Clinical use of the co-formulation of insulin degludec and insulin aspart.

AIMS: To provide a review of the available data and practical use of insulin degludec with insulin aspart (IDegAsp). Premixed insulins provide basal and prandial glucose control; however, they have an intermediate-acting prandial insulin component and do not provide as effective basal coverage as true long-acting insulins, owing to the physicochemical incompatibility of their individual components, coupled with the inflexibility of adjustment. The molecular structure of the co-formulation of IDegAsp, a novel insulin preparation, allows these two molecules to coexist without affecting their individual pharmacodynamic profiles. METHODS: Clinical evidence in phase 2/3 trials of IDegAsp efficacy and safety in type 1 and type 2 diabetes mellitus (T1DM and T2DM) have been assessed and summarised. RESULTS: In people with T2DM, once- and twice-daily dosing provides similar overall glycaemic control (HbA1c ) to current modern insulins, but with lower risk of nocturnal hypoglycaemia. In prior insulin users, glycaemic control was achieved with lower or equal insulin doses vs. other basal+meal-time or premix insulin regimens. In insulin-naïve patients with T2DM, IDegAsp can be started once or twice-daily, based on individual need. People switching from more than once-daily basal or premix insulin therapy can be converted unit-to-unit to once-daily IDegAsp, although this strategy should be assessed by the physician on an individual basis. CONCLUSIONS: IDegAsp offers physicians and people with T2DM a simpler insulin regimen than other available basal-bolus or premix-based insulin regimens, with stable daytime basal coverage, a lower rate of hypoglycaemia and some flexibility in injection timing compared with premix insulins.

Practical guidance on intensification of insulin therapy with BIAsp 30: a consensus statement.

BACKGROUND: Basal insulin and premix insulin are commonly prescribed first-line insulin therapies for patients failing to maintain glycaemic control on oral therapy. When control on these insulins starts to drift, premix analogues, such as biphasic insulin aspart 30/70 (BIAsp 30), are a simple and effective tool for intensification as they can be injected up to three-times daily (TID). However, at present, international recommendations for intensification of insulin therapy using premix analogues are limited and specific guidance on dosing is not available for many scenarios. METHODS: In October 2008, an international expert panel met to review the current guidelines for insulin intensification with BIAsp 30 in patients with type 2 diabetes, with the aim of developing practical guidance for general and specialist practitioners. RESULTS: Simple treatment algorithms have been developed for (i) patients on basal insulin (human or analogue) once daily or twice daily (BID) who need intensification to BIAsp 30 BID, and (ii) patients on BIAsp 30 once daily or BID who can be intensified to BIAsp 30 BID or TID. As well as these algorithms, specific guidance has been provided on dose transfer (from basal insulin to BIAsp 30), dose split (when intensifying from once daily to BID), and combination oral therapies. In addition, a guide to dose titration is included. CONCLUSIONS: The guidelines presented here should enable general or specialist practitioners to use BIAsp 30 to intensify the insulin therapy of patients failing on basal insulin or BIAsp 30 once or twice daily.

Biphasic insulin aspart in type 2 diabetes mellitus: an evidence-based medicine review.

