Modern Insulin Research Articles

Achieving better outcomes in pregnancies complicated by type 1 and type 2 diabetes mellitus

Background: Pregnancy in type 1 and type 2 diabetes mellitus (DM) is associated with an increased rate of adverse outcomes for both mother and fetus. Objective: This article reviews the data available on achieving better outcomes in pregnancies complicated by DM. Methods: Background materials for this article were gathered based on a PubMed search of English-language articles (up to and including August 2007) using the search terms diabetes mellitus, pregnancy, glycemic control, mortality, and morbidity. This review article was based on a presentation given at a satellite symposium entitled “Realising the Value of Modern Insulins: Reaching Further with Rapid-Acting Insulin Analogues” that was convened during the XIXth World Diabetes Congress, December 3, 2006, in Cape Town, South Africa. Results: There is clear evidence that optimized metabolic control, from preconception through pregnancy, can reduce the risk of maternal and fetal complications in women with DM. The risk of fetal congenital abnormalities in pregnant women with DM is intricately related to the level of glycemic control in early pregnancy; thus, strict metabolic targets as close to normal glycosylated hemoglobin (HbA 1c) (ie, 4.0%–6.0%) as possible are recommended. However, these HbA 1c and postprandial plasma glucose targets are challenging for the physician and the patient. The rapid-acting insulin analogues, insulin aspart and insulin lispro, may be useful because they can reduce postprandial hyperglycemia without increasing the risk for hypoglycemia and even provide a small improvement in HbA 1c compared with regular human insulin. In a recent, prospective, randomized controlled study of pregnant women with type 1 DM (N = 322), maternal hypoglycemia, metabolic control, and tolerability, including perinatal outcomes, were compared between those randomized to mealtime insulin aspart or human insulin. The results from this study suggest that insulin aspart is at least as effective and well tolerated as human insulin in basal-bolus therapy with neutral protamine Hagedorn insulin. Overall, 80% of study participants in both groups achieved HbA 1c levels ≤=6.5% in the second trimester. In addition, insulin aspart was associated with lowered postprandial blood glucose levels, as well as reduced risk of hypoglycemia, suggesting that it may offer clinical advantages in this population. Conclusions: Women with DM who are of reproductive age should be identified as members of a high-risk group. Access to specialized prepregnancy clinics should be made available where their DM can be intensively managed throughout pregnancy by a combined obstetrical/endocrine multidisciplinary team. Use of multiple insulin injection regimens, including use of insulin aspart during pregnancy, is both well tolerated and effective and may offer some benefits with respect to postprandial glycemic control.

Use of rapid-acting insulin analogues in the treatment of patients with type 1 and type 2 diabetes mellitus: Insulin pump therapy versus multiple daily injections

Background: Replicating endogenous insulin production is the goal of treatment for diabetes mellitus (DM) and is necessary to minimize the risk of vascular complications. The 2 main methods of achieving this goal are continuous subcutaneous insulin infusion (CSII) and multiple daily injections (MDIs) comprising basal and prandial injections. Objective: The objective of this article was to discuss the use of a rapid-acting insulin analogue, insulin aspart, in CSII and MDI compared with other insulins in adult patients with type 1 or type 2 DM. Methods: This article was based on a presentation given by the author at a satellite symposium entitled “Realising the Value of Modern Insulins: Reaching Further with Rapid-Acting Insulin Analogues” that was convened during the XIXth World Diabetes Congress, December 3, 2006, in Cape Town, South Africa. Results: In patients with type 1 DM, CSII using the rapid-acting insulin analogue insulin aspart has been reported in clinical trials to improve glycemic control compared with MDI therapy using neutral protamine Hagedorn plus insulin aspart (for basal and mealtime coverage, respectively). In patients with type 2 DM, the CSII and MDI regimens offered similar efficacy and tolerability; CSII therapy may be less burdensome, however, with fewer social limitations than MDIs. Not all insulins are equally suited for use in CSII treatment. Although the efficacy of insulin aspart in CSII was comparable to other rapid-acting insulins, the frequency of hypoglycemia was shown to be significantly lower with insulin aspart compared with human insulin or insulin lispro in patients with type 1 DM. The compatibility of insulin aspart and insulin lispro for use in CSII pumps was compared in an 8-week, double-blind, 2-period, crossover study of patients with type 1 DM. The overall adverse-effect score was significantly lower ( P < 0.005) with insulin aspart than with insulin lispro, as were scores for pain/burning and inflammation (both, P < 0.01) and dermal redness ( P < 0.001). Furthermore, a stability study reported on the suitability of insulin aspart for use in CSII pumps. Quality-of-life scores with CSII have been reported to be higher than with MDI therapy. Conclusion: CSII with the rapid-acting insulin analogue insulin aspart is a viable choice for patients with type 1 or type 2 DM who want close-to-physiologic insulin treatment.

