Endogenous Insulin Release Research Articles

Expression of Concern: The antidiabetic β3-adrenoceptor agonist BRL 26830A works by release of endogenous insulin (Am J Clin Nutr 1992;55:237S-41S)

Expression of Concern: The antidiabetic β3-adrenoceptor agonist BRL 26830A works by release of endogenous insulin (Am J Clin Nutr 1992;55:237S-41S)

Insulin Management for Gestational and Type 2 Diabetes in Pregnancy.

Insulin is preferred as the first-line agent for glucose management of gestational diabetes mellitus and type 2 diabetes in pregnancy when nutritional and lifestyle modifications are unable to achieve pregnancy-specific glucose targets. Individual heterogeneity in defects of insulin secretion or sensitivity in liver and muscle, unique genetic influences on pregnancy glycemic regulation, and variable cultural and lifestyle behaviors that affect meal, activity, sleep, and occupational schedules necessitate a personalized approach to insulin regimens. Newer insulin preparations have been developed to mimic the physiologic release of endogenous insulin, maintaining appropriate basal levels to cover hepatic gluconeogenesis and simulate the rapid, meal-related, bolus rise of insulin. Such physiologic basal-bolus dosing of insulin can be administered safely, achieving tighter glycemic control while reducing episodes of hypoglycemia. Insulin initiation and titration require understanding the pharmacodynamics of different insulin preparations in addition to a patient's glycemic profiles, effect of variable nutritional intake and mealtimes, physical activity, stress, timing of sleep cycles, and cultural habits. Educating and empowering patients to learn how their glucose responds to insulin, portion and content of meals, and physical activity can increase personal engagement in therapy, flexibility in eating patterns, and improved glycemic control. This Clinical Expert Series article is focused on optimizing insulin management (initiation, dosing, and titration) of gestational and type 2 diabetes in pregnancy.

Abstract #1403051: Hypoglycemia After Ingestion of Street “Valium” Containing Glyburide, Alcohol, and Cocaine

Sulfonylureas increase the release of endogenous insulin, which can lead to hypoglycemia with overdose or ingestion by nondiabetic patients. Alcohol is metabolized by the liver resulting in decreased gluconeogenesis which can lead to hypoglycemia. Cocaine is not known to cause hypoglycemia but cocaine use and hypoglycemia can have a similar clinical presentation. A 33-year-old male with a history of narcotic dependence and anxiety was admitted after being found unresponsive and diaphoretic. Paramedics reported a glucose of 18 milligram per deciliter (mg/dL) that increased to 109 mg/dL after D50W administration. He regained consciousness at the scene but developed recurrent hypoglycemia. Prior to the medical encounter, the patient bought on the street and ingested 2 unmarked light blue pills thought to be valium to treat his anxiety. Subsequently, he developed diaphoresis and weakness and consumed cocaine and alcohol in attempt to relieve these symptoms. Twenty hours after the initial ingestion of the light blue pills, patient lost consciousness. Venous glucose in the emergency room was 15 mg/dL. Initiation of D50W infusion progressively improved blood glucose values over twenty hours. Once alert and oriented, the patient reported no personal or family history of diabetes. Toxicology screen was positive for benzodiazepines, cannabis, and cocaine. Laboratory values were notable for insulin of 47.4 milli-international units per milliliter (mIU/mL) (2.6-24.9), C-peptide of 5.4 nanograms per milliliter (ng/mL) (1.1-4.4), and glucose of 44 mg/dL. Patient underwent a 72 hour fast which did not suggest insulinoma. Sulfonylurea screen was positive for glyburide. Patient was discharged home in stable condition. Sulfonylurea induced hypoglycemia leads to clinical sedation, mimicking the effects of benzodiazepines and opioids. Sulfonylureas can be sold on the street, misbranded as benzodiazepines, or mixed with opioids. This has opened a window of opportunity for misuse of these medications. Alcohol consumption can cause hypoglycemia, however the mechanism differs from sulfonylurea, opioid, or benzodiazepine induced hypoglycemia. When taken in combination, severe hypoglycemia can result. Physicians should be aware of this possibility and consider intentional or unintentional sulfonylurea abuse, with or without other drugs.

Diabetes Technology and the Human Factor.

Diabetes Technology and the Human Factor.