The efficacy benefits of biphasic insulin aspart formulation (BIAsp 30) in patients with diabetes mellitus have been reported in several studies. BIAsp 30 has been shown to be more effective in terms of glycaemic control than standard biphasic human insulin 30 (BHI 30). In addition to gauging the treatment in terms of clinical evidence of benefits provided, it is also important to evaluate the strength of the evidence supporting the therapeutic improvements offered by BIAsp 30. In this paper, we evaluated the strength of the available data that relate to the use of BIAsp 30 in the treatment of patients with type 2 diabetes based on a comprehensive literature review. Selected publications that provided relevant data were obtained via a literature search and from the manufacturer, Novo Nordisk. These were graded in terms of the strength of the evidence they provided using the Oxford Centre for Evidence-Based Medicine (CEBM) system in the following categories: (i) twice-daily use versus basal insulin; (ii) twice-daily use versus other treatments; (iii) once-daily use; (iv) thrice-daily use; (v) use in combination with thiazolidinediones; and (vi) use in comparison with BHI 30. A total of 30 publications for BIAsp 30 were identified and graded. For the majority of categories (four out of six), the evidence supporting the use of BIAsp 30 was given an overall CEBM grade of A (highest quality); evidence supporting clinical efficacy in the other two categories (twice-daily use versus basal insulin and thrice-daily BIAsp 30 administration) was graded B. In most of the studies examined, the efficacy of BIAsp 30 was evaluated in terms of glycaemic control (glycosylated haemoglobin [HbA(1c)] reduction, proportion of patients achieving HbA(1c) target of <6.5% or <7%, fasting blood glucose, blood glucose profile and/or prandial and postprandial glucose increments). In some studies, efficacy was further evaluated using plasma insulin and glucose infusion rates, plasma C-peptide levels, mean serum fructosamine levels, postprandial hyperlipidaemia, overall well-being, treatment satisfaction and quality of life. Safety was evaluated using physical and laboratory investigations and assessment of incidence of adverse events, including, in many of the studies reviewed, specific evaluation of those events known to be associated with antidiabetic treatment, hypoglycaemia and weight gain. Strong evidence was provided for better glycaemic control with BIAsp 30 without increases in the incidence of major hypoglycaemia or nocturnal hypoglycaemic episodes. Overall, weight gain with BIAsp 30 was minimal and not significantly greater than with basal insulin or BHI 30. Thus, we can confirm that the reported efficacy and tolerability of BIAsp 30 in the treatment of diabetes based on a variety of clinical endpoints is supported by a good body of evidence relating to its use in different dosage regimens and in comparison with other insulin treatment regimens.

Why, when and how to initiate insulin therapy in patients with type 2 diabetes.

Type 2 diabetes is characterised by insulin resistance and progressive beta-cell deterioration. As beta-cell function declines, most patients with type 2 diabetes will require insulin therapy. Clinical studies show that tight control of blood glucose levels prevents the development of the microvascular and macrovascular complications caused by diabetes. Insulin is the most potent drug currently available to achieve tight glycaemic control; however, often it is not used early or aggressively enough for patients to achieve the glycaemic targets needed to prevent chronic complications. New basal insulin analogues and premixed insulin analogues, which have more physiological time-action profiles compared with human insulin formulations, offer flexibility and convenience, thereby improving quality of life. It is crucial that doctors initiate insulin therapy as soon as other diabetes therapies are no longer effective. This article reviews the improvements provided by basal insulin analogues, premixed insulin analogues, and insulin delivery systems; provides sample algorithms for initiating and titrating the various insulin analogue preparations; and discusses how to individualise treatment regimens to maximise outcomes in patients with type 2 diabetes.

N-cadherin is a major glycoprotein component of isolated rat forebrain postsynaptic densities.

We have previously described a monoclonal antibody, PAC 1, that recognises two postsynaptic density (PSD)-enriched glycoproteins (pgps) of apparent M(r) 130,000 (pgp130) and 117,000 (pgp117). Immunodevelopment of western blots of rat forebrain homogenate, synaptic membrane (SM), and PSD samples with PAC 1 and an N-cadherin antiserum shows that pgp130 and N-cadherin are of identical apparent M(r) and show identical patterns of enrichment in these fractions. The apparent molecular masses of pgp130 and N-cadherin are both lowered by 11 kDa following removal of N-linked carbohydrate with endoglycosidase-F containing N-glycopeptidase. The two molecules show an identical pattern of migration when separated by two-dimensional electrophoresis. A single 130-kDa band immunoprecipitated from solubilised PSD preparations by the N-cadherin antiserum is recognised by PAC 1 on western blots. We conclude that pgp130 is N-cadherin. Development of western blots of two-dimensional gel separations of SM and PSD glycoproteins shows that N-cadherin is a major glycoprotein component of PSDs. The immunoprecipitation experiments show that the M(r) of N-cadherin is greater than that of the major pgp, PSD gp116. The PAC 1 antibody recognises two concanavalin A-binding glycoproteins with apparent molecular masses of 136 and 127 kDa in liver samples. The 136-kDa band is also recognised by the N-cadherin antiserum. These observations, together with data showing that the PAC 1 epitope is intracellular, suggest that PAC 1 is a pan-cadherin antibody and recognises an epitope on the conserved cadherin intracellular carboxyl-terminal domain.

