Application of pH-responsive polymers to oral dosage forms for insulin]

The potential of graft copolymer networks with poly(methacrylic acid-g-ethylene glycol; P(MAA-g-EG)) for oral dosage forms to enhance insulin absorption is reviewed. The polymer exhibited unique pH-responsive characteristics in which interpolymer complexes were formed and dissociated, respectively, in acidic and neutral/basic environments. Correspondingly, the polymer was capable of highly incorporating and rapidly releasing insulin in vitro. This insulin loaded polymer successfully enhanced oral insulin absorption in rats with significant hypoglycemic effects. The polymer was also shown to possess mucoadhesive properties. Furthermore, the polymer demonstrated high calcium binding which may affect the proteolytic activity of calcium-dependent enzymes and/or reduce transepithelial resistances. Thus, the polymer has the potential to be used as a carrier for oral dosage forms of insulin to enhance its mucosal absorption.     

Uptake of heavy metal ions from aqueous media by hydrogels and their conversion to nanoparticles for generation of a catalyst system: two-fold application study

Poly(methacrylic acid) (P(MAA)), poly(acrylamide) (P(AAm)) and poly(3-acrylamidopropyltrimethyl ammonium chloride) (P(APTMACl)) were synthesized as anionic, neutral and cationic hydrogels, respectively. The synthesized hydrogels have the ability to be used as absorbents for the removal of selected heavy metal ions such as Cu²⁺, Co²⁺, Ni²⁺ and Zn²⁺ from aqueous media. Absorption studies revealed that the absorption of metal ions by the hydrogels followed the order Cu²⁺ > Ni²⁺ > Co²⁺ > Zn²⁺. For the mechanism of absorption, both Freundlich and Langmuir absorption isotherms were applied. Metal ion entrapped hydrogels were treated using an in situ chemical reduction method in order to convert the metal ions into metal nanoparticles for the synthesis of hybrid hydrogels. The synthesis and morphology were confirmed using FT-IR and SEM, while the absorbed metal amounts were measured using TGA and AAS. The hybrid hydrogels were further used as catalysts for the reduction of macro (methylene blue, methyl orange and congo red) and micro (4-nitrophenol and nitrobenzene) pollutants from the aqueous environment. The catalytic performance and re-usability of the hybrid hydrogels were successfully investigated.

Poly(methacrylic acid) (P(MAA)), poly(acrylamide) (P(AAm)) and poly(3-acrylamidopropyltrimethyl ammonium chloride) (P(APTMACl)) were synthesized as anionic, neutral and cationic hydrogels respectively.     

Oral delivery of insulin associated to polymeric nanoparticles in diabetic rats.

Nanoparticles prepared with a blend of a biodegradable polyester (poly(-epsilon-caprolactone)) and a polycationic non-biodegradable acrylic polymer (Eudragit RS) have been used as a drug carrier for oral administration of insulin. The rate of encapsulation of insulin was around 96%. The therapeutic efficiency of oral insulin nanoparticles (25, 50 and 100 IU/kg) in diabetic rats and the intestinal uptake of fluorescein isothiocyanate (FITC) labelled insulin were studied. When administered orally by force-feeding to diabetic rats, insulin nanoparticles decreased fasted glycemia in a dose dependant manner with a maximal effect observed with 100 IU/kg. These insulin nanoparticles also increased serum insulin levels and improved the glycemic response to an oral glucose challenge for a prolonged period of time. FITC-Insulin-loaded nanoparticles strongly adhered to the intestinal mucosa and labeled insulin, either released and/or still inside nanoparticles, was mainly taken up by the Peyer's patches. It is concluded that polymeric nanoparticles allows the preservation of insulin's biological activity. In addition, the antidiabetic effect can be explained by the mucoadhesive properties of the polycationic polymer (Eudragit) RS) allowing the intestinal uptake of insulin.     

