Pattern of insulin delivery affects hepatic insulin sensitizing substance (HISS) action and insulin resistance

Hepatic insulin sensitizing substance (HISS) action accounts for 55% of the glucose disposal effect of a bolus of insulin in the fed state. To determine the effect of continuous versus pulsatile insulin delivery on HISS action in male Sprague-Dawley rats, insulin sensitivity was assessed using the rapid insulin sensitivity test (RIST) before and after a continuous, pulsatile, or bolus insulin (60 mU/kg i.v.) delivery. There was a significant difference in the RIST index after a continuous insulin infusion (247.9 mg/kg before, 73.2 mg/kg after) but not after 3 pulses where insulin action returned to baseline between pulses (211.6 mg/kg before, 191.0 mg/kg after) or single bolus (205.8 mg/kg before, 189.9 mg/kg after) insulin infusion. If a 3-pulse infusion was timed so that insulin action did not return to baseline between pulses, HISS action was suppressed. Continuous insulin infusion (10-30 min) showed progressive postinfusion blockade of HISS action. To maintain HISS-dependent insulin action, continuous insulin infusions should be avoided.     

Stimulation of glucose uptake in skeletal muscle using bolus or continuous insulin delivery

We investigated glucose uptake in the non-cyclically perfused rat hindlimb in response to continuous infusion (CI) or bolus injection (BI) of insulin. Ten mM glucose was infused at 3 ml/min, venous glucose was monitored at two minute intervals, and glucose uptake was calculated on the basis of arteriovenous-difference and expressed as micron/min/100 g body wt. Insulin BI given every ten minutes equaled the amount of insulin given by CI for ten minutes. Insulin doses of 1500, 3000, 6000, and 45,000 microU/30 min showed no significant difference between the two modes of delivery in either onset of stimulation or maximal stimulation of glucose uptake. At the lowest insulin dose tested (1500 microU/30 min) neither BI nor CI stimulated glucose uptake above the control of 1.849 micron/min/100 g. A dose response curve for glucose uptake was obtained using insulin boluses ranging from 2000 to 20,000 microU. Insulin uptake by the muscle was always greater when insulin was administered CI. Net disappearance of immunoreactive insulin over the entire 30 minutes of perfusion was 29.4 +/- 2.6% for CI but only 7.1 +/- 1.6% for BI. Thus in the perfused rat hindlimb, stimulation of glucose uptake in skeletal muscle is comparable with BI and CI delivery of insulin but insulin uptake by the muscle is several-fold greater with CI delivery.     

Hepatic glucagon clearance during insulin induced hypoglycemia

Studies concerning the importance of glucagon secretion in hypoglycemic counterregulation have assumed that peripheral levels of glucagon are representative of rates of pancreatic glucagon secretion. The measurement of peripheral levels of this hormone, however, may be a poor reflection of secretion rates because of glucagon's metabolism by the liver. Therefore, in order to understand the relationship between pancreatic glucagon secretion and levels of glucagon in the peripheral blood during hypoglycemia, we evaluated hepatic glucagon metabolism during insulin induced hypoglycemia. Four dogs received an insulin infusion to produce glucose levels less than 50 mg/dl for 45 minutes. In response to this, the delivery of glucagon to the liver increased from 36.7 +/- 5.9 ng/min in the baseline to 322.6 +/- 6.3 ng/min during hypoglycemia. Hepatic glucagon uptake increased proportionally from 13.6 +/- 7.2 ng/min to 103.1 +/- 28.3 ng/min and the percentage of delivered hormone that was extracted did not change (30.8 +/- 13.8% vs 32.9 +/- 11.6%). The absolute amount of glucagon metabolized by the liver was dependent on the rate of delivery and was not directly affected by plasma glucose level per se. To directly study the effect of hypoglycemia on hepatic glucagon metabolism, five dogs were given an exogenous infusion of somatostatin followed by an infusion of glucagon and then administered insulin to produce hypoglycemia. The percent of glucagon extracted by the liver (19.5 +/- 4.9% and 21.3 +/- 6.4%) was not affected by a fall in the plasma glucose level.(ABSTRACT TRUNCATED AT 250 WORDS)     

A glucose-controlled insulin infusion system for diabetic women during labour.