Reassessment of circadian profile of blood pressure and heart rate in diabetic patients with autonomic neuropathy.

Previous studies have shown that the normal circadian blood pressure fall is absent in patients with diabetic autonomic neuropathy, while the reported rise in blood pressure during the night in the same patients is controversial. This study analyzed the circadian profile in 19 diabetic patients with established autonomic neuropathy. Twenty-four hour ambulatory systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate were recorded every 20 minutes during the day and every 60 minutes at night in 29 patients, 19 with diabetic autonomic neuropathy and 10 nondiabetic hypertensive patients as controls. Twelve diabetic patients with autonomic neuropathy with unknown hypertension were found to have hypertension based on 24 hour ambulatory blood pressure monitoring. Repeated measured analysis of variance (ANOVA) and trend analysis indicated that the linear systolic blood pressure increased from night to morning to afternoon while mean arterial pressure and diastolic blood pressure increased from night to morning but decreased from morning to afternoon. In practice, the early morning rise in systolic blood pressure in diabetic neuropathy is not different from that in normal or hypertensive patients and requires appropriate treatment. The absence of the nocturnal rise in the blood pressure revealed a subgroup of patients with diabetic neuropathy which demonstrated no fatal cardiovascular or renal events over 18 to 24 months of follow-up.

Postprandial hypoglycemia in islet beta cell hyperplasia with adenomatosis of the pancreas.

Organic hyperinsulinism causing hypoglycemia in adults is caused by insulinoma, islet hyperplasia, or a combination of adenomata and hyperplasia. We present a patient with long-standing symptoms of postprandial hypoglycemia occurring within 15 minutes of meals in the absence of fasting hypoglycemic symptoms. An intravenous glucagon stimulation test resulted in a rise of plasma insulin from 194 to 21,883 pmol/L at 7.5 minutes. Blood glucose simultaneously rose from 4.9 to 5.9 mmol/L. A glucose tolerance test revealed an exuberant insulin response. A euglycemic hyperinsulinemic clamp demonstrated incomplete suppression of plasma C-peptide. At surgery, three nodules were found and a 50-60% distal pancreatectomy was performed. The pancreas revealed a combination of multiple beta-cell islet adenomata and islet hyperplasia with no evidence of nesidioblastosis. The coexistence of islet adenomata with hyperplasia must be considered in the differential diagnosis of postprandial hypoglycemia.

Diabetic ketoacidosis and insulin resistance with subcutaneous terbutaline infusion: a case report.

Diabetic ketoacidosis may occur in women treated with intravenous beta-sympathomimetic agents for tocolysis. We describe diabetic ketoacidosis and transient severe insulin resistance in a woman with diabetes who was treated with subcutaneous terbutaline infusion. Subcutaneous terbutaline infusion may precipitate transient insulin resistance and diabetic ketoacidosis in women with diabetes.

Thyrotoxicosis in the very old.

The records of 25 patients older than 75 years of age with the diagnosis of hyperthyroidism were reviewed. The mean age of the group (22 women and three men) was 81.5 years, the eldest being 95 years old. Twenty-one patients had Graves' disease, three had multinodular goiter, and one had toxic adenoma. Major presenting symptoms included weight loss (44 percent), palpitations (36 percent), and weakness (32 percent). The average number of thyrotoxic symptoms was only two per patient. Two patients were asymptomatic. Clinical signs included fine skin (40 percent), tremor (36 percent), atrial fibrillation (32 percent), and tachycardia (28 percent). The thyroid was palpable in only three patients with Graves' disease. Mean blood thyroxine level was 15.6 micrograms/dl (range, 11.5 to 24); blood triiodothyronine level was elevated in only half of the patients. One patient had triiodothyronine toxicosis. Mean 24-hour radioiodine uptake was 52 percent. Five patients had normal uptake. No correlation could be established between age, clinical symptoms, signs, and hormone blood levels. Because signs and symptoms of hyperthyroidism in the very old may be too subtle for clinical diagnosis, all elderly subjects should have periodic screening of blood thyroxine levels.

