Factors associated with reaching or not reaching target HbA1c after initiation of basal or premixed insulin in patients with type 2 diabetes.

AIMS: To evaluate factors associated with reaching or not reaching target glycated haemoglobin (HbA1c) levels by analysing the respective contributions of fasting hyperglycaemia (FHG), also referred to as basal hyperglycaemia, vs postprandial hyperglycaemia (PHG) before and after initiation of a basal or premixed insulin regimen in patients with type 2 diabetes. METHODS: This post-hoc analysis of insulin-naïve patients in the DURABLE study randomised to receive either insulin glargine or insulin lispro mix 25 evaluated the percentages of patients achieving a target HbA1c of <7.0% (<53mmol/mol) per baseline HbA1c quartiles, and the effect of each insulin regimen on the relative contributions of PHG and FHG to overall hyperglycaemia. RESULTS: Patients had comparable demographic characteristics and similar HbA1c and FHG values at baseline in each HbA1c quartile regardless of whether they reached the target HbA1c. The higher the HbA1c quartile, the greater was the decrease in HbA1c, but also the smaller the percentage of patients achieving the target HbA1c. HbA1c and FHG decreased more in patients reaching the target, resulting in significantly lower values at endpoint in all baseline HbA1c quartiles with either insulin treatment. Patients not achieving the target HbA1c had slightly higher insulin doses, but lower total hypoglycaemia rates. CONCLUSION: Smaller decreases in FHG were associated with not reaching the target HbA1c, suggesting a need to increase basal or premixed insulin doses to achieve targeted fasting plasma glucose and improve patient response before introducing more intensive prandial insulin regimens.

Basal insulin peglispro versus insulin glargine in insulin-naïve type 2 diabetes: IMAGINE 2 randomized trial.

AIMS: To compare, in a double-blind, randomized, multi-national study, 52- or 78-week treatment with basal insulin peglispro or insulin glargine, added to pre-study oral antihyperglycaemic medications, in insulin-naïve adults with type 2 diabetes. MATERIAL AND METHODS: The primary outcome was non-inferiority of peglispro to glargine with regard to glycated haemoglobin (HbA1c) reduction (margin = 0.4%). Six gated secondary objectives with statistical multiplicity adjustments focused on other measures of glycaemic control and safety. Liver fat content was measured using MRI, in a subset of patients. RESULTS: Peglispro was non-inferior to glargine in HbA1c reduction [least-squares (LS) mean difference: -0.29%, 95% confidence interval (CI) -0.40, -0.19], and had a lower nocturnal hypoglycaemia rate [relative rate 0.74 (95% CI 0.60, 0.91); p = .005), more patients achieving HbA1c <7.0% without nocturnal hypoglycaemia [odds ratio (OR) 2.15 (95% CI 1.60, 2.89); p < .001], greater HbA1c reduction (p < .001), and more patients achieving HbA1c<7.0% [OR 1.97 (95% CI 1.57, 2.47); p < .001]. Total hypoglycaemia rate and fasting serum glucose did not achieve statistical superiority. At 52 weeks, peglispro-treated patients had higher triglyceride (1.9 vs 1.7 mmol/L). alanine transaminase (34 vs 27 IU/L), and aspartate transaminase levels (27 vs 24 IU/L). LS mean liver fat content was unchanged with peglispro at 52 weeks but decreased 3.1% with glargine [difference: 2.6% (0.9, 4.2); p = .002]. More peglispro-treated patients experienced adverse injection site reactions (3.5% vs 0.6%, p < .001). CONCLUSIONS: Compared with glargine at 52 weeks, peglispro resulted in a statistically superior reduction in HbA1c, more patients achieving HbA1c targets, less nocturnal hypoglycaemia, no improvement in total hypoglycaemia, higher triglyceride levels, higher aminotransferase levels, and more injection site reactions.

Individualizing treatment of type 2 diabetes by targeting postprandial or fasting hyperglycaemia: Response to a basal vs a premixed insulin regimen by HbA1c quartiles and ethnicity.

