肠促胰素与糖尿病性骨质疏松症的研究进展

糖尿病（Diabetes,DM）、骨质疏松症（Osteoporosis,OP）是两种常见的慢性病,在DM患者中存在的代谢紊乱可致OP发生的风险机率大大增加,严重影响患者的生活质量,而由此导致的OP称为糖尿病性骨质疏松症(Diabetic osteoporosis,DOP),主要指糖尿病所致骨量减少,骨组织微结构破坏,骨脆性增加,易于骨折的一种全身性代谢性疾病 。对DOP的治疗首先要控制血糖,血糖是基础,而肠促胰素（Incretin）作为一种降糖药物已应用于临床,在减重及降糖方面效果突出,但最近研究显示肠促胰素在降糖的同时对OP有一定的改善,本文将简单阐述肠促胰素对DOP的影响。     

Title: Differentiating the effects of whey protein and guar gum preloads on postprandial glycemia in type 2 diabetes

Background and aimsWhey protein and guar gum have both been reported to reduce postprandial glycemia in health and type 2 diabetes, associated with stimulation of glucagon-like peptide-1 (GLP-1) and/or slowing of gastric emptying. Our aim was to evaluate, in type 2 diabetes, the acute effects of low dose “preloads” of whey and guar, given alone or in combination before a meal, on postprandial glycemia, insulin, GLP-1, and gastric emptying.Methods21 patients with type 2 diabetes, managed by diet or metformin alone, were each studied on 4 days. They received a preload “shake” 15min before a mashed potato meal (368.5 kcal) labeled with ¹³C-octanoic-acid. The preloads comprised either (i) 17 g whey (W), (ii) 5 g guar (G), (iii) 17 g whey + 5 g guar (WG) each sweetened with 60 mg sucralose, and (iv) 60 mg sucralose alone (control; C), all dissolved in 150 mL water. Venous blood was sampled frequently for measurements of glucose, insulin, and GLP-1 concentrations. Gastric half-emptying time (T50) was calculated from breath ¹³CO₂ excretion over 240 min.ResultsPostprandial blood glucose concentrations were lower with W and WG compared to C (each P < 0.0001, treatment × time interaction), and lower after G than C only at 30min. Insulin, GLP-1, and glucagon concentrations were higher after W than WG, G, or C (P < 0.05, treatment × time interaction), without differences between the latter three. Gastric emptying was slower with W (T50: 179.6 ± 6.1 min, P < 0.05) and WG (T50: 197.6 ± 9.7 min, P < 0.0001) when compared to C (T50: 162.9 ± 6.2 min), but did not differ between G (T50: 171.3 ± 7.0) and C (P > 0.99).ConclusionBoth whey and whey/guar preloads reduced postprandial glycemia, associated with slowing of gastric emptying. Low dose guar was less effective as a preload for glucose-lowering and did not slow gastric emptying.Clinical Trial Registry number and websiteAustralian and New Zealand Clinical Trials Registry, Trial ID ACTRN12615001272583, http://www.anzctr.org.au     

Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs

Aims/hypothesis The insulinotropic hormone, glucagon-like peptide-1 (GLP-1), is rapidly degraded in vivo as a result of the combination of extensive enzymatic degradation and renal extraction. The GLP-1 receptor agonist, exendin-4, has a longer duration of action, and has recently been approved as a new agent for the treatment of type 2 diabetes mellitus. Exendin-4 is less prone to enzymatic degradation, but it is still unclear what other factors contribute to the increased metabolic stability. Materials and methods The overall metabolism of GLP-1 and exendin-4 was directly compared in anaesthetised pigs (n=9). Results Metabolism of GLP-1 (C-terminal RIA; t _1/2 2.0±0.2 min, metabolic clearance rate [MCR] 23.2±2.8 ml min⁻¹ kg⁻¹; N-terminal RIA; t _1/2 1.5±0.2 min, MCR 88.1±10.6 ml min⁻¹ kg⁻¹) was significantly faster than the metabolism of exendin-4 (t _1/2 22.0±2.1 min, p<0.0001; MCR 1.7±0.3 ml min⁻¹ kg⁻¹, p<0.01). Differences in arteriovenous concentrations revealed organ extraction of GLP-1 by the kidneys (C-terminal 56.6±2.6%; N-terminal 48.3±5.9%), liver (N-terminal 41.4±3.8%), and peripheral tissues (C-terminal 42.3±6.0%; N-terminal 33.0±7.8%), whereas organ extraction of exendin-4 was limited to the kidneys (21.3±4.9%). While the renal extraction of exendin-4 (6.9±2.5 pmol/min) did not differ significantly from the amount undergoing glomerular filtration (8.4±2.0 pmol/min), the renal extraction of C-terminal GLP-1 (9.0±1.1 pmol/min), exceeded the amount which could be accounted for by glomerular filtration (4.2±0.5 pmol/min, p<0.0005). Conclusions/interpretation In addition to an increased resistance to enzymatic degradation, the increased stability of exendin-4 is the result of reduced differential organ extraction compared to GLP-1. The data suggest that in the anaesthetised pig, extraction occurs only in the kidney and can be fully accounted for by glomerular filtration.     