An Unusual Cause of Acidosis in a Man With Clostridium difficile Colitis

An Unusual Cause of Acidosis in a Man With Clostridium difficile Colitis

Fixed-ratio combination of insulin glargine plus lixisenatide (iGlarLixi) improves ß-cell function in people with type 2 diabetes.

AimMultiple studies support the efficacy of combining a glucagon‐like peptide 1 receptor agonist (GLP‐1RA) with basal insulin in people with type 2 diabetes inadequately controlled on dual/triple oral therapy. Fixed‐ratio combinations of basal insulin + GLP‐1RA represent a further advance to facilitate management. We assessed the impact of fixed‐ratio combination basal insulin + GLP‐1RA treatment on β‐cell function.Materials and MethodsWe analysed data from 351 participants in the LixiLan‐G trial (NCT02787551) randomized to receive iGlarLixi (insulin glargine 100 U/ml + lixisenatide) or to continue daily/weekly GLP‐1RA, both on top of metformin. Participants received a 2‐h meal tolerance test before randomization and at study end (26 weeks), with timed plasma glucose and C‐peptide determinations. β‐cell function parameters were resolved using mathematical modelling.ResultsIn the GLP‐1RA group (n = 162), both body weight and glycated haemoglobin decreased at week 26, yet none of the insulin secretion/β‐cell function parameters changed significantly. In contrast, in the iGlarLixi group (n = 189), glycated haemoglobin decreased significantly more than in the GLP‐1RA group (p < .0001) despite an increase in body weight (+1.7 ± 3.9 kg, p < .0001). Fasting and stimulated insulin secretion decreased at Week 26 (both p < .0001 vs. GLP‐1RA), while β‐cell glucose sensitivity increased by a median 35% (p = .0032 vs. GLP‐1RA). The incremental meal tolerance test glucose area showed a larger reduction with iGlarLixi versus GLP‐1RA (p < .0001).ConclusionsIn people with type 2 diabetes on metformin, 26‐week treatment with iGlarLixi resulted in a marked improvement in β‐cell function concomitant with sparing of endogenous insulin release and a reduction in meal absorption.

Fasting C-peptide values among adolescents in the National Health and Nutrition Examination Surveys.

To report fasting C-peptide values and variations across demographics in healthy non-diabetic adolescents included in the National Health and Nutrition Examination Surveys (NHANES) dataset. In this analysis, we used fasting C-peptide data from the 1999 to 2004 NHANES dataset for participants aged 12 to <18 years (n=2063). The mean ± SE age of the participants was 14.99 ± 0.06 years. The participants included 992 girls and 1071 boys, and more than 80% of participants had a body mass index (BMI) percentile of <85%. Among boys, the most notable finding was the increase in geometric mean C-peptide level from 0.51 nmol/L at age 12, to 0.65 nmol/L at age 15 years. Among girls, levels fluctuated around a geometric mean of 0.67 nmol/L. Girls had significantly higher mean log-transformed C-peptide concentrations than boys (P < 0.0001) after adjusting for age, race and BMI percentile category. After adjusting for age and BMI percentile category, non-Hispanic Black boys and girls had significantly lower C-peptide levels than non-Hispanic White (P=0.0026 and P=0.0093) and Mexican American boys and girls (P < 0.0001 and P < 0.0001), respectively. Despite these findings, both insulin and homeostatic model assessment of insulin resistance were greater in non-Hispanic Black compared to non-Hispanic White participants. Here we describe fasting C-peptide levels in a non-diabetic adolescent population. These data provide crucial insight into evaluating racial differences in endogenous insulin release and clearance and will provide novel information which can be used in assessing residual β-cell function and response to intervention therapy.

LIFE-SAVER INSULIN: "THE MORE THE BETTER"