AIM: This study evaluated the proportions of prandial (PHG) vs fasting hyperglycaemia (FHG) over 24h in a group of patients with type 2 diabetes (overall and for Caucasian vs Asian patients), and tested the hypothesis that an insulin regimen with a prandial component allows a greater response than basal insulin at low glycated haemoglobin (HbA1c) levels with a higher proportion of PHG than FHG. METHODS: Relative contributions of PHG and FHG to overall hyperglycaemia were analyzed by baseline HbA1c quartiles and by ethnicity at baseline and after 24-week treatment with either insulin glargine or insulin lispro mix 25 in the DURABLE study. RESULTS: With increasing baseline HbA1c, the mean relative contribution of PHG to the total area under the curve decreased (from 41% to 27%) while FHG was increased (from 59% to 73%). Both insulins decreased FHG, but only insulin lispro mix 25 decreased PHG. More patients with baseline HbA1c < 9%, where PHG was more relevant, achieved the target HbA1c of < 7% at endpoint with insulin lispro mix 25 compared with glargine. On average, Asians had a 10% larger contribution of PHG at all HbA1c quartiles, and a lower proportion of Asians reached the HbA1c target of < 7% with either insulin treatment compared with Caucasians. CONCLUSION: At baseline, the contribution of FHG to overall hyperglycaemia predominated at all HbA1c quartiles, whereas PHG was more clinically relevant at lower HbA1c levels and with a greater response to insulin lispro mix 25. Asians had a greater proportion of PHG and a lesser response to either insulins compared with Caucasians. Thus, responses to diabetes drugs by baseline HbA1c and ethnicity are worth investigating to better target and individualize treatment.

Optimization of insulin therapy in patients with type 2 diabetes mellitus: beyond basal insulin.

AIMS: To describe patients with Type 2 diabetes mellitus treated with basal insulin, with or without oral antidiabetics in UK primary care, and evaluate insulin treatment patterns and factors explaining changes in therapy. METHODS: Retrospective analysis of patients with Type 2 diabetes within The Health Improvement Network UK primary care database. Patients receiving basal insulin between January and June 2006 were followed until July 2009. RESULTS: Analysis included 3185 patients, mean age 65.6 years [standard deviation (SD) 12.4], 50.9% men, median diabetes duration 9.6 years, median basal insulin use 1.3 years, 86.5% had received oral antidiabetics in the previous 12 months. Mean follow-up was 2.9 years (SD 1.0), 59.8% patients maintained basal insulin throughout follow-up with a mean HbA(1C) of 69 mmol/mol (SD 19; 8.4%, SD 1.7) at baseline and 65 mmol/mol (SD 17; 8.1%, SD 1.6) during follow-up. During follow-up, 6.9% of patients discontinued, 19.3% intensified with and 14.1% switched to prandial or premixed insulin. Patients who intensified (prandial) had a mean HbA(1c) of 77 mmol/mol (SD 18; 9.2%, SD 1.6) before change and a mean HbA(1c) of 71 mmol/mol (SD 21; 8.6%, SD 2.0) at the end of the study. Those switching to premixed insulin had a mean HbA(1c) of 80 mmol/mol (SD 18; 9.5%, SD 1.7) before change and a mean HbA(1c) of 69 mmol/mol (SD 17; 8.5%, SD 1.5) at the end of the study. Increasing HbA(1c) and longer diabetes duration explained intensification and switch. CONCLUSIONS: The majority of patients had HbA(1c) above the 53 mmol/mol (< 7%) target at baseline and post-intensification/switch. The HbA(1c) levels were reduced by intensification/switch suggesting that insulin changes did have some impact. Most patients did not change insulin treatment despite having higher than recommended HbA(1c) levels. Reasons for not changing treatment in face of unsatisfactory clinical outcomes are unclear. Further research is warranted to explore barriers towards therapy change.

Effect of two starting insulin regimens in patients with type II diabetes not controlled on a combination of oral antihyperglycemic medications.

