Design and evaluation of oral bioadhesive controlled release formulations of miglitol, intended for prolonged inhibition of intestinal α-glucosidases and enhancement of plasma glucagon like peptide-1 levels

α-Glucosidase enzyme is present ubiquitously throughout the lumen of the small intestine. It is responsible for the breakdown of complex into simple carbohydrates. α-Glucosidase inhibitors such as miglitol, are drugs that have greater affinity towards this enzyme in comparison to carbohydrates. Miglitol regulates the postprandial glucose levels directly by inhibiting the enzyme reversibly and also indirectly by including the secretion of glucagon like peptide-1 (GLP-1). The aims of this study were (i) to design a controlled release (CR) mucoadhesive (in the intestine) formulation of miglitol which would inhibit the α-glucosidase enzyme for a longer duration of time (in comparison to the non-controlled release (IR) formulation) thus reducing the dosing frequency, and also controlling the postprandial glucose levels more effectively over a longer period of time; (ii) to assess the effect of different formulation parameters on the release of miglitol in vitro from the CR pellets; (iii) to evaluate the mucoadhesion of pellets in the intestine ex vivo; (iv) to study the effect of formulation parameters on plasma GLP-1 levels; and (v) to find out the effect of formulations on postprandial glucose levels. The data obtained was analysed to find out whether there was a correlation between these different parameters. Four controlled release formulations (CR1, CR2, CR3 and CR4) of miglitol comprising of multilayered pellets were designed successfully. The CR4 formulation containing 30% of 20 cps of ethyl cellulose (the retarding layer of the formulation) displayed slowest release of miglitol in vitro in comparison to other formulations. We designed an ex vivo experimental setup for studying the mucoadhesion of the pellets in the lumen of the intestine. Results indicated that amongst all of the adherent pellets, 5% were found to be adhering in the duodenal region, 61% in the jejunum, 32% in the ileum and 2% in the colon. Two of the controlled release formulations CR1 and CR4 were evaluated in vivo in dogs. Both the formulations displayed significantly higher and more prolonged (greater AUC) levels of GLP-1 in comparison to either the placebo or the immediate release (IR) formulations. They even displayed a significantly better control of postprandial glucose in comparison to either placebo or IR formulations. However, a comparison between the two controlled release formulations (CR1 and CR4) revealed that the plasma GLP-1 (AUC by CR1 = 63.1 ± 1.32 and CR4 = 66.2 ± 0.82) and postprandial glucose values due to both the formulations were rather similar despite their differences in in vitro release as well as pharmacokinetic profiles (plasma miglitol AUC of CR1 = 16.17 ± 4.11 and CR4 = 27.17 ± 4.33).     

Uptake of postprandial lipoproteins into bone in vivo: impact on osteoblast function

Dietary lipids and lipophilic vitamins are transported by postprandial lipoproteins and are required for bone metabolism. Despite that, it remains unknown whether bone cells are involved in the uptake of circulating postprandial lipoproteins in vivo. The current study was performed to investigate a putative participation of bone in the systemic postprandial lipoprotein metabolism in mice, to identify potentially involved cell type populations and to analyze whether lipoprotein uptake affects bone function in vivo. As a model for the postprandial state, chylomicron remnants (CR) were injected intravenously into mice. Next to the liver and compared to other organs, bone appeared to be the second most important organ for the clearance of radiolabeled CR particles from the circulation in vivo. In addition, uptake of radiolabeled CR by primary murine osteoblasts and hepatocytes was quantified to be in a similar range in vitro. A complementary approach with fluorescently labeled CR and immunohistochemical staining for apoE proved that intact CR particles were taken up into bone and liver. Electron microscopy localization studies of bone sections revealed CR uptake into sinusoidal endothelial cells, macrophages and osteoblasts. The relative amount of radiolabeled CR uptake into femoral cortical bone, representing predominantly osteoblasts, and bone marrow, representing predominantly non-osteoblast cells, was within the same range. Most importantly, the injection of vitamin K1-enriched CR resulted in an increase of the degree of osteocalcin carboxylation in vivo while total osteocalcin concentrations remained unaffected, giving functional proof that osteoblasts process CR in vivo. In conclusion, here we demonstrate that bone is involved in the postprandial lipoprotein metabolism in mice. Osteoblasts participate in CR clearance from the circulation, which has a direct impact on the secretory function of osteoblasts.     

