Low-dose Insulin Research Articles

Association of insulin dosage with mortality or major adverse cardiovascular events: a retrospective cohort study

Existing studies have shown conflicting evidence regarding the safety of exogenous insulin therapy in patients with type 2 diabetes. In particular, observational studies have reported an increased risk of death and cardiovascular disease among users of higher versus lower doses of insulin. We aimed to quantify the association between increasing dosage of insulin exposure and death and cardiovascular events, while taking into account time-dependent confounding and mediation that might have biased previous studies. We did a cohort study using primary care records from the UK-based Clinical Practice Research Datalink (CPRD). New users of metformin monotherapy were identified in the period between Jan 1, 2001, and Dec 31, 2012. We then identified those in this group with a new prescription for insulin. Insulin exposure was categorised into groups according to the mean dose (units) per day within 180-day time segments throughout each patient's follow-up. Relative differences in mortality and major adverse cardiovascular events (non-fatal myocardial infarction, non-fatal stroke, cardiovascular-related mortality) were assessed using conventional multivariable Cox proportional hazards models. Marginal structural models were then applied to reduce bias introduced by the time-dependent confounders affected by previous treatment. We identified 165 308 adults with type 2 diabetes in the CPRD database. After applying our exclusion criteria, 6072 (mean age 60 years [SD 12·5], 3281 [54%] men, mean HbA1c 8·5% [SD 1·75], and median follow-up 3·1 years [IQR 1·7-5·3) were new add-on insulin users and were included in the study cohort; 3599 were new add-on insulin users and were included in the subcohort linked to hospital records and death certificate information. Crude mortality rates were comparable between insulin dose groups; <25 units per day (46 per 1000 person-years), 25 to <50 units per day (39 per 1000 person-years), 50 to <75 units per day (27 per 1000 person-years), 75 to <100 units per day (34 per 1000 person-years), and at least 100 units per day (32 per 1000 person-years; p>0·05 for all; mean rate of 31 deaths per 1000 person-years [95% CI 29-33]). With adjustment for baseline covariates, mortality rates were higher for increasing insulin doses: less than 25 units per day [reference group]; 25 to <50 units per day, hazard ratio (HR) 1·41 [95% CI 1·12-1·78]; 50 to <75 units per day, 1·37 [1·04-1·80]; 75 to <100 units per day, 1·85 [1·35-2·53]; and at least 100 units per day, 2·16 [1·58-2·93]. After applying marginal structural models, insulin dose was not associated with mortality in any group (p>0·1 for all). In conventional multivariable regression analysis, higher insulin doses are associated with increased mortality after adjustment for baseline covariates. However, this effect seems to be confounded by time-dependent factors such as insulin exposure, glycaemic control, bodyweight gain, and the occurrence of cardiovascular and hypoglycaemic events. This study provides reassurance of the overall safety of insulin use in the treatment of type 2 diabetes and contributes to our understanding of the contrasting conclusions from non-randomised and randomised studies regarding dose-dependent effects of insulin on cardiovascular events and mortality. Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and the Newfoundland and Labrador Research and Development Corporation.

Effect of insulin pump infusion on comprehensive stress state of patients with diabetic ketoacidosis

Purpose: To assess changes in the comprehensive stress state of patients with diabetic ketoacidosis (DKA) following treatment with insulin infusion pump. Methods: A total of 240 patients suffering from DKA who received treatment at The First Affiliated Hospital of Zhengzhou University from Feb. 2011 to Feb. 2014 were selected randomly and divided into a control group (120 cases), administered continuous intravenous insulin, and a treatment group (120 cases), administered insulin with an infusion pump. Relevant diabetes-associated serum indices, oxidative stress and stress hormone levels were compared between the groups at different time points. Results: Levels of glycosylated haemoglobin (HbAlc), fasting blood glucose (FBG) and anion gap (AG) were lower (p < 0.05) in the treatment group than in the control group at various time points. Carbon dioxide combining power (CO 2 -CP) and C-reactive peptide levels in the treatment group were higher (p < 0.05) than those of the control group at different time points. Except for the level of methane dicarboxylic aldehyde (MDA), the values of other oxidative stress indices were higher (p < 0.05) in the treatment group than in the control group at various time points. Moreover, the treatment group had lower serum cortisol (Cor) and noradrenalin (NA) levels and higher levels of free triiodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) than those of (p < 0.05). Conclusion: Insulin pump infusion effectively relieves the comprehensive stress state of patients suffering from DKA, and its therapeutic effect is superior to that of continuous instillation of low-dose insulin. Keywords: Diabetic ketoacidosis, Insulin pump, Comprehensive stress state, Blood glucose, Carbon dioxide combining power, C-reactive peptide

