Alteration in insulin action: role of IRS-1 serine phosphorylation in the retroregulation of insulin signalling

Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterised by a decrease in insulin effect on glucose transport in muscle and adipose tIssue. Tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) and its binding to phosphatidylinositol 3-kinase (PI 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. Modification of IRS-1 by serine phosphorylation could be one of the mechanisms leading to a decrease in IRS-1 tyrosine phosphorylation, PI 3-kinase activity and glucose transport. Recent findings demonstrate that "diabetogenic" factors such as FFA, TNFalpha, hyperinsulinemia and cellular stress, increase the serine phosphorylation of IRS-1 and identified Ser307/612/632 as phosphorylated sites. Moreover, several kinases able to phosphorylate these serine residues have been identified. These exciting results suggest that serine phosphorylation of IRS-1 is a possible hallmark of insulin resistance in biologically insulin responsive cells or tIssues. Identifying the pathways by which "diabetogenic" factors activate IRS-1 kinases and defining the precise role of serine phosphorylation events in IRS-1 regulation represent important goals. Such studies may enable rational drug design to selectively inhibit the activity of the relevant enzymes and generate a novel class of therapeutic agents for type 2 diabetes.     

Hormonal and metabolic disturbances during acute and subacute myocardial infarction in man

Summary To investigate the cause of glucose intolerance (GIT), frequently seen during acute myocardial infarction (AMI), seventeen males without history of diabetes were studied with intravenous glucose tolerance tests within seventy-two hours after uncomplicated myocardial infarction and again three weeks later. Seventy percent (12/17) of the patients showed GIT during AMI. In 7 of these patients (41%) glucose tolerance (GT) remained abnormal after 3 weeks. In addition, all 7 showed markedly diminished insulin responses to glucose during both the acute and subacute phase. Therefore, their GIT was considered to be due to newly-recognized chemical diabetes. In the remaining patients in whom the initially depressed GT improved during SMI elevated serum levels of FF A, insulin, HGH and cortisol suggested the temporary presence of insulin antagonism. Increased adrenal medullary activity was not found to be a major factor inhibiting glucose tolerance.Supported in part by the Genesee Valley Heart Association, Rochester, New York and PHS Research Grant No. 5 MOI RR349.     

Einfluß der Gewichtsreduktion auf Metabolite des Kohlenhydrat- und Fettstoffwechsels und auf das Verhalten des Seruminsulins bei Adipositas

Zusammenfassung Um Anhaltspunkte dafür zu gewinnen, welche der bei der Fettsucht beobachteten Stoffwechselanomalien durch eine Reduktionsdiät rückbildungsfähig sind, untersuchten wir unter ambulanten Bedingungen 37 adipöse Patienten mit einem mittleren Übergewicht von 71% nachBroca. Ein klinisch-manifester Diabetes und endokrine Erkrankungen wurden ausgeschlossen. 20 der Probanden zeigten Störungen der Kohlenhydrattoleranz. Bei 17 lagen der i.v. und der orale Glucosetoleranz-Test im Normbereich. Beide Teilkollektive behandelten wir mit einer 1000 Cal.-Mischkost und sahen darunter eine Gewichtsabnahme von 21.2 bzw. 17.5 kg, entsprechend 34 bzw. 28% nachBroca, d.h. im Durchschnitt etwas weniger als die Hälfte des bestehenden Übergewichtes. — Beim Teilkollektiv mit gestörter Kohlenhydrattoleranz traten dabei folgende Veränderungen ein: — 1. Signifikante Besserung der Glucosetoleranz mit weitgehender Normalisierung des Nüchternblutzuckers und des 120 Minuten-Wertes nach oraler Glucosegabe, sowie derk-Werte für die i.v. und oralen Glucosetoleranz-Teste. — 2. Ein hochsignifikanter Abfall der stark erhöhten Nüchternwerte für das freie Serumglycerin mit Normalisierung des Quotienten: Freie Fettsäuren/ Glycerin im Nüchternblut. — 3. Signifikanter Rückgang der überhöhten Werte für die insulinähnliche Aktivität und für das immunologisch reagierende Insulin. — Unter den gleichen Bedingungen fanden wir im Teilkollektiv mit normaler Kohlenhydrattoleranz lediglich einen mäßigen Anstieg der freien Fettsäuren 90 und 120 nach Glucose. — Im Gesamtkollektiv der Fettsüchtigen war unter der Reduktionsdiät ein signifikanter Rückgang der Esterfettsäuren festzustellen. — Die unter 1–3 geschilderten Veränderungen traten unter dieser Diätbehandlung deutlicher hervor als bei den bisher beschriebenen Fastenkuren und betreffen vorwiegend das Teilkollektiv mit gestörter Kohlenhydrattoleranz. Die Befunde deuten daraufhin, daß der Hyperinsulinismus, der von einigen Autoren als ursächlich für die Fettsucht angesehen wird, eher adaptiver Natur ist.