A glucose-controlled insulin infusion system was used to control blood glucose concentration during labour or caesarean section in six insulin-dependent diabetics. The mean blood glucose concentration during the four hours of labour immediately before delivery was 4.6-5.2 mmol/1 (82.9-93.7 mg/100 ml). Feedback control of insulin delivery by blood glucose concentration should decrease the risk of postpartum hypoglycaemia in the infant and allow normal obstetric management for the insulin-dependent diabetic in labour.     

Initially more rapid small intestinal glucose delivery increases plasma insulin, GIP, and GLP-1 but does not improve overall glycemia in healthy subjects

The rate of gastric emptying of glucose-containing liquids is a major determinant of postprandial glycemia. The latter is also dependent on stimulation of insulin secretion by glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Although overall emptying of glucose approximates 1-3 kcal/min, the "early phase" of gastric emptying is usually more rapid. We have evaluated the hypothesis that increased stimulation of incretin hormones and insulin by a more rapid initial rate of small intestinal glucose delivery would reduce the overall glycemic response to a standardized enteral glucose load. Twelve healthy subjects were studied on two separate days in which they received an intraduodenal (id) glucose infusion for 120 min. On one day, the infusion rate was variable, being more rapid (6 kcal/min) between t = 0 and 10 min and slower (0.55 kcal/min) between t = 10 and 120 min, whereas on the other day the rate was constant (1 kcal/min) from t = 0-120 min, i.e., on both days 120 kcal were given. Between t = 0 and 75 min, plasma insulin, GIP, and GLP-1 were higher with the variable infusion. Despite the increase in insulin and incretin hormones, blood glucose levels were also higher. Between t = 75 and 180 min, blood glucose and plasma insulin were lower with the variable infusion. There was no difference in the area under the curve 0-180 min for blood glucose. We conclude that stimulation of incretin hormone and insulin release by a more rapid initial rate of id glucose delivery does not lead to an overall reduction in glycemia in healthy subjects.     

Intraduodenal osmolality directly enhances insulin secretion in the rat.

To elucidate the direct effect of an intestinal osmolality on insulin release, we investigated the insulin response to intra-duodenal infusion of mannitol in rats. After the anesthesia with intraperitoneal pentobarbital sodium, one milliliter of mannitol solution (10% or 20%) was infused into the duodenum. Portal and femoral blood insulin concentrations significantly increased at 30, 60, and 120 min after intra-duodenal infusion of mannitol, although the blood glucose level did not change. Subcutaneous pre-administration of propranolol (0.4mg/kg) or metoprolol (25mg/kg) completely abolished this phenomenon. These results suggest that intestinal osmolality can directly enhance insulin secretion and that beta 1-adrenergic mechanism is involved in this phenomenon.     

Effect of intestinal osmolality on insulin secretion to subsequent intravenous glucose or arginine in the rat

To elucidate the effect of intestinal osmolality on insulin secretion, we investigated insulin response to a subsequent intravenous infusion of glucose or arginine after intragastric or intraduodenal mannitol or NaCl instillation in the rat. After anesthesia with intraperitoneal pentobarbital sodium, mannitol solution (10% or 20%) or 2.7% NaCl was instillated into the stomach or duodenum for 5 min at a flow rate of 0.5 ml/min, and 20% glucose (0.5 g/kg) or 10% L-arginine (0.5 g/kg) was infused bolus into the femoral vein 45 min after intestinal instillation. Insulin response to intravenous glucose was significantly higher in the rat with intragastric or intraduodenal mannitol or NaCl infusion than in control rats with intragastric or intraduodenal instillation of distilled water. Insulin response to intravenous arginine was almost the same in all groups. Subcutaneous preadministration of propranolol (0.4 mg/kg), atropine (1.2 mg/kg), or phentolamine (0.8 mg/kg) did not alter the present phenomenon. These results suggest that intestinal osmolality may enhance insulin release to intravenous glucose, but not to arginine in the rat.     

A method for maintaining normoglycemia during labour and delivery in insulin-dependent diabetic women.

