Dose-response effect of a single administration of oral hexyl-insulin monoconjugate 2 in healthy nondiabetic subjects

OBJECTIVE: 1) To evaluate the effect of a single oral dose of hexyl-insulin monoconjugate 2 (HIM2) on the rate of whole-body glucose disposal (Rd) and endogenous glucose production (EGP) in healthy nondiabetic subjects, 2) to examine the reproducibility of HIM2 on glucose metabolism, and 3) to compare the results obtained with HIM2 with those using a bioequivalent dose of subcutaneous lispro insulin. RESEARCH DESIGN AND METHODS: Six healthy subjects ([means +/- SE] aged 31 +/- 5 years and BMI 23.1 +/- 3.9 kg/m2) participated in four studies performed in random order on separate days. Subjects ingested a single dose of HIM2 (0.125, 0.5, and 0.75 mg/kg) or received subcutaneous lispro insulin (0.1 units/kg). Studies were performed with [3-3H]glucose, and plasma glucose concentration was maintained at basal levels for 4 h with the euglycemic clamp technique. After 6 weeks, subjects participated in two repeat studies to examine the reproducibility of HIM2 (0.5 mg/kg) and lispro insulin (0.1 units/kg). RESULTS: Fasting plasma insulin (7 muU/ml) increased to a maximum of 102, 321, and 561 muU/ml at 60 min after all three HIM2 doses (0.125, 0.5, and 0.75 mg/kg, respectively). A dose-related decrease in basal EGP was observed as the HIM2 dosage was increased from 0 to 0.125 to 0.5 mg/kg (P <0.05 vs. each preceding dose). Suppression of EGP was similar with the 0.5- and 0.75-mg/kg HIM2 doses. A dose-related stimulation of basal Rd was observed as the HIM2 dosage was increased from 0 to 0.125 to 0.5 (P <0.05 vs. each preceding dose) to 0.75 mg/kg (P <0.10 vs. preceding dose). Rd (0-240 min) was increased by 0.5 mg/kg oral HIM2 to a value similar to 0.1 units/kg lispro insulin. The 0.125-mg/kg HIM2 dose reduced EGP (0-240 min) to a value that was similar to 0.1 units/kg lispro insulin. The variability in the effect of HIM2 and lispro on Rd (25 +/- 7 vs. 27 +/- 1%, respectively) and on suppression of EGP (19 +/- 1 vs. 19 +/- 0.7%, respectively) was similar. CONCLUSIONS: Oral HIM2 suppresses EGP and increases tissue Rd in a dose-dependent manner. The effects of HIM2 on EGP and Rd persisted at 240 min, even though plasma insulin concentration had returned to basal levels. Oral HIM2 may provide an effective and reproducible means of controlling postprandial plasma glucose excursions in diabetic patients.     

Comparison of pharmacokinetic and pharmacodynamic properties of single-dose oral insulin spray and subcutaneous insulin injection in healthy subjects using the euglycemic clamp technique

