Altered islet Beta-cell function before the onset of Type 1 (insulin-dependent) diabetes mellitus

Summary To define the glucose to insulin dose-response relationship before the onset of diabetes, we studied 22 nondiabetic co-twins of patients with Type 1 (insulin-dependent) diabetes mellitus and nine control subjects. All had intravenous glucose tests at 0.02, 0.1 and 0.5 g/kg and were followedup prospectively for at least 6 years. Seven twins developed diabetes a mean of 7 months later; the remaining 15 are now unlikely to develop diabetes. The seven pre-diabetic twins had higher fasting insulin levels than control subjects (4.2±2.0 vs 1.8±1.8 nmol/l; p<0.05); but lower glucose clearance (1.0±0.5 vs 1.9±0.7 %/min; p<0.05), first phase insulin response at 0.5 g/kg (21.1±23.2 vs 143±50 nmol/l; p<0.0001), and total insulin responses at 0.1 g/kg (p<0.05) and 0.5 g/kg (p<0.00005). Using a curve-fitting programme, the normal glucose to insulin relationship was lost in prediabetic twins who had lower coefficient of determination (R²) than control subjects (p<0.01). In contrast, 15 low-risk twins and their nine control subjects had similar fasting glucose and insulin levels, glucose clearance, R² and insulin secretory responses to different glucose loads. The positive predictive values of subnormal R² and subnormal first phase insulin response were 67 % and 58 % respectively. These observations demonstrate an altered glucose to insulin dose-response relationship and loss of maximum insulin secretory response to glucose before the onset of Type 1 diabetes.     

甲状腺功能亢进症患儿合并糖代谢紊乱10例临床分析

目的：探讨儿童甲亢患者糖代谢紊乱的特点。方法：用SUPER GLUCOCARD^TM血糖仪和放射免疫方法检测29例甲亢患儿餐前、餐后60min、120min血糖和餐前、餐后60min胰岛素、C肽、胰高糖素、皮质醇及T3、T4、TSH、TGA、TMA（其中10例糖耐量减低为甲亢1组，另19例糖耐量正常为甲亢2组），并与20例健康儿童进行比较。结果：（1）34．5％甲亢患儿出现糖代谢紊乱，病程大于1年和小于1年糖代谢紊乱发生率为50％，9％（P＜0．05）。（2）甲亢1组餐后60min胰岛素、胰岛素／血糖、胰岛素／胰高糖素显著升高（P＜0．05）。结论：甲亢儿童存在糖代谢紊乱现象，表现为葡萄糖耐量减低和胰岛素拮抗，其发生与病程有关，病程较长，发生率较高。糖代谢紊乱可能与自身免疫、胰岛β细胞功能受损及胰岛素拮抗有关。     

Nitric oxide is not involved in the initiation of insulin secretion from rat islets of Langerhans

Summary The involvement of nitric oxide as an intracellular messenger in the control of insulin secretion from pancreatic Beta cells was studied in rat islets of Langerhans by measuring: (i) nitric oxide generation in response to physiological insulin secretagogues; (ii) the effects of inhibitors of nitric oxide synthesis on insulin secretory responses to physiological secretagogues, and on insulin synthesis; (iii) changes in islet cyclic guanosine monophosphate in response to secretagogues; (iv) the effects of exogenous cyclic guanosine monophosphate and dibutyryl cyclic guanosine monophosphate on insulin secretion from electrically permeabilised islets and from intact islets, respectively. These studies produced no evidence that nitric oxide generation is required for the initiation of insulin secretion by common secretagogues. However, the results of our experiments suggest that the generation of nitric oxide may be involved in long-term, glucose-dependent increases in cyclic guanosine monophosphate content of islet cells, although the physiological relevance of these changes requires further investigation.     

Hyperglycaemia compensates for the defects in insulin-mediated glucose metabolism and in the activation of glycogen synthase in the skeletal muscle of patients with Type 2 (non-insulin-dependent) diabetes mellitus

Summary Insulin resistance and a defective insulin activation of the enzyme glycogen synthase in skeletal muscle during euglycaemia may have important pathophysiological implications in Type 2 (non-insulin-dependent) diabetes mellitus. Hyperglycaemia may serve to compensate for these defects in Type 2 diabetes by increasing glucose disposal through a mass action effect. In the present study, rates of whole-body glucose oxidation and glucose storage were measured during fasting hyperglycaemia and isoglycaemic insulin infusion (40 mU·m^–2min^–1, 3 h) in 12 patients with Type 2 diabetes. Eleven control subjects were studied during euglycaemia. Biopsies were taken from the vastus lateralis muscle. Fasting and insulin-stimulated glucose oxidation, glucose storage and muscle glycogen synthase activation were all fully compensated (normalized) during hyperglycaemia in the diabetic patients. The insulin-stimulated increase in muscle glycogen content was the same in the diabetic patients and in the control subjects. Besides hyperglycaemia, the diabetic patients had elevated muscle free glucose and glucose 6-phosphate concentrations. A positive correlation was demonstrated between intracellular free glucose concentration and muscle glycogen synthase fractional velocity insulin activation (0.1 mmol/l glucose 6-phosphate: r=0.65, p<0.02 and 0.0 mmol/l glucose 6-phosphate: r= 0.91, p<0.0001). In conclusion, this study indicates an important role for hyperglycaemia and elevated muscle free glucose and glucose 6-phosphate concentrations in compensating (normalizing) intracellular glucose metabolism and skeletal muscle glycogen synthase activation in Type 2 diabetes.     