Reduced Postprandial Energy Expenditure in Women Predisposed to Type 2 Diabetes

Type 2 (non-insulin dependent) diabetes is so common that it has been hypothesized that in the course of evolution the predisposition to it may have conferred some advantage, before or during the reproductive years. It is frequently preceded by gestational diabetes. In order to test the basis for the hypothetical advantage, energy expenditure was investigated in 10 women with documented transient diabetes in a previous pregnancy. They were studied early in a subsequent pregnancy while glucose tolerance was still normal and 9 were re-studied after pregnancy. Their results were compared with normal matched controls. During pregnancy, resting energy expenditure was similar in the study group and controls (6.58 (5.77–7.55) median (range) vs 6.91 (6.56–7.36) MJ day^-1, respectively). However, the energy response to a mixed meal (42 kJ kg^-1 lean body mass) was decreased in the study group (45 (33–68) vs 76 (50–89) kJ, p<0.05). After pregnancy resting energy expenditure was again similar in the two groups, but the decrease in postprandial thermogenesis persisted (78 (59–84) vs 92 (79–105) kJ, p<0.05). The patients were resistant to exogenous insulin, 0.05 U kg^-1 intravenously (slope of the plasma glucose decline in the 15 min after insulin; during pregnancy patients 52 (37–92) vs controls 111 (104–121) μmol l^-1 min^-1, p<0.01; after pregnancy 130 (88–156) vs controls 186 (152–221) μmol l^-1 min^-1, p<0.01). The postprandial energy saving in these women could constitute an evolutionary advantage. Insulin resistance may be the mechanism for limiting postprandial thermogenesis.     

The effect of acute aerobic exercise on pulse wave velocity and oxidative stress following postprandial hypertriglyceridemia in healthy men

Oxidative stress is postulated to be responsible for the postprandial impairments in vascular function. The purpose of this study was to measure pulse wave velocity (PWV) and markers of postprandial oxidative stress before and after an acute bout of moderate exercise. Ten trained male subjects (age 21.5 ± 2.5 years, VO₂ max 58.5 ± 7.1 ml kg⁻¹ min⁻¹) participated in a randomised crossover design: (1) high-fat meal alone (2) high-fat meal followed 2 h later by a bout of 1 h moderate (60% max HR) exercise. PWV was examined at baseline, 1, 2, 3, and 4 h postprandially. Blood Lipid hydroperoxides (LOOHs), Superoxide dismutase (SOD) and other biochemical markers were measured. PWV increased at 1 h (6.49 ± 2.1 m s⁻¹), 2 h (6.94 ± 2.4 m s⁻¹), 3 h (7.25 ± 2.1 m s⁻¹) and 4 h (7.41 ± 2.5 m s⁻¹) respectively, in the control trial (P < 0.05). There was no change in PWV at 3 h (5.36 ± 1.1 m s⁻¹) or 4 h (5.95 ± 2.3 m s⁻¹) post ingestion in the exercise trial (P > 0.05). LOOH levels decreased at 3 h post ingestion in the exercise trial compared to levels at 3 h (P < 0.05) in the control trial. SOD levels were lower at 3 h post ingestion in the control trial compared to 3 h in the exercise trial (0.52 ± 0.05 vs. 0.41 ± 0.1 units μl⁻¹; P < 0.05). These findings suggest that a single session of aerobic exercise can ameliorate the postprandial impairments in arterial function by possibly reducing oxidative stress levels.     

老年疗养员餐后低血压的调查

目的调查95例老年疗养员餐后血压变化情况，以便了解老年疗养员餐后低血压（PPH）的发生率和临床表现。方法选择来院疗养的95名老年疗养员，用动态血压监测方法进行餐前和餐后20、40、60、80、100min血压检测。结果①95例老年疗养员三餐后血压均有不同程度下降，平均下降幅度以早餐后下降较大，高龄老年人餐后血压下降幅度较低龄老年人餐后血压下降幅度为大（P〈0.01）。②基础疾病和药物对血压下降影响无统计学意义（P〉0．05）。③老年人餐后低血压的发生率为30．5％，出现临床症状者仅占PPH的3．2％。④老年人PPH一般发生在餐后20-80min，个别老年人PPH餐后即可发生。结论老年疗养员PPH比较常见，可以引发严重心脑血管事件，应对老年人加强健康知识宣传，预防PPH及心脑事件的发生。     

Improved postprandial glycaemic controls with insulin Aspart in type 2 diabetic patients treated with insulin