Linagliptin is associated to increased treatment adherence and satisfaction in elderly outpatients with diabetes and advanced chronic kidney disease

The treatment of diabetes in frail elderly patients with decreased renal function is challenging and insufficiently supported by evidence. Due to their good tolerability and low hypoglycemic risk, oral dipeptidyl peptidase- 4 (DPP-4) inhibitors have emerged as a reasonable option for glycemic control in the elderly. The aim was to evaluate the efficacy and safety of linagliptin, a long acting, oral DPP-4 inhibitor with a predominantly nonrenal elimination route, in elderly patients with severe chronic kidney disease (CKD). This was a retrospective, observational study in outpatients with type 2 diabetes and advanced-stage CKD (estimated glomerular filtration rate &amp;lt;30 mL/min per 1.73 m&lt;sup&gt;2&lt;/sup&gt;) referring to a diabetes clinic in Italy. Patients were switched from basal insulin to oral linagliptin 5 mg once daily and observed for 14 months. Assessed variables included glycemic control (HbA1c target, 7.5%-8.0%), adherence to treatment (Morisky questionnaire) and patient satisfaction (&lt;em&gt;diabetes treatment satisfaction questionnaire&lt;/em&gt;). Adverse events, including hypoglycemic episodes, were also recorded. Thirty patients [mean (±standard deviation) age 70.2 (±8.2) years, HbA1c 7.6% (±0.3), fasting blood glucose 173.9 (±23.5) mg/dL] with type-2 diabetes and advanced CKD were included. The switch to linagliptin did not affect significantly glycemic control, was well tolerated and associated with a reduction in hypoglycemic episodes. Adherence to treatment was better with linagliptin than basal insulin and patient satisfaction significantly improved after switching. Linagliptin appears as a valid option for glycemic control in elderly diabetes patients with severe CKD in treatment with low-dose insulin. However adequately designed longterm studies are needed to confirm these findings.

Only minor changes in thrombin generation of children and adolescents with type 1 diabetes mellitus – A case-control study

BackgroundMicro- and macrovascular diseases are frequent complications in patients with diabetes. Hypercoagulability may contribute to microvascular alterations. ObjectiveIn this study, we investigated whether type 1 diabetes in children is associated with a hypercoagulable state by performing a global function test of coagulation – the thrombin generation assay. Subjects75 patients with type 1 diabetes aged between 2 and 19years were compared to an age-matched healthy control group. Diabetes patients were divided into high-dose and low-dose insulin cohorts with a cut-off at 0.8Ukg−1d−1. MethodsMeasurements were performed with platelet poor plasma using Calibrated Automated Thrombography and 1 pM or 5 pM tissue factor. Additionally, we quantified prothrombin fragments F1+2, thrombin-antithrombin complex, prothrombin, tissue factor pathway inhibitor, and antithrombin. ResultsPatients with type 1 diabetes exhibited a significantly shorter of lag time as well as decreased thrombin peak and endogenous thrombin potential compared to control subjects with 5 pM but not with 1 pM tissue factor. In high-dose insulin patients peak thrombin generation was higher and time to peak shorter than in low-dose patients. Thrombin-antithrombin complex was decreased in patients with type 1 diabetes, whereas prothrombin fragments F1+2 was comparable in both groups. Thrombin generation parameters did not correlate with parameters of metabolic control and the duration of diabetes. ConclusionsTaken together, we found only minor changes of thrombin generation in children and adolescents with type 1 diabetes which - in contrast to type 2 diabetes - do not argue for a hypercoagulable state.

Challenging the One-Dose-Fits-All Model for Insulin in the Acute Treatment of Pediatric Diabetic Ketoacidosis. A Critical Appraisal of "Low-Dose Versus Standard-Dose Insulin in Pediatric Diabetic Ketoacidosis: A Randomized Clinical Trial" by Nallasamy et al (JAMA Pediatrics 2014; 168:999-1005).