胰岛素吸入给药降血糖的效果评价

背景:口服胰岛素易被胃酸及胃肠道内的各种酶降解,难以透过胃肠道上皮细胞膜,针剂形式也至少需要36 h注射1次.近年正在不断研究各种肺部给药制剂如干粉型吸入剂、吸入气雾剂、电喷雾剂、胰岛素纳米化技术和吸收增强剂等,具有较好的应用前景.目的:观察胰岛素溶液经正常大鼠吸入后的降血糖作用.方法:体质量(220±30)g的健康雄性大鼠30只,随机分为7组.其中3组分别予吸入胰岛素溶液1.0,5.0,10.0U/kg,每组4只:另3组分别给予吸入2.0 U/kg胰岛素溶液+5％的卵磷脂、2.0 U/kg胰岛素溶液+1％的油酸、2.0 U/kg胰岛素溶液+1％DTPA,每组5只;剩余3只为空白对照组.分别于给药后0,30,60,120,180,240 min从大鼠尾部取血15 Μl,使用ONE TOUCH~(TM)BASIC~(TM)PLUS稳捷基础倍加型血糖仪测定血糖,计算不同条件下胰岛素溶液的药理生物利用度.结果与结论:1 U/kg的胰岛素溶液经大鼠吸入后即有明显的降血糖作用,随着剂量的增加,大鼠体内血糖下降幅度随之增大,10 U/kg的剂量降血糖最低可降至14.5％.1 U/kg的胰岛素溶液经吸入后,在不加吸收促进剂的条件下的药理生物利用度为11.5％.吸收促进剂油酸、DTPA和卵磷酯的加入均能显著地增强胰岛素溶液的降血糖作用.     

Modulation of kidney cell protein degradation by insulin

Insulin is an established regulator of intracellular proteolysis in several mammalian tissues but little is known about its role in the kidney. The present study was undertaken to determine whether insulin influences protein degradation in isolated rat renal proximal tubules and to investigate its mechanism of action in cultured proximal-like tubular epithelial cells from the opossum kidney. Long-lived protein degradation was determined from the release of carbon 14-labeled valine from previously labeled cellular protein under conditions designed to minimize label reutilization. In isolated tubules, the mean control rate of proteolysis was 2.18% per hour, indicating an appreciable turnover of cellular protein. Insulin (10(-6) mol/L) decreased the rate by 23%. In cultured kidney cells, the rate of protein degradation averaged 1.25% per hour in the presence of serum and 1.68% per hour in its absence, an increase of 34%. High insulin concentrations suppressed this acceleration completely, and physiologic levels inhibited it partially. No evidence was obtained to indicate that insulin action is mediated through stimulation of Na(+)-H+ antiport or through increased amino acid utilization. Ammonium chloride, however, strongly attenuated the serum deprivation response and the inhibitory effect of insulin. The exact mechanisms whereby insulin inhibits proteolysis is not known, but these findings are consistent with an inhibitory action of insulin on the lysosomal pathway.     

On the mechanism of impaired insulin secretion in chronic renal failure.

It has been suggested that a sustained rise in resting levels of cytosolic calcium [Ca2+]i of pancreatic islets is responsible for impaired insulin secretion in chronic renal failure (CRF). Evidence for such an event is lacking and the mechanisms through which it may affect insulin secretion are not known. Studies were conducted in normal, CRF, and normocalcemic, parathyroidectomized (PTX) CRF rats to answer these questions. Resting levels of [Ca2+]i of islets from CRF rats were higher (P less than 0.01) than in control of CRF-PTX rats. [3H]2-deoxyglucose uptake and cAMP production by islets were not different in the three groups. Insulin content of, and glucose-induced insulin secretion by islets from CRF rats was lower (P less than 0.01) than in control and CRF-PTX rats. In contrast, glyceraldehyde-induced insulin release by CRF islets was normal. Basal ATP content, both glucose-stimulated ATP content and ATP/ADP ratio, net lactic acid output, Vmax of phosphofructokinase-1, and Ca2+ ATPase of islets from CRF rats were lower (P less than 0.02-less than 0.01) than in normal or CRF-PTX animals. Data show that: (a) Glucose but not glyceraldehyde-induced insulin secretion is impaired in CRF; (b) the impairment in glucose-induced insulin release in CRF is due to a defect in the metabolism of glucose; (c) this latter defect is due to reduced ATP content induced partly by high [Ca2+]i of islets; and (d) the high [Ca2+]i in islets of CRF rats is due to augmented PTH-induced calcium entry into cells and decreased calcium extrusion from the islets secondary to reduced activity of the Ca2+ ATPase.     