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Calcium channel blockers (CCB) are cardiovascular drugs that act on L-type calcium channels. Toxic exposures related to CCB is estimated to be 4.16% of all prescription overdoses. Toxicity leads to peripheral vasodilation, conduction blockade, and reduction in myocardial contractility. Additionally, high doses of CCBs inhibit the release of endogenous insulin and induce a state of hypoinsulinemia. In this state, myocardial cells are unable to uptake glucose for metabolic activity, which can be detrimental in the setting of shock. Treatment of CCB overdose revolves around administration of fluids, calcium, vasopressors, and ionotropic agents. Furthermore, cases involving cardiogenic shock should consider prompt addition of hyperinsulinemic-euglycemic therapy (HIET). The mechanisms by which HIET treats CCB overdose is theorized to be due to improved glucose uptake by myocardial cells, a concentration dependent ionotropic effect and systemic vasodilation. CASE PRESENTATION: A 41-year-old male with hypertension and major depressive disorder presented in shock after he intentionally ingested 600mg amlodipine in combination with alcohol. Despite aggressive initial measures with intravenous fluids, glucagon, calcium gluconate and high-dose vasopressor therapy ((nor-)epinephrine, vasopressin and angiotensin II), his condition worsened. He was intubated and started on HIET (bolus of intravenous insulin 1unit/kg followed by an infusion which was steadily increased to 8units/kg/hr). A continuous infusion of D25W was administered to maintain euglycemia and plasmapheresis was started to aid in the removal of amlodipine.The patient's course was further complicated by acute renal failure which led to overt volume overload. Continuous renal replacement therapy (CRRT) and eventually intermittent hemodialysis were started. Ultimately, he was gradually weaned off vasopressor support over 7 days while on HIET. DISCUSSION: The presented case highlights the importance of HIET in treating refractory cardiogenic shock caused by CCB overdose. Concomitant renal failure can be additive to the patient's clinical picture due to high quantities of intravenous volume needed with HIET. To our knowledge this is the first case to successfully utilize prolonged HIET with CRRT for CCB overdose. This case demonstrates that there may be promise in the utility of prolonged HIET for cases of complex CCB overdose with refractory shock. Due to lack of large sample sizes and randomized controlled studies, consideration for prolonged therapy or its role in renal failure should be given on a case-by-case scenario. CONCLUSIONS: Prolonged HIET is a promising treatment for cases of complex CCB overdose with refractory shock. REFERENCE #1: Gummin DD, Mowry JB, Spyker DA, Brooks DE, Fraser MO, Banner W. 2016 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 34th Annual Report. Clin Toxicol (Phila) 2017;55:1072–252 REFERENCE #2: Graudins A, Lee HM, Druda D. Calcium channel antagonist and beta-blocker overdose: antidotes and adjunct therapies. BrJ Clin Pharmacol 2016;81:453–61 DISCLOSURES: No relevant relationships by Shijo Benjamin, source=Web Response No relevant relationships by Md Islam, source=Web Response No relevant relationships by Maulin Patel, source=Web Response No relevant relationships by Mirja Wirtz, source=Web Response

Chronic binge alcohol impairs glucose‐insulin dynamics in SIV‐infected female rhesus macaques

Background Antiretroviral therapy (ART) has significantly reduced mortality of people living with HIV (PLWH). Older PLWH, especially post-menopausal women, experience complex interactions of HIV, ART, hormonal status, and lifestyle behaviors such as at-risk alcohol use, increasing the risk of metabolic comorbidities. We have previously shown that chronic binge alcohol (CBA) reduces the acute insulin response to a glucose challenge in SIV-infected male macaques and that at-risk alcohol use decreases HOMA-β (a marker for pancreatic beta cell function) in PLWH. Meanwhile, the role of estrogen in pancreatic health maintenance is not fully understood. The objective of this study was to determine the effect of CBA and ovarian hormone loss, resulting from ovariectomy (OVX), on glucose-insulin dynamics and pancreatic integrity in SIV-infected female rhesus macaques. Hypothesis We hypothesized that chronic binge alcohol and ovariectomy would decrease insulin response to a glucose challenge and impair insulin and glucagon expression in pancreatic islets. Methods 28 adult female macaques were used in the study. CBA or isovolumetric water (VEH) was administered through an intragastric catheter for 30 minutes, 5 days a week, with blood alcohol concentrations reaching 50-60 mM. Three months after initiation of CBA/VEH administration, macaques were infected with SIVMac251 and 2.5 months later initiated on ART. After 1 month of ART, macaques underwent sham surgery or ovariectomy. Using a modified frequently sampled intravenous glucose tolerance test (FSIVGTT), blood glucose and serum insulin values were measured. Glucose and insulin dynamic measures including the acute insulin response to glucose (AIRg), insulin sensitivity (Si), disposition index (DI), and glucose effectiveness (Sg) were determined using minimal model software. Insulin and glucagon expression was determined in formalin-fixed, paraffin-embedded pancreatic tissue collected at study endpoint. Corrected total cell fluorescence for insulin and glucagon were calculated using ImageJ software. To confirm these results, total RNA was isolated from pancreas and mRNA expression of insulin and glucagon determined using quantitative PCR. Results There was a main effect of CBA to decrease AIRg (p=0.02) and increase Si (p=0.01). There were no statistically significant effects of OVX on AIRg (p=0.06) or Si (p=0.4). There were also no statistically significant effects of CBA or OVX on DI or Sg. Neither CBA nor OVX altered the protein or mRNA expression of insulin and glucagon in pancreatic islets. Conclusion CBA decreased the acute endogenous insulin release in response to a glucose challenge without significantly altering basal pancreatic islet expression of insulin and glucagon, while OVX did not significantly alter any of these measures. These results indicate that CBA impairs the immediate release of insulin from beta cell insulin secretory vesicles, and we speculate that CBA dysregulates the metabolic signaling pathway of insulin secretion. Determining mechanisms of pancreatic endocrine dysfunction will inform therapeutic strategies to improve alcohol-mediated impaired glucose insulin dynamics in the context of SIV/HIV.