Insulin binding to trophoblast plasma membranes and placental glycogen content in well-controlled gestational diabetic women treated with diet or insulin,in well-controlled overt diabetic patients and in healthy control subjects

Summary Insulin binding to trophoblast plasma membranes and the placental glycogen content were measured in twelve healthy women, in eleven well-controlled gestational diabetic women who were treated either with diet alone (n=4) or with insulin (n=7) and in 18 women with well-controlled overt diabetes mellitus (six White B; four White C; eight White D). The competitive binding assay was carried out with 22 concentrations of unlabelled insulin. Binding data were analysed by a non-linear direct model fitting procedure assuming one non-cooperative binding site. Maximum specific binding was unchanged in the total collective of gestational diabetic women, but was decreased by 30% in those treated with diet (6.2±2.2%) and increased by 90% in insulin-treated women (16.4±10.2%) as compared to the control subjects (8.7±2.5%). The diet-treated women had only 40% as many and those treated with insulin had more than twice as many receptors compared to control subjects on a per mg protein basis and if expressed per total placenta. In patients with overt diabetes mellitus maximum specific binding (18.5±10.6 %) was higher (p<0.05) due to more receptors compared to control subjects but was similar to the insulin-treated gestational diabetic patients. Maximum specific binding and receptor concentrations did not correlate linearly with maternal plasma insulin levels. Receptor affinities were virtually similar in all groups (1.8·10⁹ l/mol). The placental glycogen content was reduced (p<0.05) to about 80% of that of control subjects in the diet-treated collective, whereas it was unchanged compared to control subjects in the insulin-treated gestational diabetic women despite a 40% increase (p<0.001) of the maternal-to-cord serum glucose ratio. In overt diabetic patients the maternal-to-cord serum glucose ratio and the placental glycogen content were higher (p<0.05) than in the control subjects. We conclude that trophoblast plasma membranes from gestational diabetic women treated with diet alone express less and those from women treated with insulin express more insulin receptors than those from a healthy control group in vitro. These differences could not have been disclosed without consideration of the mode of treatment. Trophoblast plasma membranes from overt diabetic women have more insulin receptors than those from healthy control subjects.     

Acute actions of insulin-like growth factor II on glucose metabolism in adult rats

Summary The metabolic potency of recombinant human insulin-like growth factor II was studied in anaesthetized adult rats by obtaining dose-response curves for the hypoglycaemic action and for the stimulation of glucose metabolism during euglycaemic clamping. Compared to insulin, about 50 times higher doses of insulin-like growth factor II were required to result in identical in vivo responses, with half-maximally effective serum concentrations for the stimulation of glucose disposal during clamp studies of about 0.8 and 50 pmol/ml, respectively. A similar difference in potency was observed for the dose-dependent stimulatory actions on glucose metabolism in individual target tissues. Half-maximally effective serum concentrations in the range of 0.8 to 3.0 pmol/ml for insulin and of 40 to 70 pmol/ml for insulin-like growth factor II were seen to be required for 2-deoxyglucose uptake, glycogen formation in skeletal muscle and lipogenesis in epididymal fat. Maximal responses were identical with both peptides. These data suggest that in vivo acute metabolic actions of insulin-like growth factor II on carbohydrate metabolism occurred through insulin receptors.     

Effect of compressive follower preload on the flexion-extension response of the human lumbar spine.

Traditional experimental methods are unable to study the kinematics of whole lumbar spine specimens under physiologic compressive preloads because the spine without active musculature buckles under just 120 N of vertical load. However, the lumbar spine can support a compressive load of physiologic magnitude (up to 1200 N) without collapsing if the load is applied along a follower load path. This study tested the hypothesis that the load-displacement response of the lumbar spine in flexion-extension is affected by the magnitude of the follower preload and the follower preload path. Twenty-one fresh human cadaveric lumbar spines were tested in flexion-extension under increasing compressive follower preload applied along two distinctly different optimized preload paths. The first (neutral) preload path was considered optimum if the specimen underwent the least angular change in its lordosis when the full range of preload (0-1200 N) was applied in its neutral posture. The second (flexed) preload path was optimized for an intermediate specimen posture between neutral and full flexion. A twofold increase in flexion stiffness occurred around the neutral posture as the preload was increased from 0 to 1200 N. The preload magnitude (400 N and larger) significantly affected the range of motion (ROM), with a 25% decrease at 1200 N preload applied along the neutral path. When the preload was applied along a path optimized for an intermediate forward-flexed posture, only a 15% decrease in ROM occurred at 1200 N. The results demonstrate that whole lumbar spine specimens can be subjected to compressive follower preloads of in vivo magnitudes while allowing physiologic mobility under flexion-extension moments. The optimized follower preload provides a method to simulate the resultant vector of the muscles that allow the spine to support physiologic compressive loads induced during flexion-extension activities.     

