The effects of human proinsulin on glucose turnover and intermediary metabolism

We compared the effects of human proinsulin and human insulin on glucose disposal, suppression of hepatic glucose production (HGP), and intermediary carbohydrate and lipid metabolism. Six young, lean, subjects underwent eight separate euglycemic clamps with low-dose intravenous (IV) infusions of insulin and proinsulin (four each). The insulin infusions gave steady-state levels of 0.08 +/- 0.004 (I1), 0.12 +/- 0.003 (I2), 0.18 +/- 0.07 (I3), and 0.25 +/- 0.06 nmol/L (I4). The proinsulin infusions were chosen to give steady-state levels approximately 20-fold higher on a molar basis than insulin, based on previous findings that proinsulin has only 5% to 10% the biological potency of insulin. Steady-state proinsulin levels were 1.2 +/- 0.04 (P1), 2.8 +/- 0.07 (P2), 4.5 +/- 0.3 (P3), and 6.9 +/- 0.3 nmol/L (P4). HGP was suppressed equally by proinsulin and insulin at the four dose levels. Percentage elevation of glucose disposal was significantly increased during each of the insulin infusions compared with proinsulin: I1 107% +/- 4%, P1 87% +/- 4% (P = .03); I2 143% +/- 7%, P2 125% +/- 12% (P = .01); I3 238% +/- 38%, P3 173% +/- 22% (P = .03); I4 283% +/- 17%, P4 178% +/- 11% (P = .002). Dose-response curve analysis demonstrated that proinsulin stimulated glucose disposal approximately 3.3% compared with insulin. The effectiveness of proinsulin in suppressing HGP was approximately 5% compared with insulin. Plasma nonesterified fatty acids, blood glycerol, and 3-hydroxybutyrate were suppressed by similar amounts during each of the four insulin and proinsulin doses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Direct effects of glucose on proinsulin synthesis and processing during desensitization

Prolonged exposure of isolated islets to glucose (11 mM) results in desensitization of insulin secretion. In this study, both glucose-regulated proinsulin biosynthesis and its processing during glucose-induced desensitization were examined at critical periods during 24 h. Although insulin secretion declined at 24 h to one third the 3 h maximum rate, the total rate of proinsulin biosynthesis, assessed by [3H]leucine incorporation, was unchanged at 0, 3, and 24 h of glucose (11 mM) exposure. Total insulin recovery measured by immunoreactive insulin in islets and media after 24 h was approximately 172% of the initial islet content. After correction for insulin degradation, and since proinsulin biosynthesis was unchanged, the synthesis rate was calculated to be a constant 3.5 +/- 1.1%/h of the initial islet content. Results suggest that desensitization may occur at the release mechanism rather than at a step in glucose metabolism common for the stimulation of synthesis and secretion. In contrast, the conversion rate of proinsulin to insulin progressively increased with prolonged prior glucose exposure, the major increase occurring by 3 h of glucose preincubation. Low glucose (2 mM), when used during the 3-h prelabeling period, did not affect the conversion rate. Furthermore, cycloheximide added during the 3-h preexposure to glucose (11 mM) completely prevented glucose-induced activation of the conversion process. These results indicate that the conversion rate of proinsulin to insulin is a glucose-regulated process requiring synthesis of a pool of either converting enzyme(s) or other regulating protein before initiation of proinsulin synthesis.     

The effect of metformin on glycaemic control, intermediary metabolism and blood pressure in non-insulin-dependent diabetes mellitus

Fourteen non-insulin-dependent diabetics (9 female, 5 male), aged 46 to 64 years, uncontrolled by diet (fasting plasma glucose greater than or equal to 8 mmol/l), were treated with metformin, 1-3 g daily, and followed prospectively at 1 week, then at 2-weekly intervals for 6 months. The fasting plasma glucose fell significantly (p less than 0.01) after 1 week of therapy and HbA1 showed a significant reduction, 13.4 +/- 2.5% (mean +/- SD) to 10.7 +/- 1.8% (normal range 5.1-9.3%) at 8 weeks (p less than 0.001). There was no significant change in body weight, plasma insulin, serum cholesterol or triglycerides, blood lactate, pyruvate, glycerol, alanine, 3-hydroxybutyrate or acetoacetate concentration. Systolic, diastolic, and mean arterial blood pressures, along with resting heart rate remained unchanged. This study shows that metformin effectively lowers plasma glucose without hyperinsulinism or significant rise in fasting blood lactate and other gluconeogenic precursors.     

