Peak Serum Insulin Concentrations Research Articles

Protein ingestion impairs insulin‐stimulated net muscle carnitine uptake in healthy young men (LB812)

Carbohydrate ingestion promotes insulin‐mediated muscle carnitine accretion, but the effect of protein ingestion is unknown. Six healthy males (age 24 ± 5 yrs, BMI 23 ± 3 kg/m²) ingested 80g carbohydrate (CHO), 40g whey protein + 40g CHO (PRO), or flavoured water (CON) beverages (500 ml) 1 hr following ingestion of 3g L‐carnitine (0.1% ²H3‐L‐carnitine) on 3 randomised 3‐hr visits. The rate of disposal (Rd) and arterio‐venous (AV) forearm carnitine balance (determined from arterialised‐venous and venous plasma ²H3‐carnitine and carnitine concentrations), and brachial artery blood flow (BAF; Doppler ultrasound) were measured, together with serum insulin concentrations, at baseline and 20 min intervals for 3 hrs. Carnitine Rd at 100 min was 4.4 fold greater in CHO compared to CON (0.3 ± 0.1 vs 0.1 ± 0.1 µmol/min; P<0.05), which coincided with peak serum insulin concentration in CHO (64 ± 10 mU/L). However, despite similar insulin responses in CHO and PRO (3‐hr area under curve [AUC] was 4.6 ± 0.8 and 3.9 ± 0.7 U/L•min, respectively) compared to CON (0.4 ± 0.04 U/L•min; P<0.001) and increases in BAF (15 ± 3 and 12 ± 5%) above CON (P<0.05), net carnitine balance AUC increased in CHO (P<0.01), but not PRO, compared to CON (9.3 ± 4.0 and ‐3.9 ± 5.7 vs ‐1.2 ± 1.5 µmol•min, respectively) over the 2 hrs following beverage ingestion. Carbohydrate stimulates insulin mediated muscle carnitine balance, but protein may antagonise this process.

Accelerated Pharmacokinetics and Glucodynamics of Prandial Insulins Injected With Recombinant Human Hyaluronidase

This phase 1 study investigated the pharmacokinetics (PK) and glucodynamics of insulin lispro (Humalog; Eli Lilly and Co., Indianapolis, IN) or regular human insulin (Humulin R; Eli Lilly and Co.) administered with or without (+/-) recombinant human hyaluronidase (rHuPH20). Healthy male volunteers (n = 26), 18-55 years old with body mass index 18-28 kg/m(2), weight >70 kg, and normal fasting glucose, were randomized to a crossover sequence of two subcutaneous injections, each followed by a 6-h euglycemic clamp targeting glucose 90-110 mg/dL: Cohort 1 received 20 U of Humalog +/- 300 U of rHuPH20 (11.3 microg/mL), whereas Cohort 2 received 20 U of Humulin R +/- 240 U of rHuPH20 (10 microg/mL). Pharmacokinetic parameters included peak serum insulin concentration (C(max)), time to C(max) (t(max)), and area under the curve (AUC) of serum concentration versus time. Glucodynamic parameters included time to maximal glucose infusion rate (tGIR(max)) and area under the GIR-versus-time curve (G). For Humalog and Humulin R, respectively, rHuPH20 co-administration reduced t(max) by 51% (P = 0.0006) and 58% (P = 0.0002), increased C(max) by 90% (P = 0.0003) and 142% (P < 0.0001), increased early exposure (AUC(0-2h)) by 85% (P < 0.0001) and 211% (P < 0.0001), and reduced late exposure (AUC(4-6h)) by 41% (P < 0.0001) and 48% (P < 0.0001). Similarly, rHuPH20 reduced tGIR(max) by 41% (P = 0.006) and 35% (P = 0.01), increased early metabolism (G(0-2h)) by 52% (P = 0.001) and 127% (P < 0.0001), and reduced late metabolism (G(4-6h)) by 29% (P = 0.002) and 26% (P = 0.03) for Humalog and Humulin R, respectively. Injections were well tolerated. Co-administration of rHuPH20 accelerated the PK and glucodynamics of both insulin formulations. Additional studies are necessary to evaluate the clinical relevance of these findings in patients with diabetes.