Acute hyperglycaemia enhances both vascular endothelial function and cardiac and skeletal muscle microvascular function in healthy humans.

Multiple clinical studies report that acute hyperglycaemia (induced by mixed meal or oral glucose) decreases arterial vascular function in healthy humans. Feeding, however, impacts autonomic output, blood pressure, and insulin and incretin secretion, which may themselves alter vascular function. No prior studies have examined the effect of acute hyperglycaemia on both macro- and microvascular function while controlling plasma insulin concentrations. Macrovascular and microvascular functional responses to euglycaemia and hyperglycaemia were compared. Octreotide was infused throughout both protocols to prevent endogenous insulin release. Acute hyperglycaemia (induced by intravenous glucose) enhanced brachial artery flow-mediated dilatation, increased skeletal muscle microvascular blood volume and flow, and expanded cardiac muscle microvascular blood volume. Compared to other published findings, the results suggest that vascular responses to acute hyperglycaemia differ based on the study population (i.e. normal weight vs. overweight/obese) and/or glucose delivery method (i.e. intravenous vs. oral glucose). High glucose concentrations acutely provoke endothelial cell oxidative stress and are suggested to trigger diabetes-related macro- and microvascular injury in humans. Multiple clinical studies report that acute hyperglycaemia (induced by mixed meal or oral glucose) decreases arterial vascular function in healthy humans. Feeding, however, impacts autonomic output, blood pressure, and insulin and incretin secretion, which may each independently alter vascular function and obscure the effect of acute hyperglycaemia per se. Surprisingly, no studies have examined the acute effects of intravenous glucose-induced hyperglycaemia on both macro- and microvascular function while controlling plasma insulin concentrations. In this randomized study of healthy young adults, we compared macrovascular (i.e. brachial artery flow-mediated dilatation, carotid-femoral pulse wave velocity and post-ischaemic brachial artery flow velocity) and microvascular (heart and skeletal muscle perfusion by contrast-enhanced ultrasound) functional responses to euglycaemia and hyperglycaemia. Octreotide was infused throughout both protocols to prevent endogenous insulin release. Acute intravenous glucose-induced hyperglycaemia enhanced brachial artery flow-mediated dilatation (P=0.004), increased skeletal muscle microvascular blood volume and flow (P=0.001), and expanded cardiac muscle microvascular blood volume (P=0.014). No measure of vascular function changed during octreotide-maintained euglycaemia. Our findings suggest that unlike meal-provoked acute hyperglycaemia, 4h of intravenous glucose-induced hyperglycaemia enhances brachial artery flow-mediated dilatation, provokes cardiac and skeletal muscle microvascular function, and does not impair aortic stiffness. Previous findings of acute large artery vascular dysfunction during oral glucose or mixed meal ingestion may be due to differences in study populations and meal-induced humoral or neural factors beyond hyperglycaemia per se. (ClinicalTrials.gov number NCT03520569.).

Intraperitoneal insulin administration in pigs: effect on circulating insulin and glucose levels

IntroductionThe effect of intraperitoneal insulin infusion has limited evidence in the literature. Therefore, the aim of the study was to investigate the pharmacokinetics and pharmacodynamics of different intraperitoneal insulin boluses....