The origin of intermediary metabolism

The core of intermediary metabolism in autotrophs is the citric acid cycle. In a certain group of chemoautotrophs, the reductive citric acid cycle is an engine of synthesis, taking in CO(2) and synthesizing the molecules of the cycle. We have examined the chemistry of a model system of C, H, and O that starts with carbon dioxide and reductants and uses redox couples as the energy source. To inquire into the reaction networks that might emerge, we start with the largest available database of organic molecules, Beilstein on-line, and prune by a set of physical and chemical constraints applicable to the model system. From the 3.5 million entries in Beilstein we emerge with 153 molecules that contain all 11 members of the reductive citric acid cycle. A small number of selection rules generates a very constrained subset, suggesting that this is the type of reaction model that will prove useful in the study of biogenesis. The model indicates that the metabolism shown in the universal chart of pathways may be central to the origin of life, is emergent from organic chemistry, and may be unique.     

Ovine placental lactogen: acute effects on intermediary metabolism in pregnant and non-pregnant sheep.

The intravenous administration of ovine placental lactogen to pregnant and non-pregnant sheep produced significant acute decreases in plasma free fatty acid, glucose and amino nitrogen concentrations. Plasma insulin concentrations decreased 1 h after administration of ovine placental lactogen and then increased significantly above baseline concentrations. The results suggest that, like human placental lactogen, ovine placental lactogen is important in the modulation of intermediary metabolism during pregnancy. The sheep is an excellent animal model for the investigation of the physiology of placental lactogen.     

Increased renal glucose metabolism in Type 1 diabetes mellitus.

AIMS: In poorly controlled diabetes, increased renal glucose uptake has been implicated in the pathogenesis of diabetic nephropathy by promoting nonenzymatic glycosylation of proteins, activation of protein kinase C, and increased polyol pathway flux. However, whether glucose uptake by the diabetic kidney is actually increased, especially in patients with Type 1 diabetes, is unclear. METHODS: To examine this question, we used a combination of net balance and isotopic techniques to compare renal glucose uptake in 12 subjects with Type 1 diabetes before and after restoration of near normoglycaemia by infusion of insulin with that in 15 postabsorptive nondiabetic volunteers. RESULTS: Prior to insulin infusion, the diabetic subjects were markedly hyperglycaemic (arterial glucose 15.8 +/- 0.9 vs. 4.4 +/- 0.1 mm) and their renal tissue glucose uptake (i.e. total glucose disappearance across the kidney minus glycosuria) was increased more than 2 1/2-fold (388 +/- 43 vs. 148 +/- 12 micromol/min, P < 0.001). This was wholly explained by the mass action effects of hyperglycaemia since the diabetic subjects had normal renal blood flow (1575 +/- 82 vs. 1492 +/- 68 mL/min, P = 0.46) and reduced renal tissue glucose fractional extraction (1.7 +/- 0.2 vs. 2.3 +/- 0.1%, P = 0.027). Insulin infusion for three hours, which restored near normoglycaemia (arterial glucose 7.6 +/- 0.7 mm), reduced renal tissue glucose uptake toward normal (258 +/- 41 micromol/min, P = 0.006) without altering renal blood flow (1557 +/- 110, P = 0.63) or renal tissue glucose fractional extraction (2.1 +/- 0.3%, P = 0.35). Renal and hepatic glucose release, which had been increased (419 +/- 49 and 960 +/- 54 vs. 204 +/- 9 and 734 +/- 32 micromol/min, both P < 0.001), were suppressed by insulin to 138 +/- 22 and 520 +/- 53 micromol/min, respectively (both P < 0.001). CONCLUSIONS: In poorly controlled Type 1 diabetes, renal glucose uptake is markedly increased, which provides a link between hyperglycaemia and biochemical processes implicated in the pathogenesis of diabetic nephropathy. Its reversal by restoration of near normoglycaemia with insulin may explain the benefit of intensive insulin therapy in preventing diabetic nephropathy.     

