Detemir vs neutral protamine Hagedorn insulin for diabetes mellitus in pregnancy: a comparative effectiveness, randomized controlled trial.

BACKGROUND: Insulin detemir, being used increasingly during pregnancy, may have pharmacologic benefits compared with neutral protamine Hagedorn. OBJECTIVE: We evaluated the probability that compared with treatment with neutral protamine Hagedorn, treatment with insulin detemir reduces the risk for adverse neonatal outcome among individuals with type 2 or overt type 2 diabetes mellitus (gestational diabetes mellitus diagnosed at <20 weeks' gestation). STUDY DESIGN: We performed a multiclinic randomized controlled trial (September 2018 to January 2020), which included women with singleton gestation with type 2 or overt type 2 diabetes mellitus who sought obstetrical care at ≤21 weeks' gestation. Participants were randomized to receive either insulin detemir or neutral protamine Hagedorn by a clinic-stratified scheme. The primary outcome was a composite of adverse neonatal outcomes, including shoulder dystocia, large for gestational age, neonatal intensive care unit admission, respiratory distress (defined as the need of at least 4 hours of respiratory support with supplemental oxygen, continuous positive airway pressure or ventilation at the first 24 hours of life), or hypoglycemia. The secondary neonatal outcomes included gestational age at delivery, small for gestational age, 5-minute Apgar score of <7, lowest glucose level, need for intravenous glucose, respiratory distress syndrome, need for mechanical ventilation or continuous positive airway pressure, neonatal jaundice requiring therapy, brachial plexus injury, and hospital length of stay. The secondary maternal outcomes included hypoglycemic events, hospital admission for glucose control, hypertensive disorder of pregnancy, maternal weight gain, cesarean delivery, and postpartum complications. We used the Bayesian statistics to estimate a sample size of 108 to have >75% probability of any reduction in the primary outcome, assuming 80% power and a hypothesized effect of 33% reduction with insulin detemir. All analyses were intent to treat under a Bayesian framework with neutral priors (a priori assumed a 50:50 likelihood of either intervention being better; National Clinical Trial identifier 03620890). RESULTS: There were 108 women randomized in this trial (57 in insulin detemir and 51 in neutral protamine Hagedorn), and 103 women were available for analysis of the primary outcome (n=5 for pregnancy loss before 24 weeks' gestation). Bayesian analysis indicated an 87% posterior probability of reduced primary outcome with insulin detemir compared with neutral protamine Hagedorn (posterior adjusted relative risk, 0.88; 95% credible interval, 0.61-1.12). Bayesian analyses for secondary outcomes showed consistent findings of lower adverse maternal outcomes with the use of insulin detemir vs neutral protamine Hagedorn: for example, maternal hypoglycemic events (97% probability of benefit; posterior adjusted relative risk, 0.59; 95% credible interval, 0.29-1.08) and hypertensive disorders (88% probability of benefit; posterior adjusted relative risk, 0.81; 95% credible interval, 0.54-1.16). CONCLUSION: In our comparative effectiveness trial involving individuals with type 2 or overt type 2 diabetes mellitus, use of insulin detemir resulted in lower rates of adverse neonatal and maternal outcomes compared with neutral protamine Hagedorn.

Insulin Regimens to Treat Hyperglycemia in Hospitalized Patients on Nutritional Support: Systematic Review and Meta-Analyses.