BACKGROUND: Oral insulin spray is a new, noninjectable method of insulin delivery. This system delivers an aerosol of uniform-sized droplets containing regular human insulin at a high velocity into the oropharyngeal cavity for local transmucosal absorption. OBJECTIVE: The purpose of this study was to compare the pharmacokinetic and pharmacodynamic properties of single-dose oral insulin spray and SC insulin injection in healthy subjects. METHODS: Healthy male volunteers aged 21 to 25 years participated in this open-label study conducted at the Diabetes Unit, Hadassah-Hebrew University Hospital, Jerusalem, Israel. Subjects presented at 2 visits separated by 7 to 14 days. At both visits, the euglycemic clamp technique was used to maintain a constant blood glucose level. At one visit, subjects received regular human insulin 0.1 U/kg by SC injection. At the other visit, subjects received 15 puffs (150 U) of oral insulin spray. The pharmacokinetic (insulin absorption) and pharmacodynamic (glucose uptake) properties of the drugs were evaluated using blood analyses over the subsequent 360 minutes. RESULTS: Six volunteers were enrolled (mean [SD] age, 22.8 [1.2] years; mean [SD] body mass index, 23.2 [2.2] kg/m(2)). The mean (SD) baseline-corrected C(max) was significantly higher with oral insulin spray compared with SC insulin (54.0 [20.3] vs 30.8 [6.1] microU/mL; P = 0.028). Mean (SD) T(max) was significantly shorter with oral insulin spray compared with SC insulin (23.3 [5.2] vs 83.3 [42.2] minutes; P = 0.027). The mean (SD) time to maximal metabolic effect (maximum glucose infusion rate [GIR(max)]) (44.2 [8.6] vs 100.0 [35.6] minutes) and late time to half-maximal effect (101.0 [41.0] vs 257.2 [27.8] minutes) were shorter with oral insulin spray compared with SC insulin (both, P = 0.028). The baseline-corrected GIR(max) (6.8 [3.3] vs 6.2 [2.3] mg/kg . min) and glucose consumption (396.7 [178.0] vs 432.1 [226.0] mg/kg) during the 120 minutes after study drug administration were comparable between oral and SC insulin, respectively. CONCLUSIONS: In this study in a small, selected population of healthy male subjects under euglycemic conditions, oral insulin spray was associated with a higher C(max), shorter T(max), and faster time to peak glucose uptake compared with SC insulin. The short T(max) and the 120-minute duration of effect of oral insulin spray suggest it may be a promising alternative for fulfilling meal-related insulin requirements in persons with diabetes.     

Dose-response relationship after single oral dose administrations of morphine and oxycodone using laser-evoked potentials on UVB- and capsaicin-irritated skin in healthy male subjects

The aim of the study was to evaluate the analgesic/antihyperalgesic efficacy and to establish the dose-response relationship of morphine immediate release (IR) and oxycodone IR in a human experimental algesimetric model. Calculated effect ratios for peak-to-peak (PtP) amplitudes of laser-evoked potentials (LEPs) and visual analog scales (VAS) postlaser pain on UVB-irradiated skin (main target variables) were 1.68 and 1.18 respectively for oxycodone 10mg/morphine 20mg, 3.00 and 1.63 respectively for oxycodone 15 mg/morphine 30 mg, and 1.12 and 1.25 respectively for oxycodone 20mg/morphine 40 mg. The effect on the laser-PtP amplitude of morphine at the highest dose (40 mg) and of oxycodone at all doses (10, 15, 20mg) was considered to be clinically relevant based on a difference from placebo of ≥ 2.5 μV. For both compounds, a statistically significant linear trend was observed between dose groups in at least 1 of the 2 main target variables (adjusted P value for both end points <.001 at all doses). Hyperalgesia developed over time vs baseline due to acute exposure to UVB irradiation and to topical/occlusive 1% capsaicin solution. For both compounds, the principal onset of analgesic/antihyperalgesic drug effects was around 0.5 hours with an average peak at about 1 to 2 hours and the effect lasting for more than 3 hours (morphine 20 and 30 mg) or 6 hours (morphine 40 mg and oxycodone all doses). In conclusion, the study demonstrated a solid outcome of a mixed objective/subjective human experimental algesimetric model to approach dose-response relationships and analgesic/antihyperalgesic effects of 2 opioids.     

Dose-response relationship of an oral insulin spray in six patients with type 1 diabetes: a single-center, randomized, single-blind, 5-way crossover study