Impaired glucose tolerance is characterized by multiple abnormalities in the regulation of intermediary metabolism.

The responses of circulating intermediary metabolites to a low-dose sequential insulin infusion (basal, 0.005, 0.01, and 0.05 U kg-1 h-1) were assessed in eight non-obese men with Impaired Glucose Tolerance (IGT), and in eight healthy control subjects with normal glucose tolerance matched for age, gender, and body mass index. Fasting hyperinsulinaemia was observed in the subjects with IGT (7.4 +/- 1.0 vs 2.9 +/- 0.3 mU I-1, p less than 0.001). While there was no significant difference (p greater than 0.1) in fasting venous glucose levels between the groups, fasting concentrations of lactate (p less than 0.02), alanine (p less than 0.01), and glycerol (p less than 0.05) were significantly elevated in the subjects with IGT. During the incremental insulin infusion, overall concentrations of glucose (p less than 0.05), lactate (p less than 0.05), alanine (p less than 0.05), glycerol (p less than 0.05), immunoreactive insulin (p less than 0.001), and C-peptide (p less than 0.01) were significantly higher in the subjects with IGT. Linear dose-response relationships (p less than 0.005) for circulating immunoreactive insulin (log) vs metabolite concentrations were demonstrated by analysis of variance for glucose, non-esterified fatty acids (NEFA), glycerol, and total ketone bodies. For glucose, glycerol, and NEFA, group dose-response regression lines for the subjects with IGT were displaced significantly to the right (p less than 0.001 for each) of those for the normal control subjects, implying insulin insensitivity. In addition to the recognized defect in glucose homeostasis, these results indicate impaired regulation of multiple aspects of intermediary metabolism including lipolysis in IGT.     

Abnormal regulation of intermediary metabolism after oral glucose ingestion in myotonic dystrophy

The responses of plasma insulin and blood intermediary metabolites to oral glucose (75 g) were determined in 10 subjects with myotonic dystrophy. Results were compared with responses in 10 normal control subjects matched for age, sex, and body mass index. Fasting hyperinsulinemia was observed in the myotonic subjects (7.5 +/- 1.6 v 2.4 +/- 0.4 mU/L; P less than .005) and plasma insulin concentration remained significantly higher following oral glucose (F = 38.09; P less than .001). Total cumulative insulin release was markedly higher in the myotonic subjects (4,984.3 v 1,286.6 mU/L; P less than .0001). Basal blood glucose concentration was normal (4.8 +/- 0.2 v 4.7 +/- 0.1 mmol/L), although overall blood glucose was elevated in the myotonic subjects following oral glucose ingestion (F = 5.37; P less than .05). Glucose tolerance was normal in all subjects. Fasting blood lactate was higher in the myotonic subjects (1.31 +/- 0.13 v 0.94 +/- 0.08 mmol/L; P less than .05) and remained significantly elevated following the ingestion of glucose (F = 7.22; P less than .02). Blood pyruvate response was also higher in the myotonic subjects (F = 5.88; P less than .05). Basal blood glycerol was elevated in the myotonic subjects (0.12 +/- 0.02 v 0.05 +/- 0.01 mmol/L; P less than .005) and remained elevated following oral glucose (F = 11.31; P less than .005). No significant overall differences were observed in ketone bodies, alanine, or fatty acids between the groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of human proinsulin C-peptide on erythrocyte deformability in patients with Type I diabetes mellitus

Aims/hypothesis. In recent years, evidence has arisen that proinsulin C-peptide exerts biological effects especially on microcirculation, e. g. C-peptide has been shown to increase skin microcirculation in patients with Type I (insulin-dependent) diabetes mellitus and to activate endothelial nitric oxide synthase. This study aimed to investigate the influence of proinsulin C-peptide on erythrocyte deformability which was assessed by means of laser diffractoscopy. Methods. Blood samples from healthy control subjects (n = 10) and Type I diabetic patients (n = 15) completely deficient of C-peptide were analysed at shear stresses ranging from 0.3 to 30 Pa. Results. Erythrocyte deformability was lower in the group of Type I diabetic patients than in the control subjects. Preincubation of the diabetic blood samples with various concentrations of human proinsulin C-peptide for 8 h restored the deformability of erythrocytes, almost reaching the values of control samples. In contrast, proinsulin C-peptide did not modify the erythrocyte deformability of control subjects. Conclusion/interpretation. We conclude that proinsulin C-peptide is able to ameliorate the impaired deformability of erythrocytes in Type I diabetic patients and we hypothesise that this effect is mediated by restoration of Na⁺-K⁺-ATPase activity, which is known to be attenuated in diabetic patients. [Diabetologia (1999) 42: 465–471] Received: 27 August 1998 and in final revised form: 15 December 1998     