BACKGROUND: The best insulin regimen to treat hyperglycemia in hospitalized patients on nutritional support (NS) is unclear. METHODS: We searched electronic databases to identify cohort studies or randomized clinical trials in order to evaluate the efficacy of different insulin regimens used to treat hyperglycemia in hospitalized patients on NS on diverse outcomes: mean blood glucose (MBG), hypoglycemia, length of stay in hospital, and mortality. RESULTS: Seventeen studies from a total of 5,030 were included. Enteral Group included 8 studies; 1,203 patients using rapid, glargine, NPH, or Premix insulin; MBG 108-225 mg/dL; hypoglycemia 0-13%. In indirect meta-analyses, NPH insulin ranked best for glucose control (MD 95% CI -2.50 mg/dL [2.65 to -2.35]). Parenteral Group included 4 studies; 228 patients using regular and glargine or NPH insulin; MBG 137-202 mg/dL; hypoglycemia 0-40%. In meta-analyses comparing regular insulin added to parenteral nutrition bag with glargine, MBG (MD 95% CI -3.78 mg/dL [-11.93 to 4.37]; I2 = 0%) or hypoglycemia frequency (RR 95% CI 1.37 [0.43-4.32]; I2 = 70.7%) did not differ. The description related to hospital length of stay and mortality was inconsistent between groups. CONCLUSIONS: The best insulin regimen to treat hyperglycemia in hospitalized patients on NS has not been established; best results using insulin regimens with NPH in enteral nutrition do not seem to be clinically relevant.

Retrospective Evaluation of Glycemic Control With Basal-Bolus or Neutral Protamine Hagedorn Insulin Regimens in Patients Receiving Continuous Enteral Nutrition Therapy in Medicine Wards.

Reasonable glycemic control is difficult to achieve in patients with diabetes mellitus (DM) receiving continuous enteral nutrition therapy (CENT). There are no solid evidence-based medicine guidelines regarding this issue in these patients. The purpose of this study was to determine if the use of a basal-bolus insulin regimen is more effective than neutral protamine Hagedorn (NPH) insulin alone in controlling blood glucose in non-critically ill patients with DM receiving CENT. We performed a retrospective, records-based review comparing basal-bolus with NPH insulin regimen in these patients, hospitalized in the internal medicine wards in our hospital. Number of hypoglycemic episodes, mean blood glucose, and time-to-target (time needed to reach 3 successive glucose readings in the appropriate target of 140-180 mg/dL) were evaluated in each regimen. Mean blood glucose was 199.22 mg/dL (95% confidence interval [CI], 179.8-218.5 mg/dL) in the basal-bolus vs 190.73 mg/dL (95% CI, 172.1-209.2 mg/dL) in the NPH insulin regimen ( P = .538). Time-to-target was an average of 3.65 ± 1.75 days in the basal-bolus group and 4.33 ± 2.42 days in the NPH group ( P = .364). There were no statistically significant differences in frequency of hypoglycemia ( P = .364). Rate of death was high (around 40%) in both groups. We conclude that hospitalized hyperglycemic patients receiving CENT can be treated by either basal-bolus or NPH insulin regimens. However, the overall glucose levels remain elevated during hospitalization irrespective of the insulin therapy. There is an urgent need to define glucose targets in this population of patients and to evaluate prospectively head-to-head different insulin protocols.

Association between post-dinner dietary intakes and nocturnal hypoglycemic risk in adult patients with type 1 diabetes.

AIMS: To describe (i) current bedtime nutritional practices and (ii) the association between post-dinner dietary intake and the occurrence of non-severe nocturnal hypoglycemia (NH) in real-life conditions among adult patients with type 1 diabetes using insulin analogs. METHODS: One hundred adults (median [interquartile range]: age 46.4 [36.0-55.8] years, HbA1c 7.9 [7.3-8.6] % (63 [56-70] mmol/mol)) using multiple daily injections (n=67) or insulin pump (n=33) wore a blinded continuous glucose monitoring system and completed a food diary for 72-h. RESULTS: NH occurred on 28% of 282 nights analyzed. (i) Patients reported post-dinner dietary intakes on 63% of the evenings. They injected rapid-acting insulin boluses on 64 occasions (23% of 282 evenings). These insulin boluses were mostly injected with (n=37) dietary intakes. (ii) Post-dinner dietary intake was not associated with NH occurrence in univariate analyses. In multivariate analyses, the injection of rapid-acting insulin modulated the association between post-dinner dietary intake and NH: with insulin, post-dinner carbohydrate intake was positively associated with NH (odds ratio (OR): 1.16 [95% confidence interval, CI: 1.04-1.29] per 5g increase, p=0.008); without insulin, post-dinner protein intake was inversely associated with NH occurrence (OR [95% CI]: 0.88 [0.78-1.00] per 2g increase, p=0.048). CONCLUSIONS: NH remains frequent in adults with type 1 diabetes. There is a complex relationship between post-dinner dietary intake and NH occurrence, including the significant role of nutrient content and rapid-acting insulin injection that requires further investigation.