To review the findings and discuss the implications of the use of low-dose insulin infusions in pediatric diabetic ketoacidosis compared with standard-dose insulin. A search of the electronic PubMed database was used to perform the clinical query as well as to search for additional relevant literature. The article by Nallasamy K et al "Low-Dose vs Standard-Dose Insulin in Pediatric Diabetic Ketoacidosis: A Randomized Clinical Trial. JAMA Pediatrics 2014; 17:e477-e480" was selected for critical appraisal and literature review. The authors performed a randomized controlled trial among 50 consecutive patients of 0-12 years old presenting to the emergency department in diabetic ketoacidosis. They found that low-dose (0.05 U/kg/hr) insulin infusion was noninferior to standard-dose (0.1 U/kg/hr) insulin in terms of resolution of hyperglycemia and acidosis with a trend toward lower rates of therapy-related complications in the low-dose group. Low-dose insulin infusion is noninferior to standard-dose insulin in the treatment of younger pediatric patients with diabetic ketoacidosis and may lead to fewer therapy-related complications.

Effects of saxagliptin add-on therapy to insulin on blood glycemic fluctuations in patients with type 2 diabetes: A randomized, control, open-labeled trial.

Background:To investigate whether saxagliptin add-on therapy to continuous subcutaneous insulin infusion (CSII) further improve blood glycemic control than CSII therapy in patients with newly diagnosed type 2 diabetes (T2D).Methods:This was a single-center, randomized, control, open-labeled trial. Newly diagnosed T2D patients were recruited between February 2014 and December 2015. Subjects were divided into saxagliptin add-on therapy to CSII group (n = 31) and CSII therapy group (n = 38). The treatment was maintained for 4 weeks. Oral glucose tolerance test was performed at baseline. Serum samples were obtained before and 30 and 120 minutes after oral administration for glucose, insulin, and C-peptide determination. Continuous glucose monitoring (CGM) was performed before and endpoint.Results:A total of 69 subjects were admitted. After 4-week therapy, CGM data showed that patients with saxagliptin add-on therapy exhibited further improvement of mean amplitude glycemic excursion (MAGE), the incremental area under curve of plasma glucose >7.8 and 10 mmol/L compared with that of control group. In addition, the hourly mean blood glucose concentrations, especially between 0000 and 0600 in patient with saxagliptin add-on therapy, were significantly lower compared with that of the control patients. Furthermore, patients in saxagliptin add-on group needed lower insulin dose to maintain euglycemic control. In addition, severe hypoglycemic episode was not observed from any group.Conclusion:Saxagliptin add-on therapy to insulin had the ability of further improve blood glycemic controlling, with lower insulin dose required by patients with T2D to maintain euglycemic controlling.

Insulin-Mediated Downregulation of Apolipoprotein A-I Gene in Human Hepatoma Cell Line HepG2: The Role of Interaction Between FOXO1 and LXRβ Transcription Factors.

Apolipoprotein A-I (ApoA-I) is a key component of high density lipoproteins which possess anti-atherosclerotic and anti-inflammatory properties. Insulin is a crucial mediator of the glucose and lipid metabolism that has been implicated in atherosclerotic and inflammatory processes. Important mediators of insulin signaling such as Liver X Receptors (LXRs) and Forkhead Box A2 (FOXA2) are known to regulate apoA-I expression in liver. Forkhead Box O1 (FOXO1) is a well-known target of insulin signaling and a key mediator of oxidative stress response. Low doses of insulin were shown to activate apoA-I expression in human hepatoma HepG2 cells. However, the detailed mechanisms for these processes are still unknown. We studied the possible involvement of FOXO1, FOXA2, LXRα, and LXRβ transcription factors in the insulin-mediated regulation of apoA-I expression. Treatment of HepG2 cells with high doses of insulin (48 h, 100 nM) suppresses apoA-I gene expression. siRNAs against FOXO1, FOXA2, LXRβ, or LXRα abrogated this effect. FOXO1 forms a complex with LXRβ and insulin treatment impairs FOXO1/LXRβ complex binding to hepatic enhancer and triggers its nuclear export. Insulin as well as LXR ligand TO901317 enhance the interaction between FOXA2, LXRα, and hepatic enhancer. These data suggest that high doses of insulin downregulate apoA-I gene expression in HepG2 cells through redistribution of FOXO1/LXRβ complex, FOXA2, and LXRα on hepatic enhancer of apoA-I gene. J. Cell. Biochem. 118: 382-396, 2017. © 2016 Wiley Periodicals, Inc.