Gamma-Cyclodextrin Lowers Postprandial Glycemia and Insulinemia without Carbohydrate Malabsorption in Healthy Adults

Objective: Preliminary in vitro and animal studies have shown that gamma-cyclodextrin (GCD) is a slowly and completely digestible carbohydrate. The objective of this study was to determine the glycemic and insulinemic responses to GCD in humans. Breath hydrogen excretion was measured simultaneously to evaluate carbohydrate malabsorption.Methods: Healthy adult subjects (N = 32) received 50 g of carbohydrate from GCD or a rapidly digested maltodextrin (MD) in a double-masked, randomized, crossover design. Plasma glucose (fingerstick) and serum insulin (venous) concentrations were measured at baseline and at 15, 30, 45, 60, 90, 120, 150, and 180 min postprandially. Breath hydrogen excretion was monitored hourly for 8 h postprandially. The severity of gastrointestinal symptoms (nausea, cramping, distension, flatulence) was rated by the subjects on a ranked scale for two 24-h periods postprandially.Results: The mean baseline-adjusted peak plasma glucose concentration was 47% lower (P < 0.001), and the mean baseline-adjusted peak serum insulin concentration was decreased by 45% (P < 0.001) after subjects consumed GCD compared with MD. Positive incremental area under the curve (0–120 min) was reduced 45% for plasma glucose and 49% for serum insulin by GCD compared with MD (P < 0.001 in each case). There were no differences between GCD and MD in the proportion of positive breath hydrogen tests and both carbohydrates were equally well tolerated.Conclusions: GCD effectively lowers postprandial glycemia and insulinemia compared with MD, without resulting in appreciable carbohydrate malabsorption or gastrointestinal intolerance.

Twice-daily biphasic insulin aspart 30 versus biphasic human insulin 30: A double-blind crossover study in adults with type 2 diabetes mellitus

Objective: The purpose of this study was to compare the pharmacokinetics and pharmacodynamics of the premixed insulin analogue biphasic insulin aspart (BIAsp 30) with the equivalent premixed biphasic human insulin (BHI 30), administered twice daily, in patients with type 2 diabetes mellitus. Methods: In this randomized, double-blind, crossover trial, 13 patients (mean age, 64 years; baseline mean glycosylated hemoglobin, 7.7%; mean body mass index, 28.1 kg/m 2) received 2 weeks of treatment with BIAsp 30 and 2 weeks of BHI 30 administered immediately before dinner and breakfast. At the end of each 2-week treatment period, 24-hour serum insulin and glucose profiles were determined using specific 2-sided enzymelinked immunosorbent assays. All pharmacodynamic and pharmacokinetic end points were analyzed using analysis of variance. Results: Total daily insulin exposure was similar between treatment periods. Mean area under the total insulin concentration-time profile during the 2 hours following administration of BIAsp 30 was 17% greater than that of BHI 30 after dinner and 44% greater after breakfast; both differences were statistically significant. The maximum serum insulin aspart concentrations following BIAsp 30 were significantly higher after dinner (18%) and breakfast (35%). Peak serum insulin concentration was reached 1 hour earlier after breakfast and 45 minutes earlier after dinner in the BIAsp 30 group; differences were significant only after breakfast. The mean daily prandial glucose excursion was significantly lower for BIAsp 30 (16.2 mmol·h·L −1) than BHI 30 (17.9 mmol·h·L −1). Postprandial 4-hour glucose excursions were significantly lower with BIAsp 30 than with BHI 30 after dinner and breakfast, but were significantly greater after lunch. Mean 24-hour and nocturnal serum glucose concentrations were similar, and both insulins were associated with ≤7 minor and no major hypoglycemic events. Conclusions: Premeal injection of BIAsp 30 in a twice-daily regimen significantly reduced overall postprandial glucose excursions. This effect may be of importance when improvement in postprandial glucose control is desired.