---

Influence of weight reduction on carbohydrate and fat metabolism and on serum insulin response in obesity

Summary To find out which of the metabolic changes observed in obesity are reversible by a reducing diet, we examined 37 obese out-patients with a mean overweight of 71%Broca. A manifest diabetes mellitus and endocrine diseases were excluded by clinical means. 20 subjects showed disturbances of carbohydrate-tolerance. Oral and i.v. glucose-tolerance tests gave normal results in 17. Both subgroups were put on a 1000 cal. mixed diet and had mean weight-losses of 21.2, vs. 17.5 kg, corresponding to 34% vs. 28%Broca, i.e. less than half of their overweight. — The following changes were observed in the subgroup with impaired carbohydrate-tolerance: — 1. Significant improvement of glucose-tolerance with beginning normalization of fasting blood sugar, 120 value after oral glucose and of thek-values for i.v. and oral glucose-tolerance tests. — 2. Highly significant reduction of the elevated fasting values for free serum glycerol with normalization of the quotient: free fatty acids/glycerol in fasting serum. — 3. Significant fall of the high levels for insulin-like activity and for immunologically reacting insulin. — Under identical conditions the subgroup with normal carbohydrate-tolerance showed only a moderate increase of free fatty acids 90 and 120 after glucose. In the obese group as a whole, we found a reduction of serum esterified fatty acids under low calorie diet. — The changes described under 1–3 were more pronounced with this dietary treatment than in fasting periods generally described until now, and occurred predominantly in the subgroup with impaired carbohydrate-tolerance. Our findings indicate that hyperinsulinism held responsible for obesity up to now by some authors is probably adaptive.

Mit dankenswerter Unterstützung der Deutschen Forschungsgemeinschaft und des Landesamtes für Forschung des Landes Nordrhein-Westfalen. — Die Befunde wurden auszugsweise auf dem 6. Kongreß der Internationalen Diabetes Föderation vom 30. 7. — 4. 8. 1967 in Stockholm vorgetragen.     

训练时间、负荷内容对血液三羧酸循环产物和游离脂肪酸组分影响的观察

采用气相色谱法分析表明:发展脂代谢能力,提高血液中红细胞含量,不仅可以通过选择负荷内容,而且可通过选择最佳负荷时间。实验显示,早晨训练对三羧循环和FFA(游离脂肪酸)及其组分影响最大。     

外科病人围手术期血脂代谢的变化及其临床意义

对二组外科择期手术病人围手术期血浆游离脂肪酸即软脂酸（C16：0）、硬脂酸（C18：0）、油酸（C18：0）、亚油酸（C18：2）、花生四烯酸（C20：4）和甘油三脂及胆固醇水平变化的观察，发现手术后早期即有血脂水平的全面降低。血脂的降低随创伤应激的加重而具显著性且持久，提示在创伤应激早期机体主要通过利用血脂而获得能量，同时血糖应激性升高以保证神经细胞和红细胞的能量供应，并减少了乳酸生成，有利于维持重要的生命中枢功能和体液内环境稳定。本研究还发现，创伤后存在着显著而持久的低胆固醇血症，且血胆固醇水平与创伤程度及病人预后有较密切关系。创伤后在保证机体氧合状态正常的前提下，早期补充脂肪酸（特别是多不饱和脂肪酸）和胆固醇，将有助于减轻机体组织的分解代谢，稳定细胞结构和功能，保护机体内环境，防止多器官功能障碍的发生。     

A comparative study of metabolic and hormonal responses to somatostatin and propranolol in man

Summary The aim of this study was to compare the metabolic and hormonal effects of somatostatin to those of propranolol, a β-adrenergic blocking agent known to reduce basal insulin secretion. For this purpose, 6 normal subjects received somatostatin (4 μg/min) per 60 min and 6 subjects were infused with propranolol (0.08 mg/min). Somatostatin resulted in a significant decrease of basal insulin (p<0.05) and glucagon (p<0.01) and raised plasma FFA levels from a mean basal value of 417±24 μEq/l (x±SEM) to 600±46 μEq/l at 60 min (p<0.01). Propranolol significantly decreased basal insulin (p<0.05) and glucagon (p<0.05); FFA levels rose slightly at the end of propranolol administration (p>0.05). The levels of FFA which were significantly higher (p<0.025) during somatostatin as compared to those observed during propranolol, seem to suggest a role for this tetradecapeptide in lipid metabolism independent of its inhibiting action on islet hormone release.     