The protective effects of insulin and natural honey against hippocampal cell death in streptozotocin-induced diabetic rats.

We investigated the effects of insulin and honey as antioxidants to prevent the hippocampal cell death in streptozotocin-induced diabetic rats. We selected sixty Wister rats (5 groups of 12 animals each), including the control group (C), and four diabetic groups (control (D) and 3 groups treated with insulin (I), honey (H), and insulin plus honey (I + H)). Diabetes was induced by streptozotocin injection (IP, 60 mg/kg). Six weeks after the induction of diabetes, the group I received insulin (3-4 U/kg/day, SC), group H received honey (5 mg/kg/day, IP), and group I + H received a combination of the above at the same dose. Groups C and D received normal saline. Two weeks after treatment, rats were sacrificed and the hippocampus was extracted. Neuronal cell death in the hippocampal region was examined using trypan blue assay, "H & E" staining, and TUNEL assay. Cell viability assessment showed significantly lower number of living cells in group D than in group C. Besides, the mean number of living cells was significantly higher in group I, H, and I + H compared to group D. Therefore, it can be concluded that the treatment of the diabetic rats with insulin, honey, and a combination of insulin and honey can prevent neuronal cell death in different hippocampal areas of the studied samples.

Transitional NPH insulin therapy for critically ill patients receiving continuous enteral nutrition and intravenous regular human insulin.

BACKGROUND: The intent of this study was to evaluate the efficacy and safety of transitioning from a continuous intravenous (IV) regular human insulin (RHI) or intermittent IV RHI therapy to subcutaneous neutral protamine Hagedorn (NPH) insulin with intermittent corrective IV RHI for critically ill patients receiving continuous enteral nutrition (EN). METHODS: Data were obtained from critically ill trauma patients receiving continuous EN during transitional NPH insulin therapy. Target blood glucose concentration (BG) range was 70-149 mg/dL. BG was determined every 1-4 hours. RESULTS: Thirty-two patients were transitioned from a continuous IV RHI infusion (CIT) to NPH with intermittent corrective IV RHI therapy. Thirty-four patients had NPH added to their preexisting supplemental intermittent IV RHI therapy (SIT). BG concentrations were maintained in the target range for 18 ± 3 and 15 ± 4 h/d for the CIT and SIT groups, respectively (P < .05). Thirty-eight percent of patients experienced a BG <60 mg/dL, and 9% had a BG <40 mg/dL. Hypoglycemia was more prevalent for those who were older (P < .01) or exhibited greater daily BG variability (P < .01) or worse HgbA1C (p < 0.05). CONCLUSION: Transitional NPH therapy with intermittent corrective IV RHI was effective for achieving BG concentrations within 70-149 mg/dL for the majority of the day. NPH therapy should be implemented with caution for those who are older, have erratic daily BG control, or have poor preadmission glycemic control.

Metformin compared with insulin in the management of gestational diabetes mellitus: a randomized clinical trial.

AIMS: To evaluate the effect of metformin and insulin in glycemic control and compare pregnancy outcome in women with gestational diabetes mellitus (GDM). METHODS: This randomized controlled trial was conducted in GDM women with singleton pregnancy and gestational age between 20 and 34 weeks who did not achieve glycemic control on diet were assigned randomly to receive either metformin (n=80) or insulin (n=80). The primary outcomes were maternal glycemic control and birth weight. The secondary outcomes were neonatal and obstetric complications. RESULTS: Two groups were comparable regarding the maternal characteristics. Two groups were similar in mean FBS (P=0.68) and postprandial measurements (P=0.87) throughout GDM treatment. The neonates of metformin group had less rate of birth weight centile >90 than insulin group (RR: 0.5, 95% CI: 0.3-0.9, P=0.012). Maternal weight gain was reduced in the metformin group (P<0.001). Two groups were comparable according to neonatal and obstetric complications (P>0.05). In metformin group 14% of women needed to supplemental insulin to achieve euglycemia. CONCLUSION: Metformin is an effective and safe alternative treatment to insulin for women with GDM. This study does not show significant risk of maternal or neonatal adverse outcome with the use of metformin.