Insulin lispro: its role in the treatment of diabetes mellitus.

To introduce a rapid-acting human insulin analog, insulin lispro; to review its pharmacology, therapeutics, pharmacokinetics, dosing guidelines, adverse effects, and drug interactions; and to summarize the clinical trials of its efficacy and safety alone and in comparison with regular human insulin in the treatment of diabetes mellitus. A MEDLINE database search was completed to identify all relevant articles, including reviews; Eli Lilly and Co.; published articles and abstracts; and review chapters from medical textbooks. Due to the relatively few citations listed in MEDLINE (12 as of December 1995), most of the studies reported were found from abstracts summarizing the clinical action, adverse effects, or pharmacokinetics of insulin lispro in healthy volunteers or patients with diabetes mellitus. A few of the studies used patients with diabetes mellitus in multicenter, randomized, crossover trials of insulin lispro. All clinical trials that were available prior to submission of this manuscript for publication, including unpublished reports, were reviewed. The human insulin analog, insulin lispro, which is biosynthetically made by inverting the amino acid sequence of human insulin at B-28 and B-29, is more effective than regular human insulin in improving postprandial glucose control. Subcutaneous injections of insulin lispro result in decreased blood glucose peaks following meals and a potential decreased risk of hypoglycemic episodes, including nighttime hypoglycemia in patients with type 1 diabetes. Insulin lispro in comparison with regular human insulin provides equal or slightly better blood glucose control. When compared with subcutaneous injections of regular human insulin, the peak serum insulin concentration of insulin lispro is three times higher, time to peak is 4.2 times faster, the absorption rate constant is double, and the duration of action is half as long. Insulin lispro is similar to regular human insulin with reference to dose, toxicity, adverse effects, drug interactions, and immunogenicity. When insulin lispro is mixed with human NPH (isophane) or Lente insulins, insulin lispro should be drawn into the syringe first, mixed with the long-acting insulin, and injected immediately after mixing. Patients using insulin lispro perceive an improvement in their well-being and quality of life due to flexible injection times and less frequent hypoglycemic reactions. Insulin lispro is believed to be suitable for patients using insulin infusion pumps. Insulin lispro is equipotent to human insulin and has a much more rapid onset and shorter duration of action than human insulin does, which may reduce the risk of hypoglycemia. In addition, insulin lispro improves the dosing convenience for patients with diabetes and provides a more natural control of blood glucose concentrations. Insulin lispro is a useful new agent in the treatment of diabetes mellitus.

Comparison of two ultralente insulin preparations with protamine zinc insulin in clinically normal cats

Summary The absorption kinetics and glycemic effects of 3 long-acting insulin preparations (protamine zinc beefpork insulin, ultralente beef-pork insulin, and ultralente human insulin) were evaluated in 9 healthy, adult, domestic shorthair cats (6 males, 3 females). A triple crossover study was performed, in which the serial serum concentrations of insulin and glucose were determined over a 24-hour period after SC administration of the 3 insulin preparations (dosage, 1.0 U/kg of body weight) at 3-week intervals. A control study was also performed in 4 of the cats by serially collecting samples for insulin and glucose determinations after administration of insulin diluent. After administration of protamine zinc insulin (pzi), mean (± sem) serum insulin concentration increased significantly (P &lt; 0.05) above baseline, reached a peak value (484 ± 287 pmol/L) at 1 hour, and remained significantly (P &lt; 0.05) higher than baseline at 24 hours. After administration of ultralente human insulin, the serum insulin curve was similar to that obtained after pzi administration, but mean serum insulin concentration took longer to peak (538 ± 177 pmol/L at 4 hours). After administration of ultralente beef-pork insulin, mean peak serum insulin concentration was lower (220 ± 54 pmol/L, not statistically significant) than that obtained after administration of pzi and ultralente human insulins; it then decreased to values statistically indistinguishable from baseline by 16 hours. The area under the serum insulin concentration curve for pzi (5,063 ±681 pmol • h/L) and ultralente human insulin (4,138 ± 439 pmol • h/L) was significantly (P &lt; 0.05) larger than that for ultralente beef-pork insulin (2,378 ± 561 pmol • h/L). Serum glucose concentration decreased after administration of all 3 insulins, but the decrease was not different from that observed after diluent (control) administration. Results of this study indicate that differences may exist between absorption of pzi, ultralente human, and ultralente beef-pork insulins. Of the 2 ultralente insulin preparations, human insulin appears better absorbed than beef-pork insulin, but these findings need to be confirmed in cats with naturally acquired diabetes mellitus.