Variability in Insulin Action: Mechanisms, Implications, and Recent Advances

An important drawback of conventional human insulin formulations is their variable absorption and unpredictable insulin activity. Modern insulin analogs offer several clinical advantages over conventional human insulin therapies, including a more predictable and physiologically accurate profile of insulin absorption and action. Accumulating evidence suggests that insulin therapies exhibiting less within-patient variability are associated with greater convenience, a reduced risk of hypoglycemia, and in some cases, reduced weight gain.

Les nouvelles insulines : intérêts et inconvénients

Modern insulin treatment, known as “basal-bolus” is based on the physiology of insulin secretion with a permanent basal secretion over the 24 h and a peak of secretion at the time of the meals. The objective of this treatment is obtaining a strict normoglycemia (80 to 120 mg/dl fasting, less than 140 mg/dl postprandial, bringing glycosylated hemoglobin to around 6.5–7%) while minimizing the hypoglycemic risk and ensuring the best possible quality of life. The ideal basal insulin must meet the interprandial insulin needs, to provide stable interprandial blood glucose levels. Hitherto the basal insulin treatment was mainly provided by 2–3 daily NPH- or 1–2 daily ultralente insulin injections. The average duration of action of NPH insulin, 8-16 h, explains the need for multiplying the injections to cover the nyctemer. Its peak of action, 3–4 h after the injection, increases the risk of hypoglycemia at the end of the morning and at night. Insulin ultralente is no more available in France to the profit of analogues of long duration of action aiming at ensuring better glycemic stability (better reproducibility) and improved quality of life. These analogues of insulin are soluble, i. e. they do not require agitation, thus limiting educational time and the risk of error. The time of onset of action of conventional insulin explains the need for carrying out the injection 1/2–3/4 h before the meal to optimize the control of the postprandial blood glucose. This has a non-negligible impact on the quality of life. The long (5–8 h) duration of action of conventional insulin promotes hypoglycemias. Fast analogues of insulin were developed to improve these kinetics characteristics: they have shorter time of onset and shorter duration of action. When associated with a basal insulin treatment, fast-acting insulin, injected right before the meals, authorizes flexible hours of meals. Skipping meals is also possible. A new educational method, called “functional insulin treatment”, makes it possible, amongst other things, to give the keys to the patients using basal-bolus insulin regimen to adjust the amount of fast-acting insulin to variable quantities of glucids at the price of intensive self-monitoring of blood glucose levels.

Risk and benefits of continuous subcutaneous insulin infusion (CSII) treatment in school children and adolescents

Continuous subcutaneous insulin infusion (CSII) therapy with technically advanced modern insulin pumps is a treatment option enabling patients and multidisciplinary diabetes teams to achieve all current goals for the treatment of children and adolescents with type 1 diabetes mellitus (T1DM): near-normoglycemia, low rate of hypoglycemia, preventing or delaying long-term complications and increasing quality of life. Clinical studies demonstrate that CSII therapy reduces glycosylated hemoglobin A1c (HbA1c) with a concomitant decrease in the rate of hypoglycemic events, without excessive weight gain and with an increase of patients' treatment satisfaction in all pediatric age groups. With the development of continuous glucose sensing coupled with an insulin pump, patients can hope for an ever-increasing technological support for the management of insulin therapy in the foreseeable future.

