Insulin Self-association And The Relationship To Pharmacokinetics And Pharmacodynamics
Domain-minimized insulin receptors (IRs) have enabled crystallographic analysis of insulin-bound "micro-receptors." In such structures the C-terminal segment of the insulin B chain inserts between conserved IR domains, unmasking an invariant receptor-binding surface that spans both insulin A- and B chains. This "open" conformation not only rationalizes the inactivity of single-chain insulin (SCI) analogs (in which the A and B chains are directly linked), but also suggests that connecting (C) domains of sufficient length will bind the IR. Here, we report the high-resolution solution structure and dynamics of such an active SCI. The hormone's closed-to-open transition is foreshadowed by segmental flexibility in the native state as probed by heteronuclear NMR spectroscopy and multi-conformer simulations of crystallographic protomers as described in a companion article. We propose a model of the SCI's IR-bound state based on molecular-dynamics simulations of a micro-receptor complex. In this model a loop defined by the SCI's B and C domains encircles the C-terminal segment of the IR -subunit (CT). This binding mode predicts a conformational transition between an ultra-stable closed state (in the free hormone) and an active open state (on receptor binding). Optimization of this switch within an ultra-stable SCI promises to circumvent insulin's complex global cold chain. The analog's biphasic activity, which serendipitously resembles current premixed formulations of soluble insulin and microcrystalline suspension, may be of particular utility in the developing world. The propensity of various insulins and their analogs to oligomerize was investigated by mass spectrometric methods including measurement of the relative abundances of oligomers in the gas phase and the kinetics Continue reading >>
Pharmacokinetic And Pharmacodynamic Advantages Of Insulin Analogues And Premixed Insulin Analogues Over Human Insulins: Impact On Efficacy And Safety
Abstract Human insulin preparations administered to patients with diabetes mellitus fail to reproduce the normal physiologic pattern of insulin secretion. Modifications have been made in the amino acid sequence of the insulin molecule with the aim of overcoming the pharmacokinetic shortcomings of human insulins. Such modifications have produced long-acting analogues, with relatively flat time–action profiles, for controlling glycemic levels between meals; and rapid-acting analogues with a fast onset and short duration of action, for controlling postprandial hyperglycemia. Premixed formulations of the rapid-acting analogues, containing both rapid-acting soluble and intermediate-acting protaminated forms, are also available. Trials of long-acting insulin analogues have consistently shown efficacy in controlling fasting plasma glucose and glycosylated hemoglobin (HbA1c), as well as a markedly reduced risk of hypoglycemia compared with neutral protamine Hagedorn insulin. The rapid-acting and premixed analogues offer better control of postprandial glucose excursions than do regular human insulin, resulting in similar or lower HbA1c levels. Furthermore, the analogues can offer patients greater flexibility and more convenience in administration compared with human insulins. This review provides an overview of the insulin analogues available today and describes their structure, pharmacokinetics, pharmacodynamics, efficacy, and safety. Continue reading >>
Insulin Analogs: What Are The Clinical Implications Of Structural Differences?
US Pharm. 2010;35(5)(Diabetes suppl):3-7. In healthy adults, basal insulin concentrations of 5 to 15 µU/mL help to maintain fasting plasma glucose concentrations (FIGURE 1).1 Immediately following a meal, insulin concentration peaks at 60 to 80 µU/mL, returning to basal levels 1 to 3 hours later. In type 2 diabetes mellitus, progressive loss of beta cells results in the disruption of endogenous insulin secretion, in turn leading to requirement for insulin therapy. Considering that the daily pattern of normal insulin secretion is complex, close replication of this pattern is needed to address both fasting and prandial glucose control. In human insulin preparations, such as regular human insulin (RHI), insulin molecules typically self-aggregate to form dimers, which in turn stabilize around zinc ions to form hexamers.2 Following injection, the subcutaneous insulin depot is diluted by the interstitial fluid, causing hexamers to break down into dimers and biologically active monomers. The dissociation of hexamers into dimers and monomers is a rate-limiting step in absorption for all insulins and contributes to the delay in the effect of RHI. Because insulin hexamers are too bulky to be transported across the vascular endothelium, there is a 30- to 60-minute lag phase between injection and onset of action, which requires careful dose administration and food consumption. In addition to slow onset, a slow clearance can result in prolonged periods of elevated insulin and “delayed” hypoglycemia. Exogenous basal insulin delivery has traditionally involved single or twice-daily injections of neutral protamine Hagedorn (NPH) insulin, which is a formulation of protamine insulin in a zinc suspension. Protamine prolongs the absorption of NPH insulin, causing an intermediate dura Continue reading >>
Insulin Pharmacokinetics.
