Severe Hypoglycemia Risk With Long-Acting Insulin Analogs vs Neutral Protamine Hagedorn Insulin.

Importance: Previous studies have found that the risk of severe hypoglycemia does not differ between long-acting insulin analogs and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes. However, these studies did not focus on patients 65 years or older, who are at an increased risk for hypoglycemia, or did not include patients with concomitant prandial insulin use. Objective: To examine the risk of emergency department (ED) visits or hospitalizations for hypoglycemia among older community-residing patients with type 2 diabetes who initiated long-acting insulin or NPH insulin in real-world settings. Design, Setting, and Participants: This retrospective, new-user cohort study assessed Medicare beneficiaries 65 years or older who initiated insulin glargine (n = 407 018), insulin detemir (n = 141 588), or NPH insulin (n = 26 402) from January 1, 2007, to July 31, 2019. Exposures: Insulin glargine, insulin detemir, and NPH insulin. Main Outcomes and Measures: The primary outcome was time to first ED visit or hospitalization for hypoglycemia, defined using a modified validated algorithm. Propensity score-weighted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs. The risk of recurring hypoglycemia events was estimated using the Andersen-Gill model. Post hoc analyses were conducted investigating possible effect modification by age. Results: Of the 575 008 patients initiating use of insulin (mean [SD] age 74.9 [6.7] years; 53% female), 407 018 used glargine, 141 588 used detemir, and 26 402 used NPH insulin. The study included 7347 ED visits or hospitalizations for hypoglycemia (5194 for glargine, 1693 for detemir, and 460 for NPH insulin, with a median follow-up across the 3 cohorts of 0.37 years (interquartile range, 0.20-0.76 years). Initiation of glargine and detemir use was associated with a reduced risk of hypoglycemia compared with NPH insulin use (HR for glargine vs NPH insulin, 0.71; 95% CI, 0.63-0.80; HR, detemir vs NPH insulin, 0.72; 95% CI, 0.63-0.82). The HRs were similar for the recurrent event analysis. The protective association of long-acting insulin analogs varied by age and was not seen with concomitant prandial insulin use. Conclusions and Relevance: In this cohort study, initiation of long-acting analogs was associated with a lower risk of ED visits or hospitalizations for hypoglycemia compared with NPH insulin in older patients with type 2 diabetes in Medicare. However, this association was not seen with concomitant prandial insulin use.

Effects of Exenatide and Humalog Mix25 on Fat Distribution, Insulin Sensitivity, and ß-Cell Function in Normal BMI Patients with Type 2 Diabetes and Visceral Adiposity.

In China, most normal BMI (body mass index of ≥18.5 to <25 kg/m2) adults with type 2 diabetes (T2DM) exhibit visceral adiposity. This study compared the effects of exenatide and humalog Mix25 on normal BMI patients with T2DM and visceral adiposity. A total of 95 patients were randomized to receive either exenatide or humalog Mix25 treatment for 24 weeks. Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were quantified by magnetic resonance imaging (MRI) and liver fat content (LFC) by liver proton magnetic resonance spectroscopy (1H MRS). Each patient's weight, waist circumference, BMI, blood glucose, insulin sensitivity, pancreatic ß-cell function, and fibroblast growth factor 21 (FGF-21) levels were measured. Data from 81 patients who completed the study (40 and 41 in the exenatide and humalog Mix25 groups, respectively) were analysed. The change in 2 h plasma blood glucose was greater in the exenatide group (P = 0.039). HOMA-IR and MBCI improved significantly after exenatide therapy (P < 0.01, P = 0.045). VAT and LFC decreased in both groups (P < 0.01 for all) but to a greater extent in the exenatide group, while SAT only decreased with exenatide therapy (P < 0.01). FGF-21 levels declined more in the exenatide group (P < 0.01), but were positively correlated with VAT in the entire cohort before (r = 0.244, P = 0.043) and after (r = 0.290, P = 0.016) the intervention. The effects of exenatide on glycaemic metabolism, insulin resistance, pancreatic ß-cell function, and fat deposition support its administration to normal BMI patients with T2DM and visceral adiposity.

Comparison of analog insulin mix 50:50 with human insulin mix 30:70 in persons with type 2 diabetes during Ramadan.