Clinical study on local application of low-dose insulin for promoting wound healing after operation for deep burns.

Transplanted free skin flaps are often needed to treat deep burns; their survival, however, is less than optimal. This study examined whether local low-dose insulin injections can promote flap survival and wound healing after surgery. A total of 165 patients who underwent free skin flap transplantation for simple deep burns were enrolled in the study and divided into 5 groups of 33 patients each: Blank control group (no local subcutaneous drug injections), saline control group (saline injections), low-dose insulin group (0.5 units regular insulin injections), medium-dose group (1.0 units regular insulin injections) and high-dose group (2.0 units regular insulin injections). Wound healing and flap survival conditions were assessed and compared among groups. The best wound healing rate found was that of the low-dose insulin injection group where all the parameters measured improved significantly: The healing time was shorter; the blood flow volume, the flap survival, the number of fibroblasts and new vessels increased; the re-epithelialization occurred faster; the infiltration of inflammatory cells was reduced; the expression levels of heat shock protein-90, vascular endothelial growth factor, transforming growth factor-β and interleukin-1 were higher; and the plasma glucose levels only fluctuated slightly. The results clearly demonstrate that a local low-dose insulin regime after flap transplantation can accelerate the healing time and improve the surgical outcome without exerting detrimental secondary effects on the glucose plasma level of deep burn patients.

Glycemic control and maternal and fetal outcomes in pregnant women with type 1 diabetes according to the type of basal insulin

ObjectiveTo examine the potential role of the type of basal insulin on glycemic control and maternal and foetal outcomes in pregnant women with type 1 diabetes (T1DM). Study designRetrospective cohort study of pregnancies attended at 18 Spanish tertiary hospitals. Inclusion criteriaT1DM, singleton pregnancies, delivery between 2002–2010, and use of the same basal and prandial insulin from before pregnancy until delivery. ResultsA total of 1534 pregnancies were included. The basal insulin most commonly used was Neutral Protamine Hagedorn (NPH) (51.7%), followed by glargine (23.2%) and continuous subcutaneous insulin infusion (CSII) (21.1%). CSII users had longer diabetes duration. Multiple logistic regression analysis showed that CSII was independently associated with lower doses of insulin, higher glycated haemoglobin (HbA1c) in all trimesters, and higher rates of miscarriage, preterm birth and neonatal hypoglycemia. Glargine was related to a higher risk of preterm birth and a small-for-gestational age infant (SGA). The odds ratios (OR) of the associations between insulin type and clinical outcomes (from 0.642 to 4.894) have a relevant magnitude. ConclusionsIn this observational study of pregnant women with T1DM, the type of basal insulin was independently associated with metabolic variables and foetal outcomes.

Diabetic ketosis during hyperglycemic crisis is associated with decreased all-cause mortality in patients with type 2 diabetes mellitus.

Patients with type 2 diabetes mellitus have impaired ketogenesis due to high serum insulin and low growth hormone levels. Evidence exists that ketone bodies might improve kidney and cardiac function. In theory, improved ketogenesis in diabetics may have positive effects. We aimed to assess the impact of diabetic ketosis on all-cause mortality in patients with type 2 diabetes mellitus presenting with hyperglycemic crisis. We analyzed 486 patients with diabetic ketosis and 486 age and sex-matched patients with non-ketotic hyperglycemia presenting to the emergency department. Cox proportional hazard models were used to analyze the link between patient characteristics and mortality. During an observation time of 33.4 months, death of any cause occurred in 40.9 % of the non-ketotic hyperglycemia group and 30.2 % of the DK group (hazard ratio in the diabetic ketosis group, 0.63; 95 % confidence interval 0.48-0.82; P = 0.0005). Patients with diabetic ketosis had a lower incidence of symptomatic heart failure and had improved renal function. They used less furosemide and antihypertensive drugs, more metformin and lower insulin doses, all of which was independently associated with decreased mortality. Plasma glucose and glycated hemoglobin levels were similar in both groups. Patients with hyperglycemic crisis and diabetic ketosis have decreased all-cause mortality when compared to those with non-ketotic hyperglycemia. diabetic ketosis might be a compensatory mechanism rather than a complication in patients with hyperglycemic crises, but further prospective studies are warranted.