Abstract Where adjustments of diet, physical activity, and dosage of insulin are well known to diabetologists and diabetic patients, present-day knowledge of factors of importance to the pharmacokinetics of insulin is frequently ignored. The pharmacokinetics of insulin comprise the absorption process, the distribution including binding to circulating insulin antibodies, if present, and to insulin receptors, and its ultimate degradation and excretion. The distribution and metabolism of absorbed insulin follow that of endogenous insulin. The distribution and metabolism cannot be actively changed, except in the case of circulating insulin antibodies, which in rare cases also may cause insulin resistance. The use of insulin preparation of low immunogeneity will avoid or reduce this course of variation in action. The absorption process, the detailed mechanisms of which are still unknown, is influenced by many variables where some can be controlled, thereby reducing the intrapatient variability in insulin absorption, which may reach 35%, causing a corresponding metabolic lability. Besides the known differences in timing among different preparations, the size of dose, the injected volume, and the insulin concentration are determinants of absorption role. Fortuitous injection technique contributes to variance, as do changes in blood flow of the injected tissue. This may be induced by changes in ambient temperature, exercise of injected limb, or local massage. Regional differences are also due to differences in blood flow. Serum insulin peaks may peak up to 1 h after injection of soluble insulin into the thigh versus into the abdominal wall. Local degradation of insulin seems of less importance but may, in rare cases, be the cause of high insulin "requirements." Available eviden Continue reading >>
Pharmacokinetics
Pharmacokinetics (abbreviated as PK in medical reading material) is basically the study of how a drug travels through the body. It's a "road map", if you will, of the "trip" drugs take through one's system. By measuring things like the plasma concentration of the drug over a given time period, measuring them in both the same and in different subjects, many "maps" are created. Studying them provides a picture of how a given drug behaves in most who use or take it. Things like the life or halflife of a drug in the system, onset, peak, absorption, and duration all come from pharmacokinetic measurements. [2][3] It's pharmacokinetics which allows a doctor to know how Drug X at Y mg dosage will work in a patient--when the drug begins working, when it works hardest, or peaks, and when the drug wanes and is leaving the system. [4][5] This knowledge is why you are sometimes told to take medications more than once a day. We tend to focus more on the pharmacokinetics and pharmacodynamics of insulins [6][7][8], dealing with diabetes, but all drugs have pharmacokinetic and pharmacodynamic profiles. When reading various medical literature about insulin and its actions, one often sees the terms kinetics and dynamics used. Knowing what each means in terms of blood glucose can help you understand where it applies to you or your pet. Insulin Kinetics refers to the time when an insulin can be measured in the bloodstream. It's important to understand that even though it's "officially" made its way there, the insulin has not yet done so in sufficient quantity to effectively begin to lower blood glucose. Insulin Dynamics is the point where it has an effect on blood glucose levels. [9][10][11] A good illustration of kinetics and dynamics is having a headache and taking an aspirin for it. You Continue reading >>
Pharmacokinetics Of Long-acting (ultralente) Insulin Preparations