AIM OF THE STUDY: To test if changing the Iftar insulin to a 50:50 mixed analog insulin from a 30:70 human insulin at the same total dose leads to improvement in the postprandial blood glucose (taken as after the main meal). Since the intermediate acting insulin dose is effectively lowered, the pre-Suhur blood glucose is also tested to see if this rises. METHODS: The Iftar human 30:70 mixed insulin is substituted for a 50:50 one using insulin lispro protamine suspension and 50% insulin lispro (Humalog® Mix50/50™), whilst maintaining the same total dose. The participants were also changed to 75% insulin lispro protamine suspension and 25% insulin lispro (Humalog® Mix75/25™) at the same pre-Ramadan dose for their Suhur injection (Experimental group). A similar number of controls continued their 30:70 mixed human insulin at the same dose during Ramadan (Control group). Pre-Ramadan and during Ramadan fasting and postprandial (3 hours) and pre-Suhur blood glucose (BG) are tested in 20 subjects and 20 controls by the patients using home glucose meters. Hypoglycaemia, defined as a BG of ≤ 70 mg%, was tested for by the patients and noted if they experience symptoms of it. Severe hypoglycaemia occurred if the patient needed assistance for recovery. No insulin dose adjustments are made in either group and any other anti-diabetic treatment was continued. Pre- and post-Ramadan HbA1 c and body weight are measured. The number of days fasted and baseline characteristics are age, gender, and duration of diabetes are also noted. Differences between groups in parameters were assessed using ANCOVA to adjust for pre-Ramadan values of age, gender, and duration of diabetes. RESULTS: All the participants fasted for at least 29 days. The 2 groups were not significantly different at baseline. During Ramadan, mean postprandial BG in the Experimental group was lower by 21.1 mg% (1.2 mmol/l) (95% CI 12.6, 29.7; P < 0.001). Similarly, after Ramadan mean HbA1 c in the Experimental group was lower by 0.4% (95% CI 0.1%, 0.8%; P = 0.01). No significant differences between the groups were detected in mean bodyweight after Ramadan (P = 0.86) or mean fasting BG during Ramadan (P = 0.07). There was no difference in incidence of hypoglycaemia. CONCLUSIONS: Switching from human insulin mix 30:70 to analog insulin mix 50:50 results in better post main meal control in Ramadan, without affecting HbA1c, or increasing the incidence of hypoglycaemia.

Insulin promotes macrophage phenotype transition through PI3K/Akt and PPAR-γ signaling during diabetic wound healing.

Overactivation and persistent chronic inflammation are the major pathogenic characteristics of diabetic-impaired healing, and diabetic wound healing can be promoted by stimulating the transition of macrophage phenotype from pro-inflammatory (M1) to anti-inflammatory (M2). Our previous studies found that the application of insulin induced an advanced initiation and resolution of inflammatory response. To further explore the mechanism, we have investigated the effect of insulin on macrophage phenotype switch utilizing a diabetic rat model and a human monocytic THP-1 cell. We have utilized the high glucose (HG) and HG plus insulin to stimulate the M1 macrophages derived from lipopolysaccharide-treated THP-1 cells. We studied the secretion of inflammatory mediator and related signaling pathways by using western blot test, immunofluorescence, and Rac1 pull-down assay. We have found that the production of pro-inflammatory mediators, which thereafter induced macrophage polarization toward M1 phenotype, has been elevated due to consistent HG exposure. HG plus insulin stimulation, on the other hand, promoted anti-inflammatory effects. Experiments performed on diabetic burn wounds indicated that the insulin modulated macrophages transition from M1 to M2 phenotype. We found that PI3K/Akt/Rac-1 and PPAR-γ signaling pathways are involved in the anti-inflammatory effect of insulin. Insulin inhibited HG-induced activation of p38, NF-κB, and STAT1 transcriptional activity by activating Akt-Rac-1 signaling. Moreover, insulin performs anti-inflammatory effects through upregulation of PPAR-γ expression and induced P38-mediated dephosphorylation of PPAR-γ (Ser112). In conclusion, insulin downregulates inflammatory response, regulates M1 macrophage transition in response to HG, and thus improves chronic wound healing.

Impact of the mode of protraction of basal insulin therapies on their pharmacokinetic and pharmacodynamic properties and resulting clinical outcomes.