Pharmacological control of blood sugar

Diabetes is a chronic and progressive metabolic disorder characterized by hyperglycaemia. The two main types of diabetes are type 1 diabetes (T1DM) where there is complete lack of insulin and type 2 diabetes (T2DM) which may be due to a combination of insulin resistance and relative insulin deficiency due to impaired β-cell function. Good control of blood glucose near physiological limits is vital to reduce long-term microvascular and macrovascular complications of diabetes. Insulin replacement is a life-saving measure in individuals with T1DM whereas the mainstay of therapy in T2DM includes oral agents, non-insulin injectables (incretin mimetics) and insulin. In T2DM, the incretin mimetics have revolutionized recent treatment options by reducing blood glucose, promoting weight loss and improving β-cell function. Moreover, the emergence of a new class of drugs such as the sodium–glucose transporter inhibitors for patients with T2DM holds much promise. Despite the availability of several drugs to treat this chronic debilitating condition, the management of hyperglycaemia remains challenging. The role of diet, lifestyle changes and patient education is of paramount importance and should be pursued aggressively. This review will look at drugs currently used to optimize blood glucose control and briefly discuss the role of newer therapeutic agents.     

肠促胰素的胰腺外作用研究进展

肠促胰素是经食物刺激后由肠道细胞分泌入血、能够刺激胰岛素分泌的一类激素.人体中,胰升糖素样肽1(GLP-1)和糖依赖性胰岛素释放肽((GIP)发挥肠促胰素效应.本文简要介绍肠促胰素的胰腺作用,重点回顾其胰腺外生理作用,以全面评价肠促胰素类药物的临床应用前景.

Abstract：

Incretin is defined as an intestinal hormone released in response to nutrient ingestion, which potentiates the glucose-induced insulin response. In human body, the incretin's effect is mainly induced by two peptide hormones, glucagon-like peptide-I (GLP-I)and glucose-dependent insulinotropic polypeptide (GIP). In order to fully evaluate the clinical advantages of novel agents based on incretin, this review introduces the islet actions of incretin in brief, and mainly focuses on the extra-islet effect of incretin.     

Secretion of incretin hormones and the insulinotropic effect of gastric inhibitory polypeptide in women with a history of gestational diabetes

Aims/hypothesis The insulinotropic effect of gastric inhibitory polypeptide (GIP) is reduced in patients with type 2 diabetes and around 50% of their first-degree relatives under hyperglycaemic conditions. It is unknown whether this is a result of a specific defect in GIP action or of a general reduction in beta cell function. Moreover, impaired secretion of glucagon-like peptide 1 (GLP-1) has been described in patients with type 2 diabetes. Therefore, we studied the insulinotropic effect of GIP in women with previous gestational diabetes (pGDM) under euglycaemic fasting conditions and during a hyperglycaemic clamp experiment. The secretion of GIP and GLP-1 was assessed following oral glucose ingestion.Materials and methods On separate occasions we performed an OGTT and administered an i.v. bolus of 20 pmol GIP/kg body weight in 20 women with pGDM and 20 control women. An additional hyperglycaemic clamp experiment (140 mg/dl [7.8 mmol/l] over 120 min) with i.v. infusion of GIP (2 pmol kg^–1 min^–1; 30–90 min) was performed in 14 women in each group. Capillary and venous blood samples were drawn for the measurement of glucose (glucose oxidase), insulin, C-peptide, GIP and GLP-1 (specific immunoassays). Indices of insulin sensitivity and beta cell function were calculated. Statistical analyses were carried out using repeated measures ANOVA.Results Following oral glucose ingestion, plasma glucose, insulin and C-peptide concentrations increased to higher levels in the women with pGDM than in the control women (p<0.05). The women with pGDM were characterised by a higher degree of insulin resistance than the control women (p=0.007 for the Matsuda index), but showed no overt defects in glucose-stimulated insulin secretion (p=0.40 for the insulinogenic index following i.v. glucose). The secretion of GLP-1 and GIP was not different between the groups (p=0.87 and p=0.57, respectively). The insulin secretory response to GIP administration was similar in the two groups both after GIP bolus administration and during the hyperglycaemic clamp experiment (p=0.99 and p=0.88, respectively). A hyperbola-like relationship was found between the degree of insulin sensitivity (Matsuda index) and the insulin secretory response to GIP and i.v. glucose administration.Conclusions/interpretation These results do not support the hypothesis of an early defect in GIP action as a risk factor for subsequent development of diabetes in women with previous gestational diabetes. The inverse relationship between insulin resistance and the insulin secretory response to glucose or GIP suggests that beta cell secretory function in response to different stimuli increases adaptively when insulin sensitivity is diminished.     