Improvement of Glucose Tolerance in Type 2 Diabetic Patients: Traditional vs. Modern Insulin Regimens (Results from the Austrian Biaspart Study)

Major advantages of modern insulin regimens containing premixed insulin analogues in comparison to traditional insulin regimens have not been evaluated yet. The aim of the present study was to investigate whether meal-related (breakfast, lunch, dinner) application of biphasic insulin aspart 30 (BIAsp 30) provides better glycaemic control than administration of biphasic human insulin 30 (BHI 30) twice per day. In a multi-centre, randomized, open-label parallel trial, a total of 177 patients with type 2 diabetes mellitus were exposed to the two different insulin regimens described above over a study period of 24 weeks. HbA1c and glycemic exposure parameters were measured at predefined intervals. The mean difference between treatment groups in HbA1c after 24 weeks of treatment was 0.08% (p = 0.6419). Analysing the 7-point blood-glucose (BG) profiles, significant differences in BG levels were observed after lunch (156 vs. 176 mg/dl, p = 0.0289), before dinner (142 vs. 166 mg/dl p = 0.006) and after dinner (154 vs. 182 mg/dl p = 0.002) in favour of BIAsp 30 insulin. Prandial BG increment was lower in the BIAsp 30 group at breakfast (p = 0.057) and lunch (p < 0.0005). No difference was found regarding safety parameters in the two treatment groups. This study demonstrates that meal-related BIAsp 30-insulin maintains postprandial BG control more effectively than traditional BHI 30 insulin twice per day in type 2 diabetic patients.

EEG abnormalities with and without relation to severe hypoglycaemia in adolescents with type 1 diabetes

The aim of the present study was to identify whether adolescents with type 1 diabetes receiving modern multiple insulin injection therapy (MIT) have abnormal EEGs, and to elucidate possible correlations with a history of severe hypoglycaemia, poor metabolic control and nerve conduction defects. We investigated 35 patients (age 14-19 years) with disease duration 7.6+/-4.6 years, and 45 healthy control subjects. EEG spectral components were obtained from 15-min recordings in resting, awake subjects. Nerve conduction was measured bilaterally in motor and sensory fibres in the median, peroneal and sural nerves. The EEGs of patients showed an increase in slow activity (delta and theta) and a reduction in alpha peak frequency, both of which were most pronounced in the frontal regions (p<0.001). They also showed a decrease in fast activity, which was most pronounced bilaterally in the posterior temporal regions (alpha p<0.001, beta p<0.01, gamma p<0.001). A history of severe hypoglycaemia was correlated with a global increase in theta activity (p<0.01-0.05). Poor metabolic control, measured as acute and long-term HbA1c levels, was correlated with an increase in delta activity and a decrease in alpha peak frequency. The decrease in fast activity in the temporal regions was a separate type of abnormality because it had a different distribution, and was not correlated with the increase in delta/theta power, poor metabolic control or with hypoglycaemia. Recurrent severe hypoglycaemia and poor metabolic control are risk factors for EEG abnormalities in adolescents with type 1 diabetes receiving MIT treatment. In addition, we found pronounced abnormalities in the temporal regions that were not related to these risk factors.

Impaired microvascular function related to poor metabolic control in young patients with diabetes

The purpose of the present study was to identify whether young patients with type 1 diabetes using modern multiple insulin injection therapy (MIT) have signs of microvascular dysfunction and to elucidate possible correlations with various disease parameters. Skin blood flow on the dorsum of the foot was measured with laser Doppler perfusion imaging in 37 patients (age 10-21 years, disease duration 6.0-16 years) and 10 healthy controls. Measurements were performed at rest, after change in posture (the leg was lowered below heart level) and during postocclusive hyperaemia. Following a change in posture blood flow increased instead of decreased in a majority of the study subjects. Patients with acute HbA1c >7.5% (n = 22) had an increase in skin blood flow at rest and a significantly reduced blood flow when the leg was lowered below heart level as compared with patients with HbA1c <7.5% (0.26 V versus 0.17 V, P<0.01 and 0.12 V versus 0.23 V, P<0.05, respectively) and healthy controls. Following occlusion of the macrocirculation for 3 min a small non-significant decrease in the hyperaemic response was seen in the patients. The postocclusive hyperaemic response and the venoarteriolar reflex were not correlated to duration of disease, long-term metabolic control or electrophysiological signs of peripheral nerve dysfunction. It is concluded that signs of microvascular dysfunction related to poor metabolic control are present in young patients with MIT treatment and rather well-controlled diabetes. Low resting blood flow levels are suggested to contribute to the absence of postural vasoconstrictor response.