Manufacturers of insulin products for diabetes therapy have long sought ways to modify the absorption rate of exogenously administered insulins in an effort to better reproduce the naturally occurring pharmacokinetics of endogenous insulin secretion. Several mechanisms of protraction have been used in pursuit of a basal insulin, for which a low injection frequency would provide tolerable and reproducible glucose control; these mechanisms have met with varying degrees of success. Before the advent of recombinant DNA technology, development focused on modifications to the formulation that increased insulin self-association, such as supplementation with zinc or the development of preformed precipitates using protamine. Indeed, NPH insulin remains widely used today despite a frequent need for a twice-daily dosing and a relatively high incidence of hypoglycaemia. The early insulin analogues used post-injection precipitation (insulin glargine U100) or dimerization and albumin binding (insulin detemir) as methods of increasing therapeutic duration. These products approached a 24-hour glucose-lowering effect with decreased variability in insulin action. Newer basal insulin analogues have used up-concentration in addition to precipitation (insulin glargine U300), and multihexamer formation in addition to albumin binding (insulin degludec), to further increase duration of action and/or decrease the day-to-day variability of the glucose-lowering profile. Clinically, the major advantage of these recent analogues has been a reduction in hypoglycaemia with similar glycated haemoglobin control when compared with earlier products. Future therapies may bring clinical benefits through hepato-preferential insulin receptor binding or very long durations of action, perhaps enabling once-weekly administration and the potential for further clinical benefits.

Lipid changes during basal insulin peglispro, insulin glargine, or NPH treatment in six IMAGINE trials.

Basal insulin peglispro (BIL) is a novel basal insulin with hepato-preferential action resulting from reduced peripheral effects. This report provides an integrated summary of lipid changes at 26 weeks with BIL and comparator insulins (glargine, NPH) from phase III studies in type 1 diabetes (T1D), insulin-naïve patients with type 2 diabetes (T2D), patients with T2D on basal insulin only and patients with T2D on basal-bolus therapy. BIL treatment had little effect on HDL cholesterol and LDL cholesterol in all patients. The effect of both BIL and glargine treatment on triglycerides (TG) depended on whether patients had been previously treated with insulin. When BIL replaced conventional insulin glargine or NPH treatments, increases in TG levels were observed. When BIL or comparator insulins were given for 26 weeks to insulin-naïve patients with T2D, TG levels were unchanged from baseline with BIL but decreased with either glargine or NPH. The decreased peripheral action of BIL may reduce suppression of lipolysis in peripheral adipose tissue resulting in increased free fatty acid delivery to the liver and, hence, increased hepatic TG synthesis and secretion.

Protamine zinc insulin combined with sodium selenite improves glycometabolism in the diabetic KKAy mice.

Long-term, high dosage protamine zinc insulin (PZI) treatments produce adverse reactions. The trace element selenium (Se) is a candidate for the prevention of diabetes due to anti-oxidative stress activity and the regulation of glycometabolism. In this study, we aimed to investigate the anti-diabetic effects of a combination of PZI and Se on type 2 diabetes. Diabetic KKAy mice were randomized into the following groups: model group and groups that were subcutaneously injected with PZI, Se, high or low dose PZI + Se for 6 weeks. PZI combined with Se decreased the body weight and fasting blood glucose levels. Moreover, this treatment also improved insulin tolerance, as determined by the reduced values from the oral glucose tolerance test and insulin tolerance test, and increased insulin levels and insulin sensitivity index. PZI combined with Se ameliorated skeletal muscle and ß-cell damage and the impaired mitochondrial morphology. Oxidative stress was also reduced. Furthermore, PZI combined with Se upregulated phosphatidylinositol 3-kinase (PI3K) and downregulated protein tyrosine phosphatase 1B (PTP1B). Importantly, the low dosage combination produced effects similar to PZI alone. In conclusion, PZI combined with Se improved glycometabolism and ameliorated the tissue and mitochondrial damage, which might be associated with the PI3K and PTP1B pathways.

Replacing Insulin Glargine with Neutral Protamine Hagedorn (NPH) Insulin in a Subpopulation of Study Subjects in the Action to Control Cardiovascular Risk in Diabetes (ACCORD): Effects on Blood Glucose Levels, Hypoglycemia and Patient Satisfaction.