OBJECTIVE: This study evaluated the pharmacokinetic and pharmacodynamic properties and dose-response effects of an oral insulin spray formulation compared with those of subcutaneously injected regular insulin and placebo in patients with type 1 diabetes mellitus. METHODS: This was a single-center, randomized, single-blind, open-label, 5-way crossover study in which patients with type 1 diabetes received 5, 10, and 20 puffs of the oral insulin spray; regular insulin 0.1 U/kg SC; and placebo spray. The pharmacokinetic parameters of interest were the maximum serum insulin concentration (Ins-C(max)); the incremental insulin AUC from 0 to 120 minutes (Ins-AUC(0-120)), from 0 to 240 minutes, and from 0 to 360 minutes; and the time to maximum serum insulin concentration (Ins-T(max)). The pharmacodynamic parameters of interest were the maximum glucose infusion rate (GIR(max)); the incremental glucose AUC from 0 to 120 minutes (GIR-AUC(0-120)), from 0 to 240 minutes, and from 0 to 360 minutes; the time to maximum GIR (GIR-T(max)); the time to early half-maximal GIR (early T50%); and the time to late half-maximal GIR (late T50%). Pharmacokinetic and pharmacodynamic parameters were assessed using the euglycemic clamp technique. RESULTS: The study enrolled 6 white men with type 1 diabetes (mean [SD] age, 37.5 [16.2] years, mean weight, 82.7 [17.0] kg). Ins-T(max) was shorter for 5, 10, and 20 puffs of oral insulin spray than for SC insulin (26.7 [13.7], 29.2 [7.4], 23.3 [5.2], and 142.5 [73.2] min, respectively; P < 0.05). There was no effect of dose on Ins-T(max). The Ins-AUC(0-120) for 5, 10, and 20 puffs of oral insulin spray (304.8 [277.9], 689.2 [353.0], and 1808.8 [1252.6] microU/mL per min, respectively; P < 0.05) and the corresponding Ins-Ca(max) (12.9 [8.7], 26.7 [14.5], and 47.6 [40.1] microU/mL; P < 0.05) suggested a dose-response relationship. Five, 10, and 20 puffs of oral insulin spray had an earlier onset of action than SC insulin (early T50%: 23.3 [15.1], 28.3 [12.3], 31.2 [111.8], and 87.0 [39.6] min, respectively; P < 0.05), an earlier maximal effect (GIR-T(max): 40.0 [23.7], 45.8 [22.7], 44.2 [5.8], and 145.0 [43.7] min; P < 0.05), and a shorter duration of action (late T50%: 56.5 [31.0], 70.2 [12.9], 75.5 [6.0], and 290.8 [84.0] min; P < 0.05). Dose-dependent increases in maximal metabolic effect were observed with 5, 10, and 20 puffs: the GIR(max) was 0.9 (0.5), 2.0 (1.3), and 3.9 (2.5) mg/kg per minute, respectively (P < 0.05), and the GIR-AUC(0-120) was 39.6 (34.9), 76.8 (67.4), and 189.1 (163.0) mg/kg per minute (P < 0.05). CONCLUSIONS: In this study in patients with type 1 diabetes, oral insulin spray had a faster onset and shorter duration of action than subcutaneously injected regular insulin. A dose-response relationship was noted in the metabolic effect and absorption of oral insulin spray.     

Effect of atropine on insulin secretion in healthy subjects

The effect of an anti-cholinergic drug (atropine) on insulin secretion was studied in a double-blind manner by the glucagon C-peptide secretion test in five healthy subjects and controlled with saline only (placebo) in four subjects. Blood C-peptide increased only by 157% in the group given atropine and by 252% in the group given placebo. The blood glucose concentration increased by 25% and 32%, respectively. Thus, it is concluded that the cholinergic system, probably through the vagus nerve, has an insulin secretion stimulating effect. The results also suggest that denervation of the vagus nerve, e.g. in gastric surgery, may partly explain post-prandial hyperglycaemia particularly found in dumping.     

Kinetics of intravenous and oral pentoxifylline in healthy subjects

The kinetics of a sustained-release formulation of pentoxifylline were compared with those of a capsule and an intravenous infusion. Ten healthy subjects received each of the oral pentoxifylline formulations (400 mg) three times a day for 9 days in a random crossover fashion. Pentoxifylline (200 mg) was also given intravenously on a separate day. After intravenous pentoxifylline, plasma levels declined in a biphasic manner, with a terminal t1/2 of 1.63 +/- 0.8 hr. Plasma clearance was 1333 +/- 481 ml/min and the volume of distribution was 168 +/- 82.3 l. Cumulation of pentoxifylline in plasma after repeated dosing was minimal. Plasma levels of the active 5-hydroxylated metabolite were generally higher than those of the parent drug after both routes of administration. Urinary excretion of two acid metabolites after oral and intravenous dosing indicated almost complete absorption of drug-related substances from both of the oral formulations, although bioavailability averaged 20% to 30%.     

