Optimal provision of daytime NPH insulin in patients using the insulin analog lispro

OBJECTIVE: Insulin lispro improves early postprandial blood glucose control but can result in late interprandial hyperglycemia. As an approach to resolving this problem, we performed a randomized, crossover study with four treatment arms, comparing the daytime metabolic profile after either premeal lispro alone or premeal lispro with optimal daytime NPH insulin and with standard human regular insulin. RESEARCH DESIGN AND METHODS: Twelve C-peptide negative type 1 diabetic patients were studied on four separate study days, at least 7 days apart. On each study day, patients received one of the four study insulin treatments, in random order, with identical meals and snacks. The four treatments were 1) premeal human regular insulin before lunch and supper at unchanged dose; 2) premeal lispro (unchanged dose) at lunchtime and dinner; 3) pre-lunch reduced-dose lispro (70%) before lunch and supper with supplemental lunchtime NPH and with a 6-h interval until dinner; and 4) pre-lunch reduced-dose lispro (70%) before lunch and supper with supplemental lunchtime NPH and with a 8-h interval until dinner. All patients were using their usual premeal plus basal insulin regimen during the period of the study, with human regular insulin before meals and NPH insulin at bedtime. RESULTS: Postprandial blood glucose concentrations (1230-1500) were lower after reduced or usual lispro dose compared with human regular insulin (5.5+/-0.2 and 5.6+/-0.2 vs. 8.2+/-0.5 mmol/l, P < 0.001), with no difference between the lispro doses. However, prepran-Dial (1800) blood glucose levels deteriorated to higher levels after usual-dose lispro alone compared with either human regular insulin (P < 0.05) or reduced-dose lispro plus NPH (P < 0.05) (8.9+/-0.3 vs. 7.1+/-0.8 and 6.4+/-0.4 mmol/l), with no difference between human regular insulin and reduced-dose lispro plus NPH. During the 2 h between the usual and delayed mealtime, blood glucose concentrations remained controlled on lispro plus NPH (2000: 6.5+/-0.4 mmol/l). CONCLUSIONS: Reduced-dose lunchtime lispro plus NPH maintained the improvement in postprandial blood glucose control with no deterioration in interprandial blood glucose control, even up to a late meal.     

Insulin lispro, a new insulin analog

Insulin lispro is a rapid-acting insulin analog to regular insulin. Inversion of the proline-lysine amino acid sequence at positions 28 and 29 on the B chain is responsible for its more rapid absorption, faster onset, and shorter duration of action compared with regular insulin. The fast onset of action allows for greater flexibility in dosing and mealtime scheduling. Insulin lispro provides equivalent or slightly improved glycemic control in patients with types I and II diabetes mellitus compared with regular insulin, without subsequent increases in hypoglycemic episodes. It also results in greater reduction in postprandial blood glucose excursion than regular insulin. Compared with other insulins, insulin lispro represents a more physiologic approach to exogenous insulin therapy.     

Resolution of lipohypertrophy following change of short-acting insulin to insulin lispro (Humalog)

Lipohypertrophy as a local complication of insulin therapy is well recognized. Despite improvements in insulin purity and the introduction of recombinant human insulin its prevalence has remained high. Rotation of injection sites can reduce the frequency of the problem but does not abolish it. The importance of this complication is not only cosmetic but also in its impact on insulin absorption, and hence glycaemic control. We report a patient who had intractable lipohypertrophy with human recombinant insulin but experienced no such problem when converted onto the insulin analogue lispro. We suggest that the faster speed of absorption of insulin lispro may lead to less hypertrophic stimulation of subcutaneous adipocytes. This difference may be clinically useful in susceptible individuals.     

Use of the short-acting insulin analogue lispro in intensive treatment of type 1 diabetes mellitus: importance of appropriate replacement of basal insulin and time-interval injection-meal