Absorption kinetics of regular, isophane, and protamine zinc insulin in normal cats

Absorption kinetics of regular, isophane (NPH), and protamine zinc (PZI) insulin were evaluated in seven clinically normal domestic shorthair cats by measurement of serial serum concentrations of insulin after subcutaneous administration of each insulin preparation. These results were compared to measurements of serial serum insulin concentrations after similar dosages of regular insulin were administered intravenously. Regular insulin administered subcutaneously was better absorbed than NPH and PZI insulins (mean bioavailability index 45.4% vs. 33.0% for NPH and 27.3% for PZI), and resulted in a significantly greater maximal increase in mean circulating insulin concentrations above baseline values (3529 pM vs. 1044 pM for NPH and 344 pM for PZI, P<0.05). The mean time interval between insulin administration and time to reach peak concentrations was significantly shorter for regular insulin than for NPH or PZI insulin (0.5 hr vs. 1.6 hr for NPH and 4.1 hr for PZI, P<0.05). There was also a significant difference (P<0.05) in the mean time interval between insulin injection and return of serum insulin concentrations to baseline values between regular insulin (5.6 hr) and NPH (7.7 hr) or PZI (13.1 hr) insulins. When compared with PZI, NPH insulin showed a significantly (P<0.05) greater maximal increase in mean serum insulin concentrations over baseline values. In addition, the interval between insulin administration and time to reach peak concentrations, as well as the time between insulin injection and return of serum insulin concentrations to baseline values, were also significantly shorter with NPH insulin than with PZI. These results suggest that NPH and PZI insulins administered subcutaneously to cats may require a short time to reach peak serum insulin concentrations as well as a relatively short time for circulating insulin concentrations to return to baseline values. If the absorption kinetics are similar to that in this study, most cats with diabetes mellitus would need twice daily injection of NPH or PZI insulin to adequately control the diabetic state.

Do antihypertensive drugs precipitate diabetes in predisposed men?

To evaluate the influence of antihypertensive treatment and metabolic characteristics on the development of diabetes mellitus in middle aged men. Prospective study over an average of nine years. Community based health survey of middle aged men carried out at the University of Uppsala. Seventy three hypertensive men aged 49-54 and 65 normotensive controls matched for body mass index, glucose disappearance rate (k value) at an intravenous glucose tolerance test, and serum triglyceride and cholesterol concentrations. Hypertensive group was treated with beta blockers, thiazides, hydralazine, or combinations of these drugs. Treatment was not randomised. Intravenous glucose tolerance, fasting blood glucose and serum lipid and insulin concentrations, body weight and height, three skinfold measurements, and blood pressure were recorded both during an initial health screening survey in 1970-3 and at a follow up survey in 1980-3. In the period between the two surveys 12 hypertensive men and two controls developed diabetes. Review of values obtained at the initial survey showed that the hypertensive men who developed diabetes or impaired glucose tolerance could be distinguished from those hypertensive men who did not by virtue of a higher fasting serum insulin concentration (26.1 v 15.2 mU/l (confidence interval of difference -15.2 to -6.2)), a lower peak serum insulin concentration (78.9 v 94.3 mU/l (confidence interval of difference -1.1 to 41.1)), and a lower k value (1.29 v 1.68 (confidence interval of difference -0.02 to 0.68)). The insulin index (peak insulin concentration divided by fasting insulin concentration), however, decreased significantly in the hypertensive men over time irrespective of whether they developed diabetes but did not change in the controls. Furthermore, the serum triglyceride concentration increased in the treated group and decreased in the controls. A severalfold difference in the incidence of diabetes between treated hypertensive and non-treated, normotensive men may be a consequence of the treatment, which may be particularly deleterious in men predisposed to diabetes.