Targeting the Glucagon Receptor Signaling Pathway As a Novel Strategy to Counteract PI3K Inhibitor Induced Hyperglycemia While Sustaining Tumor PI3K Inhibition

Pathologic activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is an oncogenic driver for many malignancies, including lymphomas1. Although validated as a therapeutic oncologic target, the PI3K signaling pathway is also implicated in normal glucose homeostasis. Specifically, since the PI3K subunit p110α is chiefly responsible for downstream insulin receptor (INSR) signaling, PI3K signaling inhibition that includes p110α leads to severe hyperglycemia. Both compensatory endogenous insulin release as well as treatment of hyperglycemia with exogenous insulin/insulin mimetics activate INSR-associated PI3K signaling, ultimately limiting blockade of tumor associated PI3K signaling2. Aggressive lymphomas driven by pathologic PI3K signaling respond to combined PI3Kα and δ/γ inhibition, but this is likely submaximal due to endogenous insulin feedback, and more intense dosing is difficult to achieve safely due to severe hyperglycemia3. Therefore, a novel strategy to maintain blockade of tumor associated PI3K signaling while reducing hyperglycemia is needed. We hypothesized that inhibition of glucagon receptor (GCGR) signaling, a pathway that does not depend on PI3K, may normalize PI3K inhibitor induced hyperglycemia without disrupting antitumor PI3K blockade. GCGR blockade with a GCGR specific monoclonal antibody (REMD-477, a human anti-GCGR antibody, or REMD2.59c, a murine equivalent) may allow for the safer use of more potent PI3K inhibitors or more intensive dosing schedules in the treatment of aggressive lymphomas. The effect of GCGR blockade on PI3K inhibitor induced hyperglycemia was first evaluated in a non-tumor bearing mouse model using REMD2.59c. The PI3K inhibitor copanlisib was administered by tail vein injection to CB17 SCID mice in the control group every other day at the reported MTD of 15 mg/kg. REMD2.59c was administered by intraperitoneal injection to the treatment group intermittently on the day prior to copanlisib injection. Blood glucose levels were measured 2 hours after copanlisib injection. Significant hyperglycemia was observed after copanlisib treatment, and this was corrected by REMD2.59c pretreatment, confirming the effectiveness of GCGR blockade (Figure A-B). Having demonstrated that GCGR blockade controls hyperglycemia caused by PI3K inhibition with copanlisib in a mouse model, we next treated a 54 year old non-diabetic woman with relapsed and refractory peripheral T cell lymphoma (PTCL) on an IRB-approved clinical pilot study of copanlisib in combination with REMD-477. Following copanlisib 60mg IV alone, glucose increased from a baseline of 100mg/dl to a maximum of 592 mg/dl at 5 hours. For the following weekly doses of copanlisib, she was pre-treated with 70mg REMD-477 SQ, and copanlisib induced hyperglycemia was significantly ameliorated (Figure C). The patient tolerated treatment with REMD-477 well without significant episodes of hypoglycemia. With improved glycemic control on REMD-477, our patient did not require dose reductions or treatment delays, and experienced clinical improvement in lymphadenopathy on copanlisib. She had previously progressed through 6 lines of therapy, including duvelisib, a selective PI3K δ/γ inhibitor which necessitated dose reduction due to gastrointestinal toxicity. Our study of the GCGR mAb REMD-477 as a novel strategy to counteract PI3K inhibitor induced hyperglycemia and insulin feedback is an important advance that may allow for more effective and safer use of potent PI3K inhibitors in the treatment of aggressive lymphomas.

Toxicity of agents used for opioid withdrawal: a case-based approach.

Toxicity of agents used for opioid withdrawal: a case-based approach.

SAT-142 Enhanced Recovery Protocol (ERP) in Patients with Diabetes: Consider It More Often

