Insulin analogues and their potential in the management of diabetes mellitus

Bolli, Geremia B.; Marchi, Richard D. Di; Park, G. D.; Pramming, Stig; Koivisto, Veikko A.

doi:10.1007/s001250051286

Cited by 323 publications

(229 citation statements)

References 126 publications

(115 reference statements)

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“…A variety of studies have documented significant improvements in the therapy of type 1 and 2 diabetes due to the introduction of different insulin analogues into clinical use [1][2][3][4][5][6][7]. Advantages of short-acting artificial insulin molecules compared with conventional insulin preparations are better blood glucose control, faster onset of action and the short duration time [8].…”

Section: Introductionmentioning

confidence: 99%

IGF-1 receptor signalling determines the mitogenic potency of insulin analogues in human smooth muscle cells and fibroblasts

et al. 2007

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Aims/hypothesis Mitogenic activity of insulin and insulin analogues and the involvement of the IGF-1 receptor (IGF-1R) is still a controversial issue. We compared levels of the proteins IGF-1R and insulin receptor (InsR) in fibroblasts and smooth muscle cells from healthy donors and assessed the downstream signalling and growth-promoting activity of insulin and insulin analogues. Methods DNA synthesis was monitored in human fibroblasts and coronary artery smooth muscle cells. Using small interfering RNAs, the levels of IGF-1 and InsR were reduced by 95 and 75%, respectively. Results Enhanced mitogenic potency of insulin and insulin analogues was observed which correlated with increased levels of IGF-1R and/or IRS-1. A reduction in the IGF-1R level significantly blunted stimulation of Akt phosphorylation by IGF-1, AspB10 and glargine by 72, 58 and 40%, respectively. Akt phosphorylation in response to insulin remained unaffected. Silencing of InsR did not significantly alter Akt phosphorylation in response to IGF-1, AspB10 and glargine. IGF-1R knockdown reduced the stimulation of DNA synthesis in response to IGF-1 and glargine to a level identical to that produced by insulin. Conclusions/interpretation These data show a prominent role of IGF-1R/Akt signalling in mediating the mitogenic effects of insulin analogues. Regular insulin stimulates DNA synthesis by exclusively activating InsR, whereas insulin analogues mainly signal through IGF-1R. It is suggested that inter-individual differences in the levels of proteins of the IGF-1R system may function as a critical determinant of the mitogenic potency of insulin analogues.

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Section: Introductionmentioning

confidence: 99%

IGF-1 receptor signalling determines the mitogenic potency of insulin analogues in human smooth muscle cells and fibroblasts

et al. 2007

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“…apidly absorbed and acting insulin analogs are increasingly being used to improve postprandial metabolic control (1), which may help in reducing cardiovascular-related and all-cause mortality in patients who already have good metabolic control (A1C Ͻ8%) (2). Insulin glulisine is a new insulin analog (3) and, unlike other insulin analog products, is formulated without added zinc to achieve sufficient physical shelf life (4).…”

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confidence: 99%

Dose-Response Relationship of Insulin Glulisine in Subjects With Type 1 Diabetes

et al. 2007

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KLAUS RAVE, MD2 R apidly absorbed and acting insulin analogs are increasingly being used to improve postprandial metabolic control (1), which may help in reducing cardiovascular-related and all-cause mortality in patients who already have good metabolic control (A1C Ͻ8%) (2). Insulin glulisine is a new insulin analog (3) and, unlike other insulin analog products, is formulated without added zinc to achieve sufficient physical shelf life (4). This unique formulation allows for the immediate availability of monomeric and dimeric insulin glulisine molecules after injection, which is key for rapid absorption into the blood stream from subcutaneous tissue (5). Pharmacokinetic, pharmacodynamic, and safety studies of insulin glulisine in healthy volunteers and patients with diabetes have shown that subcutaneous injection of insulin glulisine more closely mimics physiologic postprandial insulin action than regular human insulin (RHI) (6). Indeed, superior metabolic control was achieved with insulin glulisine compared with RHI in subjects with type 1 diabetes on effectively titrated basal insulin regimens (7). However, despite the increasing use of rapid-acting insulin analogs, surprisingly little is known about dose escalation on systemic insulin concentrations and metabolic activity in subjects with diabetes. This study was conducted to investigate the dose-exposure and dose-response relationships of insulin glulisine compared with RHI in subjects with type 1 diabetes. RESEARCH DESIGN ANDMETHODS -In a single-center, randomized, euglycemic, glucose clamp trial, 18 male patients with type 1 diabetes were included in the study (aged 35.0 Ϯ 9.2 years, BMI 24.5 Ϯ 2.7 kg/m 2 , A1C 7.7 Ϯ 0.9%). The study included a screening visit, three glucose clamp visits with insulin glulisine, three glucose clamp visits with RHI, and a follow-up visit.Basal insulin supplementation was replaced with short-acting insulin for a minimum of 24 h before the study began. Subjects were attached to a Biostator (Life Science Instruments), and overnight blood glucose levels were manually maintained at 80 -150 mg/dl (4.4 -8.3 mmol/l) with intravenous RHI infusion (Insuman Rapid U100; sanofi-aventis). On the morning of treatment, blood glucose was adjusted to 100 mg/dl (5.5 mmol/l) before medication and maintained throughout the euglycemic clamp with an algorithm-based automated infusion of 20% glucose solution. Intravenous RHI infusion was discontinued immediately before the injection of insulin glulisine or RHI in a preset sequence of doses (0.075, 0.15, or 0.3 units/kg body wt). The glucose clamp was stopped when blood glucose levels reached Ն180 mg/dl (Ն10 mmol/l) for 30 min in the absence of an intravenous glucose infusion (endof-dose phenomenon) or after 10 h, depending on which came first. Insulin was sampled at predefined times, while blood glucose and glucose infusion rates (GIRs) were recorded throughout the glucose-clamp period on a minute-tominute basis by the Biostator and the data smoothed.Both insulin exposure and metabolic response we...

