V. A. Koivisto

Exercise-induced hypoglycaemia in IDDM patients treated with a short-acting insulin analogue

SummaryIn order to examine the effect of shortacting insulin analogue on the exercise-induced hypoglycaemia in insulin-dependent diabetes mellitus (IDDM) patients we compared the glycaemic response of 40 min cycle ergometer exercise performed either shortly (40 min) or later (180 min) after a breakfast meal and subcutaneous injection of either short-acting insulin analogue [Lys(B28) Pro(B29)] or soluble human insulin (Humulin Regular) in ten IDDM patients with long duration of the disease. Both preparations had been used 1 month before respective studies. Changes in blood glucose, insulin and counterregulatory hormones were assayed. As compared to human insulin, after the analogue injection the peak insulin concentration came earlier, was 56% higher (p<0.05) and disappeared faster, and the postprandial blood glucose response was lower (p<0.05). In the analogue-treated patients the exercise-induced hypoglycaemia was 2.2-fold greater (p<0.01) during the early exercise, but 46% less (p<0.05) during late exercise as compared to the treatment with human insulin. Serum insulin or analogue concentration at the beginning of the exercise correlated closely with the fall in blood glucose during exercise (r=0.74,p<0.01;r=0.73,p<0.02, respectively). In the analogue-treated patients, fasting serum glucagon and adrenalin concentrations were higher than during human insulin therapy (p<0.05) and remained so throughout the study. As compared to soluble human insulin, a much faster absorption of insulin analogue: 1) reduces post-prandial hyperglycaemia, 2) can either augment or reduce exercise-induced hypoglycaemia depending on the time interval between insulin injection and the time of exercise. Since exercise in usually not performed until 2–3 h after a meal, short-acting insulin analogue may be more feasible than soluble human insulin for active IDDM patients. [Diabetologia (1995) 38: 106–111]

Troglitazone reduces hyperglycaemia and selectively acute-phase serum proteins in patients with Type II diabetes

Aims/hypothesis. Inflammation could play a part in insulin resistance. Thiazolidinediones, new antidiabetic drugs, possess anti-inflammatory effects in vitro. We investigated if acute-phase serum proteins are increased in patients with Type II (non-insulin-dependent) diabetes mellitus who had been treated with insulin and whether troglitazone has anti-inflammatory effects in vivo.¶Methods. A total of 27 patients (age 63.0 ± 1.7 years, HbA1 c 8.8 ± 0.3 %, BMI 32.7 ± 0.8 kg/m2, duration 15.2 ± 1.4 years, insulin dose 73.3 ± 7.0 U/day) participated in the study. The patients received daily either 400 mg troglitazone or placebo for 16 weeks. Blood samples were taken at baseline, at the end of therapy and after a follow-up time of 23 ± 4 days.¶Results. The concentrations of serum amyloid A (6.2 ± 1.1 mg/l) and C-reactive protein (6.1 ± 1.1 mg/l) were increased (p < 0.001) and complement protein C3 (1.69 ± 0.05 g/l) was also above the reference range for healthy subjects. Placebo treatment had no effect on glucose or inflammation, whereas troglitazone reduced fasting glucose (from 10.4 ± 0.6 mmol/l to 8.1 ± 0.5 mmol/l, p < 0.01), HbA1 c (from 8.7 ± 0.3 % to 7.5 ± 0.3 %, p < 0.01), insulin requirements (from 75 ± 10 U/day to 63 ± 10 U/day, p < 0.05), serum amyloid A (from 6.3 ± 1.5 mg/l to 4.0 ± 1.3 mg/l, p = 0.001), α-1-acid glycoprotein (from 906 ± 51 mg/l to 729 ± 52 mg/l, p = 0.001) and C3 (from 1.72 ± 0.07 g/l to 1.66 ± 0.06 g/l, p < 0.05) but not α-1-antitrypsin, ceruloplasmin, C-reactive protein or haptoglobin significantly. Concentrations of glucose and acute-phase reactants had returned to those before treatment at the follow-up visit.¶Conclusion/interpretation. In Type II diabetic patients serum amyloid A and complement protein C3 are raised. Troglitazone exerts a selective reversible action on some acute-phase proteins and C3 but not on others in conjunction with the improvement in glucose metabolism. [Diabetologia (1999) 42: 1433–1438]

Plasma Acylation Stimulating Protein Concentration and Subcutaneous Adipose Tissue C3 mRNA Expression in Nondiabetic and Type 2 Diabetic Men