To establish whether lispro may be a suitable short-acting insulin preparation for meals in intensive treatment of Type 1 diabetes mellitus (DM) in patients already in chronic good glycaemic control with conventional insulins, 69 patients on intensive therapy (4 daily s.c. insulin injections, soluble at each meal, NPH at bedtime, HbA1c <7.5%) were studied with an open, cross-over design for two periods of 3 months each (lispro or soluble). The % HbA1c and frequency of hypoglycaemia were assessed under four different conditions (Groups I-IV). Lispro was always injected at mealtime, soluble 10-40 min prior to meals (with the exception of Group IV). Bedtime NPH was continued with both treatments. When lispro replaced soluble with no increase in number of daily NPH injections (Group I, n = 15), HbA1c was no different (p = NS), but frequency of hypoglycaemia was greater (p < 0.05). When NPH was given 3-4 times daily, lispro (Group II, n = 18), but not soluble (Group III, n = 12) decreased HbA1c by 0.35 +/- 0.25% with no increase in hypoglycaemia. When soluble was injected at mealtimes, HbA1c increased by 0.18 +/- 0.15% and hypoglycaemia was more frequent than when soluble was injected 10-40 min prior to meals (Group IV, n = 24) (p < 0.05). It is concluded that in intensive management of Type 1 DM, lispro is superior to soluble in terms of reduction of % HbA1c and frequency of hypoglycaemia, especially for those patients who do not use a time interval between insulin injection and meal. However, these goals cannot be achieved without optimization of basal insulin.     

The short-acting insulin analog Lispro (Humalog) in the treatment of diabetes--comparison of preprandial and postprandial administration and comparison with treatment using Humulin R

The results of a clinical trial comprising 162 type 1 and 2 diabetics who took for 12 weeks Humalog in cartridges revealed that administration of this insulin before or 20 minutes after a meal does not affect the blood sugar level in a major way. None of the patients developed after Humalog administration local or general allergic manifestations. Hypoglycaemic episodes grade I and II were not more frequent during treatment with human insulins. The mean compensation of diabetes (HbA1c) remained unchanged. 80% of the diabetics are statistically significantly satisfied with Humalog treatment as compared with Humulinem R administration.     

Successful treatment with insulin analog lispro in IDDM with delayed absorption of subcutaneously applied human regular insulin and complicated intraperitoneal insulin infusion. A case report

OBJECTIVE: To subcutaneously administer the insulin analog lispro in a patient with delayed absorption of subcutaneously applied human regular insulin whose continuous intraperitoneal insulin infusion (CIPII) with a percutaneous access device had required multiple surgical interventions because of complications. RESEARCH DESIGN AND METHODS: In a 35-year-old woman with long-term IDDM and delayed absorption of subcutaneously applied human regular insulin, a 3-year CIPII with human regular insulin via a percutaneous access device was complicated by three catheter obstructions and one subcutaneous abscess. Each complication required the implantation of a new percutaneous access device. During a 2-day trial with continuous subcutaneous insulin infusion (CSII) of the insulin analog lispro at basal infusion rates of 0.5-1.1 U/h, stable metabolic control was achieved. A 5-h intermediate attempt with human regular insulin in CSII, however, increased blood glucose concentrations from 6.0 to 28.8 mmol/l, despite identical basal rates and additional injection of 16 U of human regular insulin. Restarting with CSII of the insulin analog lispro reinforced stable metabolic control. CONCLUSIONS: It is suggested that the insulin analog lispro is a promising approach in the treatment of IDDM with delayed absorption of subcutaneously applied human regular insulin and a suitable alternative therapy for patients with complications attributed to percutaneous access devices for CIPII.     

Modification of postprandial hyperglycemia with insulin lispro improves glucose control in patients with type 2 diabetes

OBJECTIVE: Insulin lispro is a rapid-acting analog of human insulin that can be used to target the postprandial rise in plasma glucose. We designed an open-label randomized crossover study of type 2 diabetic patients with secondary failure of sulfonylurea therapy to determine whether improvement of postprandial hyperglycemia would affect total daily glucose control. RESEARCH DESIGN AND METHODS: Twenty-five type 2 diabetic patients who were poorly controlled on a maximum dose of sulfonylureas were studied in a university hospital clinical research center. In one arm of the study, patients continued therapy with maximum-dose sulfonylureas. In the other arm, patients used a combination therapy with insulin lispro before meals and sulfonylureas. After 4 months, patients were crossed over to the opposite arm. Fasting plasma glucose (FPG) and 1- and 2-h postprandial glucose (after a standardized meal), HbA1c, total, HDL, and LDL cholesterol, and triglyceride levels were measured at the end of each arm of the study. RESULTS: Insulin lispro in combination with sulfonylurea therapy significantly reduced 2-h postprandial glucose concentrations compared with sulfonylureas alone, from 18.6 to 14.2 mmol/l (P < 0.0001), and incremental postprandial glucose area from 617.8 to 472.9 mmol.min.1-1 (P < 0.0007). FPG levels were decreased from 10.9 to 8.5 mmol/l (P < 0.0001), and HbA1c values were reduced form 9.0 to 7.1% (P < 0.0001). Total cholesterol was significantly decreased in the lispro arm from 5.44 to 5.10 mmol/l (P < 0.02). HDL cholesterol concentrations were increased in the lispro arm from 0.88 to 0.96 mmol/l (P < 0.01). The patients weighed significantly more after lispro therapy than after sulfonylureas alone, but the difference was small in absolute terms (sulfonylurea therapy alone, 90.6 kg; lispro therapy, 93.8 kg; P < 0.0001). Two episodes of hypoglycemia (glucose concentrations, < 2.8 mmol/l) were reported by the patients while using lispro. CONCLUSIONS: Previously, it has not been possible to address the effect of treatment of postprandial hyperglycemia specifically. We have now shown that the treatment of postprandial hyperglycemia with insulin lispro markedly improves overall glucose control and some lipid parameters in patients with type 2 diabetes.     

