 2 diabetic patients (P= 0·0001). H⁺ efflux showed a significant correlation with both systolic (at pHi 5·8, r = 0·473, P= 0·001; at pHi 6·2, r = 0·357, P= 0·016) and diastolic blood pressure (at pHi 5·8, r = 0·600, P= 0·0001; at pHi 6·2, r = 0·555, P= 0·0001). Therefore, our study demonstrates that the hyperactivity of the Na⁺/H⁺ exchanger in peripheral blood lymphocytes is also a marker of arterial hypertension in obesity and in type 2 diabetes mellitus, and that the exchanger activity is not increased in these two conditions in the absence of arterial hypertension.     

2-型糖尿病血清中游离脂肪酸与血糖及胰岛素抵抗关系的比较

【目的】探讨 2 型糖尿病 ( 2 DM )患者血清中游离脂肪酸 (FFA)浓度与胰岛素抵抗 (IR)的关系。【方法】放射免疫法 (RIA)测定胰岛素浓度、己糖激酶法测定葡萄糖 (GLU)、酶产色法测定空腹FFA浓度、2hFFA浓度 (PFFA)及其他生化指标。 86例患者 ,5 0例健康对照组行口服葡萄糖耐量试验 (OGTT)和胰岛素释放试验 ,计算 30min后胰岛素和GLU浓度变化的比值 (△I3 0 /△G3 0 )、葡萄糖曲线下面积 (AUCG)和胰岛素曲线下面积 (AUCIN)。根据Cederholm公式计算胰岛素敏感指数 (ISI)。【结果】与正常对照比较 ,2 DM空腹和2hFFA、AUCG、AUCIN、TG浓度显著升高 (P <0 .0 1) ,ISI、△I3 0 /△G3 0 显著降低 (P <0 .0 1)。 2 DM患者FFA与AUCG、AUCIN呈显著正相关 ,与△I3 0 /△G3 0 、ISI呈显著负相关。【结论】2 DM患者空腹血清FFA、胰岛素浓度升高 ;高浓度FFA使葡萄糖刺激胰岛素分泌受损 ,血糖浓度升高 ;并且间接反映IR的程度     

Direct determination of leucine metabolism and protein breakdown in humans using L-[1-13C, 15N]-leucine and the forearm model

Abstract. We have used the forearm model to study protein metabolism in six normal healthy subjects in the fed state using L-[1 –¹³C, ¹⁵N]-leucine as the substrate tracer.
Deep venous and arterialized venous blood samples from the forearm were collected at 10-min intervals 2±5 h into a primed-continuous infusion of the dilabelled tracer. Arterialized venous blood was obtained using a 'hot-box' technique and forearm blood flow was measured by mercury strain-gauge plethysmography.
The concentration and isotope enrichment of leucine and its metabolites, α-ketoisocaproic acid and CO₂, in deep venous and arterialized venous blood were measured by gas chromatography-mass spectrometry and isotope ratio-mass spectrometry.
The rates of leucine deamination and reamination were 388 ± 24 (mean ± SEM) and 330 ± 23 nmol (100 ml)^-1 min^-1 respectively, whilst protein synthesis and breakdown rates were 127 ± 11 and 87 ± 10 nmol (100 ml)^-1 min^-1 respectively across the forearm in the fed state. We have demonstrated that the use of doubly labelled leucine as tracer and application of the mathematical model developed in this study, permits the comprehensive quantification of leucine kinetics including protein breakdown.     

Studies on the Metabolic Clearance Rate, Apparent Distribution Space and Plasma Half-Disappearance Time of Unlabelled Human Growth Hormone in Normal Subjects and in Patients with Liver Disease, Renal Disease, Thyroid Disease and Diabetes Mellitus

Abstract. The metabolic clearance rate (MCR), half-disappearance time (T½ and apparent distribution space (DS) of unlabelled human growth hormone (HGH) have been studied using the priming dose – constant infusion technique. In 11 normal subjects MCR averaged 2.99 ml/kg/min., T½ 19.0 min. and DS 79.3 ml/kg. There were no differences between males and females and MCR was constant at HGH levels ranging from 5 to 50 ng/ml. In 10 out of 17 patients with chronic liver disease of varying severity MCR/kg was reduced below the lower limit of normal. TV₂ was prolonged in 15 of these patients. There was a very close correlation between MCR/kg and DS/kg in liver disease (r = 0.8219). Increased DS/kg accounted for the normal MCR/kg seen in some patients with severe hepatocellular failure. MCR/kg was markedly reduced in three patients'with chronic renal failure. T7₂ and DS/kg were both significantly increased in this group (48.0 min. and 117.0 ml/kg, respectively). MCR/kg and T7₂ were normal in one patient with the nephrotic syndrome but normal glomerular filtration rate. MCR/kg was not significantly different from normal in patients with thyrotoxicosis, myxoedema and uncontrolled diabetes mellitus, despite the fact that T½ shorter than normal in thyrotoxicosis and longer than normal in myxoedema. It is suggested that HGH does not normally diffuse freely from the vascular to extravascular extracellular fluid, and that normally a substantial concentration gradient exists between the vascular and extravascular compartments; under these circumstances, the liver and kidneys are the major sites of HGH metabolism. In hepatic and renal failure, this gradient is reduced and extravascular degradation sites may assume more importance in the metabolism of growth hormone. Acute fluctuations in the peripheral blood concentrations of growth hormone indicate alterations in secretion rate and not alterations in metabolism.     

Cardiometabolic Health Outcomes Associated With Discordant Visceral and Liver Fat Phenotypes: Insights From the Dallas Heart Study and UK Biobank

ObjectiveTo evaluate the cardiometabolic outcomes associated with discordant visceral adipose tissue (VAT) and liver fat (LF) phenotypes in 2 cohorts.Patients and MethodsParticipants in the Dallas Heart Study underwent baseline imaging from January 1, 2000, through December 31, 2002, and were followed for incident cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) through 2013. Associations between VAT-LF groups (low-low, high-low, low-high, and high-high) and outcomes were assessed using multivariable-adjusted regression and were replicated in the independent UK Biobank.ResultsThe Dallas Heart Study included 2064 participants (mean ± SD age, 44±9 years; 54% female; 47% black). High VAT–high LF and high VAT–low LF were associated with prevalent atherosclerosis, whereas low VAT–high LF was not. Of 1731 participants without CVD/T2DM, 128 (7.4%) developed CVD and 95 (5.5%) T2DM over a median of 12 years. High VAT–high LF and high VAT–low LF were associated with increased risk of CVD (hazard ratios [HRs], 2.0 [95% CI, 1.3 to 3.2] and 2.4 [95% CI, 1.4 to 4.1], respectively) and T2DM (odds ratios [ORs], 7.8 [95% CI, 3.8 to 15.8] and 3.3 [95% CI, 1.4 to 7.8], respectively), whereas low VAT–high LF was associated with T2DM (OR, 2.7 [95% CI, 1.1 to 6.7]). In the UK Biobank (N=22,354; April 2014-May 2020), only high VAT–low LF remained associated with CVD after multivariable adjustment for age and body mass index (HR, 1.5 [95% CI, 1.2 to 1.9]).ConclusionAlthough VAT and LF are each associated with cardiometabolic risk, these observations demonstrate the importance of separating their cardiometabolic implications when there is presence or absence of either or both in an individual.