Challenges of LADA Diagnosis and Treatment: Lessons From 2 Case Reports

Latent autoimmune diabetes in adults (LADA) is a subtype of autoimmune diabetes, which shares characteristics of both Type 1 and 2 diabetes (T1D and T2D), and for this reason, it is often confused with other types of diabetes, misdiagnosed, and inappropriately treated. Two cases were presented (41-year-old and 50-year-old females), one occasionally diagnosed during routine health checkup, the other one identified as having T2D, and as far as misclassified and not optimally treated. Now, after approximately 9 months of LADA diagnosis, the first patient has an optimal metabolic control while maintaining the values of glycated hemoglobin to around 7% with small doses of analogue insulin (lispro 4-6 UI) before meals and long acting insulin (glargine 4-6 UI) at bedtime. The second patient, after approximately 2 years from the LADA diagnosis, has an optimal metabolic control, with maintenance of glycated hemoglobin to around 6.5%, and stable C-peptide level (around 1.5 ng/mL), only with dietary and exercise habits. To avoid misclassification, any patient who does not fit the typical T2D profile, or with poor glycemic control, and who does not follow the expected clinical course, as become insulin dependent sooner than expected, should be investigated to exclude LADA. To define the best therapeutic approach, each patient must be evaluated and therapy tailored on his/her specific profile, considering as very low insulin doses may be effective to maintain a successful metabolic control and the only dietary approach may be sufficient until the insulin-secretory capacity remains good.

Local application of low-dose insulin in improving wound healing after deep burn surgery.

The clinical effects of local application of low-dose insulin in improving wound healing after deep burn self-skin transplantation surgery were examined. Fifty-eight patients with deep burns were selected and randomly divided into 3 groups. In the blank control group, normal saline was injected to the subcutaneous tissue of wounds; in large dose insulin group, 1.0 µ long-term suspended zinc insulin was locally injected; and in the low-dose insulin group, 0.1 µ long-term suspended zinc insulin was locally injected. The healing effects were compared. After 7 and 14 days of treatments, wound surface area in the low-dose group was significantly smaller than in the other groups, and differences were statistically significant (P<0.05); wound healing duration and infection rate for patients in the low-dose group were significantly lower, class A healing rate was significantly improved, and the differences were statistically significant (P<0.05). Insulin resistance index (HOMA-IR) in the low-dose group was significantly lower, insulin secretion index (HOMA-β) and the insulin sensitivity index (HOMA-ISI) significantly increased. The expression levels of vascular endothelial growth factor and tumor necrosis factor-α in local tissue for the low-dose group were significantly higher than those in the other two groups. Differences were statistically significant (P<0.05). In conclusion, local application of low-dose insulin can effectively improve wound healing after deep burn surgeries.

PP.10.03] SUCCESSFUL RENAL DENERVATION FOR RESISTANT HYPERTENSION FAILS TO IMPROVE INSULIN RESISTANCE AS ASSESSED BY HYPERINSULINEMIC EUGLYCEMIC STEP-CLAMP AND GLUCOSE TRACER INFUSION

Objective: The purpose of this study was to determine whether insulin sensitivity is improved after successful renal denervation (RDN) treatment for resistant hypertension. Design and method: Non-randomized, prospective study of 23 non-diabetic patients with resistant hypertension undergoing a two-step hyperinsulinemic euglycemic clamp with glucose tracer and labeled glucose infusion (HEC) as well as an oral glucose tolerance test (OGTT) before and 6 months after RDN. Whole body glucose disposal (WGD) and endoogenous glucose release (EGR) were calculated. Results: Eighteen of the 23 patients had metabolic syndrome at baseline, and body mass index (32 ± 5 kg/m2 at baseline) was stable during the study. At baseline, fasting plasma glucose was 5.9 ± 0.7 mmol/L, plasma insulin was 147 ± 93 pmol/L and plasma c-peptide was 1456 ± 502 pmol/L. No significant changes in these parameters were observed after 6 months. Basal glu-cose turnover rate and glucose infusion rate during two-step clamping remained unchanged. Suppression of endogenous glucose release during low-dose insulin infusion decreased from 0.9 ± 0.4 to 0.8 ± 0.4 mg/kg/min (p = 0.02), but remained unchanged during high insulin infu-sion. Area under the curve 0–120 min for glucose and insulin during OGTT, homeostasis model assessment-insulin resistance (HOMA-IR), Quantitative Insulin Sensitivity Check Index (ISQUICKI), the Simple Index assessing Insulin Sensitivity oral glucose tolerance (SIisOGTT) did not change significantly. Whole body glucose disposal did not change from basal levels at follow-up (Figure 1).Conclusions: Despite a significant effect on blood pressure, RDN treatment did not improve peripheral or hepatic insulin sensitivity, in this group of non-diabetic patients with resistant hypertension, as assessed by two-step HEC with glucose tracer infusion as well as indices derived from OGTT and fasting blood samples 6 months after RDN.