OBJECTIVE: To ensure patient safety when replacing insulin glargine (IG) with neutral protamine Hagedorn (NPH) insulin and to determine differences in blood glucose control, frequency of hypoglycemia, insulin dosing, health resource utilization and quality of life between users of IG and NPH insulin. METHODS: A single-site, open-label, randomized, 6-month comparative study of 66 patients from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Randomization was 1:1 to receive IG or NPH insulin. Data regarding blood glucose control, insulin dosage adjustment and recording of hypoglycemia episodes were obtained through telephone calls; office visits were conducted to measure weight, glycated hemoglobin, fasting plasma glucose and blood glucose profile. The Diabetes Treatment Satisfaction Questionnaire (DTSQ) was used to measure patients' satisfaction with their diabetes treatment. RESULTS: Rates of symptomatic hypoglycemia did not differ significantly between groups: 37.5±2.2 for the IG group and 31.1±2.1 for the NPH group. However, patients treated with NPH insulin had higher frequencies of severe hypoglycemia (6.1±0.9) compared with 2.7±0.6 for the IG group. A significant difference in changes in glycated hemoglobin (A1C) was observed between the groups: the mean ± standard error A1C decreases from baseline were -0.34%±0.11 for the IG group, vs -0.01%±0.10 for the NPH insulin group. The data obtained from the DTSQ showed greater treatment satisfaction in the IG group compared with the NPH insulin group. CONCLUSIONS: Switching from IG to NPH insulin resulted in more than double the rate of severe hypoglycemias and led to decreased metabolic control. Greater treatment satisfaction was observed with IG, compared with NPH insulin, as measured by change from baseline in the DTSQ scores.

Insulin Detemir Is Transported From Blood to Cerebrospinal Fluid and Has Prolonged Central Anorectic Action Relative to NPH Insulin.

Insulin detemir (DET) reduces glycemia comparably to other long-acting insulin formulations but causes less weight gain. Insulin signaling in the brain is catabolic, reducing food intake. We hypothesized that DET reduces weight gain, relative to other insulins, owing to increased transport into the central nervous system and/or increased catabolic action within the brain. Transport of DET and NPH insulin into the cerebrospinal fluid (CSF) was compared over several hours and after the administration of different doses peripherally in rats. DET and NPH had comparable saturable, receptor-mediated transport into the CSF. CSF insulin remained elevated significantly longer after intraperitoneal DET than after NPH. When administered acutely into the 3rd cerebral ventricle, both DET and NPH insulin reduced food intake and body weight at 24 h, and both food intake and body weight remained lower after DET than after NPH after 48 h. In direct comparison with another long-acting insulin, insulin glargine (GLAR), DET led to more prolonged increases in CSF insulin despite a shorter plasma half-life in both rats and mice. Additionally, peripheral DET administration reduced weight gain and increased CSF insulin compared with saline or GLAR in mice. Overall, these data support the hypothesis that DET has distinct effects on energy balance through enhanced and prolonged centrally mediated reduction of food intake.

Effect of subcutaneous insulin detemir on glucose flux and lipolysis during hyperglycaemia in people with type 1 diabetes.

AIMS: To investigate, using a novel non-steady-state protocol, the differential effects of subcutaneous (s.c.) detemir and NPH insulin on glucose flux and lipid metabolism after insulin withdrawal. METHODS: After a period of insulin withdrawal resulting in whole-blood glucose concentration of 7 mmol/l, 11 participants (five men, mean age 41.0 years, mean body mass index 25 kg/m(2)) with type 1 diabetes (mean glycated haemoglobin concentration 57 mmol/mol, mean diabetes duration 14 years) received 0.5 units per kg body weight s.c. insulin detemir or NPH insulin in random order. Stable isotopes of glucose and glycerol were infused intravenously throughout the study protocol. RESULTS: Glucose concentration decreased after insulin treatment as a result of suppression of endogenous glucose production, which occurred to a similar extent with both detemir and NPH insulin. The rate of glucose disappearance (Rd) was not increased significantly with either type of insulin. When the effect of detemir and NPH insulin on glucose flux at glucose concentrations between 9 and 6 mmol/l was examined, glucose rate of appearance (Ra) was similar with the two insulins; however, glucose Rd was greater with NPH insulin than with detemir at glucose concentrations of 8.0, 8.5, 7.0 and 6.0 mmol/l (p < 0.05) The percentage change in glycerol Ra, a measure of lipolysis, was greater in the NPH group than in the detemir group (p = 0.04). CONCLUSIONS: The results of the study are consistent with the hypothesis that detemir has a lesser effect on the periphery, as evidenced by a lesser effect on peripheral glucose uptake at specific glucose concentrations.

