胰高血糖素样肽-1类似物治疗2型糖尿病的研究进展

胰高血糖素样肽-1（GLP-1）受体激动剂（GLP-1RA）艾塞那肽（exenatide）和利拉鲁肽（liraglutide）的作用机制是增加胰岛素分泌,抑制胰高血糖素释放,减轻胰岛素抵抗,抑制食欲并减缓胃排空。这些降糖作用具有葡萄糖浓度依赖性可避免严重低血糖。除了有确切的降糖作用外,还有降血压、保护心血管、减轻脂肪肝、调脂和减轻体质量的作用,动物实验中,这类药物有助于保护β细胞功能,可以安全地与二甲双胍、磺酰脲类药物、噻唑烷二酮类和胰岛素联合治疗糖尿病,其代表性药物利拉鲁肽和艾塞那肽为控制高血糖和降低体质量提供了另一种治疗选择。     

Insulin resistance in type 1 diabetes

Insulin resistance plays a larger role in the type 1 diabetes disease process than is commonly recognized. The onset of type 1 diabetes is often heralded by an antecedent illness and/or the onset of puberty, both conditions associated with insulin resistance. In the face of a damaged beta-cell and thus reduced insulin secretion, this change is enough to manifest hyperglycemia. During the first year of clinical disease, considerable evidence suggests that the occurrence of clinical remission or 'honeymoon period' is due to a temporary resolution of the insulin-resistant state present at diagnosis. Intensive diabetes management is associated with both improved insulin sensitivity and beta-cell function. This indicates that the historical data on the changes in insulin secretion post-diagnosis may be inappropriate when designing current studies. The known physiological relationship between beta-cell function and insulin sensitivity complicates interpretation of insulin secretion data obtained as part of prevention or intervention trials. While it is recommended that at least a subset of subjects participating in these trials undergo formal measurements of insulin sensitivity to evaluate effects of therapy on this parameter independent of effects on the beta-cell, the sample size must be sufficient to determine an effect if present. Finally, one could speculate that it is possible that subsets of people with mild manifestations of the type 1 autoimmune disease process could benefit from treatments aimed at improving the insulin-resistant state.     

Glucagon receptor antibody completely suppresses type 1 diabetes phenotype without insulin by disrupting a novel diabetogenic pathway