Abstract—We studied the effect of an oral fat load on plasma acylation stimulating protein (ASP) concentrations in 9 lean healthy (age 59±2 years, body mass index[BMI] 23.2±0.4 kg/m2; both mean±SEM), 9 obese nondiabetic (58±2 years, BMI 29.4±0.5 kg/m2), and 12 type 2 diabetic (60±2 years, BMI 29.6±1.0 kg/m2) men. Because ASP is a cleavage product of complement protein C3 (C3adesArg) and its secretion is regulated by insulin, we also examined the subcutaneous adipose tissue expression of C3 mRNA before and after a 240-minute euglycemic hyperinsulinemic clamp in a subgroup of these men. Plasma ASP concentration and adipose tissue C3 mRNA expression were higher in the obese groups than in the lean men. Plasma ASP concentration did not change significantly after the fat load. Fasting plasma ASP concentration and C3 mRNA expression were correlated negatively with insulin sensitivity and positively with the magnitude of postprandial lipemia in nondiabetic but not in type 2 diabetic men. The expression of C3 mRNA was not regulated by insulin. These data suggest that ASP is associated with whole-body glucose and lipid metabolism in nondiabetic individuals, whereas metabolic disturbances in diabetes may overcome the regulatory role of ASP in lipid and glucose metabolism.

Serum leptin concentration and fuel homeostasis in healthy man

We studied the interrelationship between the obese gene product serum leptin, insulin and counterregulatory hormone concentrations and glycogen synthesis in 26 healthy men. A 4‐h euglycaemic insulin clamp with muscle biopsies was performed after a resting control day in 26 subjects, and in 14 of them also after heavy, glycogen‐depleting (32%, Pu2003<u20030.01) exercise. Serum leptin concentrations were at baseline 34% (0.67u2003u2003±u2003u20030.18 vs. 1.03u2003u2003±u2003u20030.13u2003ngu2003L−1, Pu2003u2003±u2003u20030.05) lower after the exercise, and rose during hyperinsulinaemia by 56% (to 1.38u2003u2003±u2003u20030.19u2003ngu2003L−1, Pu2003<u20030.001) and 34% (to 1.05u2003±u20030.20u2003ngu2003L–1, Pu2003<u20030.01) after the post‐exercise and control studies respectively. Basal serum leptin concentration correlated positively with body mass index (ru2003=u20030.42, Pu2003<u20030.05), serum cortisol concentration (ru2003=u20030.70, Pu2003<u20030.001) and the rise in muscle glycogen content during the clamp (ru2003=u20030.43, Pu2003<u20030.05) and inversely with serum growth hormone concentration (ru2003=u2003−0.43, Pu2003<u20030.05). There was a positive correlation between serum leptin after hyperinsulinaemia and serum insulin concentration during the hyperinsulinaemia (ru2003=u20030.42, Pu2003<u20030.05). After exercise, basal serum leptin level correlated with serum triglyceride concentration (ru2003=u20030.82, Pu2003<u20030.001) and after hyperinsulinaemia serum leptin correlated positively with muscle glycogen content (ru2003=u20030.56, Pu2003<u20030.05). It was concluded that serum leptin concentrations correlate directly with serum insulin, cortisol and triglyceride and inversely with growth hormone concentrations. They are decreased by glycogen‐depleting exercise and increase during hyperinsulinaemic clamp. These data suggest that leptin is associated with factors regulating fuel homeostasis and its hormonal control in man.

Insulin-independent glucose transport regulates insulin sensitivity

The glucose transport proteins (GLUT1 and GLUT4) facilitate glucose transport into insulin‐sensitive cells. GLUT1 is insulin‐independent and is widely distributed in different tissues. GLUT4 is insulin‐dependent and is responsible for the majority of glucose transport into muscle and adipose cells in anabolic conditions. We suggest the hypothesis that insulin resistance is dependent on whether glucose is entering through GLUT1 or GLUT4 and on the two functional compartments of glucose 6‐phosphate formation within the cell. Glucose entering the muscle cell through GLUT4 and phosphorylated by hexokinase II is mainly directed to glycogen synthesis and glycolysis. If glucose is entering through GLUT1 and phosphorylated by hexokinase I, the glucose 6‐phosphate so formed is available for all metabolic pathways, including the hexosamine pathway. Hexosamines have a negative feedback effect on GLUT4, and reduced GLUT4 activity decreases insulin‐mediated glucose uptake. Thus, insulin‐independent glucose transport through GLUT1 can meet the basal needs of the muscle cell. If glucose entrance through GLUT1 and the activation of the hexosamine pathway is abundant, it can decrease the insulin‐mediated glucose transport through GLUT4 leading to insulin resistance.

Dyslipidemia and a reversible decrease in insulin sensitivity induced by therapy with 13-cis-retinoic acid.

13‐cis‐Retinoic acid (Roaccutan®) treatment is associated with disturbances in lipid and sometimes also in glucose metabolism. Thus, we investigated whether 13‐cis‐retinoic acid treatment decreases insulin sensitivity.