The effectiveness of combining the subcutaneous administration of short- and intermediate-acting insulin with the intravenous infusion of glucose in maintaining normoglycemia during labour and delivery in insulin-dependent diabetic women was tested. Fifty women were given intermediate-acting insulin twice daily in doses that were fractions of their usual dose, based on the projected duration of labour. In addition, they were given regular (i.e., short-acting) insulin every 6 hours, the dose being 1% of their total daily insulin dose for every increase of 10 mg/dl above 100 mg/dl (5.6 mmol/l) in the plasma glucose level 1 hour previously; the levels were measured every 3 hours. All the patients were fasting and received a basal intravenous infusion of 6 g/h of glucose; the rate of infusion was increased by 1 g/h for every decrease of 10 mg/dl in the plasma glucose level below 100 mg/dl. The mean plasma glucose levels (+/- standard deviation) were 90 +/- 46 mg/dl after 3 hours of labour, 92 +/- 35 mg/dl after 6 hours, 97 +/- 49 mg/dl after 9 hours and 107 +/- 65 mg/dl after 12 hours. With only one exception, in a premature infant, the 5-minute Apgar scores were identical to those of the infants of nondiabetic women.     

Oral bioavailability of insulin contained in polysaccharide nanoparticles

The pharmacological activity of insulin-loaded dextran sulfate/chitosan nanoparticles was evaluated following oral dosage in diabetic rats. Nanoparticles were mucoadhesive and negatively charged with a mean size of 500 nm, suitable for uptake within the gastrointestinal tract. Insulin association efficiency was over 70% and was released in a pH-dependent manner under simulated gastrointestinal conditions. Orally delivered nanoparticles lowered basal serum glucose levels in diabetic rats around 35% with 50 and 100 IU/kg doses sustaining hypoglycemia over 24 h. Pharmacological availability was 5.6 and 3.4% for the 50 and 100 IU/kg doses, respectively, a significant increase over 1.6%, determined for oral insulin alone in solution. Confocal microscopic examinations of FITC-labeled insulin nanoparticles showed adhesion to rat intestinal epithelium, and internalization of insulin within the intestinal mucosa. Encapsulation of insulin into dextran sulfate/chitosan nanoparticles was a key factor in the improvement of the bioavailability of its oral delivery over insulin solution.     

Acute supplementation of amino acids increases net protein accretion in IUGR fetal sheep

Placental insufficiency decreases fetal amino acid uptake from the placenta, plasma insulin concentrations, and protein accretion, thus compromising normal fetal growth trajectory. We tested whether acute supplementation of amino acids or insulin into the fetus with intrauterine growth restriction (IUGR) would increase net fetal protein accretion rates. Late-gestation IUGR and control (CON) fetal sheep received acute, 3-h infusions of amino acids (with euinsulinemia), insulin (with euglycemia and euaminoacidemia), or saline. Fetal leucine metabolism was measured under steady-state conditions followed by a fetal muscle biopsy to quantify insulin signaling. In CON, increasing amino acid delivery rates to the fetus by 100% increased leucine oxidation rates by 100%. In IUGR, amino acid infusion completely suppressed fetal protein breakdown rates but increased leucine oxidation rate by only 25%, resulting in increased protein accretion rates by 150%. Acute insulin infusion, however, had very little effect on amino acid delivery rates, fetal leucine disposal rates, or fetal protein accretion rates in CON or IUGR fetuses despite robust signaling of the fetal skeletal muscle insulin-signaling cascade. These results indicate that, when amino acids are given directly into the fetal circulation independently of changes in insulin concentrations, IUGR fetal sheep have suppressed protein breakdown rates, thus increasing net fetal protein accretion.     

Safety of insulin glulisine when given by continuous subcutaneous infusion using an external pump in patients with type 1 diabetes.

This twelve-week, European, multicenter, controlled, open-label, randomized (1 : 1), parallel-group trial compared the safety of insulin glulisine with insulin as part used in continuous subcutaneous insulin infusion. Patients with type 1 diabetes (n=59) and continuous subcutaneous insulin infusion experience (mean values: HbA1c 6.9 % [insulin glulisine: 6.8 % VS. insulin as part: 7.1 %]; age 45.8 years; body mass index 26.0 kg/m2) were enrolled. HbA1c levels at endpoint (insulin glulisine: 7.0 % VS. insulin as part: 7.2 %), daily insulin doses, blood glucose profiles and adverse event rates were similar in both groups. The median (minimum-maximum) catheter occlusion rate was low for insulin glulisine and insulin as part (0 [0 - 0.7] VS. 0 [0 - 1.1] occlusions/month. Unexplained hyperglycemia occurred in six insulin glulisine-treated patients and twelve insulin as part-treated patients. Patients were expected to change their catheters every 2 days (15 changes/month); the catheter change rate was similar for insulin glulisine and insulin as part (14.1 VS. 14.8 changes/month). The frequency of infusion site reactions and hypoglycemia, and the time between catheter changes were similar for both insulin forms. Diabetic ketoacidosis was not reported. This study supports the safety of insulin glulisine in continuous subcutaneous insulin infusion administered via an external pump in type 1 diabetes.     