N2 - The aim of this study was to define and characterize time course of biological action and pharmacokinetics of long-acting ultralente insulin preparations. A further aim was to compare influence of species of origin (beef, pork, human) and specific commercial formulation (Lilly, Novo) on these parameters. Five preparations were studied in 6 to 9 healthy volunteers perpreparation. Dosage was 0.4 U/kg administered subcutaneously in the abdomen. Glucose was clamped for 40 hr at basal levels. Rate of dextrose infusion required to maintain euglycemia was used as the primary means of quantifying biological effectiveness. All ultralente preparations had onset of action between 3.0 and 7.5 hr, with no statistical difference between preparations for onset of action. Likewise, there was no statistical difference between preparations for duration of action, which was greater than 30 hr for all preparations. On the other hand, Lilly human ultralente had an earlier peak of action (8.5 0.9 hr) than beef ultralente, which showed only a subtle peak at a mean of 20.6 3.3 hr. Novo human ultralente resulted in greater total glucose infusion than beef ultralente. Greatest reproducibility of action was with Lilly human ultralente. Curves depicting plasma insulin levels were similar in shape to dextrose infusion profiles for each preparation, thus validating the method. Compared to the total duration of insulin action seen, the peaks of action seen with the pork and human ultralente insulin preparations were quite broad and of relatively small magnitude. As a consequence of the breadth of the action peaks and the prolonged duration of action of ultralente insulin, any of the ultralente formulations should be suitable to provide basal insulinemia. AB - The aim of this study was to define Continue reading >>
A Comparison Of Pharmocodynamics And Pharmacokinetics Of Biphasic Insulin Aspart 30, 50, 70 [amp] Pure Insulin Aspart In Type 1 Diabetes
A Comparison of Pharmocodynamics and Pharmacokinetics of Biphasic Insulin Aspart 30, 50, 70 [amp] Pure Insulin Aspart in Type 1 Diabetes Studies comparing the clinical Studies comparing the clinical pharmacological characteristics of different formulations of an insulin analogue are few. We investigated the pharmacokinetic and pharmacodynamic profiles of four different formulations of the aspart insulin analogue: Pure Insulin Aspart (IAsp), Biphasic Insulin Aspart 30 (BIAsp30), Biphasic Insulin Aspart 50 (BIAsp50) and Biphasic Insulin Aspart 70 (BIAsp70), in patients with type 1 diabetes. The numbers indicate the proportion of short acting insulin aspart, while the rest is protaminated insulin aspart. The trial was an open-label, randomised cross-over study. Nineteen type 1 diabetic patients received identical doses of the 4 different insulin preparations on 4 separate visits. Long and intermediate acting insulin were terminated at least 24 hours before. Insulin injection and a standard meal were given in the morning following a night with glucose control by i.v. human insulin. Plasma glucose and serum insulin aspart were recorded from the morning and 12 hours ahead. During the first 4 hours of the study IAsp had statistically higher area under the curve for insulin aspart concentration (AUCins) as compared to the other 3 treatments, followed by BIAsp70, BIAsp50 and BIAsp30 (p[lt]0.05). In the last 4 hours of the study BIAsp30 had significantly higher AUCins as compared to the other insulin preparations (p[lt]0.05). The pharmacodynamics of the 4 different preparations reflected the pharmacokinetics. Thus, the highest area under the curve for glucose concentration (AUCglu) during the initial 4 hours was seen following BIAsp30 as compared to the other 3 treatments (p[lt] Continue reading >>
- Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes
- Prevalence of and Risk Factors for Diabetic Peripheral Neuropathy in Youth With Type 1 and Type 2 Diabetes: SEARCH for Diabetes in Youth Study
- New type of diabetes discovered - Could YOU be showing symptoms of type 1.5 NOT type 2?