In an open-label, 24-week, parallel-group study, 135 patients inadequately controlled with oral antihyperglycemic medications (OAMs) were treated with maximally tolerated doses of metformin and glibenclamide for at least 8 weeks and then randomized to bedtime neutral protamine Hagedorn (NPH) insulin plus maximally tolerated dose of glibenclamide BID (glib/NPH group) or insulin lispro mix 50 (50% lispro, 50% insulin lispro protamine suspension [ILPS]) pre-breakfast and lispro mix 25 (25% lispro, 75% ILPS) pre-dinner (LM50/LM25 group) (both OAMs discontinued). The LM50/LM25 group had significantly lower 2-hour postprandial BG (both meals combined) compared with glib/NPH after 12 (11.70+/-3.40 mmol/L vs. 13.15+/-2.44 mmol/L, p=0.010) and 24 weeks (11.13+/-3.31 mmol/L vs. 14.46+/-2.93 mmol/L, p =0.0001). Both regimens significantly decreased HbA1c. The reduction was greater with LM50/LM25 (-1.31+/-2% vs. -0.5+/-1.6%; P=0.01). At endpoint, the overall hypoglycemia rate increased with LM50/LM25 and decreased with glib/NPH compared with baseline (0.22+/-0.9 vs. -0.08+/-0.72 episodes/patient/30 days; p =0.037). Treatment with LM50/LM25 compared with glib/NPH in patients with inadequate control on combined OAMs yielded better postprandial and overall glycemic control with a higher rate of hypoglycemia.

Effect of chronic hyponatremia on central and peripheral oxytocin and vasopressin secretion in rats.

Previous studies have shown that many treatments that stimulate the peripheral secretion of oxytocin (OT) and vasopressin (AVP) from the pituitary simultaneously increase the levels of these peptides in the cerebrospinal fluid (CSF). Since osmotically and nonosmotically stimulated pituitary secretion of OT and AVP is markedly blunted in hyponatremic rats, the present studies evaluated whether central OT and AVP secretion into the CSF is similarly inhibited during sustained hyponatremia. Adult male rats with indwelling cisterna magna cannulae were rendered hyponatremic (plasma [Na+] < 110 mmol/l) by s.c. infusion of desmopressin (dDAVP; 10 ng/h) in combination with ingestion of a liquid diet for 3 days, then subjected to osmotic (i.v. or i.p. injection of 2 M NaCl; HS) or nonosmotic (6 mmol/kg of 0.15 M LiCl i.p.) stimulation. In normonatremic rats both i.v. and i.p. HS caused marked increases in plasma OT and AVP levels 30 min after treatment. Significant elevations of OT, but not AVP, were also present in CSF. Despite similar increases in plasma Na+ concentrations, plasma OT responses in the hyponatremic rats were absent after HS i.v. and were significantly blunted after HS i.p., but neither group had increased plasma AVP. In parallel with the plasma results, CSF OT responses were absent in hyponatremic rats given HS i.v. and significantly blunted in hyponatremic rats given HS i.p., but neither group had increased CSF AVP. Nonosmotic stimulation with isotonic LiCl increased OT levels both in plasma and CSF in normonatremic rats 20 min after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

[Repeated serious water intoxication in an aged patient. (Data on the relationship between the inappropriate antidiuretic hormone syndrome and the atrial natriuretic factor)]. / Ismétlödö súlyo vízmérgezések egy idös betegben (Adatok az "inappropriate antidiuretic hormone" syndroma és az atrialis natriureticus factor kapcsolatához).

An old women was in an 8-year-period 9 times admitted to the hospital because of severe mental disturbances. The average serum sodium concentration was 126.25 +/- 2.43 mmol/l at the admissions; it increased to 139.44 +/- 1.40 mmol/l after intravenous infusion of hypertonic solutions accompanied with the disappearance of the mental disturbances. The patient was usually chronically hyponatremic due to the increased water intake and the insufficient water excretion. The latter was induced by the augmented vasopressin levels. The remarkable feature of the syndrome of inappropriate antidiuretic hormone secretion was its association with lowered blood level of atrial natriuretic factor accompanied by sodium, and volume depletion. Discontinuation of the exaggerated water intake resulted in the elimination of the permanent hyponatremia; no episode of water intoxication occurred during the last 3 and 1/2 years.