Insulin monotherapy can neither maintain normoglycemia in type 1 diabetes (T1D) nor prevent the long-term damage indicated by elevated glycation products in blood, such as glycated hemoglobin (HbA1c). Here we find that hyperglycemia, when unaccompanied by an acute increase in insulin, enhances itself by paradoxically stimulating hyperglucagonemia. Raising glucose from 5 to 25 mM without insulin enhanced glucagon secretion ∼two- to fivefold in InR1-G9 α cells and ∼18-fold in perfused pancreata from insulin-deficient rats with T1D. Mice with T1D receiving insulin treatment paradoxically exhibited threefold higher plasma glucagon during hyperglycemic surges than during normoglycemic intervals. Blockade of glucagon action with mAb Ac, a glucagon receptor (GCGR) antagonizing antibody, maintained glucose below 100 mg/dL and HbA1c levels below 4% in insulin-deficient mice with T1D. In rodents with T1D, hyperglycemia stimulates glucagon secretion, up-regulating phosphoenolpyruvate carboxykinase and enhancing hyperglycemia. GCGR antagonism in mice with T1D normalizes glucose and HbA1c, even without insulin.Ninety years of insulin treatment in patients with type 1 diabetes (T1D) have made it clear that insulin alone cannot normalize glucose homeostasis or glycated hemoglobin (HbA1c) levels. Even optimally controlled patients may exhibit postprandial surges of glucose levels to three or four times normal (1, 2), which may explain why HbA1c levels below 6% are so rare in patients with T1D. Current thinking attributes these spikes in peripheral plasma glucose to insufficient uptake of incoming dietary glucose by peripheral target tissues as a result of a lack of insulin. As a consequence, they are often managed by a preprandial bolus of insulin and restriction of dietary carbohydrate. This strategy results in chronic iatrogenic hyperinsulinemia (3) in patients with “well-controlled” T1D and is responsible for a high incidence of hypoglycemic events, which can be life-threatening.In nondiabetic subjects, a glucose load suppresses glucagon levels by stimulating an acute transient rise in paracrine insulin from β-cells juxtaposed to the glucagon-producing α cells (4–6). This glucagon suppression converts the liver from an organ of glucose production to an organ of glucose storage (7). In T1D, paracrine insulin is lacking and is replaced by peripherally injected insulin. The resulting intraislet insulin concentrations are but a small fraction of the paracrine concentrations of undiluted insulin that suppress glucagon in nondiabetic subjects (8, 9). In 1974, it was reported that hyperglycemia paradoxically stimulates glucagon secretion in dogs with chemically induced diabetes (10). More recently, plasma glucagon concentrations were reported to rise, with a tripling of hepatic glucose production, in normal rats continuously infused with glucose at a constant rate (11). Thus, there is evidence that in the absence of adequate insulin, elevated glucose might stimulate glucagon production, which in turn aggravates hyperglycemia. In this setting, the liver would not be reprogrammed to store incoming glucose but, rather, would continue to produce glucose as if it were still in the unfed state (12). This may play a major role in postprandial hyperglycemia (10).Here we find that in T1D, hyperglycemia stimulates, rather than suppresses, glucagon secretion. This suggests that in T1D, a positive hormonal feedback loop enhances hyperglycemia by adding endogenously produced glucose to diet-derived glucose. If this is an important factor in the hyperglycemic surges that plague patients with T1D, then suppressing glucagon secretion or blocking glucagon action should eliminate the surges of hyperglycemia observed in T1D in mice.To measure the normal response of pancreatic islets to elevated glucose, pancreata were isolated from normal mice and perfused with 5 or 25 mM glucose. Glucagon concentrations were measured in the perfusate. Raising the glucose concentration fivefold decreased glucagon concentration in the perfusate approximately sixfold (Fig. 1A). To determine the effect of increased glucose concentration on glucagon secretion without paracrine insulin, we measured glucagon levels in the medium of cultured InR1-G9 α cells in 5, 10, and 25 mM glucose. The rise from 5 to 10 mM glucose caused an approximately threefold increase in glucagon secretion, and the rise from 10 to 25 mM caused another twofold rise (Fig. 1B). Because cultured cells may not reflect the behavior of native α cells in situ in T1D, we isolated pancreata from streptozotocin-induced insulin-deficient T1D rats and perfused them with 5, 10, and 25 mM glucose concentrations. When the perfusate glucose was increased from 5 to 10 mM, glucagon secretion increased fourfold (Fig. 1C). An increase in glucose from 10 to 25 mM increased glucagon secretion another fourfold. Insulin concentrations in all of these perfusates were below the detection limit of a radioimmune assay (RIA) (EMD Millipore). Previously, we reported that the streptozotocin treatment protocol we used resulted in the destruction of 93.4% of β cells (13).Fig. 1.In the absence of paracrine insulin, glucagon secretion increases in response to increases in glucose. (A) An increase from 5 to 25 mM in the glucose perfused into the isolated pancreata of nondiabetic mice causes profound suppression of glucagon secretion. ...The fact that elevations of glucose stimulated glucagon secretion in the absence of an acute paracrine insulin release suggested that in animals with T1D, any rise in glucose would stimulate glucagon secretion and give rise to a cycle of self-enhancing