Human Insulin Microcrystals with Lactose Carriers for Pulmonary Delivery

Dry powder formulations for pulmonary delivery are attractive because many issues of solubility and stability can be minimized. Human insulin microcrystals with lactose carriers were produced for pulmonary delivery. The average particle diameter was 2.3 μm, with a narrow, monodispersed size distribution. The percentages of high molecular weight proteins (%HMWPs), other insulin-related compounds (%OIRCs), and A-21 desamido insulin (%D_es) were very low throughout the microcrystal preparation process. Administration of the microcrystal powder by intratracheal insufflation significantly reduced the blood glucose levels of Sprague-Dawley rats. The percent minimum reductions of the blood glucose concentration (%MRBG) produced by the insulin microcrystal powder and by an insulin solution reached 40.4% and 33.4% of the initial glucose levels respectively, and their bioavailability relative to subcutaneous injection (F) was 15% and 10% respectively. These results confirm that the insulin microcrystal powder prepared is suitable for pulmonary delivery in an effective dosage form.     

智能胰岛素递送系统用于糖尿病治疗的研究进展

糖尿病是继癌症和心血管疾病之后危害人类健康的第三大疾病。1型糖尿病或2型糖尿病治疗需要每日注射或持续输注外源性胰岛素,以调节体内血糖达到正常水平。然而目前胰岛素的治疗手段受到低血糖风险的限制。以生物材料为载体构建递送系统可提高胰岛素的生物利用度,减少不良反应的发生。因此,基于智能胰岛素递送系统的研究开发对提高胰岛素给药的可控性是必要的。对近年来胰岛素的不同给药方法进行综述,阐述智能胰岛素递送系统的作用机制,并探讨不同给药方法下智能胰岛素递送系统的研究现状及存在的问题。     

Effects of imidapril, an angiotensin-converting enzyme inhibitor, on insulin sensitivity and responsiveness in streptozotocin-induced diabetic rats.

We have studied the effect of imidapril, an angiotensin-converting enzyme inhibitor, on streptozotocin-induced diabetic rats. A sequential euglycemic hyperinsulinemic clamp procedure was used (insulin infusion rates: 3 and 30 mU/kg BW/min) in 30 diabetic rats. The rats were divided in 6 groups: a control group, a control group with N-monomethyl-L-arginine (L-NMMA, 1 mg/kg/min, a nitric oxide synthase inhibitor) infusion, a streptozotocin-induced diabetic group, a diabetic group with L-NMMA infusion, a diabetic group involving imidapril infusion (5 microg/kg/min), and a diabetic group involving simultaneous imidapril and L-NMMA infusion. Glucose concentrations were maintained around 140 mg/dl during the clamp studies. Plasma insulin levels during the 3 and 30 mU/kg BW/min insulin infusions were 30 and 400 microU/ml, respectively. Glucose infusion rates (GIR) in STZ-induced diabetic rats showed a significant decrease compared to controls. At both insulin infusion rates, imidapril-infused diabetic rats showed an increased GIR, compared with the saline infused ones. There was no significant difference in GIR between L-NMMA and saline infusion in diabetic rats. Simultaneous infusion of imidapril and L-NMMA did not significantly decrease GIR with low-dose insulin infusion, but the increase in GIR induced by imidapril with high-dose insulin infusion was impaired by 100 % by L-NMMA infusion in diabetic rats. These results suggest that imidapril may improve insulin action, in part, via nitric oxide.     