Pharmacokinetics And Pharmacodynamics Of Insulin Analogs In Special Populations With Type 2 Diabetes Mellitus
Go to: Abstract The goal of insulin therapy in patients with either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) is to match as closely as possible normal physiologic insulin secretion to control fasting and postprandial plasma glucose. Modifications of the insulin molecule have resulted in two long-acting insulin analogs (glargine and detemir) and three rapid-acting insulins (aspart, lispro, and glulisine) with improved pharmacokinetic/pharmacodynamic (PK/PD) profiles. These agents can be used together in basal-bolus therapy to more closely mimic physiologic insulin secretion patterns. This study reviews effects of the multiple demographic and clinical parameters in the insulin analogs glargine, detemir, lispro, aspart, and glulisine in patients with T2DM. A search was conducted on PubMed for each major topic considered (effects of injection site, age, race/ethnicity, obesity, renal or hepatic dysfunction, pregnancy, exercise, drug interactions) using the topic words and name of each type of insulin analog. Information was also obtained from the prescribing information for each insulin analog. The PK/PD profiles for insulin analogs may be influenced by many variables including age, weight, and hepatic and renal function. However, these variables do not have equivalent effects on all long-acting or rapid-acting insulin analogs. Rapid-acting and long-acting insulin analogs represent major advances in treatment for patients with T2DM who require insulin therapy. However, there are potentially important PK and PD differences between the two long-acting agents and among the three rapid-acting insulin analogs, which should be considered when designing treatment regimens for special patient groups. Keywords: insulin analogs, type 2 diabetes mellitus, pha Continue reading >>
A Comparison Of The Pharmacokinetics And Metabolic Effects Of Human Regular And Nph Insulin Mixtures - Sciencedirect
A comparison of the pharmacokinetics and metabolic effects of human regular and NPH insulin mixtures Author links open overlay panel S.N.Davis Get rights and content The effects of three human premixes (Mixtard, Actraphane, Humulin M3), syringe mixed 30% regular and 70% NPH insulin, regular insulin alone and NPH insulin alone, on intermediary metabolism, plasma free insulin levels and action profiles were compared using the euglycemic clamp technique. Seven normal volunteers received 20 IU of each insulin subcutaneously in a randomized fashion on separate days. The first and last 60 min of the 6 h clamp were chosen as summary measures of clinical importance. Significantly elevated plasma free insulin levels were found with all treatments compared to NPH insulin alone during the first hour, although by the final hour only Mixtard produced significantly higher levels compared to NPH (19.4 1.2, 10.5 0.3 mU/l P < 0.01, respectively). Analysis of area under the incremental insulin absorption curve demonstrated that Mixtard produced significantly increased levels compared to syringe-mixed regular: NPH (7.6 0.8), Actraphane (9.6 1.0) and Humulin M3 (9.0 0.8 mU/l all P < 0.05). Mixtard also resulted in significantly higher glucose infusion rates compared to the other premixes. No difference in action was found between regular and pre- or syringe-mixed human insulins during the first hour of the studies. The effects on intermediary carbohydrate and lipid metabolism were similar for syringe and premixed insulins. We conclude that: (1) fixed human insulin mixtures with NPH cause no blunting of the action of the soluble component. (2) Actraphane and Humulin M3 are similar but Mixtard may have a greater effect on some aspects of insulin action. (3) In clinical practice, fixed human Continue reading >>
Ultra-rapid - Afrezza Inhaled Insulin
Insulin is classified as: Rapid-acting - Humalog (H), Novolog (NL), Apidra (AP) Short-acting - Regular (R) Intermediate-acting - (NPH) Long-acting - Lantus (Glargine), Levemir (detremir) Pre-mixed: Novolin® 70/30 - Humulin® 70/30 Novolog® Mix 70/30 Humalog® Mix 75/25 All insulin prescribed in the U.S. is chemically similar to human insulin. Human insulin is manufactured using recombinant DNA technology and has replaced insulin derived from pork and beef organs. Beef insulin differed from human insulin at 3 amino acid sites and pork insulin differed at one site. As a result, beef and pork insulin caused more allergic reactions and are no longer sold in the U.S. Each insulin preparation has a different pharmacokinetic profile, i.e., onset, peak effect, and duration. To further complicate things, dosage can significantly modify the profile even within the same commercial product. Therefore replacing one insulin product with another is not a simple substitution. Changing an insulin medication should only be done under the supervision of a health professional with expertise in diabetes management. If a patient is admitted to the hospital, the type of insulin he or she has been using should not be changed indiscriminately. In all instances of insulin use, dosages must be individualized and balanced with medical nutrition therapy and exercise. Instant Feedback: Ultra-rapid insulin - Afrezza is an inhaled human insulin, recently approved by the FDA, for use by adult patients with diabetes mellitus (DM). In patients with type 1 DM (T1D), Afrezza must be used in conjunction with a long-acting insulin. Afrezza is rapidly absorbed with a peak serum concentration occurring within 12-15 minutes and a half-life of ≈28-39 minutes. Peak action occurs in about 60 minutes and a dura Continue reading >>