Impact of pharmaceutical dosage forms on the pharmacokinetics of roxithromycin in healthy human volunteers

OBJECTIVES: The impact of two different pharmaceutical preparations on the pharmacokinetics of roxithromycin was investigated in healthy human volunteers. METHODS: The degradation kinetics and products of roxithromycin were investigated in simulated gastric fluid and simulated intestinal fluid. Two oral dosage forms of roxithromycin were employed: enteric-coated pellets and dispersible tablets. RESULTS: The degradation half-time of roxithromycin in simulated gastric fluid was 0.23 h, and three main degradation products were characterized. In contrast, roxithromycin was stable in simulated intestinal fluid and remained unchanged after a 1.00 h incubation. The roxithromycin enteric-coated pellets exhibited higher bioavailability and a more potent serum antibacterial activity than the dispersible tablets. CONCLUSIONS: The type of oral dosage forms of roxithromycin altered its pharmacokinetics. Whether or not this affects the in vivo antibacterial efficacy requires further study.     

Effects of potassium supplementation on insulin binding and insulin action in human obesity: protein-modified fast and refeeding

To investigate the role of potassium deficiency in the development of glucose intolerance during caloric deprivation, potassium balance was maintained within normality with oral potassium supplementation in a group of obese subjects who underwent protein-modified fast and the results of the study of carbohydrate metabolism (oral glucose test, insulin receptors on monocytes and peripheral glucose utilization as assessed by euglycaemic clamp) were compared with those obtained in a group of obese subjects admitted to protein-modified fast without potassium supplementation. Caloric deprivation without oral potassium supplementation was followed by a negative potassium balance and a decrease of serum potassium levels; a decrease of the peripheral levels of insulin along with an increase in insulin receptors and a striking reduction of peripheral glucose utilization were also observed. The maintenance of normal potassium balance and normal serum potassium levels with oral potassium-chloride supplementation was associated with higher peripheral levels of insulin (P less than 0.01) and improvement of peripheral glucose utilization (P less than 0.01) whereas the binding of insulin to monocytes was unchanged. The data suggest that potassium depletion during protein-modified fast causes a decrease of the peripheral levels of insulin and a resistance to insulin action at the postreceptors sites which is reversed by potassium supply.     

Triple therapy in type 2 diabetes: insulin glargine or rosiglitazone added to combination therapy of sulfonylurea plus metformin in insulin-naive patients