Similar glucose control with basal-bolus regimen of insulin detemir plus insulin aspart and thrice-daily biphasic insulin aspart 30 in insulin-naive patients with type 2 diabetes: Results of a 50-week randomized clinical trial of stepwise insulin intensification.

OBJECTIVE: This study aimed to demonstrate the non-inferiority of 50-week treatment with stepwise insulin intensification of basal-bolus insulin analogues [insulin detemir (IDet) and aspart (IAsp)] versus biphasic insulin aspart 30 (BIAsp30) in insulin-naive type 2 diabetes mellitus (T2DM) patients not controlled by oral glucose-lowering drugs (OGLDs). RESEARCH DESIGN AND METHODS: In this open-label multicentre, multinational, randomized, parallel-arm treat-to-target trial, 403 insulin-naive patients with T2DM in four African countries were randomized to either an IDet+IAsp (n = 200) or BIAsp1-2-3 (n = 203) treatment group. Stepwise insulin intensification was performed at the end of 14, 26 and 38 weeks, depending on HbA1c values. The primary endpoint was change in HbA1c after 50 weeks of treatment. Safety variables were hypoglycaemia incidence, occurrence of adverse events and weight gain. RESULTS: Non-inferiority of the IDet+IAsp versus BIAsp1-2-3 treatment regimen was demonstrated by their similar HbA1c levels at the end of trial (IDet+IAsp: baseline 8.6%, 50 weeks 7.4%; BIAsp1-2-3: baseline 8.7%, 50 weeks 7.3%; full analysis set difference: 0.1% [95% CI: -0.1, 0.3]; per protocol: 0.2% [95% CI: -0.1, 0.4]). At week 50, 40.3 and 44.9% of patients achieved HbA1c <7.0% with IDet+IAsp and BIAsp1-2-3, respectively. The rate of overall hypoglycaemia during the trial was also similar in both groups (IDet+IAsp: 9.4 events/patient-year; BIAsp1-2-3: 9.8 events/patient-year). CONCLUSION: Insulin initiation and intensification using IDet+IAsp was not inferior to BIAsp1-2-3 in insulin-naive patients with T2DM not controlled by OGLDs. Both regimens led to similar reductions in HbA1c values after 50 weeks of treatment.

Short-term effects of NPH insulin, insulin detemir, and insulin glargine on the GH-IGF1-IGFBP axis in patients with type 1 diabetes.

OBJECTIVE: Insulin regulates the GH-IGF1 axis. Insulin analogs differ from human insulin in receptor affinity and possibly liver accessibility. Therefore, we compared the GH-IGF1 axis response with human NPH insulin, insulin detemir, and insulin glargine in patients with type 1 diabetes (T1D). METHODS: A total of 17 patients (seven were women) with T1D (age of 42 (24-63) years (mean and range), BMI of 24.7 (19.5-28.3) kg/m(2), HbA1c of 7.2 (6.3-8.0) % (55 (45-64) mmol/mol), T1D duration of 26 (8-45) years) were studied using a randomized, three-period crossover design. Patients received s.c. injections of equal, individual doses of NPH, detemir, and glargine at 1800 h. Plasma glucose, serum total IGF1, bioactive IGF, IGF-binding protein (IGFBPs), and GH were measured hourly for 14 h post-injection. RESULTS: When compared with the area under the curve (AUC) following NPH and glargine, detemir resulted in the lowest 6-14 h AUC (mean and range) of IGFBP1 (1518 (1280-1800)) vs 1621 (1367-1922) vs 1020 (860-1210) µg/l×h) and GH (17.1 (14.1-20.6) vs 15.4 (12.7-18.6) vs 10.2 (8.5-12.3) µg/l×h), but in the highest AUC of bioactive IGF (3.8 (3.5-4.2) vs 3.7 (3.4-4.0) vs 4.4 (4.1-4.8) µg/l×h) (all P<0.01). These differences were unrelated to plasma glucose. By contrast, profiles of total IGF1, IGFBP2, and IGFBP3 were comparable. CONCLUSIONS: Independent of plasma glucose, a single dose of detemir caused larger suppression in serum IGFBP1 than NPH and glargine, whereas bioactive IGF was higher, thereby explaining the lower GH levels. Thus, detemir appears to be more liver specific than NPH insulin and glargine.