The human insulin analogue insulin lispro.

Insulin lispro is a newly developed analogue of human insulin where the positions of the amino acids lysine and proline have been switched at the end of the B chain of the insulin molecule. Insulin lispro with lysine at position B28 and proline at position B29 has a weaker tendency for self-association than human insulin. This leads to three major differences in the pharmacokinetics: the action begins faster, has a higher peak and the duration is shorter than with human insulin. Thus, insulin lispro has a more precise action profile for the mealtime than human regular insulin. Insulin lispro is recommended to be injected within 15 min before the meal in contrast to 30-40 min for human insulin. In clinical trials with insulin lispro, the postprandial rise of blood glucose is smaller, the rate of hypoglycaemia is lower particularly at night-time, the need for snacks is smaller and the patient preference is better than with human insulin. The long-term control as reflected by an improvement in the HbA1c level is better with insulin lispro than with human regular insulin, provided that an appropriate basal insulin regimen is used to take into account the shorter duration of action. A few patients have been described who have a severe resistance to human insulin but who have been successfully treated with insulin lispro. Insulin lispro was designed to be used as a mealtime insulin, and it is a step forward in the treatment of diabetic patients using a basal-bolus insulin regimen.

Is brain uptake of leptin in vivo saturable and reduced by fasting

Abstract. Leptin is a peptide hormone produced by adipocytes which provides a negative feedback signal to control the amount of body fat. The action of leptin on food intake and weight loss is thought to be mediated by interaction with its hypothalamic receptor. We examined the biodistribution and brain uptake of radioiodinated leptin (123I-leptin) by dynamic gamma imaging in six anaesthetized New Zealand white rabbits. Leptin uptake was seen in the brain, lungs, liver and kidneys. In the brain, increase in radioactivity as a function of time was seen in the choroid plexus area. The choroid plexus to brain radioactivity ratio (CP/BR) was used as the target to background ratio. The CP/BR ratio increased up to approximately 40–60 min, after which a steady state in CP/BR was achieved. The steady state uptake ratio was higher in the rabbits that had fasted for only 6–8 h before the experiment (CP/BR approximately 2.5) than in those that had fasted for 25–27xa0h before the experiment (CP/BR approximately 1.8). Thus, leptin uptake in vivo occurs in the choroid plexus region of the brain and in the lungs, kidney and the liver. The uptake of leptin in the choroid plexus appears to be saturable, as indicated by the achieved steady state in the CP/BR radioactivity curve 40–60xa0min following 123I-leptin injection. The lower steady state CP/BR after prolonged fasting may be the result of the downregulation of leptin receptors in the choroid plexus.

Increased fetal leptin in Type I diabetes mellitus pregnancies complicated by chronic hypoxia

Aims/hypothesis. The purpose of this study was to examine whether fetal leptin concentration correlates with severity of chronic or subchronic fetal hypoxia as indicated by increased fetal concentrations of erythropoietin in fetuses of mothers with Type I (insulin dependent) diabetes mellitus.¶Methods. We measured leptin and erythropoietin concentrations in cord plasma and amniotic fluid with radioimmunoassay in 25 pregnancies (gestational age 37.2 ± 1.0 weeks). Fetuses with amniotic fluid erythropoietin over 22.5 mU/ml were classified as hypoxic (n = 9) and those with amniotic fluid erythropoietin below 22.5 mU/ml (n = 16) as non-hypoxic.¶Results. The hypoxic fetuses had significantly higher cord leptin concentrations than non-hypoxic fetuses (median 36.8; range, 12.5–135.1 vs median 16.2; range, 3.7–52.2 μg/l), (p = 0.0066). Cord plasma leptin (n = 25) correlated directly with amniotic fluid erythropoietin (r = 0.727, p = 0.0001), with cord plasma erythropoietin (r = 0.644, p = 0.0005) and with the maternal last trimester HbA1C (r = 0.612, p = 0.0019) and negatively with cord artery pO2 (r = –0.440, p = 0.032), and pH (r = –0.414, p = 0.040).¶Conclusion/interpretation. Fetal leptin concentrations increased concomitantly with erythropoietin during chronic or subchronic hypoxia. This phenomenon could indicate a role for leptin in fetal adaptation to hypoxia. [Diabetologia (2000) 43: 709–713]

Subcutaneous adipose tissue expression of plasminogen activator inhibitor-1 (PAI-1) in nondiabetic and Type 2 diabetic subjects.

Increased plasma levels of plasminogen activator inhibitor‐1 (PAI‐1) have been suggested to be a part of the insulin resistance syndrome, and recent data suggest that adipose tissue participates in the production of PAI‐1. We examined the expression and insulin regulation of subcutaneous adipose tissue PAI‐1 mRNA and its relationship to insulin sensitivity.