Early glycemic control, age at onset, and development of microvascular complications in childhood-onset type 1 diabetes: a population-based study in northern Sweden.

The aim of this work was to study the impact of glycemic control (HbA(1c)) early in disease and age at onset on the occurrence of incipient diabetic nephropathy (MA) and background retinopathy (RP) in childhood-onset type 1 diabetes. All children, diagnosed at 0-14 years in a geographically defined area in northern Sweden between 1981 and 1992, were identified using the Swedish Childhood Diabetes Registry. From 1981, a nationwide childhood diabetes care program was implemented recommending intensified insulin treatment. HbA(1c) and urinary albumin excretion were analyzed, and fundus photography was performed regularly. Retrospective data on all 94 patients were retrieved from medical records and laboratory reports. During the follow-up period, with a mean duration of 12 +/- 4 years (range 5-19), 17 patients (18%) developed MA, 45 patients (48%) developed RP, and 52% had either or both complications. A Cox proportional hazard regression, modeling duration to occurrence of MA or RP, showed that glycemic control (reflected by mean HbA(1c)) during the follow-up was significantly associated with both MA and RP when adjusted for sex, birth weight, age at onset, and tobacco use as potential confounders. Mean HbA(1c) during the first 5 years of diabetes was a near-significant determinant for development of MA (hazard ratio 1.41, P = 0.083) and a significant determinant of RP (1.32, P = 0.036). The age at onset of diabetes significantly influenced the risk of developing RP (1.11, P = 0.021). Thus, in a Kaplan-Meier analysis, onset of diabetes before the age of 5 years, compared with the age-groups 5-11 and >11 years, showed a longer time to occurrence of RP (P = 0.015), but no clear tendency was seen for MA, perhaps due to lower statistical power. Despite modern insulin treatment, >50% of patients with childhood-onset type 1 diabetes developed detectable diabetes complications after approximately 12 years of diabetes. Inadequate glycemic control, also during the first 5 years of diabetes, seems to accelerate time to occurrence, whereas a young age at onset of diabetes seems to prolong the time to development of microvascular complications.

The state of insulin pump therapy: 2002

As new therapies emerge to care for people with diabetes, insulin therapy remains one of the main cornerstones of treatment. From the time of insulin's discovery by Macleod, Banting, and Best in the early 1920s, insulin therapy has undergone an evolution from animal-derived insulin, to human insulin, and finally to the insulin analogs. This evolution involved several attempts to modify the kinetics of insulin administered into subcutaneous tissue. First, substances such as protamine and zinc were added, then the peptide structure of insulin was altered. During this time a separate evolution regarding insulin administration occurred. The first insulin pump started as a bulky appendage with a short battery life and a limited insulin reservoir volume, and it was only able to administer insulin at a constant rate to the subcutaneous tissue. Modern insulin pumps are about the size of a pager and are used to administer fast-acting insulin analogs at precise basal and bolus rates to control blood glucose levels throughout the day and night. The newer pumps have much longer battery lives and hold approximately two times the amount of insulin of the older pumps. In this overview we will discuss how insulin pumps work, the differences between the currently available insulin pumps, and the future of insulin pump therapy.

Physiological insulin replacement in type 1 diabetes mellitus.