Insulin suppresses PDK-4 expression in skeletal muscle independently of plasma FFA

Starvation and experimental diabetes induce a stable increase in pyruvate dehydrogenase kinase (PDK) activity in skeletal muscle, which is largely due to a selective upregulation of PDK-4 expression. Increased free fatty acid (FFA) level has been suggested to be responsible for the upregulation. Because these metabolic states are also characterized by insulin deficiency, the present study was designed to examine whether insulin has a significant effect to regulate PDK mRNA expression in rat skeletal muscle. In study 1, overnight-fasted rats received an infusion of saline or insulin for 5 h (n = 6 each). During the insulin infusion, plasma glucose was clamped at basal levels (euglycemic hyperinsulinemic clamp). A third group (n = 6) received Intralipid infusion during the clamp to prevent a fall in plasma FFA. PDK-2 mRNA level in gastrocnemius muscle was not altered by insulin or FFA (i.e., Intralipid infusion). In contrast, PDK-4 mRNA level was decreased 72% by insulin (P < 0.05), and Intralipid infusion prevented only 20% of the decrease. PDK-4 protein level was decreased approximately 20% by insulin (P < 0.05), but this effect was not altered by Intralipid infusion. In study 2, overnight-fasted rats were refed or received an infusion of saline or nicotinic acid (NA, 30 micromol/h) for 5 h (n = 5 each). During the refeeding and NA infusion, plasma FFA levels were similarly (i.e., 60-70% vs. saline control) lowered. Muscle PDK-4 mRNA level decreased 77% after the refeeding (P < 0.05) but not after the NA infusion. In conclusion, the present data indicate that insulin had a profound effect to suppress PDK-4 expression in skeletal muscle and that, contrary to previous suggestions, circulating FFA had little impact on PDK-4 mRNA expression, at least within 5 h.     

Fasting and feeding variations of insulin requirements and insulin binding to erythrocytes at different times of the day in insulin dependent diabetics--assessed under the condition of glucose-controlled insulin infusion

Nine insulin-dependent diabetic patients were examined for insulin requirement, counterregulatory hormones, and receptor binding during their connection to glucose-controlled insulin infusion system. They were of 103% ideal body weight. A diet of 45% carbohydrate, 20% protein and 35% fat was divided into three meals and three snacks averaging the daily calorie intake of 1859 kcal. Following an equilibrating phase of 14 hours after the connection to the glucose-controlled insulin infusion system the blood samples were taken at 0800, 1200 and 1800. The insulin infusion rate increased at 0300 in the early morning from 0.128 mU/kg/min to 0.221 mU/kg/min (P less than 0.02). The postprandial insulin infusion rate jumped from 0.7 U/h (0700-0800) to 7.5 U/h (0800-0900). The calorie related and carbohydrate related insulin demands after breakfast were also highest and declined after lunch respectively (1.16 uU/kg/min kj vs. 0.61 uU/kg/min kj, P less than 0.05 and 236 mU/g CHO vs. 129 mU/g CHO and 143 mU/g CHO). Of the counterregulatory hormones the cortisol showed a significant diurnal rhythm to insulin demands. The insulin tracer binding was higher at 0800 before breakfast than that at 1200 before lunch (P less than 0.05). The increased binding could be better attributed to receptor concentration change than to affinity change. The cause of insulin relative insensitivity in the morning could be due to altered liver response to the cortisol peak in type 1 diabetics. The preserved variation of insulin binding in our patients might be referred to feeding.     

A complicated pregnancy in a patient with lipodystrophic diabetes attributable to a peroxisome proliferator-activated receptor gamma (PPARG) mutation

Diabet. Med. 29, e398-e401 (2012) ABSTRACT: Background We describe an unplanned pregnancy in a 19-year-old with lipodystrophic diabetes caused by a mutation in the peroxisome proliferator-activated receptor gamma (PPARG) gene. The pregnancy was complicated by poor compliance with treatment, severe hypertriglyceridaemia and pancreatitis. Case report The patient presented at 6?weeks' gestation with an HbA(1c) of 140?mmol/mol (15%), cholesterol 8.1?mmol/l and triglycerides 20.1?mmol/l. She wished to continue the pregnancy so lipid-lowering therapy was discontinued. She was severely insulin resistant and poorly compliant with diet and medication. A continuous subcutaneous insulin infusion was required for efficient delivery of large doses of basal insulin, alongside injected mealtime boluses, (up to 300?units insulin per day). At 17?weeks' gestation she developed acute pancreatitis secondary to hypertriglyceridaemia (triglycerides >?100?mmol/l) and required plasmapheresis. Lipid-lowering therapy was reinstated in the third trimester and plasmapheresis was required repeatedly to maintain triglycerides 相似文献   