Insulinotropic actions of intravenous glucagon-like peptide-1 (GLP-1) [7–36 amide] in the fasting state in healthy subjects

GLP-1 (7–36 amide) stimulates insulin and suppresses glucagon secretion in normal subjects and may, in pharmacological doses, normalize hyperglycaemia in type 2 diabetic patients. It is not known whether such pharmacological doses can actually lower blood glucose to hypoglycaemic levels. Therefore, in seven normal fasting subjects, GLP-1 (7–36 amide) was infused intravenously at 0.3, 0.9 and 2.7 pmol/kg per min for 30 min each. The plasma concentration of GLP-1 (7–36 amide) increased dose-dependently, but insulin secretion (insulin, C-peptide) was stimulated only marginally. Glucagon was slightly suppressed, and plasma glucose was reduced, but not into the hypoglycaemic range. In conclusion, when plasma glucose concentrations are in the normal fasting range, GLP-1 (7–36 amide) is not able to stimulate insulin secretion to a degree that causes hypoglycaemia. This should limit the risk of hypoglycaemic responses when GLP-1 (7–36 amide) is administered in pharmacological doses to reduce hyperglycaemia in type 2 diabetic patients.     

2008年第七届国际糖尿病联盟/西太平洋地区会议侧记

2008年3月30日-4月3日在新西兰惠灵顿召开了第七届国际糖尿病联盟/西太平洋地区(IDF/WPR)学术会议.会议交流和探讨了糖尿病相关研究进展.本文介绍了2型糖尿病治疗相关的基础和临床研究,包括2型糖尿病的手术治疗、噻唑烷二酮类药物的再认识和肠促胰岛素治疗.     

Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig

Aims/hypothesis The incretin hormone glucagon-like peptide 1 (GLP-1) has antihyperglycaemic effects, but its therapeutic usefulness is limited by its metabolic instability. Dipeptidyl peptidase IV (DPP-IV) is established as the primary inactivating enzyme, but the roles of other enzymes remain unclear.Methods The effect of candoxatril, a selective inhibitor of neutral endopeptidase (NEP) 24.11, on GLP-1 pharmacokinetics/pharmacodynamics with or without DPP-IV inhibition was examined in anaesthetised pigs.Results During GLP-1 infusion, candoxatril doubled C-terminal immunoreactivity, improving the pharmacokinetics (t_&frac; 2.3±0.1 to 8.8±1.2 min; metabolic clearance rate [MCR] 20.4±3.4 to 4.8±0.4 ml·kg^–1· min^–1; p<0.01), but had no effect upon intact GLP-1 (t_&frac; 1.4±0.1 to 1.6±0.1 min; MCR 47.9±8.0 to 38.8±5.0 ml·kg^–1·min^–1). Insulin responses to intravenous glucose were unaffected by candoxatril, but glucose tolerance was improved (AUC_{min 27–87} 118±5 to 74±14 min·mmol·l^–1; glucose elimination rate [k] 6.6±0.5 to 8.6±0.5%; p<0.05). When candoxatril was co-administered with valine pyrrolidide (a DPP-IV inhibitor), changes in C-terminal GLP-1 pharmacokinetics mirrored those seen when candoxatril alone was administered (t_&frac; 2.7±0.3 and 7.7±0.8 min; MCR 17.3±2.6 and 6.5±0.8 ml·kg^–1·min^–1 for valine pyrrolidide without and with candoxatril, respectively). However, intact GLP-1 pharmacokinetics were improved (t_&frac; 2.8±0.3 and 7.5±0.6 min; MCR 18.3±0.6 and 9.4±0.9 ml·kg^–1·min^–1; p<0.02), potentiating the antihyperglycaemic/insulinotropic effects of GLP-1 (glucose AUC_{min 27– 87} 103±8 to 62±14 min·mmol·l^–1; k 6.8±0.4 to 11.4±1.4%; insulin AUC_{min 27–87} 3,680±738 to 7,201±1,183 min·pmol·l^–1; p<0.05).Conclusions/interpretation This study confirms a role for NEP-24.11 in GLP-1 metabolism in vivo, suggesting that up to 50% of GLP-1 entering the circulation may be degraded by NEP-24.11. Furthermore, combined inhibition of DPP-IV and NEP-24.11 is superior to DPP-IV inhibition alone in preserving intact GLP-1, which raises the possibility that the combination has therapeutic potential.