Pharmacokinetics Of The Rapid-acting Insulin Analog, Insulin Aspart, In Rats, Dogs, And Pigs, And Pharmacodynamics Of Insulin Aspart In Pigs
The objective of this study was to compare the pharmacokinetics and pharmacodynamics of insulin aspart (IA), a rapidly acting insulin analog, with those of human soluble (regular) insulin (HI) in animal models after s.c. and i.v. dosing. Single doses of IA and HI were administered i.v. and s.c. to rats and dogs at three dose levels, and at one dose level to pigs; rats and dogs also underwent repeated s.c. dosing for 1 week. Plasma insulin levels were assessed at predetermined time points after dosing; plasma glucose levels were measured in pigs only. There were no significant pharmacokinetic differences between IA and HI after a single s.c. or i.v. dose in rats or dogs, and no differences were observed after repeated s.c. dosing, implying there was no accumulation. In pigs, there was a strong trend toward more rapid absorption of IA compared with HI after s.c. dosing, whereas there were no differences after i.v. administration. After s.c. dosing in pigs, IA produced significantly lower plasma glucose levels compared with HI during the period 30 to 75 min after dosing (P < .05). In conclusion, IA was more rapidly absorbed than HI after s.c. administration only in the pig; this difference was reflected in earlier and more pronounced effects on plasma glucose levels. The goal of insulin therapy in patients with type I diabetes mellitus is to mimic the pattern of endogenous insulin secretion seen in healthy individuals, characterized by a relatively constant basal level with sharp peaks after meals (Zinman, 1989). This approach is supported by the wealth of evidence demonstrating that maintenance of plasma glucose as close as possible to physiological levels reduces the risk of late diabetic complications (Wiseman et al., 1985; The Diabetes Control and Complications Trial R Continue reading >>
Pharmacokinetics And -dynamics Of Insulin Absorption
Exogenously administered insulin will never be able to exactly mimick the effects of insulin endogenously released by the pancreas. The main reason is that the pancreas releases insulin into the portal vein, so that the insulin passes the liver first. There, more than 50% of insulin is extracted, and as a result hepatic exposure to insulin is high, and peripheral (muscle, fat) exposure to insulin is low. When exogenous insulin is administered -whether i.v., s.c., i.m. or otherwise- it is distributed throughout the circulation, exposing the peripheral organs to relatively high and the liver to relatively low levels of insulin. Another problem is that the pancreas releases insulin in small bouts at short intervals, in direct response to the ambient level of glucose, whereas the dose of exogenously administered insulin thusfar is predetermined. The precise effects over time of the various exogenous insulins are however also dependent on their pharmacokinetic and pharmacodynamic characteristics and the mode of administration. Studying pharmacokinetics and -dynamics The traditional method to assess the pharmacokinetics (the plasma levels of insulin over time) and the pharmacodynamics (the resulting effects on glucose over time) of exogenous insulins is the isoglycaemic clamp study. In this, the study insulin is injected and i.v. glucose is infused to maintain a stable level of glycemia. The Glucose Infusion Rate (GIR) is considered to represent the pharmacodynamics of the insulin. When studying other subjects than those with type 1 diabetes -who do not have endogenous insulin secretion- additional steps have to be taken to make sure that (residual) endogenous insulin does not interfere with the interpretation of the results. While the technique has its disadvantages, it usua Continue reading >>
- Best insulin injection sites: Absorption time and rotation
- Strategies for Stabilizing Insulin Absorption Rates
- Relative effectiveness of insulin pump treatment over multiple daily injections and structured education during flexible intensive insulin treatment for type 1 diabetes: cluster randomised trial (REPOSE)
Insulin Glargine: Long-acting Basal Insulin Analog For Improved Metabolic Control