OBJECTIVE: To evaluate the efficacy and safety of add-on insulin glargine versus rosiglitazone in insulin-na?ve patients with type 2 diabetes inadequately controlled on dual oral therapy with sulfonylurea plus metformin. RESEARCH DESIGN AND METHODS: In this 24-week multicenter, randomized, open-label, parallel trial, 217 patients (HbA(1c) [A1C] 7.5-11%, BMI >25 kg/m(2)) on > or =50% of maximal-dose sulfonylurea and metformin received add-on insulin glargine 10 units/day or rosiglitazone 4 mg/day. Insulin glargine was forced-titrated to target fasting plasma glucose (FPG) < or =5.5-6.7 mmol/l (< or =100-120 mg/dl), and rosiglitazone was increased to 8 mg/day any time after 6 weeks if FPG was >5.5 mmol/l. RESULTS: A1C improvements from baseline were similar in both groups (-1.7 vs. -1.5% for insulin glargine vs. rosiglitazone, respectively); however, when baseline A1C was >9.5%, the reduction of A1C with insulin glargine was greater than with rosiglitazone (P < 0.05). Insulin glargine yielded better FPG values than rosiglitazone (-3.6 +/- 0.23 vs. -2.6 +/- 0.22 mmol/l; P = 0.001). Insulin glargine final dose per day was 38 +/- 26 IU vs. 7.1 +/- 2 mg for rosiglitazone. Confirmed hypoglycemic events at plasma glucose <3.9 mmol/l (<70 mg/dl) were slightly greater for the insulin glargine group (n = 57) than for the rosiglitazone group (n = 47) (P = 0.0528). The calculated average rate per patient-year of a confirmed hypoglycemic event (<70 mg/dl), after adjusting for BMI, was 7.7 (95% CI 5.4-10.8) and 3.4 (2.3-5.0) for the insulin glargine and rosiglitazone groups, respectively (P = 0.0073). More patients in the insulin glargine group had confirmed nocturnal hypoglycemia of <3.9 mmol/l (P = 0.02) and <2.8 mmol/l (P < 0.05) than in the rosiglitazone group. Effects on total cholesterol, LDL cholesterol, and triglyceride levels from baseline to end point with insulin glargine (-4.4, -1.4, and -19.0%, respectively) contrasted with those of rosiglitazone (+10.1, +13.1, and +4.6%, respectively; P < 0.002). HDL cholesterol was unchanged with insulin glargine but increased with rosiglitazone by 4.4% (P < 0.05). Insulin glargine had less weight gain than rosiglitazone (1.6 +/- 0.4 vs. 3.0 +/- 0.4 kg; P = 0.02), fewer adverse events (7 vs. 29%; P = 0.0001), and no peripheral edema (0 vs. 12.5%). Insulin glargine saved $235/patient over 24 weeks compared with rosiglitazone. CONCLUSIONS: Low-dose insulin glargine combined with a sulfonylurea and metformin resulted in similar A1C improvements except for greater reductions in A1C when baseline was > or =9.5% compared with add-on maximum-dose rosiglitazone. Further, insulin glargine was associated with more hypoglycemia but less weight gain, no edema, and salutary lipid changes at a lower cost of therapy.     

Controlled degradation of low-fouling poly(oligo(ethylene glycol)methyl ether methacrylate) hydrogels

Degradable low-fouling hydrogels are ideal vehicles for drug and cell delivery. For each application, hydrogel degradation rate must be re-optimized for maximum therapeutic benefit. We developed a method to rapidly and predictably tune degradation rates of low-fouling poly(oligo(ethylene glycol)methyl ether methacrylate) (P(EG)_xMA) hydrogels by modifying two interdependent variables: (1) base-catalysed crosslink degradation kinetics, dependent on crosslinker electronics (electron withdrawing groups (EWGs)); and, (2) polymer hydration, dependent on the molecular weight (M_W) of poly(ethylene glycol) (PEG) pendant groups. By controlling PEG M_W and EWG strength, P(EG)_xMA hydrogels were tuned to degrade over 6 to 52 d. A 6-member P(EG)_xMA copolymer library yielded slow and fast degrading low-fouling hydrogels suitable for short- and long-term delivery applications. The degradation mechanism was also applied to RGD-functionalized poly(carboxybetaine methacrylamide) (PCBMAA) hydrogels to achieve slow (∼50 d) and fast (∼13 d) degrading low-fouling, bioactive hydrogels.

To tune degradation rates of low-fouling hydrogels, a 6-member P(EG)_xMA copolymer library with different electronics and hydration levels was developed.     

Insulin attenuates agonist-mediated calcium mobilization in cultured rat vascular smooth muscle cells.