Immunosuppressive agents: effects on glucose and lipid metabolism.

Immunosuppressive therapies are critical elements in successful organ transplantation. Although immunosuppressant drugs are essential in preventing graft rejection and graft maintenance after transplantation, their use is complicated by adverse effects, many being detrimental to graft and even patient long-term survival. Commonly used agents are associated with dysregulated glucose metabolism and dyslipidemia. This article focuses on the effects of immunosuppressive agents on glucose and lipid metabolism. Adrenal effects of these drugs, where known, also are discussed.     

A comparison of the effects of corticosterone and cortisol on intermediary metabolism of Calotes versicolor.

Corticosterone and cortisol administered to Calotes versicolor significantly increased the concentrations of blood glucose and urea (liver and kidney), the specific activities of glucose-6-phosphatase (liver and kidney), and glutamic oxaloacetic transaminase (liver and heart); they markedly reduced hepatic cholesterol level and did not change the activities of acid phosphatase (liver and kidney) and glutamic pyruvic transaminase (liver), when compared to vehicle-treated controls.     

The effects of carbohydrate-enriched meals on glucose turnover and metabolic clearance rates of glucose in Type 2 diabetic patients

Summary The addition of fructose to natural meals elicits lower serum glucose and immunoreactive insulin responses when compared with that of sucrose and starch meals. Differences in rates of splanchnic glucose appearance and peripheral glucose disposal may be partly responsible. To evaluate the role of both parameters after different carbohydrate-enriched meals, we measured the arterialized venous blood glucose, immunoreactive insulin and gastric inhibitory polypeptide concentrations in seven Type 2 diabetic patients after ingestion of isocaloric test meals. Measurements were made in a random manner on three separate occasions. Fructose, sucrose, and bread supplementation constituted 68% of the total carbohydrate content of each meal. Rates of total glucose appearance, glucose utilization and metabolic clearance rates of glucose were determined by the D³-H-3glucose prime-continuous infusion technique. The mean fasting glucose levels were similar in the three groups. Mean peak glucose concentrations and integrated incremental areas were significantly lower (p < 0.02) after the fructose-enriched meals compared with that of either sucrose or bread. The basal arterialized venous blood glucose levels were similar in all three groups. The mean incremental integrated arterialized venous blood glucose area was significantly lower in the fructose group when compared with the sucrose (p < 0.05) and bread (p < 0.02) groups. The mean fasting gastric inhibitory polypeptide levels were similar in the three groups. However, the mean incremental integrated gastric inhibitory polypeptide areas were significantly lower in the fructose group compared with the sucrose and bread groups (p < 0.01 and p < 0.05 respectively). Basal hepatic glucose outputs were not significantly different in the three groups. After each test meal ingestion, the rate of total glucose appearance was lowest for the fructose group, intermediate for the bread group and highest for the sucrose group. However, the metabolic clearance rate did not change from the baseline despite variable arterialized venous blood glucose responses after each test meal. We conclude that the differences in glycaemic responses after carbohydrate-enriched meals cannot be ascribed solely to differences in peripheral glucose disposal in Type 2 diabetic patients. Rather, the rates of total splanchnic glucose output appear to determine the ultimate glycaemic responses after different carbohydrate-enriched meals in Type 2 diabetic patients.     