The role of central corticoliberin in the ether stress-induced secretion of neurohypophyseal hormones and corticosterone in the rat.

As corticotropin-releasing factor (CRF) and oxytocin (OXT) are released in response to various stressors and a role of CRF in stress-induced OXT secretion has been proposed by previous authors, the present experiments were scheduled to investigate the participation of the brain CRF system in the stress-evoked release of OXT, arginine-8-vasopressin (AVP) and corticosterone. CRF-antiserum (AS) was given into the lateral ventricle of the brain of Wistar male rats, and 24 h later, the injection was repeated 30 min prior to ether stress followed by decapitation in 5 min. Plasma OXT and AVP were measured by radioimmunoassay and corticosterone by fluorimetry. Ether stress increased the levels of corticosterone and OXT, but not that of AVP. CRF-AS alone did not change the secretion of these hormones. CRF-AS pretreatment blocked the corticosterone-releasing action of ether stress, whereas it exerted no influence on the stress-induced OXT secretion into the circulation. There was no effect of a combined application of CRF-AS and stress on the plasma AVP level. These results suggest that the central CRF system is involved in the ether stress-elicited corticosterone response, however CRF is unlikely to be connected with the regulation of OXT secretion under these experimental conditions.

Solid-phase extraction of plasma vasopressin: evaluation, validation and application.

A new solid-phase extraction method using octyl-silica columns to extract vasopressin-like immunoreactivity from plasma has been developed. The extraction was followed by a radioimmunoassay on the vacuum-dried extracts, which were reconstituted in assay buffer. The total recovery of synthetic vasopressin was ca. 100%. Based on co-elution with synthetic vasopressin after separation by reversed-phase high-performance liquid chromatography of plasma extracts from normal Wistar and Brattleboro rats, and the cross-reactivity of the antiserum used in the radioimmunoassay system, the extracted material was found to be indistinguishable from authentic vasopressin. Unknown experimental samples were interpolated on a standard curve established in "zero" plasma (plasma derived from rats subjected to waterload) spiked with known amounts of synthetic vasopressin, and not on a standard curve established in assay buffer. The limit of detection was 1 fmol of vasopressin equivalent per millilitre. The intra- and inter-assay coefficients of variance were 10-16% and 16%, respectively. The procedure reliably showed that osmotic challenge and 24-h dehydration increased, whereas ethanol ingestion decreased vasopressin-like immunoreactivity plasma levels in the rat, compared with normally hydrated controls.

Differential effects of emotional and physical stress on the central and peripheral secretion of neurohypophysial hormones in male rats.

The effects of various stressful conditions on the levels of oxytocin (OT) and vasopressin (VP) in plasma and cisternal cerebrospinal fluid (CSF) of male rats were investigated. Three experimental models were used: exposure to a novel environment for 5 min, immobilization for 15 min, and ether inhalation for 10 min resulting in anaesthesia. Novelty and immobilization induced a slight but significant increase in OT levels in the CSF immediately after the stress. The effect of ether was considerably more pronounced. The concentration of VP in the CSF was elevated only by ether stress. In plasma, the level of OT was increased immediately following immobilization and ether stress but not after novelty stress, whereas VP only showed a delayed response 20 min after immobilization. These results indicate a rapid preferential release of OT in the periphery in response to physical and pharmacological stress. In addition, they provide evidence that release of OT into the CSF is triggered by physical, pharmacological as well as emotional stress, while the central release of VP is rather resistant to emotional stress. The data suggest that OT is a stress hormone in the central nervous system.

[Regulation of vasopressin release in primary hypothyroidism and Addison's disease as well as in central diabetes insipidus]. / A vasopressin elválasztás szabályozásának vizsgálata primer hypothyreosisban és hypadreniában, valamint centrális diabetes insipidusban.