The effect on postprandial blood glucose control of an immediately pre-meal injection of the rapid acting insulin analogue Aspart (IAsp) was compared with that of human insulin Actrapid injected immediately or 30 before a test meal in insulin-treated type 2 diabetic patients with residual β-cell function. In a double-blind, double dummy crossover design, patients attended three study days where the following insulin injections in combination with placebo were given in a random order: IAsp (0.15 IU/kg body weight) immediately before the meal, or insulin Actrapid (0.15 IU/kg) immediately (Act-₀) or 30 minutes before (Act-₃₀) a test meal. We studied 25 insulin-requiring type 2 diabetic patients, including 14 males and 11 females, with a mean age of 59.7 years (range, 43–71), body mass index 28.3 kg/m² (range, 21.9–35.0), HbA_1c 8.5% (range, 6.8–10.0), glucagon-stimulated C-peptide 1.0 nmol/l (range, 0.3–2.5) and diabetes duration 12.5 years (range, 3.0–26.0). Twenty-two patients completed the study A significantly improved postprandial glucose control was demonstrated with IAsp as compared to Act₀, based on a significantly smaller postprandial blood glucose excursion (IAsp, 899 ± 609 (SD) mmol/l · min versus Act₀, 1102 ± 497 mmol/l min, p < 0.01) and supported by a significantly lower maximum serum glucose concentration (C_max) up to 360 min after dosing (IAsp, 10.8 ± 2.2 mmol/l vs. Act₀, 12.0 ±2.4 mmol/l, p < 0.02). No difference was demonstrated with a meal and Actrapid injected 30 minutes before the meal (AUC_glucose IAsp, 899 ± 609 mmol/l min vs. Act-₃₀, 868 ± 374 mmol/l min; C_max IAsp, 10.8 ± 2.2 mmol/l vs. Act-₃₀, 11.1 ± 1.8 mmol/l). No concerns about the safety of IAsp were raised. Immediate pre-meal administration of the rapid-acting insulin analogue Aspart in patients with type 2 diabetes resulted in an improved postprandial glucose control compared to Actrapid injected immediately before the meal, but showed similar control compared to Actrapid injected 30 minutes before the meal. These results indicate that the improved glucose control previously demonstrated with insulin Aspart compared to human insulin in healthy subjects and type 1 diabetic patients also applies to insulin-treated type 2 diabetic patients. Received: 3 December 1999 / Accepted in revised form: 3 March 2000     

Modulation of gastric accommodation by duodenal nutrients

AIM: To determine the relative potency and contribution of intestinal nutrients to net gastric accommodative relaxation and conscious perception. METHODS: In 12 healthy subjects, we randomly tested duodenal loads of lipids and carbohydrates (12 mL administered in 4 min) at various caloric concentrations (0.0125-0.8 kcal/mL) separated by 12-24 min wash-out periods of saline infusion. Maximal gastric relaxation was induced at the end of each experiment by i.v glucagon (5 μg/kg),as reference. The reflex gastric response was measured by a barostat, and symptom perception by a 0-6 score questionnaire. RESULTS: Lipids induced a dose-response gastric relaxation with a steep and early rise. Maximal effect (179±42 mL relaxation) reached at a relatively low concentration (0.2 kcal/mL), maximal lipid-induced relaxation was 61±6% of the glucagon effect. By contrast, duodenal infusion of carbohydrates induced weaker relaxation that became significant only at the high end of the physiological concentration range (65±14 mL with 0.8 kcal/mL). Intestinal nutrient loads, either of lipid or carbohydrates, did not induce significant changes in perception (0.6±0.4 and 0.1±0.4 score increase for the highest concentrations, respectively). CONCLUSION: Chyme entering the small bowel induces nutrient-specific gastric relaxatory reflexes by a physiologically saturable mechanism. Normally, neither the intestinal nutrient load nor the gastric accommodative response is perceived.     

Enhanced vascular function after acute fat-rich snacking in healthy males

Diets high in fat are associated with vascular dysfunction. Frequent snacking may exacerbate this problem by extending the postprandial state. We hypothesized that repeated fat-rich mixed snacks would impair peripheral endothelial function and increase oxidative stress, a purported causal factor. Second, we hypothesized that feeding a quantity of snack based on the subject's body size would not cause different effects from feeding a fixed or constant size snack. A crossover design was used where 10 healthy males followed 2 repeated-snack regimens (fixed and variable based on body surface area), 1 week apart. Each regimen consisted of 2 snacks, fed 4 hours apart (0 and 4 hours). Markers of vascular function (reactive hyperemia index [RHI]), oxidative stress, and antioxidant capacity were measured before and after each snack. Peripheral vascular function improved from fasting to 2 hours after snack 1 (RHI_2h−0h, P = .010), but the change before and after snack 2, RHI_6h−4h, was negative (P = .026), indicating reduced endothelial function after repeated snacking. The oxidative stress marker changed over time (P = .043), increasing after snack 1 and decreasing before snack 2, with no change after snack 2. The antioxidant marker increased 2 hours after each snack (P = .003). Responses to fixed snacks over time were not different from variable snacks, although power was low; the effect size was large for antioxidant capacity, medium for oxidative stress, and small for RHI. Snacking after fasting resulted in a transiently improved peripheral vascular response that disappeared with a second snack. Antioxidant capacity appeared to help limit oxidative stress from repeated snacking in these healthy male subjects.