Insulin has been shown to attenuate pressor-induced vascular contraction, but the mechanism for this vasodilatory action is unknown. This study examines the effect of insulin on angiotensin II (ANG II)-induced increments in cytosolic calcium in cultured rat vascular smooth muscle cells (VSMC). 20-min incubations with insulin (10 microU/ml to 100 mU/ml) did not alter basal intracellular calcium concentration ([Ca2+]i), but inhibited the response to 100 nM ANG II in a dose-dependent manner (ANG II alone, 721 +/- 54 vs. ANG II + 100 mU/ml insulin, 315 +/- 35 nM, P < 0.01). A similar effect of insulin on ANG II action was observed in calcium poor buffer. Moreover, insulin did not effect calcium influx. ANG II receptor density and affinity were not affected by 24-h incubation with insulin. To further clarify the mechanisms of these observations, we measured ANG II-induced production of inositol 1,4,5-triphosphate (IP3), and IP3-releasable 45Ca. Insulin treatment did not alter ANG II-stimulated IP3 production. However, IP3-stimulated release of 45Ca in digitonin permeabilized cells was significantly reduced after 5-min incubations with 100 mU/ml insulin. Thapsigargin induced release of calcium stores was also blocked by insulin. Thus, insulin attenuates ANG II-stimulated [Ca2+]i primarily by altering IP3-releasable calcium stores. Insulin effects on ANG II-induced [Ca2+]i were mimicked by preincubation of VSMC with either sodium nitroprusside or 8-bromo-cGMP. As elevations in cGMP in vascular tissue lower [Ca2+]i, it is possible that insulin affects IP3 release of calcium by a cGMP-dependent mechanism that would contribute to its vasodilatory effects.     

A hydrolytically‐tunable photocrosslinked PLA‐PEG‐PLA/PCL‐PEG‐PCL dual‐component hydrogel that enhances matrix deposition of encapsulated chondrocytes

In this study, a series of photocrosslinked hydrogels were designed composed of both poly(lactide)‐poly(ethylene glycol)‐poly(lactide) (PEL) and poly(ε‐caprolactone)‐poly(ethylene glycol)‐poly(ε‐caprolactone) (PEC) macromers. The PEL/PEC hydrogels at ratios of 100:0, 75:25, 50;50, 25:75 and 0:100 were studied for their degradation characteristics and their ability to support chondrogenesis of encapsulated chondrocytes. Difference in hydrolytic susceptibility between copolymers led to different degradation patterns where higher PEC content correlated with slower degradation. Increased chondrogenic gene expression was observed in chondrocyte‐laden hydrogels within a 4‐week culture period. Biochemical and histological evaluations revealed significant accumulation of extracellular matrix proteins such as glycosaminoglycans and collagen in the 50/50 hydrogel owing to appropriate tuning of hydrogel degradation. These results demonstrate that the dual‐component photocrosslinked hydrogel system is suitable for use as scaffold to support chondrogenesis and, moreover, the tunability of these systems opens up possibilities for use in different cell culturing applications. Copyright © 2014 John Wiley & Sons, Ltd.     

Uptake and release of budesonide from mucoadhesive, pH-sensitive copolymers and their application to nasal delivery.

Microparticles of novel, bioadhesive graft copolymers of polymethacrylic acid and polyethylene glycol (P(MAA-g-EG)) were prepared. The aims of this study were to investigate the uptake and release kinetics of budesonide from P(MAA-g-EG) in vitro as well as the pharmacokinetics following nasal administration of the polymer contained budesonide. The loading of budesonide into the pH-sensitive polymers was examined using various ethanol solutions. Ethanol was required for drug solubilization but hindered hydrogel swelling at pH 7.2. Maximum loading of the drug in the polymer was obtained using 25% ethanol solutions. The release of budesonide from the polymer swollen in 25% ethanol solutions obeyed classical Fickian release behavior after an initial rapid drug burst. For nasal administration of budesonide-containing P(MAA-g-EG) the plasma concentration of budesonide was kept constant following a peak concentration of the drug approximately 45 min after administration.     

Insulin and glucose excursion following premeal insulin lispro or repaglinide in cystic fibrosis-related diabetes