Nighttime insulin kinetics and glycemic control in type 1 diabetes patients following administration of an intermediate-acting lispro preparation

OBJECTIVE: To determine insulin kinetics and overnight glycemic control after bedtime administration of a new intermediate-acting insulin preparation called neutral protamine lispro (NPL). RESEARCH DESIGN AND METHODS: We studied 12 patients with well-controlled type 1 diabetes. The study had a double-blind, randomized, crossover design. After a lead-in period of 10-14 days two experiments were carried out with an interval of 2-7 days. During these experiments overnight insulin kinetics and fasting blood glucose levels were studied after evening administration of NPH insulin and NPL. Blood glucose levels < 3.8 mmol/l were treated by means of a variable infusion of a 20% glucose solution. RESULTS: A trend toward a shorter time to peak insulin concentration was observed after administration of NPL (P = 0.07). No differences between NPH and NPL were detected in the total area under the curve (AUC) for insulin, in insulin levels before breakfast, or in glucose levels before breakfast (P = 0.5, 0.6, and 0.4, respectively). CONCLUSIONS: We detected no major differences between NPH and NPL in the total AUC for insulin, prebreakfast glucose levels, or prebreakfast insulin levels. Therefore, we conclude that NPH and NPL are equally effective in controlling overnight glycemia.     

The action profile of lispro is not blunted by mixing in the syringe with NPH insulin

OBJECTIVE: To assess the effect of mixing the insulin analog lispro (Humalog) with NPH (Humulin I) before injection on lispro's fast, short action profile. RESEARCH DESIGN AND METHODS: A total of 12 healthy volunteers received subcutaneous abdominal injections of 0.1 U/kg regular insulin and 0.2 U/kg NPH insulin as follows: lispro and NPH injected separately (treatment group A), lispro and NPH mixed in the syringe up to 2 min before single injection (treatment group B), and human regular insulin and NPH mixed and injected as in group B (treatment group C), on separate occasions, in random order. Plasma glucose was maintained for 12 h by intravenous 20% glucose. Pharmacokinetic and pharmacodynamic parameters were compared by analysis of variance for repeated measures. RESULTS: Peak plasma insulin levels (2.6 +/- 0.8 vs. 2.2 +/- 0.6 vs. 1.9 +/- 0.6 ng/ml, P = 0.075), total glucose infused (121.5 +/- 32.8 vs. 135.0 +/- 49.0 vs. 117.3 +/- 39.9 mg.kg-1.min-1, P = 0.53), and maximum glucose infusion rate (GIRmax) (8.3 +/- 0.9 vs. 8.0 +/- 1.7 vs. 7.1 +/- 2.4 mg.kg-1.min-1, P = 0.65) were not significantly different between treatments. The times until peak insulin concentrations were similar in treatment groups A and B, but significantly shorter than in treatment group C (0.9 +/- 0.3 and 1.2 +/- 0.2 vs. 2.0 +/- 0.4 h, respectively, P = 0.042). The times until GIRmax were also not different (113.9 +/- 41 and 122.0 +/- 45 vs. 209.0 +/- 51.3 min, respectively, P = 0.002). The glucose infusion rate (GIR) then fell to 50% GIRmax more quickly in treatment groups A and B than in treatment group C (239.9 +/- 40.5 vs. 292.4 +/- 133.3 vs. 399.5 +/- 78.3, respectively, P = 0.005). CONCLUSIONS: The action profile of lispro is not attenuated by mixing lispro with NPH in the syringe immediately before injection. The advantages are available to those individuals who need to combine types of insulin before injection to achieve optimal diabetes control.     