Disposition of posaconazole following single-dose oral administration in healthy subjects

Posaconazole is a potent, broad-spectrum triazole antifungal agent currently in clinical development for the treatment of refractory invasive fungal infections. Eight healthy male subjects received a single 399-mg (81.7 microCi) oral dose of [(14)C]posaconazole after consuming a high-fat breakfast. Urine, feces, and blood samples were collected for up to 336 h postdose and assayed for total radioactivity; plasma and urine samples were also assayed for parent drug. Posaconazole was orally bioavailable, with a median maximum posaconazole concentration in plasma achieved by 10 h postdose. Thereafter, posaconazole was slowly eliminated, with a mean half-life of 20 h. The greatest peak in the radioactivity profile of pooled plasma extracts was due to posaconazole, with smaller peaks due to a monoglucuronide, a diglucuronide, and a smaller fragment of the molecule. The mean total amount of radioactivity recovered was 91.1%; the cumulative excretion of radioactivity in feces and in urine was 76.9 and 14.0% of the dose, respectively. Most of the fecal radioactivity was associated with posaconazole, which accounted for 66.3% of the administered dose; however, urine contained only trace amounts of unchanged posaconazole. The radioactivity profile of pooled urine extracts included two monoglucuronide conjugates and a diglucuronide conjugate of posaconazole. These observations suggest that oxidative (phase 1) metabolism by cytochrome P450 isoforms represents only a minor route of elimination for posaconazole, and therefore cytochrome P450-mediated drug interactions should have a limited potential to impact posaconazole pharmacokinetics.     

Peripheral and hepatic insulin sensitivity in healthy elderly human subjects

Insulin resistance has been reported in normal ageing but discrepancies between such studies may be related to compounding factors such as body composition and exercise patterns. We employed a two-step hyperinsulinaemic euglycaemic clamp to assess peripheral and hepatic tissue insulin sensitivity and glucose recycling in 13 elderly (E) and 14 young (Y) healthy subjects controlling for the above factors. There was no difference in basal hepatic glucose production (E: 2.36 +/- 0.06, Y: 2.47 +/- 0.1 mg kg-1 min-1; P = 0.4). At step 1 (insulin infusion 15 mU kg-1 h-1) glucose turnover was similar (E: 2.65 +/- 0.13, Y: 2.88 +/- 0.22 mg kg-1 min-1; P = 0.4) but hepatic glucose production was lower in the elderly group (0.20 +/- 0.16 vs 0.64 +/- 0.10 mg kg-1 min-1; P = 0.03). At step 2 (insulin infusion 50 mU kg-1 h-1) glucose turnover was similar (E: 7.60 +/- 0.24, Y: 8.05 +/- 0.34 mg kg-1 min-1; P = 0.3) and hepatic glucose production was equal but negative (E: -1.35 +/- 0.18, Y: -1.34 +/- 0.22 mg kg-1 min-1; P = 0.9). Glucose recycling did not differ between the groups at any stage. Similar serum insulin levels were achieved in both groups at each step. Decreased glucose tolerance was confirmed in E with a higher 2 h blood glucose after an OGTT (5.3 +/- 0.4 vs 4.1 +/- 0.3 mmol l-1; P = 0.03) but incremental insulin response was similar (E: 3236 +/- 289, Y: 3586 +/- 463 mU l-1 min-1; P = 0.5). We conclude that changes in hepatic tissue insulin sensitivity do not cause the deterioration in glucose tolerance observed with age. A small reduction in both peripheral tissue insulin sensitivity and late insulin secretion may be responsible.     