The DCCT and UKPDS studies have definitely established that in type 1 as well as in type 2 diabetes mellitus, long-term near-normoglycaemia strongly protects against onset and/or progression of microangiopathic complications. Therefore, implementation of insulin strategies to maintain long-term near-normoglycaemia is of key importance in the management of diabetes mellitus. To successfully reach the goal of near-normoglycaemia, insulin therapy has to be physiological, i.e. it has to mimic nature by providing a bolus of insulin at meal ingestion, and by replacing the need for basal insulin between meals and during the night. The meal-time insulin needs can be best met by s.c. injection of a short-acting insulin analogue (lispro, aspart). Short-acting insulin analogues should be preferred to human regular insulin for three main reasons. First, convenience (meal-time injection, better adaptation of insulin dose to carbohydrate content of the meal); second, lower blood glucose 2-hour after meals; third, less risk for late post-prandial hypoglycaemia. However, the benefits of meal-time treatment with short-acting insulin analogues become apparent only by the extent to which replacement of basal insulin is optimised as well. The interprandial (especially nocturnal) need for basal insulin can be best met by the continuous s.c. insulin infusion by an external minipump, the gold standard of basal insulin replacement. Continuous s.c. insulin infusion in the basal state is so good because it uses a short-acting insulin analogue (low variability in s.c. absorption, flat and peak-less action profile), not insulin preparations with retarded action (high variability of s.c. absorption, peak of action) likewise the model of multiple daily insulin injections. A second choice option is s.c. injection of an insulin preparation with retarded action. At present, the long-acting insulin analogue glargine is the retarded insulin preparation of choice because its action profile is flat, peakless and long-lasting (approximately 24 hours). This is in contrast with the peak action profile of NPH insulin which exhibits a short duration of action (10-15 h). Thus, the modern insulin strategies for intensive therapy always include use of a short-acting insulin analogue at meal-time, and use of either continuous s.c. insulin infusion, or a s.c. injection of insulin glargine to replace basal insulin. Insulin glargine reproduces closely the pharmacokinetics and pharmacodynamics of continuous s.c. insulin infusion, and should always be preferred to NPH in all insulin-requiring diabetic patients, both type 1 and type 2.

MODERN INSULIN THERAPY FOR TYPE 1 DIABETES MELLITUS

Modern insulin therapy for Type 1 diabetes is part of a comprehensive treatment program designed to achieve and maintain blood glucose levels as close to normal as possible. The insulin regimens most likely to be successful approximate physiologic insulin delivery by combining basal and meal doses. Several options are available, including constant infusion by external pump and multiple daily injection therapy. Modern therapy affords major health benefits through improved blood glucose control, as well as lifestyle benefits associated with increased flexibility and spontaneity.

Circulating stress hormone and insulin concentrations in acute coronary syndromes: identification of insulin resistance on admission.

We re-examined, in the context of modern practice, plasma insulin and stress hormone concentrations in patients admitted to hospital with acute coronary syndromes. Venous blood sampling was carried out prior to anti-thrombotic therapy in 148 patients with myocardial infarction (MI); 76 patients with unstable angina (UA) pectoris were also studied, together with 27 patients with non-cardiac chest pain (NCP). There were significant progressive increases in the concentrations of catecholamines, cortisol, glucose and insulin from NCP to UA to MI patients. Hyperglycaemia (glucose >8 mmol/l) was present in over 50% of MI patients. The plasma cortisol and insulin levels were both significantly positively correlated with the glucose concentration on admission. Only the cortisol concentration was correlated with peak cardiac enzyme levels. The glucose and insulin concentrations on admission in 141 MI and UA patients were related to insulin resistance, as judged from subsequent insulin and glucose concentrations measured while fasting and during a glucose tolerance test. The product of admission insulinxglucose (divided by 25; the admission insulin-resistance index, or AIRI) was significantly correlated with indices of insulin resistance, and was significantly higher (approximately double) in the MI group (7. 81+/-0.76) and the UA group (6.88+/-1.19) than in the control NCP group (3.59+/-0.06; Kuskul-Wallis: P=0.0001), implying that the insulin levels in the first two groups were approximately twice as high as is appropriate for the glucose levels. The ethnic origin of 20% of the patients was the Indian subcontinent; admission insulin and glucose levels in this subgroup were higher than in the non-Asians across all the groups with chest pain. Cortisol was the only stress hormone that was raised in proportion to the size of the infarct, and is a likely partial cause of the elevation in blood glucose. The high insulin levels were related to the prevalence of insulin resistance, and this was particularly important in the Asian subgroup presenting with MI and UA. Thus it appears feasible to identify acute coronary syndrome patients who are insulin-resistant at a time (on admission) when alternative early therapeutic strategies can be instituted.