Background: The perioperative use of Enhanced Recovery Protocol (ERP) has demonstrated improvement in the length of stay (LOS) and the rate of complications in multiple Randomized Control Trials (RCT)1. One of the components of this protocol is supplementation of carbohydrate solution (low dose: 10-44g or high dose: 45g or more) the night before and to two hours prior to the surgery. Carbohydrate rich drink as part of ERP improves glycemic control post-operatively most likely by inducing endogenous insulin release. This markedly improves the protein synthesis in first 24 hours after the surgery thereby improving muscle strength and nitrogen economy. However, most of the RCTs examining the impact of ERP have excluded the patients with diabetes2 due to concerns about an increased risk of poor outcomes. Patients with hyperglycemia are more likely to develop immunosuppression, impaired wound healing and perioperative infections3,4. Here we aim to study retrospectively the clinical outcomes of glucose supplementation in patients with diabetes compared to those without undergoing ERP for colorectal surgery. Methods: We conducted a retrospective chart review of 88 patients with diabetes and 437 patients without diabetes who used the ERP perioperatively for a colorectal surgery between September 2012 and February 2018. We performed an age and sex related cross match between 108 patients with diabetes (N=54) who received ERP to those without diabetes (N=54) who received ERP and compared the LOS as primary outcome. Data was summarized using descriptive statistics. Two-sample t-test/Wilcoxon rank sum test was used to compare the continuous variables including length of stay between diabetic and non-diabetic patients. Chi-squared/ Fisher’s exact test was used to see whether being diabetic or not was associated with other categorical variables such as gender. Results: Majority of the patients were white (83%) with private insurance (55%) and a mean age of 67.1 years. There was even distribution of males and females. There was no difference in the mean LOS of the patients with diabetes vs. those without diabetes (4.0 days [95% CI: 3.18 to 4.81 days] vs 4.03 days [95% CI: 3.09 to 4.98 days], P=0.95). Older age positively correlated with increased LOS, but race, insurance type and tumor pathology did not. Conclusions: Patients with diabetes undergoing colorectal surgery with use of an ERP protocol perioperatively have no significant difference in their length of stay as compared to those without diabetes. Although our study included only a small sample size, it supports the need to conduct an RCT that would further help to establish safety of utilization of ERP in patients with diabetes.

Impact of Endogenous Insulin Adjustment Methods on the Assessment of Insulin Pharmacokinetics and Pharmacodynamics

Assessing reliable insulin pharmacokinetics (PK) and pharmacodynamics (PD) following an exogenous insulin administration is a scientific challenge due to the circulating endogenous insulin. Effect of exogenous insulin on the endogenous insulin through the sensitive glucose homeostatic system in the body could further confound the PK/PD data. We compared results of PK/PD parameters of methods in literature for the estimation of insulin PK and PD, namely total method without adjustment (method 1), a simple baseline method (method 2), elimination rate constant method (method 3), empirical C-peptide correction method (method 4), and conventional PK/PD modeling method (method 5). We also developed new PK/PD modeling method reflecting the effect of glucose on endogenous insulin release based on C-peptide (method 6). Subject-level time-matching insulin and glucose concentrations without external glucose administration were collected from clinical trials with regular human insulin administration to healthy subjects under fasting conditions (n=23). Primary insulin PK parameters (i.e., the maximum concentration (Cmax) and area under the concentration-time profile (AUC)) were estimated using subjects’ insulin, glucose and C-peptide level data. Our results indicate that insulin AUC and Cmax differ by up to 32 and 17%, respectively, among different methods. Further, the contribution of endogenous insulin to total insulin AUC is estimated to be approximately 55% but varies depending upon estimation methods. Insulin PD parameters are apparently similar among different methods (e.g., area under the glucose concentration-time profile; 8121.4 and 8293.3 mg/dL*min for method 1-5 and method 6, respectively). The results call for a careful selection of the method for the assessment of insulin PK and PD parameters depending upon the objectives of study as the relationship between PK and PD could vary among methods and may lead to misinterpretation of data. Disclosure S.M. Chung: None. J.A. Penzenstadler: None. M. Khurana: None. C. Sahajwalla: None.

Diabetes medication pharmacology

Diabetes medication pharmacology

Sympathetic nervous system activity and anti-lipolytic response to iv-glucose load in subcutaneous adipose tissue of obese and obese type 2 diabetic subjects.

The study aim was to investigate the effect of endogenous insulin release on lipolysis in subcutaneous adipose tissue after adrenergic stimulation in obese subjects diagnosed with type 2 diabetes (T2D). In 14 obese female T2D subjects, or 14 obese non-T2D controls, glycerol concentration was measured in response to the α1,2,ß-agonist norepinephrine, the α1-agonist norfenefrine and the ß2-agonist terbutaline (each 10−4 M), using the microdialysis technique. After 60 minutes of stimulation, an intravenous glucose load (0.5 g/kg lean body mass) was given. Local blood flow was monitored by means of the ethanol technique. Norepinephrine and norfenefrine induced a four and three fold rise in glycerol dialysate concentration (p<0.001, each), with a similar pattern in adipose tissue. Following agonist stimulation and glucose infusion, endogenous insulin release inhibited lipolysis in the presence of norepinephrine, which was more rapid and pronounced in healthy obese controls than in T2D subjects (p = 0.024 obese vs T2D subjects). Insulin-induced inhibition of lipolysis in the presence of norfenefrine was similar in all study participants. In the presence of terbutaline the lipolysis rate increased two fold until the effect of endogenous insulin (p<0.001). A similar insulin-induced decrease in lipolysis was observed for each of the norfenefrine groups and the terbutaline groups, respectively. Adipose tissue blood flow remained unchanged after the iv-glucose load. Both norepinephrine and norfenefrine diminished blood flow slightly, but insulin reversed this response (p<0.001 over the entire time). Terbutaline alone and terbutaline plus increased endogenous insulin augmented local blood flow (p<0.001 over the entire time). In conclusion, a difference in insulin-induced inhibition of lipolysis was observed in obese T2D subjects compared to obese healthy controls following modulation of sympathetic nervous system activity and is assumed to be due to ß1-adrenoceptor mediated stimulation by norepinephrine.