OBJECTIVE: Insulin and glucose levels in response to premeal insulin lispro or repaglinide were evaluated in adult patients with cystic fibrosis-related diabetes (CFRD) without fasting hyperglycemia. RESEARCH DESIGN AND METHODS: Seven patients with CFRD were fed 1,000-kcal liquid mixed meals. Three study conditions were administered in random order on separate mornings: 1) no premeal diabetes medication, 2) insulin lispro, 0.1 unit/kg body wt premeal and 3) repaglinide 1 mg premeal. Glucose and insulin levels were measured every 20 min for 5 h. RESULTS: Fasting insulin and glucose levels were normal in patients with CFRD, but the peak glucose level was elevated. Insulin lispro significantly decreased the peak glucose level (P = 0.0004) and the 2-h (P = 0.001) and 5-h (P < 0.0001) glucose area under the curve (AUC). Repaglinide significantly decreased the 5-h glucose AUC (P = 0.03). Neither drug completely normalized cystic fibrosis glucose excursion at the doses used for this study. Insulin lispro significantly increased the 5-h insulin AUC (P = 0.04). CONCLUSIONS: In response to subcutaneous insulin lispro, postprandial glucose excursion was significantly diminished and insulin secretion was enhanced compared with a control meal in which no medication was given to patients with CFRD. The oral agent repaglinide resulted in lesser corrections in these parameters. Neither drug completely normalized glucose or insulin levels, suggesting that the doses chosen for this study were suboptimal. Placebo-controlled longitudinal studies comparing the effectiveness of repaglinide and insulin on glucose metabolic control as well as overall nutrition and body weight are needed to help determine optimal medical treatment of CFRD.     

Modulation of intestinal tight junctions by Zonula occludens toxin permits enteral administration of insulin and other macromolecules in an animal model.

The intestinal epithelium represents the major barrier to absorption of orally administered drugs and peptides into the systemic circulation. Entry of molecules through the paracellular pathway is restricted by tight junctions. We have previously reported that these structures can be modulated by Zonula occludens toxin (Zot). In the present report, we show that Zot reversibly increases rabbit intestinal permeability to insulin by 72% (P = 0.034) and immunoglobulins by 52% (P = 0.04) in vitro. When tested in vivo, Zot induced a 10-fold increase of insulin absorption in both the rabbit jejunum and ileum, whereas no substantial changes were detected in the colon. Similar results were obtained with immunoglobulins, whereby Zot induced twofold and sixfold increases of IgG absorption in the jejunum and ileum, respectively. In diabetic rats, bioavailability of oral insulin coadministered with Zot was sufficient to lower serum glucose concentrations to levels comparable to those obtained after parenteral injection of the hormone. The survival time of diabetic animals chronically treated with oral insulin + Zot was comparable to that observed in parenterally treated rats. These studies offer an innovative strategy for the oral delivery of drugs and proteins normally not absorbed through the intestine.     

Autoantibodies against CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) that impair glucose-induced insulin secretion in noninsulin- dependent diabetes patients.

Cyclic ADP-ribose (cADPR) has been shown to be a mediator for intracellular Ca2+ mobilization for insulin secretion by glucose in pancreatic beta cells, and CD38 shows both ADP-ribosyl cyclase to synthesize cADPR from NAD+ and cADPR hydrolase to hydrolyze cADPR to ADP-ribose. We show here that 13.8% of Japanese non-insulin-dependent diabetes (NIDDM) patients examined have autoantibodies against CD38 and that the sera containing anti-CD38 autoantibodies inhibit the ADP-ribosyl cyclase activity of CD38 (P </= 0.05). Insulin secretion from pancreatic islets by glucose is significantly inhibited by the addition of the NIDDM sera with anti-CD38 antibodies (P </= 0.04-0.0001), and the inhibition of insulin secretion is abolished by the addition of recombinant CD38 (P </= 0.02). The increase of cADPR levels in pancreatic islets by glucose was also inhibited by the addition of the sera (P </= 0.05). These results strongly suggest that the presence of anti-CD38 autoantibodies in NIDDM patients can be one of the major causes of impaired glucose-induced insulin secretion in NIDDM.     