Effects of nonthyroidal illness on thyroid function.

Despite the absence of thyroid disease, patients with nonthyroidal illness frequently have changes in serum thyroid hormone measurements that may suggest either hypothyroidism or hyperthyroidism. Serum T3 levels are frequently decreased mainly because of a decrease in the rate of T3 production from T4. The free T3 concentration may be either normal or reduced as well. The binding of T4 and T3 by the serum-binding proteins is almost always impaired, resulting in an increase in the dialyzable fraction (free) fraction. This is due to a decrease in the concentration of thyroxine-binding proteins and the presence of circulating inhibitors of binding. If serum T4 concentration remains within the normal range, the free T4 concentration can be increased. However, serum T4 is frequently decreased in patients with chronic and/or severe illness. The decrease in serum T4 in these patients, combined with an increase in the dialyzable fraction, results in normal free T4. In patients who are critically ill, none of the available methods for measurement of free T4 may give results that accurately reflect the euthyroid state. Since T3 is the major active thyroid hormone, it is surprising that patients with decreased serum T3 do not appear hypothyroid. The decrease in serum T3 is probably an adaptive change to nonthyroidal illness, which at least enables the sick patient to conserve protein. The clinical impression of euthyroidism is supported by the finding of a normal serum TSH level in most patients. Although TSH regulation may not be entirely normal in patients with nonthyroidal disease, it is likely that serum TSH will be increased in most sick patients who also have significant thyroid failure. The normal clinical findings in patients with decreased serum T3 may result from an augmentation of those biologic responses associated with the clinical manifestations of the euthyroid state. Several animal models of nonthyroidal disease or starvation show that cells have the ability to modulate some biologic responses to thyroid hormone. Further study should elucidate the mechanisms underlying these changes. This article has emphasized that no single laboratory measurement may reliably predict the thyroid state in patients with nonthyroidal disease. This fact emphasizes the need for careful clinical evaluation of these patients and judicious use of laboratory tests. Because the changes in thyroid hormone metabolism that occur in nonthyroidal disease probably represent adaptive changes to the illness, treatment with L-thyroxine to restore serum thyroid concentrations to the normal range is not indicated.

Thyroxine supplementation. Method for the prevention of clinical hypothyroidism.

Elevation in the blood level of thyroid-stimulating hormone (thyrotropin) is the earliest and most sensitive manifestation of thyroidal failure, and is detectable in clinically healthy and apparently euthyroid persons. Oral thyroxine supplementation designed to titrate thyrotropin back to normal levels, and readjustment of the supplementary dose as failure of the gland progresses and thyrotropin level rises again, may prevent the emergence of clinical hypothyroidism.

Animal models of nonthyroidal disease.

Rats bearing transplantable Walker 256 carcinoma provide an opportunity to assess thyroid function and activity during an interval of time when the tumor has not affected growth rate. Rats with tumor have decreased serum T4 and T3 concentration and decreased serum FT4 and FT3 as well. These changes are due to a decrease in binding of iodothyronines by the serum binding proteins, an increase in the fractional rate of T4 metabolism and a decrease in thyroidal secretion. The decrease in activity of the thyroid gland appears to be due to reduced sensitivity of the thyroid to circulating TSH. Despite decreased serum FT4 and FT3 concentrations, serum TSH remains normal, not increased as would be anticipated in a hypothyroidal animal. Nevertheless, a further experimental decrease in serum T4 and/ or T3 from the already reduced serum iodothyronine levels of the tumor bearing rat results in a normal increment in serum TSH. Thus, TSH secretion appears to be regulated normally despite decreased concentrations of pituitary nuclear T3. This finding suggests that tumor bearing rats have greater than normal sensitivity to T3 in their regulation of TSH secretion. Rats with Walker 256 carcinoma have decreased concentrations of hepatic nuclear T3 receptors and a decrease in T3 specifically bound to the receptors. The fractional occupancy of hepatic nuclear receptors appears relatively normal. The dose-response of alpha-GPD in relation to fractional nuclear T3 receptor occupancy appears shifted up and to the left in tumor bearing rats, whereas the curve for ME is shifted down to the right. The appearance rates of these enzymes are described by similar functions. These findings suggest that postreceptor factors in tumor bearing rats may result in augmentation of some and depression of other biologic responses to thyroid hormones. If the results of these studies are extended to sick patients, they may provide a possible mechanism whereby patients maintain the euthyroid clinical state despite a decrease in serum T3. Thus, postreceptor factors may enhance those thyroidal responses which characterize the euthyroid clinical state. Moreover, attenuation of other thyroidal responses related to conservation of protein may provide a distinct adaptive advantage to the patient with nonthyroidal illness with or without decreased food consumption.