A Pooled Analysis of Clinical Pharmacology Trials Investigating the Pharmacokinetic and Pharmacodynamic Characteristics of Fast-Acting Insulin Aspart in Adults with Type 1 Diabetes.

BackgroundFast-acting insulin aspart (faster aspart) is insulin aspart (IAsp) in a new formulation aiming to mimic the fast endogenous prandial insulin release more closely than currently available insulin products. In a post hoc analysis of pooled data from six clinical pharmacology trials, the pharmacological characteristics of faster aspart and IAsp were compared.MethodsThe analysis included 218 adult subjects with type 1 diabetes from six randomised, double-blind, crossover trials in the faster aspart clinical development programme. Subjects received subcutaneous dosing (0.2 U/kg) of faster aspart and IAsp. In three trials, a 12-h euglycaemic clamp was performed (target 5.5 mmol/L; 100 mg/dL) to assess pharmacodynamics.ResultsThe pharmacokinetic and pharmacodynamic profiles were left-shifted for faster aspart versus IAsp. Onset of appearance occurred 4.9 min earlier (95% confidence interval [CI] faster aspart-IAsp: [−5.3 to −4.4], p < 0.001), early exposure (AUCIAsp,0–30min) was two times greater (estimated ratio faster aspart/IAsp 2.01 [1.87–2.17], p < 0.001) and offset of exposure (t Late 50% Cmax) occurred 12.2 min earlier [−17.9 to −6.5] (p < 0.001) for faster aspart versus IAsp. Accordingly, onset of action occurred 4.9 min earlier [−6.9 to −3.0] (p < 0.001), early glucose-lowering effect (AUCGIR,0–30min) was 74% greater (1.74 [1.47–2.10], p < 0.001) and offset of glucose-lowering effect (t Late 50% GIRmax) occurred 14.3 min earlier [−22.1 to −6.5] (p < 0.001) for faster aspart versus IAsp. Total exposure and total glucose-lowering effect did not differ significantly between treatments.ConclusionsFaster aspart has the potential to better mimic the physiologic prandial insulin secretion and thereby to improve postprandial glucose control compared with IAsp. ClinicalTrials.gov identifiers: NCT02035371, NCT01924637, NCT02131246, NCT02033239, NCT02003677, NCT01618188.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-017-0514-8) contains supplementary material, which is available to authorized users.

β-cell-mimetic designer cells provide closed-loop glycemic control.

Chronically deregulated blood-glucose concentrations in diabetes mellitus result from a loss of pancreatic insulin-producing β cells (type 1 diabetes, T1D) or from impaired insulin sensitivity of body cells and glucose-stimulated insulin release (type 2 diabetes, T2D). Here, we show that therapeutically applicable β-cell-mimetic designer cells can be established by minimal engineering of human cells. We achieved glucose responsiveness by a synthetic circuit that couples glycolysis-mediated calcium entry to an excitation-transcription system controlling therapeutic transgene expression. Implanted circuit-carrying cells corrected insulin deficiency and self-sufficiently abolished persistent hyperglycemia in T1D mice. Similarly, glucose-inducible glucagon-like peptide 1 transcription improved endogenous glucose-stimulated insulin release and glucose tolerance in T2D mice. These systems may enable a combination of diagnosis and treatment for diabetes mellitus therapy.

Switching from Biphasic Human Insulin to Premix Insulin Analogs: A Review of the Evidence Regarding Quality of Life and Adherence to Medication in Type 2 Diabetes Mellitus.

Novo Nordisk.