Evaluation of glucose response to 3 types of insulin using a continuous glucose monitoring system in healthy alpacas.

BACKGROUND: Persistent hyperglycemia is common in alpacas and typically requires insulin administration for resolution; however, little is known about alpacas' response to different insulin formulations. OBJECTIVES: To evaluate the effects of 3 insulin formulations on blood glucose concentrations and the use of a continuous glucose monitoring (CGM) system in alpacas. ANIMALS: Six healthy alpacas. METHODS: The CGM was installed in the left paralumbar fossa at the start of this crossover study and recorded data every 5 minutes. Regular insulin, NPH insulin, insulin glargine, and dextrose were administered to each alpaca over a 2-week period. Blood samples were collected for glucose testing at 0, 1, 2, 4, 6, 8, and 12 hours, and then every 6 hours after each administration of insulin or dextrose. Data were compared by using method comparison techniques, error grid plots, and ANOVA. RESULTS: Blood glucose concentrations decreased most rapidly after regular insulin administration when administered IV or SC as compared to the other formulations. The NPH insulin produced the longest suppression of blood glucose. The mean CGM interstitial compartment glucose concentrations were typically lower than the intravascular compartment glucose concentrations. The alpacas had no adverse reactions to the different insulin formulations. CONCLUSIONS AND CLINICAL IMPORTANCE: The NPH insulin might be more appropriate for long-term use in hyperglycemic alpacas because of its extended duration of action. A CGM is useful in monitoring glucose trends and reducing blood collection events, but it should not be the sole method for determining treatment protocols.

Insulin therapy improves islet functions by restoring pancreatic vasculature in high-fat diet-fed streptozotocin-diabetic rats.

BACKGROUND: In a previous study, we showed early insulin therapy could improve ß-cell function in type 2 diabetic patients. However, the molecular mechanism was not clear. In the present study, we addressed this question by analyzing the pancreatic microvasculature in diabetic rats after insulin treatment. METHODS: Diabetes was induced in rats by a combination of low dose streptozotocin (STZ; 40 mg/kg) and feeding of a high-fat diet. After the induction of diabetes, rats were treated with neutral protamine Hagedorn insulin (NPH; 6­8 U/day, s.c.) for 3 weeks. Three days after the end of treatment, rats were subjected to an intraperitoneal glucose tolerance test (IPGTT). The pancreatic microvasculature and the amount and size of the islets were evaluated by immunohistochemistry. Western blot analysis was used to determine levels of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGF-R2) protein. RESULTS: Treatment with NPH improved insulin secretion from ß-cells during the IPGTT and increased pancreatic islet size. The density of the microvasculature in the pancreas was determined by quantification of CD31, a marker of endothelial cells. Insulin treatment increased CD31 protein levels, as well as the expression of VEGF and VEGFR2. CONCLUSIONS: The results suggest that insulin treatment improves islet recovery by increasing angiogenesis in the pancreas. The mechanism is related to the induction of VEGF and VEGFR2 expression in diabetic rats.

Long-acting insulins alter milk composition and metabolism of lactating dairy cows.