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“…Over time, most patients with type 2 diabetes experience progressive ␤-cell dysfunction and will require insulin therapy, either alone or in combination with oral agents, for satisfactory glycemic control (4). Attempts to mimic physiologic patterns of basal insulin secretion have been difficult because most currently available insulins have disadvantages, including variable absorption, pronounced peaks after injection, and abbreviated durations of action (5)(6)(7)(8).…”

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Basal Insulin Therapy in Type 2 Diabetes

et al. 2001

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OBJECTIVE -To determine the safety and efficacy of the long-acting analog insulin glargine compared with NPH insulin in patients with type 2 diabetes who were previously treated with insulin alone. RESEARCH DESIGN AND METHODS-A total of 518 subjects with type 2 diabetes who were receiving NPH insulin with or without regular insulin for postprandial control were randomized to receive insulin glargine (HOE 901) once daily (n ϭ 259) or NPH insulin once or twice daily (n ϭ 259) for 28 weeks in an open-label, multicenter trial. Doses were adjusted to obtain target fasting glucose Ͻ6.7 mmol/l. At study end point, the median total daily insulin dose in both treatment groups was 0.75 IU/kg. RESULTS -The treatment groups showed similar improvements in HbA 1c from baseline to end point on intent-to-treat analysis. The mean change (means Ϯ SD) in HbA 1c from baseline to end point was similar in the insulin glargine group (Ϫ0.41 Ϯ 0.1%) and the NPH group (Ϫ0.59 Ϯ 0.1%) after patients began with an average baseline HbA 1c of ϳ8.5%. The treatments were associated with similar reductions in fasting glucose levels. Overall, mild symptomatic hypoglycemia was similar in insulin glargine subjects (61.4%) and NPH insulin subjects (66.8%). However, nocturnal hypoglycemia in the insulin glargine group was reduced by 25% during the treatment period after the dose-titration phase (26.5 vs. 35.5%, P ϭ 0.0136). Subjects in the insulin glargine group experienced less weight gain than those in the NPH group (0.4 vs. 1.4 kg, P Ͻ 0.0007).CONCLUSIONS -In patients with type 2 diabetes, once-daily bedtime insulin glargine is as effective as once-or twice-daily NPH in improving and maintaining glycemic control. In addition, insulin glargine demonstrates a lower risk of nocturnal hypoglycemia and less weight gain compared with NPH insulin. Diabetes Care 24:631-636, 2001I nsulin treatment can improve and maintain glycemic control, preventing long-term complications in type 2 diabetes (1-3). Over time, most patients with type 2 diabetes experience progressive ␤-cell dysfunction and will require insulin therapy, either alone or in combination with oral agents, for satisfactory glycemic control (4). Attempts to mimic physiologic patterns of basal insulin secretion have been difficult because most currently available insulins have disadvantages, including variable absorption, pronounced peaks after injection, and abbreviated durations of action (5-8).The novel recombinant insulin analog insulin glargine (HOE 901; 21b-L-Arg-human insulin) is a modification of human insulin in which two arginines are added to the B-chain and glycine is substituted for asparagine at the A21 position of the insulin molecule. These changes cause a shift of the isoelectric point to a neutral pH (9 -11), precipitation at physiologic tissue pH, and increased hexamer stability, resulting in delayed absorption and a flat profile after injection, compared with the shorter duration of action and early peak of NPH insulin (9 -12). Short-term clinical trials in patients with type 1...

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Insulin analogues and their potential in the management of diabetes mellitus

Cited by 323 publications

References 126 publications

IGF-1 receptor signalling determines the mitogenic potency of insulin analogues in human smooth muscle cells and fibroblasts

IGF-1 receptor signalling determines the mitogenic potency of insulin analogues in human smooth muscle cells and fibroblasts

Dose-Response Relationship of Insulin Glulisine in Subjects With Type 1 Diabetes

Basal Insulin Therapy in Type 2 Diabetes

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