hyperglycemia (3, 14). To investigate the possibility of such a diabetogenic pathway, we compared plasma glucagon levels in insulin-treated NOD/ShiLtJ T1D mice during and between hyperglycemic surges (Fig. 1D). The mice were treated with 0.1 U Levemir twice daily, and blood glucose was measured in the morning 17 h after an insulin injection (high blood glucose) and in the afternoon 7 h after an insulin injection (low blood glucose) (Fig. 1E). In mice receiving this insulin regimen, glucagon averaged 138 ± 41 pg/mL and insulin 3.9 ± 1.1 ng/mL in samples in which glucose averaged 500 ± 37 mg/dL This glucagon concentration was significantly higher (P < 0.05) than the mean glucagon level of 55 ± 35 pg/mL, measured in samples from the same mice when their glucose levels averaged 130 ± 71 mg/dL and insulin averaged 14.3 ± 4.5 ng/mL These findings are consistent with a glucagon-mediated contribution to the surges of hyperglycemia.To assess directly the effect on the liver of the hyperglucagonemia accompanying hyperglycemia in the absence of endogenous insulin, we compared activation of key markers of glucagon action in liver. The phosphorylation of cAMP response element binding protein (CREB), a transducer of the glucagon signal, and the expression of a gluconeogenic glucagon target, phosphoenolpyruvate carboxykinase (PEPCK), were measured in T1D and nondiabetic mice. Compared with nondiabetic liver, there was a 3.5-fold elevation in phosphorylated CREB and a 2.5-fold increase in PEPCK expression in T1D livers (Fig. 2 A–C). To demonstrate that these differences were glucagon-mediated, we treated T1D mice with a single injection of 5 mg/kg mAb B (15), a fully human, antiglucagon receptor (GCGR) antibody drug candidate under development by REMD Biotherapeutics, Inc. (15–17). In mice treated with the monoclonal antibody mAb B, daily 10:00 AM blood glucose measurements averaged 85 ± 5 mg/dL and remained normoglycemic for 8 d (Fig. 2D), at which time livers were harvested. In the mAb B-treated T1D livers, phosphorylated CREB protein was reduced to nondiabetic levels and PEPCK protein expression was reduced below that of nondiabetic mice (Fig. 2 A–C). Thus, the activation of hepatic gluconeogenesis in T1D mice was a result of their hyperglucagonemia and disappeared when glucagon actions were blocked.Fig. 2.Glucagon action is chronically high in the livers of diabetic animals. (A) Hepatic markers of glucagon signaling (P-CREB) and of glucagon action (PEPCK) were measured by immunoblotting liver samples from nondiabetic and diabetic mice. (B) The ratio of ...If self-enhancing action of hyperglycemia is mediated by glucose-stimulated increase in glucagon in T1D, it follows that suppressing glucagon secretion should eliminate or reduce the problem. To test this, we placed T1D mice on a low dose of insulin (0.01 U twice daily) and then began continuous s.c. infusions of four peptides known to suppress glucagon directly or indirectly (18–22). A fifth, nonpeptidic suppressor (23), GABA, was given mixed in the chow. Each of the five reagents lowered glucagon levels, and in each case, this was accompanied by reduction of hyperglycemia from >600 mg/dL to 160 ± 75 mg/dL (P < 0.001; Fig. 3A). The average insulin concentrations in these samples were not correlated with either glucagon or glucose concentrations. With the exception of leptin, which reduced food intake by 50% compared with diabetic animals receiving insulin monotherapy, none of these glucagon suppressors caused a significant reduction in food intake.Fig. 3.Agents that suppress glucagon secretion or antagonize GCGR normalize glucagon action in liver and plasma glucose in diabetic mice. (A) Plasma glucose and glucagon levels in diabetic NOD mice (n= 3–10) treated with the agents shown. (B) Blood glucose ...If the glucose-lowering effects of glucagon suppressors resulted entirely from reduced glucagon secretion, rather than from off-target actions, therapy with a GCGR antibody should cause as dramatic an improvement as the glucagon-suppressing agents. Mice with chemically (streptozotocin)-induced T1D and a starting hyperglycemia of ∼325 ± 72 mg/dL were injected i.p. once each week with 7.5 mg/kg anti-GCGR antibody mAb Ac (15) (Fig. 3B), and blood glucose was measured weekly for 12 wk. Blood glucose concentrations returned to normal (∼90 mg/dL) in the mice treated with the antibody 1 wk after a single dose (first time point), and this normalization continued for the duration of treatment. Body weight did not change significantly between the control and antibody-treated groups of mice from the start to finish of the experiment. In the vehicle-treated control mice, blood glucose levels rose to 540 ± 70 mg/dL during the 12-wk study. At the end of this treatment, HbA1c was measured as an indication of chronic hyperglycemia. In the mice treated with mAb Ac, HbA1c levels were normal (4 ± 1%), whereas in the control mice, HbA1c averaged 11 ± 1% (Fig. 3C). GLP-1 averaged 3.64 ± 0.9 pmol/L in the control mice and 3.63 ± 0.52 pmol/L in the mice treated with antibody. By immunohistochemistry, the ratio of insulin-positive cells to glucagon-positive cells in islets observed in sections of pancreas taken from five control mice at the end of the study was 0.15, and using cells from five antibody treated mice, the ratio was 0.16. Because the ratio of β cells to α cells in wild-type mice is ∼6.0 (24), the ratios observed are those expected for severe ablation of β cells by streptozotocin. The fact that the ratio did not change between the two groups of animals indicates that the antibody treatment did not induce α-cell hyperplasia in this experiment.     