Glucose dependent insulinotropic polypeptide (GIP) infused intravenously is insulinotropic in the fasting state in type 2 (non-insulin dependent) diabetes mellitus

The effects of an intravenous infusion of porcine GIP on beta-cell secretion in patients with untreated type 2 diabetes mellitus have been studied. The subjects were studied on two separate days. After a 10 h overnight fast and a further 120 min basal period they were given an intravenous infusion of porcine GIP (2 pmol.kg-1.min-1) or control solution in random order from 120-140 min. Frequent plasma glucose, insulin, C-peptide and GIP measurements were made throughout and the study was continued until 200 min. Plasma glucose levels were similar throughout both tests. During the GIP infusion there was an early significant rise in insulin concentration from 0.058 +/- 0.006 nmol/l to 0.106 +/- 0.007 nmol/l (P less than 0.01) within 6 min of commencing the GIP infusion and insulin levels reached a peak of 0.131 +/- 0.011 nmol/l at 10 min (P less than 0.01). Insulin levels remained significantly elevated during the rest of the GIP infusion (P less than 0.01-0.001) and returned to basal values 20 min post infusion. No change in basal insulin values was seen during the control infusion. C-peptide levels were similarly raised during the GIP infusion and the increase was significant just 4 min after commencing the GIP infusion (P less than 0.05). GIP levels increased from 16 +/- 3 pmol/l prior to the infusion to a peak of 286 +/- 24 pmol/l 20 min later. At 4 min when a significant beta-cell response was observed GIP levels were well within the physiological range.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of sparteine sulfate on insulin secretion in normal men

This study aimed at evaluating the influence of sparteine sulfate either upon basal plasma glucose and insulin or glucose-induced insulin secretion in normal man. Thirteen overnight fasted volunteers took part in this study; five of them were submitted to sparteine sulfate bolus (15 mg in 10 ml of saline solution) followed by a slow infusion (90 mg/100 ml X 60 min) and eight subjects underwent two different glucose pulses (20 gr. i.v.) in absence or in presence of sparteine, infused as described above. In basal conditions, along with sparteine infusion, plasma glucose showed a progressive and significant decrease (P less than 0.0001) and plasma insulin was significantly higher from min 10 to 120' (P less than 0.0005-0.001). Even during the glucose-induced insulin secretion, in the presence of sparteine infusion, plasma glucose levels were significantly lower while plasma insulin levels were significantly higher when compared to those observed after glucose alone. The acute insulin response (AIR) was 42 +/- 10 microU/ml after glucose alone vs 67 +/- 9 microU/ml after glucose plus sparteine (P less than 0.05). Total insulinemic areas were significantly different being 1410 +/- 190 vs 2250 +/- 310 microU/ml/min (P less than 0.001) during glucose and glucose plus sparteine infusion, respectively. This study thereby, demonstrates that in normal man sparteine sulfate, administrated by intravenous infusion, is able to increase either basal or glucose-induced insulin secretion.     

The effect of exogenous growth hormone on insulin requirements during closed loop insulin delivery in insulin-dependent diabetes mellitus

The amount of insulin required to maintain similar blood glucose concentrations during an eight hour infusion of either saline or growth hormone (2 micrograms/kg/hr) was determined in five fed, insulin-dependent diabetic subjects during closed-loop insulin delivery. Elevations of serum growth hormone concentrations to levels previously observed in poorly controlled diabetic subjects were not accompanied by differences in the amount of insulin required to maintain blood glucose concentrations at levels comparable to those observed during the saline infusion. Specifically, no early insulin-like nor late anti-insulin effects of physiologic increases in serum growth hormone concentrations (10.27 +/- 0.23 mg/ml vs 5.69 +/- 1.5 mg/ml, P less than 0.05) on mean hourly blood glucose levels or mean hourly insulin requirements were observed. These studies suggest that serum growth hormone concentrations similar to those observed in poorly controlled diabetics do not affect the insulin requirements of well-insulinized diabetic subjects.