Exercise alleviates lipid-induced insulin resistance in human skeletal muscle-signaling interaction at the level of TBC1 domain family member 4.

Excess lipid availability causes insulin resistance. We examined the effect of acute exercise on lipid-induced insulin resistance and TBC1 domain family member 1/4 (TBCD1/4)-related signaling in skeletal muscle. In eight healthy young male subjects, 1 h of one-legged knee-extensor exercise was followed by 7 h of saline or intralipid infusion. During the last 2 h, a hyperinsulinemic-euglycemic clamp was performed. Femoral catheterization and analysis of biopsy specimens enabled measurements of leg substrate balance and muscle signaling. Each subject underwent two experimental trials, differing only by saline or intralipid infusion. Glucose infusion rate and leg glucose uptake was decreased by intralipid. Insulin-stimulated glucose uptake was higher in the prior exercised leg in the saline and the lipid trials. In the lipid trial, prior exercise normalized insulin-stimulated glucose uptake to the level observed in the resting control leg in the saline trial. Insulin increased phosphorylation of TBC1D1/4. Whereas prior exercise enhanced TBC1D4 phosphorylation on all investigated sites compared with the rested leg, intralipid impaired TBC1D4 S341 phosphorylation compared with the control trial. Intralipid enhanced pyruvate dehydrogenase (PDH) phosphorylation and lactate release. Prior exercise led to higher PDH phosphorylation and activation of glycogen synthase compared with resting control. In conclusion, lipid-induced insulin resistance in skeletal muscle was associated with impaired TBC1D4 S341 and elevated PDH phosphorylation. The prophylactic effect of exercise on lipid-induced insulin resistance may involve augmented TBC1D4 signaling and glycogen synthase activation.

The effects of adjuvant insulin therapy among pregnant women with IGT who failed to achieve the desired glycemia levels by diet and moderate physical activity.

OBJECTIVE: Evaluation of adjuvant insulin therapy effects on glycemic control, perinatal outcome and postpuerperal glucose tolerance in impaired glucose tolerance (IGT) pregnant women who failed to achieve desired glycemic control by dietary regime. METHODS: A total of 280 participants were classified in two groups: Group A patients continued with dietary regime and Group B patients were treated with adjuvant insulin therapy. Glycemic control was assessed by laboratory and ultrasonograph means. Pregnancy outcomes were evaluated by prevalence of pregnancy induced hypertension (PIH), high birth weight, neonatal hypoglycemia and caesarean section rates. Postpuerperal glucose tolerance was assessed by oral glucose tolerance test (oGTT). RESULTS: All laboratory and ultrasound indicators of glycemic control had significantly lower values in Group B. Group A women were more likely to develop the EPH (Edema, Proteinuria, Hypertension) syndrome, 20% versus 7.86% (p = 0.003). High birth weight occurred more frequently in Group A, but the difference was not significant (p = 0.197). Higher rate of caesarean delivery was in Group A than in Group B, 16.43% versus 26.43% (p = 0.041). The difference in neonatal hypoglycemia was not significant (p = 0.478). Pathological oGTT results were observed in 73 Group A patients and in 15 Group B patients. CONCLUSION: Lower caesarean section rates and the EPH syndrome incidence are the benefits of adjuvant insulin therapy in IGT patients.

Treatment with growth hormone, somatostatin, and insulin in combination with hypocaloric parenteral nutrition in gastrointestinal cancer patients after surgery.