Benefits of lispro insulin: control of postprandial glucose levels is within reach

How well would the following fit into your schedule? You must know when you will eat throughout the day, and about an hour beforehand you must inject an appropriate amount of insulin to offset the amount of carbohydrate you intend to consume. For many diabetic patients who use regular insulin, these are the requirements. Dr Bohannon describes a newly approved insulin that goes into action and gets out of the body faster, more closely mimicking the body's natural insulin response to food.     

Stimulation of glucose and amino acid transport and activation of the insulin signaling pathways by insulin lispro in L6 skeletal muscle cells

The monomeric insulin analogue insulin lispro (Lys B28, Pro B29) is a rapid-acting insulin with a shorter duration of activity than human regular insulin. This compound has the advantage of reducing early postprandial hyperglycemia and the accompanying late hypoglycemia, thereby improving overall blood glucose control. To date, all published studies of the functional properties of insulin lispro have been conducted in whole animals. This study aimed to characterize the cellular actions of insulin lispro and the signals it elicits in an insulin-sensitive muscle cell line, L6 cells. Comparing the cellular actions of insulin lispro with those of human regular insulin, a number of observations were made. (1) Insulin lispro stimulated glucose and amino acid transport into L6 myotubes with a dose dependency and time course virtually identical to those of human regular insulin. (2) Insulin lispro was as effective as human regular insulin in stimulating time-dependent phosphorylation of insulin receptor substrate 1 (IRS-1), p70 ribosomal S6 kinase, and two isoforms of mitogen-activated protein kinase (ERK1 and ERK2). (3) Insulin lispro's ability to induce the association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase was similar to that of human regular insulin. (4) As with human regular insulin, 100 nmol of the fungal metabolite wortmannin completely inhibited insulin lispro stimulation of glucose uptake. We concluded that the cellular actions of insulin lispro are similar to those of human regular insulin with respect to glucose and amino acid uptake and that the biochemical signals elicited are also comparable.     

Effect of continuous subcutaneous insulin infusion with lispro on hepatic responsiveness to glucagon in type 1 diabetes

OBJECTIVE: People with type 1 diabetes frequently develop a blunted counterregulatory hormone response to hypoglycemia coupled with a decreased hepatic response to glucagon, and consequently, they have an increased risk of severe hypoglycemia. We have evaluated the effect of insulin lispro (Humalog) versus regular human insulin (Humulin R) on the hepatic glucose production (HGP) response to glucagon in type 1 diabetic patients on intensive insulin therapy with continuous subcutaneous insulin infusion (CSII). RESEARCH DESIGN AND METHODS: Ten subjects on CSII were treated for 3 months with lispro and 3 months with regular insulin in a double-blind randomized crossover study After 3 months of treatment with each insulin, hepatic sensitivity to glucagon was measured in each subject. The test consisted of a 4-h simultaneous infusion of somatostatin (450 microg/h) to suppress endogenous glucagon, regular insulin (0.15 mU x kg(-1) x min(-1)), glucose at a variable rate to maintain plasma glucose near 5 mmol/l, and D-[6,6-2H2]glucose to measure HGP During the last 2 h, glucagon was infused at 1.5 ng x kg(-1) x min(-1). Eight nondiabetic people served as control subjects. RESULTS: During the glucagon infusion period, free plasma insulin levels in the diabetic subjects were 71.7+/-1.6 vs. 74.8+/-0.5 pmol/l after lispro and regular insulin treatment, with plasma glucagon levels of 88.3+/-1.8 and 83.7+/-1.5 ng/l for insulin:glucagon ratios of 2.8 and 3.0. respectively (NS). However, plasma glucose increased to 9.2+/-1.1 mmo/l after lispro insulin compared with 7.1+/-0.9 mmol/l after regular insulin (P < 0.01), and the rise in HGP was 5.7 +/-2.8 micromol x kg(-1) x min(-1) after lispro insulin versus 3.1+/-2.9 micromol x kg(-1) x min(-1) after regular insulin treatment (P=0.02). In the control subjects, HGP increased by 10.7+/-4.2 micromol x kg(-1) x min(-1) under glucagon infusion. CONCLUSIONS: Insulin lispro treatment by CSII was associated with a heightened response in HGP to glucagon compared with regular human insulin. This suggests that insulin lispro increases the sensitivity of the liver to glucagon and could potentially decrease the risk of severe hypoglycemia.     