Impaired insulin sensitivity, insulin secretion, and glucose effectiveness predict future development of impaired glucose tolerance and type 2 diabetes in pre-diabetic African Americans: implications for primary diabetes prevention

OBJECTIVE: We examined the determinants of impaired glucose tolerance (IGT) and type 2 diabetes in first-degree relatives of African-American type 2 diabetic patients over 5-8 years (median 6). RESEARCH DESIGN AND METHODS: A total of 81 healthy subjects (age 41.5 +/- 4.8 years; BMI 31.3 +/- 3.6 kg/m(2)) participated in the study. Each subject underwent an oral glucose tolerance test (OGTT) and a frequently sampled intravenous glucose tolerance test at baseline. Insulin sensitivity index (S(i)) and glucose effectiveness index (S(g)) were determined by the minimal model method. Homeostasis model assessment (HOMA) was used to estimate insulin resistance (HOMA-IR) and beta-cell function (HOMA-%B). A total of 18 subjects progressed to either IGT or type 2 diabetes (progressors), whereas 19 subjects maintained normal glucose tolerance (nonprogressors). RESULTS: Comparing the progressors and nonprogressors, mean fasting serum glucose levels (95 +/- 8 vs. 80 +/- 14 mg/dl, P < 0.01) and 2-h serum glucose levels (149 +/- 27 vs. 100 +/- 60 mg/dl, P < 0.01) as well as 2-h serum insulin levels (117 +/- 81 vs. 72 +/- 87 microU/ml, P < 0.01) during OGTT were higher at baseline. Mean acute first-phase insulin secretion (205 +/- 217 vs. 305 +/- 230 microU/ml), HOMA-%B (148 +/- 60 vs. 346 +/- 372, P < 01), S(i) (1.61 +/- 1.13 vs. 2.48 +/- 1.25 x 10(-4). min(-1) [microU/ml](-1)), and S(g) (1.48 +/- 0.61 vs. 2.30 +/- 0.97 x 10(-2). min(-1)) were lower in the progressors than in the nonprogressors at baseline. Mean HOMA-IR (3.31 +/- 1.64 vs. 2.36 +/- 1.64) was significantly greater in the progressors than the nonprogressors. At the time of diagnosis of glucose intolerance (IGT + diabetes), HOMA-%B (101 +/- 48 vs. 148 +/- 60, P < 0.001) and HOMA-IR (5.44 +/- 2.55 vs. 3.31 +/- 1.64, P < 0.003) deteriorated in the progressors versus baseline. CONCLUSIONS: We conclude that nondiabetic, first-degree relatives of African-American type 2 diabetic patients who progressed to IGT and type 2 diabetes manifest triple defects (decreased insulin secretion, insulin action, and glucose effectiveness) that antecede the disease.     

Insulin detemir offers improved glycemic control compared with NPH insulin in people with type 1 diabetes: a randomized clinical trial

OBJECTIVE: Insulin detemir is a soluble long-acting basal insulin analog designed to overcome the limitations of conventional basal insulin formulations. Accordingly, insulin detemir has been compared with NPH insulin with respect to glycemic control (HbA1c, prebreakfast glucose levels and variability, and hypoglycemia) and timing of administration. RESEARCH DESIGN AND METHODS: People with type 1 diabetes (n = 408) were randomized in an open-label, parallel-group trial of 16-week treatment duration using either insulin detemir or NPH insulin. Insulin detemir was administered twice daily using two different regimens, either before breakfast and at bedtime (IDet(morn+bed)) or at a 12-h interval (IDet(12h)). NPH insulin was administered before breakfast and at bedtime. Mealtime insulin was given as the rapid-acting insulin analog insulin aspart. RESULTS: With both insulin detemir groups, clinic fasting plasma glucose was lower than with NPH insulin (IDet(12h) vs. NPH, -1.5 mmol/l [95% CI -2.51 to -0.48], P = 0.004; IDet(morn+bed) vs. NPH, -2.3 mmol/l (-3.32 to -1.29), P < 0.001), as was self-measured prebreakfast plasma glucose (P = 0.006 and P = 0.004, respectively). The risk of minor hypoglycemia was lower in both insulin detemir groups (25%, P = 0.046; 32%, P = 0.002; respectively) compared with NPH insulin in the last 12 weeks of treatment, this being mainly attributable to a 53% reduction in nocturnal hypoglycemia in the IDet(morn+bed) group (P < 0.001). Although HbA1c for each insulin detemir group was not different from the NPH group, HbA1c for the pooled insulin detemir groups was significantly lower than for the NPH group (mean difference -0.18% [-0.34 to -0.02], P = 0.027). Within-person between-day variation in self-measured prebreakfast plasma glucose was lower for both detemir groups (both P < 0.001). The NPH group gained weight during the study, but there was no change in weight in either of the insulin detemir groups (IDet(12h) vs. NPH, -0.8 kg [-1.44 to -0.24], P = 0.006; IDet(morn+bed) vs. NPH, -0.6 kg [-1.23 to -0.03], P = 0.040). CONCLUSIONS: Overall glycemic control with insulin detemir was improved compared with NPH insulin. The data provide a basis for tailoring the timing of administration of insulin detemir to the individual person's needs.     