The osmoregulation of arginine-8-vasopressin (AVP) was investigated in 14 patients with primary hypothyroidism, in 6 with Addison's disease, and in 21 with central diabetes insipidus (CDI). In the latter disease the effect of histamine stimulus was also evaluated. Plasma AVP was measured by radioimmunoassay (RIA). Patients with primary hypothyroidism were classified into subgroups with elevated or normal basal levels of plasma AVP. A decreased osmotic threshold was found in hypothyroid patients with augmented basal AVP levels. Patients with Addison's disease exhibited an increased basal level of plasma AVP and a decreased osmotic threshold. CDI patients according to their AVP responses on osmotic stimulus fell into two groups: CDI I gave no response at all, while CDI II responded subnormally. CDI II exhibited blunted AVP release to histamine. The AVP reactions of the CDI I patients fell into two subgroups: CDI I/A had undetectable plasma AVP, whereas histamine evoked AVP release in CDI I/B. Patients with CDI II suffer from a partial CDI, while those with CDI I/A represent a complete form of the disease and CDI I/B presumably have an osmoreceptor failure.

Osmoregulation of arginine-8-vasopressin secretion in primary hypothyroidism and in Addison's disease.

The osmoregulation of arginine-8-vasopressin (AVP) was investigated in 14 patients with primary hypothyroidism and in 6 with Addison's disease. Plasma AVP was measured by radioimmunoassay. Patients with primary hypothyroidism were classified into subgroups with elevated (6.81 +/- 1.12 pmol/l) or normal (3.92 +/- 0.96 pmol/l) basal levels of plasma AVP. Following the infusion of 2.5% saline, a positive correlation was established between plasma AVP and plasma osmolality. A decreased osmotic threshold was found in hypothyroid patients with augmented basal AVP levels (pAVP = 0.37 (pOs-265), r = 0.71, P less than 0.01) as compared with that in hypothyroid patients with a normal AVP level (pAVP = 0.42 (pOs-280), r = 0.93, P less than 0.001). A relationship was demonstrated between the alteration in the AVP osmoregulation and the severity of the thyroid insufficiency. Patients with Addison's disease exhibited an increased basal level of plasma AVP (9.59 +/- 1.25 pmol/l) and a decreased osmotic threshold (pAVP = 0.42 (pOs-261), r = 0.63, P less than 0.01) contrasted to that of healthy volunteers (pAVP = 0.41 (pOs-280), r = 0.83, P less than 0.001). The osmoregulation disturbance of the AVP secretion may play a major role in the impaired water metabolism in primary hypothyroidism and in Addison's disease.

Stimulatory effect of intracerebroventricularly administered dopamine on vasopressin release in rats.

Experiments were designed to investigate the effects of the intracerebroventricular administration of dopamine (DA) and a DA antagonist (pimozide) on the immunoreactive-vasopressin (IR-VP) contents of the rat magnocellular nuclei (MCN), neurohypophysis (NH) and plasma. The IR-VP levels in the MCN and NH were decreased 5 min after administration of DA in a dose of 20 nmol, but that in the plasma was increased. This effect was not observed after pretreatment with pimozide. Administration of pimozide alone did not affect the IR-VP contents of the MCN, NH or plasma. The results suggest that DA given icv. has a stimulatory effect on VP release from the neurohypophysial system.

Plasma arginine-8-vasopressin responses to osmotic or histamine stimulation contribute to the differential diagnosis of central diabetes insipidus.

The arginine-8-vasopressin (AVP) responses to osmotic and histamine stimuli were evaluated in 21 patients with central diabetes insipidus (CDI) and compared to those of 10 healthy controls. Plasma AVP was measured by radioimmunoassay. Following the infusion of 2.5% saline, the AVP responses of CDI patients fell into two distinct groups: CDI I gave no response at all, while CDI II responded subnormally. Histamine increased the plasma AVP level significantly in healthy volunteers. Patients with CDI II gave subnormal AVP responses to histamine. The AVP reactions of the patients with CDI I fell into two subgroups: CDI I/A had undetectable plasma AVP, while histamine evoked AVP release in CDI I/B. Histamine trial did not lead to any change in plasma osmolality. The authors conclude that patients with CDI II suffer from a partial CDI, while those with CDI I/A represent a complete form of the disease. The remainder (CDI I/B) presumably have an osmoreceptor failure. Osmotic and non-osmotic stimulation may provide a useful tool in the differential diagnosis of CDI.