Multiple-dose safety and pharmacokinetics of oral garenoxacin in healthy subjects

Garenoxacin (T-3811ME, BMS-284756) is a novel des-F(6) quinolone that has been shown to be effective in vitro against a wide range of clinically important pathogens, including gram-positive and gram-negative aerobes and anaerobes. This study was conducted to evaluate the safety and tolerability of multiple oral doses (100 to 1200 mg/day) of garenoxacin in healthy subjects and to determine its multiple-dose pharmacokinetics. Forty healthy male and female subjects (18 to 45 years of age) were enrolled in this randomized, double-blind, placebo-controlled, sequential, multiple- and ascending-dose study. Each subject received a once-daily oral dose of garenoxacin (100, 200, 400, 800, or 1200 mg) or a placebo for 14 days. Blood and urine samples were collected for measurements of garenoxacin by validated liquid chromatography with dual mass spectrometry, and plasma garenoxacin concentration-time data were analyzed by noncompartmental methods. The effects of garenoxacin on Helicobacter pylori, psychometric test performance, and electrocardiograms were assessed, as was drug safety. Over the 14 days of dosing, geometric mean peak concentrations of garenoxacin in plasma (C(max)) at the 100- and 1200-mg doses were within the ranges of 1.2 to 1.6 and 16.3 to 24 microg/ml, respectively. The corresponding values for the geometric mean area under the concentration-time curve over the dosing interval (AUC(tau)) for garenoxacin in plasma at the 100- and 1200-mg doses were within the ranges of 11.5 to 15.7 and 180 to 307 microg. h/ml, respectively. Increases in systemic exposure to garenoxacin in terms of AUC and C(max) were approximately dose proportional over the 100- to 400-mg dose range but demonstrated increases that were somewhat greater than the dose increments at the 800- and 1200-mg doses. Median values for the time to achieve C(max) were in the range of 1.13 to 2.50 h for all doses. The mean elimination half-life for garenoxacin in plasma appeared to be independent of dose and ranged from 13.3 to 17.8 h (day 14). Approximately 30 to 50% of an administered garenoxacin dose was excreted unchanged in the urine. At doses of 100 to 400 mg, steady-state concentrations of garenoxacin in plasma appeared to be attained by the fourth dose. Multiple oral doses of garenoxacin were well tolerated and did not demonstrate clinically significant effects on QT(c) or psychometric test results. Garenoxacin administered alone for 14 days at doses of >or=400 mg demonstrated activity against H. pylori. These results suggest that multiple once-daily oral doses of garenoxacin of up to 1200 mg are safe and well tolerated and that the pharmacokinetics of garenoxacin support once-daily administration.     

Effects of oral fat load on insulin output and glucose tolerance in healthy control subjects and obese patients without diabetes

OBJECTIVE: Elevated plasma nonesterified fatty acid (NEFA) concentrations cause peripheral and hepatic insulin resistance and may play an important role in regulating glucose-induced insulin secretion. The aim of our study was to investigate the influence of physiologically elevated NEFA levels on glucose-stimulated insulin secretion in order to find evidence that NEFAs are a potential factor predisposing for type 2 diabetes and related metabolic disorders, which are known risk factors for cardiovascular disease. RESEARCH DESIGN AND METHODS: We combined an orally administered fat emulsion with an intravenous glucose tolerance test and measured the time course of NEFA, insulin, and glucose. In order to find pathological conditions we applied the experiment to healthy and obese subjects. RESULTS: The main findings are a significant increase in glucose-stimulated insulin secretion after oral fat load in both groups compared with the condition without preceding fat ingestion and a prolonged insulin secretion after fat load in obese patients compared with control subjects. CONCLUSIONS: The results provide evidence that fat ingestion modulates beta-cell function and that NEFA is a plausible mediator that acts as a link between fat and glucose metabolism by modulating glucose-stimulated insulin secretion. Under the condition of elevated plasma levels of NEFA, this mechanism may be responsible for hyperinsulinemia in obese patients and a potential target of type 2 diabetes prevention strategies.     