The effects of adjuvant insulin therapy among pregnant women with IGT who failed to achieve the desired glycemia levels by diet and moderate physical activity.

OBJECTIVE: Evaluation of adjuvant insulin therapy effects on glycemic control, perinatal outcome and postpuerperal glucose tolerance in impaired glucose tolerance (IGT) pregnant women who failed to achieve desired glycemic control by dietary regime. METHODS: A total of 280 participants were classified in two groups: Group A patients continued with dietary regime and Group B patients were treated with adjuvant insulin therapy. Glycemic control was assessed by laboratory and ultrasonograph means. Pregnancy outcomes were evaluated by prevalence of pregnancy induced hypertension (PIH), high birth weight, neonatal hypoglycemia and caesarean section rates. Postpuerperal glucose tolerance was assessed by oral glucose tolerance test (oGTT). RESULTS: All laboratory and ultrasound indicators of glycemic control had significantly lower values in Group B. Group A women were more likely to develop the EPH (Edema, Proteinuria, Hypertension) syndrome, 20% versus 7.86% (p = 0.003). High birth weight occurred more frequently in Group A, but the difference was not significant (p = 0.197). Higher rate of caesarean delivery was in Group A than in Group B, 16.43% versus 26.43% (p = 0.041). The difference in neonatal hypoglycemia was not significant (p = 0.478). Pathological oGTT results were observed in 73 Group A patients and in 15 Group B patients. CONCLUSION: Lower caesarean section rates and the EPH syndrome incidence are the benefits of adjuvant insulin therapy in IGT patients.

Insulin analogs versus human insulin in type 2 diabetes.

Oral hypoglycaemic agents become less effective as beta cell function declines. Thus many patients with type 2 diabetes will ultimately require treatment with insulin. There are two main approaches to starting insulin: (a) as a basal supplement with an intermediate to long-acting preparation (NPH, glargine or detemir) plus oral agents; (b) as a premixed insulin regimen. Almost all the studies have shown similar glucose control with both NPH and the new insulin analogs. Further analyses between these insulins have documented significant reductions in hypoglycaemia especially at night with the insulin analogs. The weight gain is an important issue in patients with diabetes. It appears that insulin detemir studies have reported weight neutrality or less weigh gain or even weight loss. However, most insulin glargine studies have reported a weight gain. On the other hand insulin analogs have the important disadvantage of high cost. It is important to take in to account all the above factors such as cost, weight gain, number of insulin injections and hypoglycaemia while prescribing insulin.

Insulin therapy and glycemic control in hospitalized patients with diabetes during enteral nutrition therapy: a randomized controlled clinical trial.

OBJECTIVE: To compare two subcutaneous insulin strategies for glycemic management of hyperglycemia in non-critically ill hospitalized patients with diabetes during enteral nutrition therapy (ENT). RESEARCH DESIGN AND METHODS: Fifty inpatients were prospectively randomized to receive sliding-scale regular insulin (SSRI) alone (n = 25) or in combination with insulin glargine (n = 25). NPH insulin was added for persistent hyperglycemia in the SSRI group (glucose >10 mmol/l). RESULTS: Glycemic control was similar in the SSRI and glargine groups (mean +/- SD study glucose 8.9 +/- 1.6 vs. 9.2 +/- 1.6 mmol/l, respectively; P = 0.71). NPH insulin was added in 48% of the SSRI group subjects. There were no group differences in frequency of hypoglycemia (1.3 +/- 4.1 vs. 1.1 +/- 1.8%; P = 0.35), total adverse events, or length of stay. CONCLUSIONS: Both insulin strategies (SSRI with the addition of NPH for persistent hyperglycemia and glargine) demonstrated similar efficacy and safety in non-critically ill hospitalized patients with type 2 diabetes during ENT.