Absorption kinetics of regular and isophane (NPH) insulin in the normal dog

Absorption kinetics of regular and isophane (NPH) insulins were evaluated in seven normal fasted dogs by measuring serial serum concentrations of insulin and glucose following the subcutaneous administration of regular and NPH insulins. These results were compared to serum insulin values determined after injecting similar doses of regular insulin intravenously. Regular insulin was better absorbed than NPH insulin (mean bioavailability index 64.6% vs. 41.1%, P<.01) resulting in a significantly greater maximal increase in mean circulating insulin concentrations above baseline values (362.2 μU/ml vs. 147.8 μU/ml, P<.05). The time interval between insulin injection and return of serum insulin values to basal concentrations was also significantly shorter for regular than for NPH insulin (4.9 hr vs. 8.6 hr, P<.05). However, there were no significant differences between regular and NPH insulins in time to reach peak serum insulin concentrations, maximal reduction in serum glucose concentrations, or time of lowest circulating glucose levels. The results of this study support previously accepted values for time-action characteristics of regular insulin, but suggest that NPH insulin may have an earlier peak and shorter duration of action than has previously been proposed in the dog.

Insulin administered intranasally as an insulin-bile salt aerosol. Effectiveness and reproducibility in normal and diabetic subjects.

Efficacy and reproducibility of insulin administered intranasally as an insulin-deoxycholate 1% (w/v) aerosol to normal and diabetic subjects were assessed by measurements of blood glucose and serum insulin levels. Following administration of 0.5 U insulin/kg with the unconjugated bile salt to fasting volunteers (N = 29), peak serum insulin levels of 103 +/- 49 microU/ml above baseline were observed at 10 min. Blood glucose concentration began to fall by 10 min, reaching 54 +/- 14% of control levels by 30 min, and returning to baseline by 60-80 min. Blood glucose response and peak serum insulin levels were reproducible when the same aerosol dose was repeatedly administered to the same subjects; however, intersubject variations were noted. By comparing serum insulin levels after i.v. and nasal routes of administration, nasal insulin absorption was approximately 10% as efficient as intravenous insulin. Dose response studies revealed that peak serum insulin concentrations were a linear function of the administered dose. In subjects with type I and type II diabetes mellitus, serum insulin levels increased in a manner similar to controls, and resulted in a prompt reduction of blood glucose concentration. However, in contrast to normal subjects, the duration of the glucose response was more prolonged, lasting as long as 5 h. Nasal administration of insulin as an aerosol with bile salts or bile salt analogs should be further evaluated as a possible nonparenteral approach to insulin therapy.

626 DECREASED GASTRIN SECRETION EVOKED BY FEEDING DURING ADMINISTRATION OF HUMAN GROWTH HORMONE (hGH)

GH stimulates gastric mucosal growth and function (Crean, Vitamins Hormones 21:215,1963). In order to determine if hGH affected gastrin secretion, serum concentrations of this peptide were determined by radioimmunoassay for three hours during a standard test meal (2 boiled eggs, 2 pieces buttered toast, 8 ounces skim milk) in patients with hyposomatotropism prior to initiation of treatment (N=14) and after six (N=12) and 12 months (N=10) of hGH administration (0.1 U/kg thrice weekly). Basal and peak concentrations (pg/ml) of gastrin were: (a. p <0.01, b. p <0.05 versus basal by paired t test) Gastrin concentrations increased during feeding at each period. The peak gastrin concentration after 12 months of hGH administration was significantly (p <0.05) lower than the peak value recorded prior to initiation of treatment. Peak serum insulin concentrations in response to the standard meal did not change significantly during hGH administration [pre Rx- 28 ±6 uU/ml (N=13); +6 months 39 ±12 (N=7); +12 months 31± 6 (N=9)]. It is concluded that long term administration hGH is associated with slightly depressed gastrin secretory response to feeding.