Kinetics and electrocardiographic changes after oral 3-OH-quinidine in healthy subjects

3-OH-quinidine, a major quinidine metabolite, has been reported to have antiarrhythmic activity in animals and is suspected to contribute to the effect of quinidine in man. Four healthy subjects received 3-OH-quinidine in increasing oral doses (35, 100, 300 mg) to achieve serum concentrations in the range of those after quinidine dosing in patients. Blood and urine were collected up to 48 hours and blood pressure, heart rate, and averaged ECG complexes were recorded during 12 hours after dosing. Kinetic analysis revealed differences from published data for the parent drug. Renal clearance was 16 L/hr. The elimination t1/2 was 12.4 hours, substantially longer than that of quinidine. No systematic ECG changes were observed in two subjects with maximum concentrations of 55 and 215 micrograms/L. In the other two subjects who achieved higher maximum concentrations (447 and 918 micrograms/L), there was a significant relationship between the length of the corrected QT interval and the serum concentration of 3-OH-quinidine. These first dynamic results indicate that 3-OH-quinidine exerts effects in man resembling those of quinidine and may contribute to the antiarrhythmic activity of quinidine.     

Bioequivalence of two oral formulations of tebipenem pivoxil hydrobromide in healthy subjects

Tebipenem pivoxil hydrobromide (TBP‐PI‐HBr) is a novel oral carbapenem prodrug of tebipenem (TBP), the active moiety, currently in development for treating serious bacterial infections. This study assessed the bioequivalence (BE) of the clinical trial and registration tablet formulations of TBP‐PI‐HBr and evaluated the effect of food on the pharmacokinetics (PKs) of tebipenem. This was a single center, open‐label, randomized, single‐dose, three‐sequence, four‐period crossover, BE, and food‐effect study. Subjects received single 600 mg oral doses of TBP‐PI‐HBr as the reference clinical trial tablet (treatment A) and test registration tablet (treatment B) formulations in alternating sequence while fasting, and then the test formulation under fed conditions. Whole blood samples were collected predose and at specified intervals up to 24 h postdose to evaluate TBP PK parameters. Safety and tolerability were monitored. Thirty‐six healthy, adult subjects were enrolled and completed the study. The criteria for BE were met for the TBP‐PI‐HBr test (registration tablet) and reference (clinical trial tablet) formulations as the 90% confidence intervals for the geometric mean ratios for TBP area under the curve (AUC)_0‐t , AUC_0‐inf, and maximum plasma concentration (C _max) fell within the established 80% to 125% BE limits. Dosing with food had no meaningful effect on TBP PK parameters. Five (14%) subjects reported adverse events (AEs) of mild severity. No deaths, serious AEs, or discontinuations due to AEs were reported, and no clinically relevant electrocardiograms, vital signs, or safety laboratory findings were observed. The study results demonstrate the BE of oral TBP‐PI‐HBr registration and clinical trial tablet formulations and indicate that TBP‐PI‐HBr can be administered without regard to meals.

Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Tebipenem pivoxil hydrobromide (TBP‐PI‐HBr) prodrug was developed as the first oral carbapenem for treatment of serious bacterial infections due to gram‐positive and gram‐negative bacteria, including drug‐resistant pathogens. The TBP‐PI‐HBr formulation was developed for use in phase I and phase III clinical studies during clinical development. However, the oral tablet formulation was modified for registration purposes. Because the registration formulation had differences than the formulation used in early clinical development, a bioequivalence (BE) study was conducted and, within the same study, a food effect evaluation arm also was included. WHAT QUESTION DID THIS STUDY ADDRESS? This study evaluated the BE of a 300 mg TBP‐PI‐HBr registration tablet (test) formulation developed for commercial use (i.e., the intended marketed formulation) and the 300 mg clinical trial tablet formulation (reference) in healthy adults under fasting conditions and the effect of food on tebipenem (TBP) pharmacokinetics (PKs) for the registration tablet formulation. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Clinical study and registration tablet formulations of oral TBP‐PI‐HBr were bioequivalent and administration of the registration tablet with food had no clinically relevant effect on the PK profile of TBP. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? The registration tablet formulation of oral TBP‐PI‐HBr is comparable to the clinical study formulation and can be administered without regard to meals for the treatment of serious bacterial infections.     