Beyond the era of NPH insulin--long-acting insulin analogs: chemistry, comparative pharmacology, and clinical application.

The new rDNA and DNA-derived "basal" insulin analogs, glargine and detemir, represent significant advancement in the treatment of diabetes compared with conventional NPH insulin. This review describes blood glucose homeostasis by insulin in people without diabetes and outlines the physiological application of exogenous insulin in patients with type 1 and type 2 diabetes. The requirements for optimal basal insulin treatment are discussed and the methods used in the evaluation of basal insulins are presented. An essential criterion in the development of an "ideal" basal insulin preparation is that the molecular modifications made to the human insulin molecule do not compromise safety. It is also necessary to obtain a clear understanding of the pharmacokinetic and pharmacodynamic characteristics of the two currently available basal insulin analogs. When comparing glargine and detemir, the different molar concentration ratios of the two insulin formulations should be considered along with the nonspecificity of assay systems used to determine insulin concentrations. However, euglycemic clamp studies in crossover study design provide a good basis for comparing the pharmacodynamic responses. When the latter is analyzed by results of intervention clinical trials, it is concluded that both glargine and detemir are superior to NPH in type 1 and type 2 diabetes. However, there is sufficient evidence to demonstrate that these two long-acting insulin analogs are different in both their pharmacokinetic and pharmacodynamic profiles. These differences should be taken into consideration when the individual analogs are introduced to provide basal insulin supplementation to optimize blood glucose control in patients with type 1 and type 2 diabetes as well. PubMed-Medline was searched for articles relating to pharmacokinetics and pharmacodynamics of glargine and detemir. Articles retrieved were reviewed and selected for inclusion if (1) the euglycemic clamp method was used with a duration >or=24 h, (2) a single subcutaneous dose of glargine/detemir was used, and (3) area under the curve for insulin concentrations or glucose infusion rates were calculated.

Risk of exercise-induced hypoglycaemia in patients with type 2 diabetes on intensive insulin therapy: comparison of insulin glargine with NPH insulin as basal insulin supplement.

AIM: Hypoglycaemia is the most common adverse event associated with intensive conventional insulin therapy (ICT). This study compared the risk of exercise-related hypoglycaemia in type 2 diabetes patients receiving either basal insulin glargine or NPH insulin. METHODS: In a prospective trial, 122 ICT patients (glargine n=60, NPH n=62) had a standardized treadmill test, monitored by capillary lactate concentration. Blood glucose (BG) profiles were performed the day before, during and the day after the exercise test, with the patients on a strict carbohydrate-defined diet. All patients had been on a stable ICT scheme for at least three months and had an HbA1c below 7.5%. RESULTS: BG at the beginning of the exercise test, BG decline and lowest BG during the test were comparable between the two groups. The episodes of mild hypoglycaemia (BG<3.3 mmol/l) and amounts of additional carbohydrate intake due to mild symptoms of hypoglycaemia (BG 3.3-5.0 mmol/l) were not significantly different. No episodes of hypoglycaemia occurred during several hours after the exercise. CONCLUSIONS: Moderate physical activity can be recommended for well-controlled type 2 diabetes patients receiving ICT, independently of glargine or NPH as basal insulin and without risk of exercise-induced hypoglycaemia.

Effects of changes in basal/total daily insulin ratio in type 2 diabetes patients on intensive insulin therapy including insulin glargine (JUN-LAN Study 6).

Intensive insulin therapy composed of bolus and basal insulin has been believed as the most powerful recipe for glycemic control of both type 1 and type 2 diabetes. In this study, we investigated the effects of changes in basal/total daily insulin ratio (B/TD ratio) in type 2 diabetes patients on intensive insulin therapy including insulin glargine. The B/TD ratio used in our Japanese patients was about 0.35, and the ratio was increased up to about 0.46+/-0.12 without change of total insulin daily dose. After 24-week-treatment, mean glycated albumin of the patients whose B/TD ratio was increased was significantly lower than those of the patients whose B/TD ratio was not changed. Our results suggest that adequate supplementation of basal insulin may be important for maximum effect of bolus insulin even in Japanese who have serious defect in postprandial rapid insulin secretion.