Turner's syndrome and carbohydrate metabolism. II. Parotid salivary insulin concentration in normal subjects and in patients with gonadal dysgenesis.

Ten children with XO gonadal dysgenesis and ten control siblings (CS) had sequential IV tolbutamide and IM glucagon tests to ascertain serum and salivary insulin concentrations, to confirm the presence of parotid salivary insulin and to determine if these concentrations were of diagnostic value in the diagnosis of insulin deficiency. After tolbutamide, peak serum insulin concentrations were lower in the patients with Turner's syndrome (TS) than in control siblings (58 +/- 10 vs 90 +/- 15 microU/ml) and fractional areas under insulin curves were significantly lower in the patients with Turner's syndrome at 10 to 15 minutes (TS: 240 +/- 16 microUmin/ml; CS: 340 +/- 46 microU-min/ml, P less than 0.05) and at 15 to 30 minutes (TS: 562 +/- 62 microU-min/ml; CS: 884 +/- 128 microU-min/ml, P less than 0.05). After glucagon, peak serum insulin concentrations were significantly lower in Turner's syndrome than in control siblings(P less than 0.02, at 45 minutes) and fractional areas under insulin curves were also lower in TS than in siblings at 30 to 45 minutes (TS: 1,062 +/- 185 microU-min/ml; CS: 2,189 +/- 402 microU-min/ml, P less than 0.02). Basal salivary immunoreactive insulin (IR) concentrations were similar in both groups: TS: 4.8 +/- 2.1 microU/min; CS: 2.1 +/- 0.4 microU/min. Peak salivary IRI concentrations after tolbutamide were 13.8 +/- 4.7 microU/min in Turner's syndrome and 8.8 +/- 1.8 microU/ml in control siblings. Peak salivary IRI values in Turner's syndrome and in control siblings after glucagon were 26.8 +/- 10.1 and 13.4 +/- 2.1 microU/min, respectively. While significant differces in insulin secretion in serum were detected in the two patient groups, no differences were noted between groups when salivary insulin concentrations were compared. These data confirm serum insulin deficiency in gonadal dysgenesis, the presence of immunoreactive insulin in parotid saliva, and suggest the possibility that extrapancreatic insulin synthesis could occur in the parotid gland.

Localization of Gastric Inhibitory Polypeptide Release by Intestinal Glucose Perfusion in Man

To determine the site of endogenous release of gastric inhibitory polypeptide (GIP), glucose perfusions (556 mmoles per liter) of duodenum, proximal jejunum, midjejunum, and ileum were performed in human volunteers using an occluding balloon perfusion technique. Preperfusion GIP concentrations were below assay sensitivity (125 pg per ml) in all subjects. After glucose perfusion, maximal serum GIP concentrations for the four groups were: duodenum, 1383 +/- 152 pg per ml; proximal jejunum, 904 +/- 87 pg per ml; midjejunum, 545 +/- 91 pg per ml, and ileum 305 +/- 38 pg per ml. Integrated GIP secretion was significantly greater with duodenal perfusion (111 +/- 21 ng-min ml-1) d proximal jejunal perfusion (69 +/- 5 ng-min ml-1), as compared to either midjejunal (47 +/- 7 ng-min ml-1) or ileal (25 +/- 6 ng-min ml-1) perfusions. Peak serum insulin concentrations and integrated insulin secretion were also significantly greater with perfusion of the duodenum or proximal jejunum. Serum glucose concentrations, integrated serum glucose, and glucose absorption were similar for the four areas perfused. The results of this study indicate that the proximal small intestine is the primary site of endogenous GIP release in man, but that smaller quantities are also released by the distal small bowel.