Long-Term Improvement in Glucose Control and Counterregulation by Islet Transplantation for Type 1 Diabetes.

Islet transplantation has been shown to improve glucose counterregulation and hypoglycemia symptom recognition in patients with type 1 diabetes (T1D) complicated by severe hypoglycemia episodes and symptom unawareness, but long-term data are lacking. To assess the long-term durability of glucose counterregulation and hypoglycemia symptom responses 18 months after intrahepatic islet transplantation and associated measures of glycemic control during a 24-month follow-up period. Ten patients with T1D disease duration of approximately 27 years were studied longitudinally before and 6 and 18 months after transplant in the Clinical & Translational Research Center of the University of Pennsylvania and were compared to 10 nondiabetic control subjects. All 10 patients underwent intrahepatic islet transplantation according to the CIT07 protocol at the Hospital of the University of Pennsylvania. Counterregulatory hormone, endogenous glucose production, and autonomic symptom responses derived from stepped hyperinsulinemic-hypoglycemic and paired hyperinsulinemic-euglycemic clamps with infusion of 6,6-2H2-glucose. Near-normal glycemia (HbA1c ≤ 6.5%; time 70-180 mg/dL ≥ 95%) was maintained for 24 months in all patients, with one returning to low-dose insulin therapy. In response to insulin-induced hypoglycemia, glucagon secretion was incompletely restored at 6 and 18 months, epinephrine was improved at 6 months and normalized at 18 months, and endogenous glucose production and symptoms, absent before, were normalized at 6 and 18 months after transplant. In patients with T1D experiencing problematic hypoglycemia, intrahepatic islet transplantation can lead to long-term improvement of glucose counterregulation and hypoglycemia symptom recognition, physiological effects that likely contribute to glycemic stability after transplant.

Recruitment Into a Pediatric Continuous Glucose Monitoring RCT.

The purpose was to identify patient/family characteristics and recruitment process characteristics associated with the decision to participate in a 2-year continuous glucose monitoring (CGM) RCT for youth with type 1 diabetes and their families. Study staff approached patients who were conditionally eligible according to medical record review or referred by a provider. We categorized families according to participation decision (agree vs decline) and timing of decision (day of approach vs later ["thinkers"]). Over 18 months, we approached 456 eligible patients; 19% agreed on the day of approach, 10% agreed later, 42% declined on the day of approach, and 30% declined later. Agreers were younger ( P = .002), had shorter diabetes duration ( P = .0003), had a lower insulin dose ( P = .02), checked blood glucose levels more often ( P = .002), and were more likely to use pump therapy ( P = .009) than decliners. Patients/families were more likely to agree in fall/winter (41%) than spring/summer (19%, P < .0001). Of decliners, 50% cited no interest in CGM as the reason for nonparticipation. Among thinkers, 49% of patients who made a decision within 2 weeks of being approached agreed; only 15% of thinkers who made a decision >2 weeks after being approached agreed to participate ( P < .0001). Recruitment is a critical and often challenging phase of clinical trials. Recruitment to pediatric CGM studies may be especially challenging due to youths' reluctance to use CGM. These data provide an opportunity to better understand and possibly optimize recruitment into future pediatric CGM studies and other studies of advanced diabetes technologies.