Insulin analogues (insulin detemir and insulin aspart) versus traditional human insulins (NPH insulin and regular human insulin) in basal-bolus therapy for patients with type 1 diabetes.

AIMS/HYPOTHESIS: The aim of the trial was to compare the efficacy and tolerability of two types of basal-bolus therapy, using either the soluble long-acting basal insulin analogue, insulin detemir, in combination with the rapid-acting analogue, insulin aspart, or NPH insulin in combination with mealtime regular human insulin. METHODS: In this 18-week, 1:1 randomised, open-labelled, parallel trial, 595 patients with Type 1 diabetes mellitus received insulin detemir or NPH insulin in the morning and at bedtime in combination with mealtime insulin aspart or regular human insulin respectively. RESULTS: Glycaemic control with insulin detemir/insulin aspart was improved in comparison with NPH insulin/regular human insulin (HbA1c: 7.88% vs 8.11%; mean difference: -0.22% point [95% CI: -0.34 to -0.10]; p<0.001). Self-measured 8-point plasma glucose profiles differed between the groups (p<0.001), with lower postprandial plasma glucose levels in the insulin detemir/insulin aspart group. Within-person day-to-day variation in plasma glucose was lower with insulin detemir/insulin aspart than with NPH insulin/regular human insulin (SD: 2.88 vs 3.12 mmol/l; p<0.001). Risk of overall and nocturnal hypoglycaemia (23.00-06.00 hours) was, respectively, 21% (p=0.036) and 55% (p<0.001) lower in the insulin detemir/insulin aspart group than in the NPH insulin/regular human insulin group. Body weight (adjusted for baseline and change in HbA1c) was 1 kg lower with insulin detemir/insulin aspart than with NPH insulin/regular human insulin (p<0.001). CONCLUSIONS/INTERPRETATION: Basal-bolus therapy using insulin detemir/insulin aspart offers a better balance of control and tolerability than with NPH insulin/regular human insulin. The low variability and more physiological action profiles generated with these insulin analogues resulted in improved glycaemic control with lower risk of hypoglycaemia and no concomitant body weight increase.

Enamel hypoplasia in a litter of rats with alloxan-induced diabetes mellitus.

Enamel hypoplasia is an important clinical problem commonly seen in children born to diabetic women. We aimed to characterize the enamel hypoplasia in Wistar rats born to alloxan-induced diabetes mellitus rats. Groups consisted of pregnant rats supplemented (ISDR) or not (NISDR) with insulin and controls, in which sterile saline solution was administered instead of alloxan or insulin. The mandibular incisors of one-month-old rats born to these mothers were analyzed. Whitish defective enamel was found macroscopically in both experimental groups (ISDR = 37.5%, NISDR = 33.3%) but not in the control group. Mild to severe enamel hypoplasia was observed by scanning electron microscopy (ISDR = 93.8%; NISDR = 100%, control = 4.2%). The severity of hypoplasia correlated positively with the maternal level of blood glucose. In conclusion, the intensity of enamel hypoplasia in the teeth of the litter born to alloxan-induced diabetic rats was variable and was dependent on the glycemic level of the pregnant rat.

Enamel hypoplasia in a litter of rats with alloxan-induced diabetes mellitus

Enamel hypoplasia is an important clinical problem commonly seen in children born to diabetic women. We aimed to characterize the enamel hypoplasia in Wistar rats born to alloxan-induced diabetes mellitus rats. Groups consisted of pregnant rats supplemented (ISDR) or not (NISDR) with insulin and controls, in which sterile saline solution was administered instead of alloxan or insulin. The mandibular incisors of one-month-old rats born to these mothers were analyzed. Whitish defective enamel was found macroscopically in both experimental groups (ISDR = 37.5 percent, NISDR = 33.3 percent) but not in the control group. Mild to severe enamel hypoplasia was observed by scanning electron microscopy (ISDR = 93.8 percent; NISDR = 100 percent, control = 4.2 percent). The severity of hypoplasia correlated positively with the maternal level of blood glucose. In conclusion, the intensity of enamel hypoplasia in the teeth of the litter born to alloxan-induced diabetic rats was variable and was dependent on the glycemic level of the pregnant rat

Six month administration of gelified intranasal insulin in 16 type 1 diabetic patients under multiple injections: efficacy vs subcutaneous injections and local tolerance.