This study investigated the effect of 2 different types of long-acting insulin on milk production, milk composition, and metabolism in lactating dairy cows. Multiparous cows (n=30) averaging 88 d in milk were assigned to one of 3 treatments in a completely randomized design. Treatments consisted of control (C), Humulin-N (H; Eli Lilly and Company, Indianapolis, IN), and insulin glargine (L). The H and L treatments were administered twice daily at 12-h intervals via subcutaneous injection for 10d. Cows were milked twice daily, and milk composition was determined every other day. Mammary biopsies were conducted on d 11, and mammary proteins extracted from the biopsies were analyzed by Western blot for components of insulin and mammalian target of rapamycin signaling pathways. Treatment had no effect on dry matter intake or milk yield. Treatment with both forms of long-acting insulin increased milk protein content and tended to increase milk protein yield over the 10-d treatment period. Analysis of milk N fractions from samples collected on d 10 of treatment suggested that cows administered L tended to have higher yields of milk protein fractions than cows administered H. Milk fat content and yield tended to be increased for cows administered long-acting insulins. Lactose content and yields were decreased by treatment with long-acting insulins. Administration of long-acting insulins, particularly L, tended to shift milk fatty acid composition toward increased short- and medium-chain fatty acids and decreased long-chain fatty acids. Plasma concentrations of glucose and urea N were lower for cows administered long-acting insulins; interactions of treatment and sampling time were indicative of more pronounced effects of L than H on these metabolites. Concentrations of nonesterified fatty acids and insulin were increased in cows administered long-acting insulins. Decreased concentrations of urea N in both plasma and milk suggested more efficient use of N in cows administered long-acting insulins. Western blot analysis of mammary tissue collected by biopsy indicated that the ratios of phosphorylated protein kinase b (Akt) to total Akt and phosphorylated ribosomal protein S6 (rpS6) to total rpS6 were not affected by long-acting insulins. Modestly elevating insulin activity in lactating dairy cows using long-acting insulins altered milk composition and metabolism. Future research should explore mechanisms by which either insulin concentrations or insulin signaling pathways in the mammary gland can be altered to enhance milk fat and protein production.

Integrating advances in insulin into clinical practice: Overview of current insulin formulations.

Defects in both insulin secretion and function play a fundamental role in the pathophysiologic mechanisms underlying both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). As the most physiologic treatment option available, insulin plays a central role in the management of patients with T1DM and a growing role in the management of patients with T2DM, as is reflected in current treatment guidelines.

Practical approach to management of inpatient hyperglycemia in select patient populations.

Hospitalized patients frequently transition between various levels of care and changing clinical situations. Optimal management of hospitalized patients with hyperglycemia includes awareness of situations that may significantly affect glucose and/or insulin metabolism. A review of published clinical trials reveals practical approaches to the management of hyperglycemia in select patient populations that may prove useful for the hospital clinician. We outline approaches to the management of hyperglycemia in hospitalized patients receiving glucocorticoids, patients with severe or end-stage renal disease undergoing hemo- or peritoneal dialysis, and patients receiving total parenteral or enteral feeding, in addition to patients transitioning from intravenous insulin infusion to subcutaneously administered insulin. Key considerations underlying these management methods include a proactive approach, frequent blood glucose monitoring, daily review of blood glucose patterns, and daily reassessment of the insulin regimen and associated orders.

Concentrations of insulin glargine and its metabolites during long-term insulin therapy in type 2 diabetic patients and comparison of effects of insulin glargine, its metabolites, IGF-I, and human insulin on insulin and igf-I receptor signaling.

We investigated 1) the ability of purified glargine (GLA), metabolites 1 (M1) and 2 (M2), IGF-I, and NPH insulin to activate the insulin receptor (IR)-A and IR-B and IGF-I receptor (IGF-IR) in vitro; 2) plasma concentrations of GLA, M1, and M2 during long-term insulin therapy in type 2 diabetic patients; and 3) IR-A and IR-B activation in vitro induced by serum from patients treated with GLA or NPH insulin. A total of 104 patients (age 56.3 ± 0.8 years, BMI 31.4 ± 0.5 kg/m(2), and A1C 9.1 ± 0.1% [mean ± SE]) were randomized to GLA or NPH insulin therapy for 36 weeks. Plasma concentrations of GLA, M1, and M2 were determined by liquid chromatography-tandem mass spectrometry assay. IR-A, IR-B, and IGF-IR autophosphorylation was induced by purified hormones or serum by kinase receptor activation assays. In vitro, M1 induced comparable IR-A, IR-B, and IGF-IR autophosphorylation (activation) as NPH insulin. After 36 weeks, M1 increased from undetectable (<0.2 ng/mL) to 1.5 ng/mL (0.9-2.1), while GLA and M2 remained undetectable. GLA dose correlated with M1 (r = 0.84; P < 0.001). Serum from patients treated with GLA or NPH insulin induced similar IR-A and IR-B activation. These data suggest that M1 rather than GLA mediates GLA effects and that compared with NPH insulin, GLA does not increase IGF-IR signaling during long-term insulin therapy in type 2 diabetes.

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.