In vivo alpha 2-adrenoceptor-mediated inhibition of isoproterenol-stimulated free fatty acid output in dog bone marrow adipose tissue

Clomdine, an α₂ agonist, inhibited the isoproterenol-induced free fatty acid outflow from perfused bone marrow adipose tissue of dog tibia. This effect was suppressed by the α₂-antagonist, yohimbine. These in vivo experiments clearly demonstrate an α₂-adrenoceptor-mediated inhibition of isoproterenol-induced lipid mobilization and argue for a physiological interplay between β- and α₂-site stimulation in the regulation of lipolysis.     

Reabsorption ofl-glutamine andl-histidine from various regions of the rat proximal convolution studied by stationary microperfusion: Evidence that the proximal convolution is not homogeneous

Summary The glycogen depletion pattern in human muscle fibers was followed throughout the course of prolonged exercise at a work load requiring 67% of the subjects' maximal aerobic power. Biopsy samples were taken from the vastus lateralis muscle at rest and after 20, 60, 120, and 180 (or when unable to continue at the prescribed load) min of exercise. Muscle fibers were identified as fast twitch (FT) or slow twitch (ST) on the basis of myofibrillar ATPase activity. The glycogen content of muscle samples was determined biochemically. At the end of the exercise total muscle glycogen content was very low. Glycogen was also estimated in the fibers with the PAS stain. ST fibers were the first to become depleted of their glycogen but as the exercise progressed, the FT fibers were also depleted. These data may suggest a preferential utilization of ST fibers during prolonged, intense exercise, with a secondary recruitment of FT occuring as the ST fibers became depleted of their glycogen stores.     

Subcellular distribution and incorporation of palmitate-U-14C into myocardial lipids: Role of endogenous and exogenous catecholamines

In order to assess the role played by exogenous catecholamine stores on the ability of cardiac muscle to incorporate palmitate-U-¹⁴C into tissue lipids, hearts from normal rabbits and from rabbits acutely reserpinized to deplete cardiac catecholamines were perfused by the Langendorff technique. The effect of exogenous norepinephrine was also evaluated. The incorporation of palmitate-U-¹⁴C into tissue lipids in the catecholamine-depleted hearts was found to be 67% of the control value and was 71% above control in norepinephrine-treated group. In catecholamine-depleted hearts, the microsomal tissue fraction was the major site of reduced incorporation of the label. Fractionation of the myocardial lipids by t.l.c. demonstrated that both ¹⁴C-phospholipids and ¹⁴C-neutral lipids were significantly reduced in the catecholamine-depleted hearts. Reduced levels of ¹⁴C-FFA in the catecholamine-depleted hearts and increased levels in norepinephrine-treated hearts suggested that norepinephrine facilitated, and catecholamine-depletion inhibited the transport of FFA across the cell membrane.     

RA患者血清FFA、hs-CRP及TNF-α的水平变化与胰岛素抵抗的关系

目的：研究类风湿性关节炎（RA）患者血清游离脂肪酸（FFA）、高敏C-反应蛋白（hs-CRP）和肿瘤坏死因子（TNF-α）水平的变化及其与胰岛素抵抗的关系。方法：测定92例RA患者（稳定期53例,活动期39例）及50例正常人血清FFA、空腹胰岛素（fINS）、空腹血糖（fPS）,同时检测hs-CRP、TNF-α、血脂等指标,并计算胰岛素敏感指数（ISI）、稳态模型胰岛素抵抗指数（Homa-IR）,分析FFA水平的变化与胰岛素抵抗的关系。结果：非活动期和活动期RA患者,FFA、hs-CRP、TNF-α、Homa-IR、TG和LP（α）水平均较正常对照组显著升高（P〈0.05或P〈0.01）,且活动期RA组FFA、hs-CRP、TNF-α、fINS、Homa-IR、TG和LP（α）水平较非活动期RA患者明显升高（P〈0.05或P〈0.01）;直线相关分析显示,血清FFA水平与hs-CRP、TNF-α、fINS、Homa-IR、TG和LP（α）呈正相关（P〈0.01）,与ISI呈负相关（P〈0.01）。结论：RA患者血清FFA水平明显升高,且与hs-CRP、TNF-α及胰岛素抵抗密切相关。