Marked Increase in Insulin Sensitivity of Human Fat Cells 1 Hour after Glucose Ingestion

The effect of glucose ingestion on insulin action was investigated in isolated human fat cells. Subcutaneous adipose tissue was obtained from eight normal adult volunteers before and 1 h after oral intake of 100 g of glucose. Lipolysis (glycerol release) and specific insulin receptor binding were determined. Insulin binding increased significantly by 20-30% after glucose ingestion. This was due to an increase in insulin binding affinity, without any change in the receptor number. The concentration of insulin producing half-maximum inhibition (ED(50)) of basal lipolysis was 50 muU/ml before and 0.25 muU/ml after glucose ingestion (P < 0.01), which represented a 200-fold difference. As regards isoprenaline-induced lipolysis, the ED(50) for insulin inhibition was 30 muU/ml before and 2.5 muU/ml after oral glucose (P < 0.01), which was a 12-fold difference. The maximum insulin-induced inhibition of basal and isoprenaline-induced lipolysis were not altered after oral glucose. It is concluded that glucose ingestion is accompanied by a marked increase in insulin sensitivity of human fat cells and this may be an important modulating factor in the overall scheme of insulin action.     

Proinflammatory cytokines, insulin resistance, and insulin secretion in chronic hepatitis C patients: A case-control study

OBJECTIVE: The purpose of this study was to explore the initial pathogenic mechanisms of diabetes associated with hepatitis C virus (HCV) infection. RESEARCH DESIGN AND METHODS: Insulin resistance, proinflammatory cytokines, and beta-cell function were evaluated in a case-control study. A total of 28 consecutive nondiabetic patients with chronic hepatitis C were included in the study (anti-HCV+). Fourteen patients with chronic hepatitis other than HCV infection served as the control group (anti-HCV-). Both groups were closely matched by the main clinical variables associated with insulin resistance and the degree of liver fibrosis. In addition, there were no differences between groups regarding hepatic insulin extraction measured by calculating the ratio between C-peptide and insulin. Serum levels of proinflammatory cytokines (tumor necrosis factor [TNF]-alpha, soluble TNF receptor [sTNFR] 1, soluble TNFR2, and interleukin-6) were measured by enzyme-linked immunosorbent assay. Insulin resistance (homeostasis model assessment [HOMA] of insulin resistance [HOMA-IR]) and insulin secretion at baseline (HOMA-beta) and after various stimulus (oral glucose tolerance test, standard food intake, and intravenous glucagon) were determined by previously validated mathematic indexes. RESULTS: HOMA-IR was higher in anti-HCV+ than in anti-HCV- patients (4.35 +/- 2.27 vs. 2.58 +/- 1.74; P = 0.01). All the proinflammatory cytokines analyzed were significantly higher in anti-HCV+ patients than in anti-HCV- patients. In addition, sTNFR1 and sTNFR2 were directly correlated to HOMA-IR. HOMA-beta as well as insulin and C-peptide responses after the intravenous glucagon test were significantly higher in anti-HCV+ patients than in anti-HC- patients. CONCLUSIONS: Insulin resistance mediated by proinflammatory cytokines, but not a deficit in insulin secretion, could be the primary pathogenic mechanism involved in the development of diabetes associated with HCV infection.