体外循环对瓣膜置换术病人血细胞胰岛素受体和红细胞ATP含量的影响

目的：观察体外循环（ＣＰＢ）对１０例瓣膜置换术病人全血细胞胰岛素受体和红细胞ＡＴＰ含量的影响。方法：利用放射配体结合试验，测定全血细胞胰岛素受体密度和亲和力；用高效液相色谱法测定红细胞ＡＴＰ含量，同时监测血糖和胰岛素浓度。结果：转流３０分钟，血细胞高亲和胰岛素受体（Ｒ１）密度明显增加（Ｐ＜０．０１），亲和力（Ｋ１）明显降低（Ｐ＜０．０１），低亲和胰岛素受体（Ｒ２）密度也明显增加（Ｐ＜０．０１），但亲和力（Ｋ２）变化不大（Ｐ＞０．０５）；停机３０分钟，上述变化有所恢复，但未到转流前的水平。转流３０分钟红细胞ＡＴＰ含量明显降低（Ｐ＜０．０１），并持续到停机后３０分钟，同时伴随血糖明显升高（Ｐ＜０．０１），胰岛素／血糖比值明显降低（Ｐ＜０．０１）。结论：ＣＰＢ可致血细胞胰岛素受体密度增加而亲和力下降，以及红细胞ＡＴＰ含量下降。     

胰岛素泵的临床应用进展

综述了胰岛素泵在不同类型及不同情况糖尿病病人中的应用,列举了胰岛素泵临床应用中的常见问题。     

Lipoprotein lipase in relation to inflammatory activity in rheumatoid arthritis

Objective. To evaluate the impact of chronic inflammation on lipoprotein lipase (LPL) levels and triglyceride metabolism in patients with rheumatoid arthritis (RA). Design. Plasma levels of LPL activity and mass before and after heparin were determined in post-menopausal women with active RA and in controls. The results were related to lipid levels and inflammatory variables. The LPL activity and mass together with triglyceride levels were also measured before and 6 h after an oral fat load. Setting. The study was performed on in- and out-patients at a University Rheumatology clinic. The controls came from the same reference area. Subjects. Altogether 17 consecutive post-menopausal female patients with RA and 16 age and sex matched controls were enrolled for the initial determination of LPL. Fifteen of the patients and 15 of the controls agreed to take part in the fat load. Of these, one patient and one control were excluded. Main outcome measures. LPL determination: basal levels and post-heparin levels of LPL activity and mass. Correlations between LPL and blood lipids (cholesterol, triglycerides), lipoprotein levels (high density lipoprotein, HDL; low density lipoprotein, LDL), erythrocyte sedimentation rate (ESR) acute phase proteins (orosomucoid, haptoglobin, fibrinogen mass) and cytokines (tumour necrosis factor α, TNF-α; interleukin 1β, IL-1β; and interleukin-6, IL-6). Fat tolerance test: LPL activity, mass and triglyceride levels before and 6 h after a per oral fat load. Results. Pre-heparin LPL mass (P<0.01) and activity (P<0.01) were significantly lower in the rheumatoid patients. Pre-heparin LPL mass showed no correlation to the lipid levels, but an inverse correlation to several inflammatory parameters; it was significant for orosomucoid (r_s=?0.63, P<0.05) and C-reactive protein (CRP) (r_s=?0.54, P<0.05) and close to significant for haptoglobin (r_s=?0.48, P=0.087) and IL-6 (r_s=?0.52, P=0.061). Six hours after a lipid load the LPL activity and mass were significantly lower in RA (P<0.05 and P<0.01, respectively) but the triglyceride level was not significantly different compared to controls. Conclusion. An inverse relationship exists between inflammatory status and pre-heparin LPL mass. Pre-heparin LPL mass reflects mainly the inactive monomeric fraction of LPL. This has been shown to hinder the uptake of remnant lipoprotein particles through competition with lipoprotein bound dimeric LPL for the LDL receptor-related protein (LRP receptor) on hepatocytes and macrophages in culture. A decrease of the level of monomeric LPL in plasma may thus be beneficial for remnant catabolism. The same mechanism may on the other hand increase macrophage uptake of lipids. This may not affect global lipid metabolism but may be important in driving the atherosclerotic process in the vessel wall.