OBJECTIVE: The metabolic response to gastrointestinal cancer in patients undergoing surgery is associated with hypermetabolism and insulin resistance. The potential use of synergetic anabolic hormones in conjunction with hypocaloric parenteral nutrition (HPN) has become a significant area of investigation. The presented study was performed to determine the clinical efficiency and safety of hormone therapy combined with HPN in patients with gastrointestinal cancer. METHODS: One hundred patients with a Nutrition Risk Screening score of 3 or 4 undergoing surgery for gastrointestinal cancer were randomized into two groups. The patients in the control group received standard total parenteral nutrition and systemic insulin. The patients in the study group received HPN and systemic insulin in addition to pretreatment with recombinant human growth hormone and octreotide. Clinical efficiency and safety were evaluated by the measurement of hormones and protein metabolites, immune function, clinical outcome, and adverse events. Follow-ups were performed to determine the influence on prognosis. RESULTS: Treatment with recombinant human growth hormone, octreotide, and insulin in combination with HPN significantly increased protein synthesis, immune function, and metabolic tolerance, decreased infectious complications, and shortened postoperative hospital stays, but did not increase the risk of tumor development and recurrence in the study group compared with the control group. CONCLUSION: The proper short-term perioperative administration of growth hormone, somatostatin, and insulin in combination with HPN can overcome the postoperative stress response through the increase of protein synthesis to improve immune function in patients with gastrointestinal cancer after surgery.

Rat C peptide I and II stimulate glucose utilization in STZ-induced diabetic rats.

AIMS: To study the effects of physiological concentrations of rat proinsulin C peptide I and II, respectively, on whole body glucose utilization in streptozotocin diabetic and healthy rats. METHODS: A sequential insulin clamp procedure was used (insulin infusion rates 3.0 and 30.0 mU.kg-1.min-1) in awake animals. C-peptide infusion rates were 0.05 and 0.5 nmol.kg-1.min-1. Blood glucose was clamped at 7.7 +/- 0.3 mmol/l in the diabetic rats and at 3.9 +/- 0.1 mmol/l in the healthy rats. RESULTS: In diabetic rats infused at lower rates of C peptide and insulin, glucose utilization increased by 79-90% (p < 0.001) compared with diabetic animals infused with saline and insulin. Increasing the rate of C-peptide infusion tenfold did not elicit a statistically significant further increase in glucose utilization. C peptide I and II exerted similar effects. The metabolic clearance rate for glucose in the diabetic animals infused with C peptide was not different from that of the healthy rats. During high-dose insulin infusion (30.0 mU.kg-1.min-1) glucose utilization increased considerably and no statistically significant C-peptide effects were observed. About 85% of the increase in glucose utilization induced by C peptide could be blocked by treatment with N-monomethyl-L-arginine. CONCLUSIONS/INTERPRETATION: Physiological concentrations of homologous C peptide stimulate whole body glucose utilization in diabetic but not in healthy rats. C peptide I and II elicit similar effects. The influence of C peptide on glucose utilization may be mediated by nitric oxide.

The effects of desferrioxamine and ascorbate on oxidative stress in the streptozotocin diabetic rat.

Oxidative stress and protein glycation are closely related processes that may contribute to the development of complications in diabetes mellitus. Treatment with antioxidants could protect against these processes at a biochemical level, and we have therefore investigated the effects of ascorbate and desferrioxamine treatment in the streptozotocin diabetic rat. Diabetic animals were given ascorbate 1 g/l in drinking water or desferrioxamine 6 mg/kg/day by subcutaneous injection and were killed after 6 weeks. In diabetic animals, oxidative stress was increased as shown by increased levels of conjugated dienes (CD) in plasma and malondialdehyde (MDA) in plasma, erythrocyte membranes, and urine. In addition, there was depletion of the nutritional antioxidants ascorbate, alpha-tocopherol, and retinol. Insulin treatment returned all of these parameters to normal. Ascorbate supplementation or desferrioxamine treatment alone failed to reduce oxidative stress, but a combination of both interventions restored MDA, CD, and antioxidant vitamins to control values. Both ascorbate and desferrioxamine also reduced HbA1c and glycated albumin levels. Treatment with antioxidants can reduce both oxidative stress and protein glycation and may help to reduce the risk of developing diabetic complications. However, ascorbate can have both prooxidant and antioxidant effects in vivo, and its use in pharmacological doses should be approached with caution.

Chronic intracerebroventricular infusion of insulin failed to alter brain insulin-binding sites, food intake, and body weight.