The primary aim of insulin therapy is to replace endogenous insulin secretion in patients with type 1 or type 2 diabetes in a physiologically sound manner, mimicking normal secretion patterns to adequately regulate glucose metabolism. The currently available human insulins for basal therapy - neutral protamine Hagedorn (NPH), Lente* and Ultralente - and analogs such as insulin glargine, differ in pharmacokinetic properties. Clinical trial data indicate that insulin glargine may satisfy basal insulin requirements, with an improved safety profile relative to other available insulins used for basal supplementation. This review describes the unique pharmacokinetic properties and clinical efficacy of insulin glargine. The primary objective of insulin therapy in the treatment of diabetes is to produce sustained near-normal glycemia by replacing or supplementing endogenous insulin secretion in as physiological a manner as possible, postprandially as well as between meals and overnight. Obtaining the low, steady level of insulin replacement to satisfy basal requirements has remained elusive because conventional human insulin preparations produce time-action profiles that differ considerably from the physiological dynamics of endogenous basal insulin secretion. In recent years, recombinant DNA technology has been used to design insulin molecules that overcome the limitations of regular insulin in mealtime supplementation. Modifications of the amino acid sequence of the insulin molecule have resulted in prandial analogs with pharmacokinetic characteristics that more closely mimic the physiological insulin response to a meal following subcutaneous injection. Two rapid-acting insulin analogs, aspart (NovoLog) and lispro (Humalog), allow for more normal control of meal-related plas Continue reading >>
Insulin Lispro: A Fast-acting Insulin Analog
Research has established the importance of maintaining blood glucose levels near normal in patients with type 1 (insulin-dependent) diabetes mellitus. Short-acting insulin analogs are designed to overcome the limitations of regular short-acting insulins. Compared with regular human insulin, the analog insulin lispro offers faster subcutaneous absorption, an earlier and greater insulin peak and a more rapid post-peak decrease. Insulin lispro begins to exert its effects within 15 minutes of subcutaneous administration, and peak levels occur 30 to 90 minutes after administration. Duration of activity is less than five hours. Rates of insulin allergy, lipodystrophy, hypoglycemia and abnormal laboratory test results are essentially the same in patients using insulin lispro and in those using regular human insulin. The Diabetes Control and Complications Trial (DCCT)1 established the importance of maintaining near-normal blood glucose levels in patients with type 1 (insulin-dependent) diabetes mellitus. In these patients, intensive therapeutic regimens have been found to delay the onset and reduce the progression of microvascular complications by 50 to 75 percent as compared with conventional regimens. Although no large-scale investigations have been completed, smaller studies have reported similar benefits for intensive therapeutic regimens in patients with type 2 (non–insulin-dependent) diabetes.2 Primary care physicians provide medical care for 75 percent of children and 90 to 95 percent of adults with diabetes.3 Regardless of the type of diabetes, improved glycemic control often can be achieved with individualized tools for patient self-management, carefully formulated nutrition plans and the use of alternative insulin regimens.4 Overview of Insulin Insulin is necessary Continue reading >>
Diabetesmanager / Insulin - Pharmacology, Types Of Regimens, And Adjustments
Binder C, Brange J 1997 Insulin chemistry and pharmacokinetics. In: Porte D, Jr., Sherwin R (eds) Ellenberg's and Rifkin's Diabetes Mellitus, 5th edition ed. Appleton and Lange, Stamford, CT, p 689 FDA/CDER resources page. Frequently asked questions about importing beef or pork insulin for personal use. Food and Drug Administration website. Available at: Accessed September 16, 2006. Binder C, Brange J 1997 Insulin chemistry and pharmacokinetics. In: Porte D, Jr., Sherwin R (eds) Ellenberg's and Rifkin's Diabetes Mellitus, 5th edition ed. Appleton and Lange, Stamford, CT, p 689 May 2004 Eli Lilly and Company. Humalog Package Insert. March 2005 Eli Lilly and Company. Humalog Mix75/25 Package Insert. February 2006 Sanofi-Aventis U.S. Lantus Package Insert. October 2005 Novo Nordisk, Inc. Novolog Package Insert. November 2005 Novo Nordisk Inc. Novolog Mix 70/30 Package Insert. January 2006 Eli Lilly and Company. Humalog Mix50/50 Package Insert. October 2005 Novo Nordisk Inc. Levemir Package Insert. November 2005 Aventis Pharmaceuticals Inc. Apidra Package Insert. Kurtzhals P, Schaffer L, Sorensen A, et al. 2000 Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 49:999-1005 Kurtzhals P, Schaffer L, Sorensen A, et al. 2000 Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 49:999-1005 Home PD, Ashwell SG 2002 An overview of insulin glargine. Diabetes Metab Res Rev 18 Suppl 3:S57-63 Schernthaner G 1993 Immunogenicity and allergenic potential of animal and human insulins. Diabetes Care 16 Suppl 3:155-65 Schernthaner G 1993 Immunogenicity and allergenic potential of animal and human insulins. Diabetes Care 16 Suppl 3:155-65 Binder Continue reading >>