Widespread blunting of hypothalamic and amygdala-septal activity and behavior in rats with long-term hyperglycemia

Anxiety and depression in diabetic patients contributes to a poor prognosis, but possible causal relationships have been controversial. Anxiety, fear, and anhedonia are mediated by interactions between different deep structures of the temporal lobe (e.g., amygdala complex and hippocampus) and other forebrain-related structures (e.g., lateral septal nucleus). Connections between these structures and the hypothalamic orexinergic system are necessary for the maintenance of energy and wakefulness. However, few studies have explored the impact of long-term hyperglycemia in these structures on anxiety. We induced long-term hyperglycemia (glucose levels of ∼500mg/dl) in Wistar rats by injecting them with alloxan and simultaneously protecting them from hyperglycemia by injecting them daily with a low dose of insulin (i.e., just enough insulin to avoid death), thus maintaining hyperglycemia and ketonuria for as long as 6 weeks. Compared with controls, long-term hyperglycemic rats exhibited a significant reduction of Fos expression in the lateral septal nucleus and basolateral amygdala, but no differences were found in cerebellar regions. Orexin-A cells appeared to be inactive in the lateral hypothalamus. No differences were found in sucrose consumption or behavior in the elevated plus maze compared with the control group, but a decrease in general locomotion was observed. These data indicate a generalized blunting of the metabolic brain response, accompanied by a decrease in locomotion but no changes in hedonic- or anxiety-like behavior.

Low-dose intensive insulin therapy in patients with Acute Coronary Syndrome accompanied by Left Ventricular Failure: audit of two UK hospitals.

To determine whether a low-dose intravenous insulin regimen reduces blood glucose levels at a timely rate and associated side effects among patients with Acute Coronary Syndrome and Left Ventricular Failure. Induced hypoglycaemia and the associated risks have questioned the benefits of intensive insulin therapy in patients presenting with raised blood glucose levels and Acute Coronary Syndromes. Local audit data identified that patients with Acute Coronary Syndrome and Left Ventricular Failure experienced more hypoglycaemic episodes than those with Acute Coronary Syndrome alone. Consequently, a new regimen of low-dose insulin for this group was implemented and audited over 12months. Audit. Thirty-six consecutive patient notes with a diagnosis of Acute Coronary Syndrome and blood glucose of ≥10mmol/l treated with a new insulin therapy regimen were analysed. Data were extracted using a standardised form and entered into an Excel spreadsheet for analysis. The mean age of the sample was 70years with 66% of subjects being men and 50% presenting with Acute Coronary Syndrome and Left Ventricular Failure. The low-dose regimen was effective in achieving normoglycaemia, (range 4-8mmol/l) for a consecutive six-hour period. This was achieved in 72% of patients and within a median time of 13hours. The audit suggests that a low-dose insulin regimen can effectively stabilise blood glucose in patients presenting with both Acute Coronary Syndrome and Left Ventricular Failure. The importance of regularly monitoring blood sugar levels is vital and highlights the role of nurses in minimising patient risk and promoting safety. Nurses are instrumental in the safe implementation of intensive insulin guidelines. Close monitoring of patients is essential, enabling timely adjustments to treatments and ensuring patient safety. Regular audits allow nurses to evaluate care provision and continue to drive practice forward.

Real-world therapeutic benefits of patients on insulin glargine versus NPH insulin.

The addition of a single injection of insulin to the oral drugs (basal supported oral therapy; BOT) has been shown to greatly reduce blood glucose levels. The intermediate-acting NPH insulin (NPH) and the long-acting insulin glargine (Lantus(®)) have been compared for use in BOT in numerous clinical trials; however, their efficacy and safety in a real-life setting have not been described. TIP (therapeutic benefits of patients on insulin glargine vs. NPH insulin being poorly controlled on prior short-time basal-insulin supported therapy with NPH insulin or insulin glargine) is a non-interventional, multicentre, observational study over 24weeks. A total of 2629 patients were enrolled and 1931 were fully evaluable (1614 insulin glargine, 303 NPH insulin). Propensity scoring (PSM) was used to match 570 patients into 2 similar cohorts of 285 patients. In the PSM cohort, a slightly greater reduction in FBG and HbA1c levels was seen in the insulin glargine group compared to the NPH group. A weight loss, which was slightly more pronounced in insulin glargine patients despite receiving a lower insulin dose relative to the NPH group, was seen in both the groups. Additionally, hypoglycaemia, including nocturnal and severe events, was more prevalent in the patients receiving BOT with NPH. The occurrence of new micro- or macro-vascular complications and adverse events was low for both groups. A large proportion of patients changed from NPH therapy to insulin glargine therapy during the study, which was mainly attributable to insufficient glucose modulation. Improvements in quality of life and treatment satisfaction were found for both types of insulin. This observational study provides evidence from a real-life setting that BOT with insulin glargine provides slightly greater reductions in weight, FBG and HbA1c levels, with a lower risk of hypoglycaemia than patients receiving NPH. This conclusion indicates that insulin glargine may be preferable to NPH insulin for BOT.