The effects of proinsulin pretreatment on the combined actions of insulin and proinsulin in normal man

With the recent availability of biosynthetic human proinsulin there has been a renewed interest in evaluating its metabolic effects, either alone or in combination with insulin. It has been suggested that pretreatment with proinsulin enhances the hypoglycemic response to subsequently administered insulin. On the other hand, the simultaneous administration of proinsulin and insulin has additive, not synergistic, effects. To clarify this question we used the euglycemic glucose clamp technique in 10 normal subjects to compare the steady state effects on glucose disposal of combined infusions of insulin (0.54 microgram/M2 . min, equivalent to 15 mU/M2 . min) and proinsulin (2.75 micrograms/M2 . min) given both simultaneously and sequentially. The mean +/- SEM steady state glucose disposal rates were similar whether the two hormones were given simultaneously (7.2 +/- 0.7 mg/min . kg), after proinsulin pretreatment (7.7 +/- 0.7 mg/min . kg), or after insulin pretreatment (7.1 +/- 0.7 mg/min . kg). The serum proinsulin concentration of 5.39 +/- 0.3 pmol/ml during the infusion of proinsulin alone was unchanged by the simultaneous infusion of insulin, suggesting that in the doses used, insulin did not affect proinsulin clearance. We conclude that in normal subjects there is no enhancement of the combined action of insulin and proinsulin to stimulate glucose disposal by pretreatment with proinsulin or insulin.     

Effect of 1,25-dihydroxycholecalciferol on glucose metabolism in gestational diabetes mellitus

Summary The effect of 1,25-dihydroxyvitamin D supplement on glucose metabolism was evaluated in 12 women with gestational diabetes mellitus (GDM). All women had an oral glucose tolerance test (OGTT) performed at inclusion in the study. Thereafter, each patient was instructed to continue their normal diet during the following 2 days, after which they received 2 μg/m² Etalpha i. v. 2 h prior to the second OGTT. During the next 14 days each patient received 0.25 μg Etalpha orally, after which a third OGTT was performed. On average the level of 1,25-dihydroxyvitamin D₃ at inclusion at baseline significantly increased after i. v. 1,25-dihydroxyvitamin D₃ (from 92 to 138 ng/l [p < 0.001]), but returned to the baseline level after 2 weeks of oral Etalpha (85 ng/l). Simultaneously, the glucose level decreased from 5.6 to 4.8 mmol/l (p < 0.01) after i. v. treatment with 1,25-dihydroxyvitamin D₃, but did not differ significantly from inclusion following 2 weeks of oral Etalpha. There was no difference between the glucose concentrations during OGTT prior to and after i. v. or oral 1,25-dihydroxyvitamin D₃, in contrast to the insulin levels which tended to be lower after both i. v. and oral supplementation. In a multiple regression model including 1,25-dihydroxyvitamin D₃, insulin , weight and height against glucose, only 1,25-dihydroxyvitamin D₃ and insulin were selected for the final model (r ² = 0.73, p < 0.0001). Our results suggest that supplements of 1,25-dihydroxyvitamin D₃ influence glucose metabolism in patients with GDM probably by increasing the insulin sensitivity. [Diabetologia (1997) 40: 40–44] Received: 9 July 1996 and in revised form: 12 September 1996     

重组人胰岛素样生长因子1的促糖代谢作用研究

目的 研究胰岛素样生长因子１对糖代谢的影响。方法 分别以Ｂａｌｂ／ｃ ３Ｔ３成纤维细胞和昆明种小鼠为对象,研究重组人胰岛素样生长因子１的降糖作用。结果 （１）ＩＧＦ１使Ｂａｌｂ／ｃ３Ｔ３细胞培养液和葡萄糖浓度降到对照组的６５％,与胰岛素的降糖能力相似;（２）ＩＧＦ１能使小鼠血糖降到正常值２０％左右,降糖作用呈剂量－效应曲线。     

Insulin-mediated effects of glucose on dopamine metabolism

Summary Administration of various doses of glucose to rats produced a significant decrease of dopamine turnover in both striatum and olfactory tubercle. From the dose response curve, a close connection between 3,4-dihydroxyphenylacetic acid (DOPAC) variation and insulin plasma level was demonstrated. However, glucose did not affect dopamine metabolism in starved or streptozotocin-treated rats. This indicates that the effect of glucose on the central dopaminergic system is mediated by pancreatic insulin, even in the presence of endogenous brain insulin. Therefore, insulin may influence synaptic transmission in the central nervous system.