Analysis of patient satisfaction with a prefilled insulin injection device in patients with type 1 and type 2 diabetes

In this issue of Journal of Diabetes Science and Technology, Hancu and colleagues present an observational 6-8-week Pan-European and Canadian prospective survey on patient satisfaction with a prefilled insulin injection device, the SoloSTAR pen device, in patients with type 1 and 2 diabetes (n = 6542). The SoloSTAR pen is one of several up-to-date insulin pens of high quality and characteristics that fit many of our patients with diabetes. The mainly excellent-good votes of the participants for the SoloSTAR are not surprising, as we have seen continuous improvements with prefilled pens, such as the SoloSTAR device. Several years ago, patients as well as health care providers found considerable differences between the available pen options. Nowadays, as almost all pen providers have clearly improved their products, the differences are much smaller; we are closer to a "perfect" prefilled pen device. Nevertheless, there is a need for more randomized controlled trials, ideally sponsored not by just one manufacturer, to be able to make clear statements toward different pen device aspects (e.g., accuracy of dosing, adherence to therapy, ease of use, and patient satisfaction). An additional handicap is the difficulty to get blinded study designs.     

Improved glycaemic control of thrice-daily biphasic insulin aspart compared with twice-daily biphasic human insulin; a randomized, open-label trial in patients with type 1 or type 2 diabetes

Aim:  This trial evaluated the potential for improving glycaemic control by intensifying a conventional twice-daily therapy with premixed human insulin (HI) to a thrice-daily regimen using premixed formulations of biphasic insulin aspart (BIAsp) in patients with type 1 or type 2 diabetes.
Methods:  This was a multicentre, open-label, parallel group trial. After a 4-week run-in period, patients were randomized 1 : 1 to 16 weeks of treatment. A total of 748 patients were screened, 664 were exposed to trial drug and 604 completed the trial.
Results:  Haemoglobin A_1c, the primary efficacy endpoint, was shown to be significantly lower for the BIAsp treatment group compared with the biphasic HI (BHI) 30 group [estimated mean difference: −0.32, 95% confidence interval (CI) (−0.48; −0.16), p = 0.0001]. The average blood glucose level was significantly lower in the BIAsp group [estimated mean difference: −0.79, 95% CI (−1.17; −0.40), p = 0.0001]. There were few major hypoglycaemic episodes, 11 in the BIAsp group and 7 in the BHI 30 group. Although intensification of insulin therapy with BIAsp three times a day was associated with a higher risk of minor hypoglycaemia (relative risk = 1.58, p = 0.0038), the overall rate of minor hypoglycaemia remained low with both the BIAsp and the BHI treatments (13.1 vs. 8.3 episodes/patient year respectively). Overall safety and patient satisfaction were similar with the two insulin therapies.
Conclusions:  This trial confirmed that a thrice-daily BIAsp regimen can safely be used to intensify treatment for patients inadequately controlled on twice-daily BHI. A treat-to-target trial is required to explore the full potential of the BIAsp regimens and evaluate their use as a viable alternative to intensification with a basal-bolus regimen.     