Comparison of LysB28, ProB29-human insulin analog and regular human insulin in the correction of incidental hyperglycemia

OBJECTIVE: To obtain clinically applicable data on the effects of regular human insulin and the LysB28,ProB29-human insulin analogue (lispro) on the correction of incidental hyperglycemia. RESEARCH DESIGN AND METHODS: The insulins were compared in a non-clamped randomized crossover study of 27 male IDDM patients. Hyperglycemia was induced by the withdrawal of the normal evening dose of insulin; the next morning patients fasted and received a single dose of study insulin according to a dosing nomogram. Blood glucose concentration and GR (a measure of glucose corrected for differences in administered insulin dose: GR = glucose concentration X BMI X insulin dose-1) were followed for 4 h. RESULTS: The time courses of blood glucose concentration and GR were significantly different after regular insulin in comparison with lispro (multiple analysis of variance, P < 0.001). At t = 120 min, glucose concentrations had decreased 1.4 mmol/l more with lispro than with regular insulin (95% confidence interval [CI] 0.6-2.3, P = 0.002). Similarly, GR had decreased 4.4 mol.kg.IU-1.m-5 more with lispro than with regular insulin (95% CI 2.6-6.2, P < 0.001). The overall difference in glucose values was 0.87 mmol/l (lispro < regular insulin, P = 0.036), and the overall difference in GR values was 1.96 mol.kg.IU-1.m-5 (lispro < regular insulin, P = NS). Unexpectedly, the intrinsic variability of GR was higher for lispro than for regular insulin. CONCLUSIONS: The more rapid action of lispro is an advantage in the correction of hyperglycemia, even though actual differences in glucose concentrations are smaller than suggested by previous clamped studies.     

Lispro analog for treatment of generalized allergy to human insulin

OBJECTIVE: To evaluate the clinical usefulness of the human insulin analog lispro in a patient with generalized allergy to human insulin. RESEARCH DESIGN AND METHODS: A 34-year-old obese female patient developed systemic allergic reactions to human insulin but tolerated insulin lispro. Sequential analyses of the anti-insulin IgE and IgG immunoglobulins were performed. RESULTS: On intradermal test, the lispro insulin produced a 50% less intense wheal-flare response, compared with human insulin, which was presumed to be due to lispro's molecular form. The intradermal reactivity to both human and lispro insulins decreased with time and disappeared by week 25. 125I-labeled lispro and human insulin binding antibody titers of both the IgE and IgG immunoglobulins were high initially, but decreased progressively, becoming very low by the end of 1 year. In in vitro immunoassay, the lispro and human insulins show a complete cross-reactivity. CONCLUSIONS: Lispro may be useful for the management of allergy to human insulin. This analog of human insulin appears to have a reduced immunogenic potency.     

Morning vs evening light treatment of patients with winter depression

BACKGROUND: According to the phase-shift hypothesis for winter depression, morning light (which causes a circadian phase advance) should be more antidepressant than evening light (which causes a delay). Although no studies have shown evening light to be more antidepressant than morning light, investigations have shown either no difference or morning light to be superior. The present study assesses these light-exposure schedules in both crossover and parallel-group comparisons. METHODS: Fifty-one patients and 49 matched controls were studied for 6 weeks. After a prebaseline assessment and a light/dark and sleep/wake adaptation baseline week, subjects were exposed to bright light at either 6 to 8 AM or 7 to 9 PM for 2 weeks. After a week of withdrawal from light treatment, they were crossed over to the other light schedule. Dim-light melatonin onsets were obtained 7 times during the study to assess circadian phase position. RESULTS: Morning light phase-advanced the dim-light melatonin onset and was more antidepressant than evening light, which phase-delayed it. These findings were statistically significant for both crossover and parallel-group comparisons. Dim-light melatonin onsets were generally delayed in the patients compared with the controls. CONCLUSIONS: These results should help establish the importance of circadian (morning or evening) time of light exposure in the treatment of winter depression. We recommend that bright-light exposure be scheduled immediately on awakening in the treatment of most patients with seasonal affective disorder.     

Metabolically inactive insulin analog prevents type I diabetes in prediabetic NOD mice

The purpose of this study was to determine the relative importance of the metabolic effects of insulin for diabetes prevention by administering insulin or an inactive insulin analog by daily subcutaneous injections to prediabetic mice. A recombinant monomeric human insulin analog, which does not bind to the insulin receptor as a consequence of an alteration of a single amino acid at position 25 of the B chain, was shown to be equally effective at diabetes prevention as was intact insulin. In contrast to native insulin, the insulin analog did not cause hypoglycemia after subcutaneous injection. The insulin analog, however, protected young adult mice from diabetes, even when it was initiated after the onset of extensive lymphocytic infiltration of the islets. Thus, preventative therapy by daily subcutaneous injections of insulin does not require the hypoglycemic response, or binding to the insulin receptor to prevent the onset of type I diabetes.