Effect of low-dose insulin on spinal N-methyl-D-aspartate receptor levels and the downstream signals in streptozotocin-induced diabetic rats

Objective To investigate the effect and its significance of low-dose insulin on N-methyl-D-aspartate receptor (NMDAR) level and its downstream signaling of c-Jun N-terminal kinase(JNK) and the extracellular signal-regulated protein kinase (ERK, p44/42MAPK) in streptozotocin-induced diabetic rats. Methods Ten-week-old male SD rats were randomly divided into 3 groups: control group, diabetic group and insulin-treated diabetes group.Diabetes was induced by streptozocin (STZ, 60mg/kg) injected intraperitoneally.Two weeks after STZ injection, insulin glargine (92u/day for 8 weeks) was subcutaneously injected in the insulin-treated diabetes group.Then, the rat lumbar spinal cords were collected.The protein levels of phospho-Insulin receptor substrate 1(P-IRS1), phospho-NMDAR NR1 subunit (P-NR1), P-JNK and P-p44/42MAPK were evaluated by Western blotting.One week before the terminal of the study, paw thermal response latency was measured in all groups. Results Blood glucose levels were tremendously high in both the diabetic group and insulin-treated diabetes group.Compared with the control group, paw thermal response latency was markedly shortened in the diabetic group (P<0.001) and the insulin-treated diabetes group (P<0.001), and the alteration was more pronounced in the diabetic group (P<0.05). Compared with the control group, the protein levels of P-IRS1, P-NR1, P-JNK and P-p44/42MAPK were increased by 79.2%, 35.1%, 47.6%, 64.3% and 87.6%, respectively in diabetic group and 49.4%, 19.1%, 16.5%, 31.8% and 39.9%, respectively in insulin-treated diabetes group (all P<0.001 or 0.05). In comparison with diabetic group, the increased amplitudes of above 4 parameters were decreased by 29.8%, 16.0%, 31.2%, 32.5% and 47.7% respectively in the insulin-treated diabetes group (all P<0.05). Conclusions NMDAR and its downstream signals, such as JNK and p42/44MARK, are involved in the pathogenesis of painful diabetic neuropathy.Although it could not efficiently control the blood glucose level, low-dose insulin treatment may partly inhibit the occurrence of thermal hyperalgesia through inhibiting NMDAR signal pathway. Key words: Diabetes mellitus; Neuralgia; Spinal cord; Receptors, N-Methyl-D-Aspartate

Expanding the indications for pancreas resection and autologous islet cell transplantation (IAT) in both adults and children

Introduction: Pancreas resection combined with IAT is a controversial procedure with limited experience in the UK and is not funded by the NHS. We present our experience of IAT in patients with chronic pancreatitis and pancreatic trauma including the UK's first paediatric transplant. Methods: We have performed 6 pancreatic resections with IAT over 18 months. 3 patients with chronic pancreatitis (2 hereditary, 1 idiopathic) have undergone total pancreatectomy and IAT. Two patients had previous Frey procedures. 3 patients (2 adults, 1 child) sustained blunt pancreatic trauma and underwent extended left pancreatectomy combined with IAT. Complications were graded according to the Clavien-Dindo classification. Results: In the chronic pancreatitis group the islet yield was low due to fibrosis /previous drainage procedures (<50,000 IEQ). The first patient is now opiate independent and the remaining 2 patients continue on reducing doses. All have marked improvement in their quality of life. All require low dose insulin analogue therapy with in vivo C-peptide secretion. In contrast the trauma patients had a much greater islet yield (99,750–298,149 IEQ). All are insulin independent. There were no complications related to portal vein infusion and no deaths, one patient required re-laparotomy for an infected collection. Conclusions: Pancreatectomy and IAT can be used as a salvage procedure in patients who have failed all other therapy but in our opinion results would be superior if performed earlier in the course of their disease. It is also a feasible management option for complex pancreatic trauma in both adults and children.