Efficacy and safety of insulin glulisine in Japanese patients with type 1 diabetes mellitus

Aim: The rapid‐acting insulin analogue insulin glulisine (glulisine) was compared with insulin lispro (lispro) for efficacy and safety in Japanese patients with type 1 diabetes mellitus (T1DM), using insulin glargine (glargine) as basal insulin. Methods: This was an open, randomized, parallel‐group, comparative non‐inferiority study. The primary efficacy measure was change in adjusted mean haemoglobin A1c (HbA1c) from baseline to endpoint. Safety and treatment satisfaction using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) were also assessed. Patients were treated for 28 weeks with either glulisine or lispro administered 0–15 min before a meal. Doses were titrated to obtain 2‐h postprandial plasma glucose (2h‐PPG) of 7.11–9.55 mmol/l (128–172 mg/dl). All patients were concomitantly treated with glargine at bedtime, titrated to obtain a fasting (prebreakfast) plasma glucose level of 5.27–7.11 mmol/l (95–128 mg/dl). Results: Baseline mean HbA1c values were similar for the glulisine (n = 132) and lispro (n = 135) groups (7.44 and 7.50% respectively). From baseline to endpoint, adjusted mean HbA1c increased by 0.10% in the glulisine group and by 0.04% in the lispro group. Non‐inferiority of glulisine compared with lispro was shown. There were no significant differences between glulisine and lispro in adjusted mean 2h‐PPG [glulisine, 9.06 mmol/l (163 mg/dl) vs. lispro, 8.13 mmol/l (146 mg/dl); p = 0.065] and change in adjusted mean daily rapid‐acting insulin dose (glulisine, 0.26 U vs. lispro, 0.26 U; p = 0.994) at study endpoint. There was a significant difference for change in adjusted mean daily basal insulin dose from baseline to study endpoint (glulisine, –0.54 U vs. lispro, 0.26 U; p = 0.013). The most common serious adverse events were hypoglycaemia‐related events (hypoglycaemia, hypoglycaemic seizure and hypoglycaemic coma) with no difference observed between the two groups [glulisine, 6.8% (9/132) vs. lispro, 4.4% (6/135); p = 0.437]. No noteworthy differences were observed for change in insulin antibodies from baseline to endpoint. Assessment of treatment satisfaction score and perceived frequency of hyperglycaemia and hypoglycaemia by DTSQ showed no changes from baseline in either group. Conclusions: Glulisine was as effective as lispro with respect to change in HbA1c and was well tolerated when used in combination with glargine in Japanese patients with T1DM.     

Safe glycemic management during closed-loop treatment of type 1 diabetes: the role of glucagon, use of multiple sensors, and compensation for stress hyperglycemia

Patients with type 1 diabetes mellitus (T1DM) must make frequent decisions and lifestyle adjustments in order to manage their disorder. Automated treatment would reduce the need for these self-management decisions and reduce the risk for long-term complications. Investigators in the field of closed-loop glycemic control systems are now moving from inpatient to outpatient testing of such systems. As outpatient systems are developed, the element of safety increases in importance. One such concern is the risk for hypoglycemia, due in part to the delayed onset and prolonged action duration of currently available subcutaneous insulin preparations. We found that, as compared to an insulin-only closed-loop system, a system that also delivers glucagon when needed led to substantially less hypoglycemia. Though the capability of glucagon delivery would mandate the need for a second hormone chamber, glucagon in small doses is tolerated very well. People with T1DM often develop hyperglycemia from emotional stress or medical stress. Automated closed-loop systems should be able to detect such changes in insulin sensitivity and adapt insulin delivery accordingly. We recently verified the adaptability of a model-based closed-loop system in which the gain factors that govern a proportional-integral-derivative-like system are adjusted according to frequently measured insulin sensitivity. Automated systems can be tested by physical exercise to increase glucose uptake and insulin sensitivity or by administering corticosteroids to reduce insulin sensitivity. Another source of risk in closed-loop systems is suboptimal performance of amperometric glucose sensors. Inaccuracy can result from calibration error, biofouling, and current drift. We found that concurrent use of more than one sensor typically leads to better sensor accuracy than use of a single sensor. For example, using the average of two sensors substantially reduces the proportion of large sensor errors. The use of more than two allows the use of voting algorithms, which can temporarily exclude a sensor whose signal is outlying. Elements such as the use of glucagon to minimize hypoglycemia, adaptation to changes in insulin sensitivity, and sensor redundancy will likely increase safety during outpatient use of closed-loop glycemic control systems.