Modern insulin therapy in children and adolescents.

Clear evidence exists that near-normal blood glucose control will prevent serious late diabetic complications. This review summarizes the targets for blood glucose control and discusses why insulin replacement therapy is so complicated in children and adolescents. It is important that diabetes treatment teams have excellent knowledge of insulin preparations, insulin pharmacokinetics and action profiles and the limitations and pitfalls of therapy. This is necessary to be able to optimize and individualize treatment. A detailed summary of different insulin regimens is given and discussed to help treatment teams choose a suitable regimen for the individual patient. The use of home blood glucose measurement is necessary to reach the targets of treatment. If economic resources are limited, alternative strategies are suggested. In wealthy countries the lifestyle of adolescents demands great flexibility and a suggestion for systematic training to increase flexibility in daily life is presented.

Subclinical nerve dysfunction in children and adolescents with IDDM

The purpose of this study was to investigate whether young insulin-dependent diabetic patients still develop peripheral nerve dysfunction when using modern multiple insulin injection therapy and to elucidate if this correlated with various disease parameters. Seventy-five patients, 7 to 20 years old with a duration of diabetes of more than 3 years, and 128 age-matched healthy control subjects underwent bilateral studies of median, peroneal, and sural nerves. Presence of diabetes lowered motor conduction velocity (p < 0.0001), sensory conduction velocity (p < 0.0001) and sensory nerve action potential (p < 0.05) in all examined nerves. The mean change in conduction velocity induced by diabetes was -4.8 m/s in the peroneal nerve, -3.3 m/s in the median motor nerve, -2.6 m/s in the sural nerve and -2.4 m/s in the median sensory nerve. Fifty-seven percent of the patients had abnormal conduction (values outside 95% predictive interval) which was seen most often in the motor nerves, especially in the peroneal nerve (41%) followed by the median nerve (24%). In multiple regression analysis, long-term poor metabolic control and increased body length correlated with nerve dysfunction identified in most examined parameters. Three patients had signs or symptoms suggestive of neuropathy. It is concluded that despite modern multiple insulin injection therapy, with reasonably good metabolic control, nerve dysfunction is still common in children and adolescents with insulin-dependent diabetes mellitus. Risk factors are increased height and long-term poor metabolic control.

Demonstration of Insulin Transformation Products in Insulin Vials by High-Performance Liquid Chromatography

To assess the importance of temperature, light, agitation, and regular withdrawal of insulin on the rates of appearance of three groups of insulin transformation products (ITPs) in vials of human and beef soluble insulin. Twelve insulin-treated patients (6 receiving human soluble insulin, 6 receiving beef soluble insulin) participated in the study. Reverse-phase high-performance liquid chromatography was used to measure ITP in serial samples from vials stored in various laboratory environments or issued to patients. Vials in the laboratory were analyzed on nine occasions over 26 wk; those issued to patients were analyzed weekly. Results were expressed as rates of change (% total protein/wk). Except for human insulin stored at 4 degrees C, sampling did not accelerate transformation. Storage at higher temperatures caused more rapid transformation to all ITP groups, and human insulin was more susceptible than beef insulin. Exposure to light accelerated transformation mainly to group 3 ITP. Fibrillation occurred in beef but not human insulin carried in a shirt pocket. Results from patients' vials were consistent with reported storage conditions. All three ITP groups form in human and beef soluble insulin. Their rate of production is a function of temperature and light exposure. Differences between the two insulins were probably due to differences in formulation. Patients should be discouraged from hoarding vials and storing insulin in direct sunlight. One or more ITPs could contribute to the residual immunogenicity of modern insulin preparations.