Retinol binding protein 4 and insulin resistance in apparently healthy elderly subjects

BackgroundInsulin resistance (IR) increases with advancing age, yet the underlying mechanism is not well established. Although adipocytokine retinol binding protein 4 (RBP4) was recently shown to be linked to IR, their relationship remains controversial and relatively little information exists regarding their roles in the elderly subjects. We investigated the association between RBP4 and IR in obese and nonobese elderly subjects.MethodsA total of 111 (68 nonobese and 43 obese) apparently healthy elderly subjects, aged 75.9 ± 4.8 y were included. IR was determined by homeostasis model assessment (HOMA-IR). Serum RBP4 was measured by enzyme-linked immunosorbent assay.ResultsIn all subjects, RBP4 levels were positively correlated with fasting insulin, HOMA-IR, and triglycerides. However, after subgroup analysis, RBP4 levels were positively correlated with fasting glucose, fasting insulin, and HOMA-IR in the obese group only. In step-wise multiple linear regression analysis, RBP4 was found to be independently associated with triglyceride levels in the nonobese group and independently associated with HOMA-IR in the obese group.ConclusionsThe reason for the differing metabolic role of RBP4 in obese and nonobese elderly subjects remains uncertain, but our findings suggest that RBP4 may be linked to IR and lipid metabolism, at least in the elderly.     

Dose-response relationships for the effects of insulin on glucose and fat metabolism in injured patients and control subjects.

1. Twenty-four patients were studied at around 7 days after musculoskeletal injuries in order to define the nature of the impairment of sensitivity to insulin. Insulin was infused at 6, 35, 200 or 1200 m-units min-1 m-2 for 2 h and the plasma glucose concentration was 'clamped' at 5 mmol/l. Forearm (uninjured) glucose extraction and blood flow were measured, and whole-body substrate oxidation and energy production rates were assessed by indirect calorimetry. The patients were compared with normal control subjects. 2. Plasma insulin concentrations during infusion were similar in patients and control subjects, showing a similar metabolic clearance of insulin. At each infusion rate, the rate of glucose infusion needed to maintain euglycaemia was less in the patients than in the control subjects. The dose-response curve for whole-body glucose infusion rate against plasma insulin concentration showed diminished sensitivity and diminished maximal response in the patients. A similar pattern was seen for forearm glucose uptake, with a marked impairment of both sensitivity to insulin and maximal responsiveness. 3. The resting metabolic rate was increased in the patients compared with the control subjects, but failed to respond to insulin infusion, so that final metabolic rates were similar in patients and control subjects. At the higher insulin infusion rates, the final rate of whole-body oxidation of carbohydrate was significantly less in the patients than in the control subjects, and that of fat was significantly greater.(ABSTRACT TRUNCATED AT 250 WORDS)     

炎症性口腔疾病与胰岛素抵抗的相关研究进展

胰岛素抵抗(IR)作为糖尿病前期(PDM)的标志,指胰岛素介导的细胞糖代谢能力减低。流行病学和动物实验研究结果均提示牙周炎可作为独立的危险因素影响非糖尿病个体的胰岛素抵抗(IR)。研究提示肝脏中TLR4+表达在促进炎性细胞因子分泌以导致IR的发展中发挥了重要作用。研究发现,白塞病(BD)和复发性口腔溃疡(ROU)也可促进IR,推断其发生机制均与促炎性细胞因子水平升高有关。因此明确牙周炎、BD和ROU等炎症性口腔疾病对IR的作用及相关机制,利用机制调控产物,可为预防IR甚至糖尿病及并发症提供新的临床依据。