The present study was performed to explore the role of exogenous insulin in CSF in the control of energy balance in the rat. For this purpose, adult male Sprague-Dawley rats carrying an indwelling cannula in the right lateral cerebral ventricle were infused for a maximum of 10 days with insulin (Actrapid) at various rates (starting at 0, 45, 85, 170, and 600 ng/day) or anti-insulin antibody (IgG fraction; diluted 1:10 wt/vol) with an osmotic minipump. All those treatments did not modify the growing rates; neither total daily food intake nor the circadian rhythm of food intake was further modified. The chronic insulin infusion starting at 600 ng/day resulted in a chronic significant increase in CSF insulin levels without changing the plasma insulin level. It failed to alter specific insulin binding sites to Triton X-100 solubilized microsomal membranes from various brain areas (cerebral cortex, olfactory bulbs, and lateral and medial hypothalami) at the end of the 5- or 10-day period of insulin infusion. Purification of insulin receptors on a wheat germ agglutinin did not reveal any further effect of insulin. From these results, it seems unlikely that the input to the brain insulin-effector systems could arise from CSF insulin.

Comparison of efficacy of human and porcine insulin in treatment of diabetic ketoacidosis.

The efficacy of semisynthetic human insulin (HI) and monocomponent porcine insulin (PI) in treatment of diabetic ketoacidosis (DKA) was compared in 10 (PI) and 11 (HI) patients in a double-blind randomized study. Insulin (8 U/h i.v.), fluid replacement (0.65% NaCl and 5% glucose), and KCl supplements were administered according to a fixed protocol. Glucose, potassium, sodium, creatinine, calcium, phosphate, and free-insulin concentrations were never significantly different during the study. At the start, mean +/- SD of pH was 7.10 +/- 0.14 in the HI group and 7.10 +/- 0.12 in the PI group. The time to reach arbitrary values for pH, bicarbonate, base excess, and beta-hydroxybutyrate was shorter during HI treatment, but the differences were not statistically significant. During HI treatment, the arbitrary value of 1.0 mM of acetoacetate was reached faster than during PI treatment (5.2 +/- 2.6 and 8.4 +/- 0.9 h, respectively; P less than .05). The concentration of acetoacetate was significantly different between the two groups after 6 and 7 h of insulin treatment (6 h: HI 0.82 +/- 0.50 mM and PI 2.19 +/- 1.65 mM, P less than .05; 7 h: HI 0.51 +/- 0.40 mM and PI 1.74 +/- 1.54 mM, P = .05). We conclude that recovery from DKA during treatment with HI might be slightly faster than during treatment with PI. If this difference is real, it does not seem clinically important.

Hypophysiotropic hormone testing in a patient with hypothalamic hypopituitarism.

A 59-year-old woman with metastatic breast carcinoma presented with weight loss, vomiting, and polyuria. Basal endocrine testing revealed low levels of thyroxine, cortisol, and gonadotropins, and the presence of diabetes insipidus. Direct stimulation of the pituitary with hypophysiotropic hormones indicated intact pituitary reserve. Insulin-induced hypoglycemia, however, failed to increase plasma cortisol or growth hormone levels significantly. On computed tomographic scanning, a lesion was found in the area of the hypothalamus. Thus, a functional abnormality of the hypothalamic-pituitary axis causing clinically significant hypothalamic hypopituitarism was not clearly apparent following administration of hypothalamic releasing factors but was demonstrable with indirect stimulation via insulin-induced hypoglycemia. Insulin-induced hypoglycemia remains an important diagnostic test in the evaluation of hypopituitarism.

Influence of heat on insulin absorption: different effects on amorphous and soluble insulins.

A rise in ambient temperature stimulates the absorption of soluble, rapid-acting insulin. In the present study, the effect of intensive heat (Finnish sauna) on the absorption of amorphous insulin from a subcutaneous injection site in eight patients with type I diabetes was examined. The rate of absorption was determined by external measurement of the disappearance rate of 125I-labelled intermediate-acting (Semilente) insulin. The sauna (twice for 25 min at 85 degrees C) failed to stimulate insulin absorption significantly or to lower blood glucose levels as compared to a control day at 22 degrees C. Thus, heat has a different effect on the pharmacokinetics of amorphous and soluble insulins.