Response of hepatic mitochondrial alpha-glycerophosphate dehydrogenase and malic enzyme to constant infusions of L-triiodothyronine in rats bearing the Walker 256 carcinoma. Evidence for divergent postreceptor regulation of the thyroid hormone response.

To characterize the hepatic response to L-triiodothyronine (T3) in an experimental nonthyroidal disease, we determined the activity of hepatic mitochondrial alpha-glycerophosphate dehydrogenase (alpha-GPD) and cytosol malic enzyme (ME) as a function of the saturation of the nuclear T3 receptor during constant T3 infusions in rats bearing the Walker 256 carcinoma. Groups of control and tumor-bearing rats were infused by minipumps (Alza Corp., Palo Alto, CA) with vehicle, 1.2 or 4.5 micrograms T3/100 body wt per day for 3 d. The range for serum T3 was 47.2 +/- 4.1 to 165 +/- 17.3 ng/dl for the control rats and 13.2 +/- 1.3 to 135 +/- 14.3 ng/dl for the tumor-bearing rats. Nuclear T3 receptor concentration was between 0.41 +/- 0.06 and 0.47 +/- 0.02 ng/mg DNA in control rats and was decreased in tumor-bearing rats to between 0.23 +/- 0.03 and 0.26 +/- 0.03 ng/mg DNA. Nuclear T3 receptor concentrations were not influenced by the T3 infusions. Specifically bound nuclear T3, determined by radioimmunoassay of extracts of isolated nuclei, was decreased nearly 50% in the tumor-bearing rats. However, the calculated percentage saturation of the T3 nuclear receptor remained similar in control and tumor-bearing rats at each level of T3 infusion. Dose-response curves for alpha-GPD and ME were curvilinear and showed an exponential increase in enzyme activity with progressive receptor saturation. In tumor-bearing rats, the activity curves or calculated appearance rate curves for alpha-GPD were shifted significantly upward and to the left, indicating greater sensitivity to T3, and those of ME were shifted downward and to the right, indicating decreased responsiveness to T3. Our findings suggest that cellular factors result in postreceptor amplification of the alpha-GPD response and diminution of the ME response to T3 in tumor-bearing rats. Augmentation of the alpha-GPD response may be a prototype for other hormonal responses that enable the tumor-bearing rat to maintain an apparent euthyroid state in association with decreased serum T3.

Protection against alloxan-induced diabetes by various urea derivatives: relationship between protective effects and reactivity with the hydroxyl radical.

Several urea derivatives (monomethylurea, monoethylurea and diethylurea) give i.p. to mice 30 min before alloxan (75 mg/kg i.v.) were able to prevent the diabetogenic actions of alloxan. Protection by these agents correlated reasonably well with their capacity to react with (scavenge) the hydroxyl radical. Protection did not correlate with the capacity of the above agents to cause a transient hyperglycemia at the point of alloxan administration, which might have also been a potential means of protection. These data extend previously published data on the capacity of hydroxyl radical scavengers to protect against alloxan and add evidence to the concept that the hydroxyl radical, generated within the beta cells, is the species derived from alloxan responsible for the damage to beta cells.