OBJECTIVE: Nasal insulin administration is a potential route for intensive insulin management, less invasive and more rapid than subcutaneous injections. Previous studies have shown poor bioavailability (less than 15%) with nasal insulin administration with various absorption enhancers. The aim of the study was to evaluate in type 1 diabetic patients, the metabolic efficacy and local tolerance of a new gelified sprayed nasal insulin containing glychocolate and methylcellulose as absorption promoters. MATERIAL AND METHODS: The study was conducted in 16 type 1 diabetic patients (HbA1c 8.6+/-0.2%) in a cross-over trial including 2 six month randomized periods: a) NPH twice daily + 3 pre-prandial nasal insulin doses + nasal supplementation in case of unexpected hyperglycaemia; b) NPH twice daily + 3 pre-prandial regular insulin injections. End points were HbA1c levels, hypoglycaemic episodes and tolerance evaluated at month 0, 2, 6 and 8 on clinical symptoms and objective nasal assessments. RESULTS: Four patients were withdrawn because of nasal burning (3 cases) and persistent sinusitis (1 case), and one patient had purulent sinusitis at the month 6 examination. At month 6, HbA1c levels were comparable (8.3 +/- 0.1 vs 8.6 +/- 0.1%, m +/- SEM, NS) for nasal and subcutaneous period respectively. The number of hypoglycaemic events was identical during the 2 periods (88 episodes). Nasal tolerance with the gelified form was better than with the already reported lyophilized form but, when present, symptoms were more marked, suggesting a potentiating additional role of methylcellulose excipient on nasal intolerance. CONCLUSIONS: 1) Gelified nasal insulin is as efficient as subcutaneous regular insulin in type 1 diabetic patients. 2) Other galenic forms should be investigated to improve nasal tolerance and bioavailability.

Acarbose vs. bedtime NPH insulin in the treatment of secondary failures to sulphonylurea-metformin therapy in type 2 diabetes mellitus.

OBJECTIVE: To evaluate the efficacy of acarbose in the treatment of secondary failures to sulphonylurea-metformin therapy, its comparison against bedtime NPH insulin, and to measure the changes in postprandial metabolism resulting from both treatments. METHODS: One hundred type 2 diabetic patients in a secondary failure were included. The study begun with a run-in diet period of 6 weeks, in which an isocaloric diet was prescribed. Only subjects who continued hyperglycaemic were randomly assigned to placebo and acarbose (n = 17) or bedtime NPH insulin (n = 12). Acarbose (300 mg/day) or placebo were administered using a randomized, double blind, crossover design. Treatment periods of 3 months were separated by a 3-week washout period. Insulin was administered during 3 months. At the beginning and the end of each treatment period, an i.v. glucose tolerance test and a meal test were performed. Safety tests were done every 4 weeks. RESULTS: Acarbose resulted in a small but significant improvement in fasting plasma glucose (13.5 +/- 2.4 vs. 11.3 +/- 3.9 mmol/l, p = 0.05), HbA1c (11.1 +/- 3.4 vs. 10.3 +/- 2.5%, P = 0.3) and in a decreased plasma glucose during the meal test. Bedtime insulin significantly decreased fasting plasma glucose (13.1 +/- 2.9 vs. 8.2 +/- 2.3 mmol/l, p < 0.01), HbA1c (11.7 +/- 2.9 vs. 9.4 +/- 2.7%, p < 0.01) and plasma cholesterol. No change in insulin secretion resulted from insulin and acarbose treatment. CONCLUSIONS: Acarbose decreases blood glucose in secondary failure to sulphonylurea-metformin therapy; however, the decrease is not enough to reach the desired metabolic control. Bedtime NPH insulin is, by far, a more effective alternative.

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.