Eficacia y Seguridad del uso de la insulina análoga de acción corta Lispro en comparación con insulina regular humana (NPH) en pacientes niños, adolescentes y adultos con Diabetes Mellitus tipo 1 / Efficacy and Safety of Using Analog Insulin of action cuts Lispro in comparison with insulin regular human function (NPH) in child patients, adolescents and adults with type 1 Diabetes Mellitus

INTRODUCCIÓN: La Diabetes Mellitus tipo (DM1) es una enfermedad que se caracteriza por una hiperglicemia persistente debido a una disminución o ausencia de células beta pancreáticas por destrucción de las mismas. Esta hiperglicemia persistente aumenta luego de cada comida, debido a la falta de insulina. Por lo tanto, como parte de la insulinoterapia, es prioritario conocer los valores previos de glicemia para poder optimizar la dosis de insulina de cada paciente, tanto para poder detectar valores elevados como valores bajos. TECNOLOGÍA SANITARIA: La insulina Lispro es un análogo de acción corta de insulina producidas mediante tecnología de ADN recombinante, que regula el metabolismo de la glucosa a través de la estimulación de la captación de glucosa en el tejido esquelético y la grasa, así como la inhibición de la producción de glucosa hepática. OBJETIVO: Evaluar la eficacia y seguridad, de la insulina Lispro en comparación de la insulina NPH en las personas con Diabetes Mellitus Tipo 1 para el desarrollo de la hipoglicemia severa, mejorar la calidad de vida y la adherencia. METODOLOGÍA: Se realizó una búsqueda sistemática en las bases de datos bibliográficas: MEDLINE (PubMed), LILACS, Cochrane Library, así́como en buscadores genéricos de Internet incluyendo Google Scholar. Así también, se hizo una búsqueda en agencias que realizan evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC). RESULTADOS: Se seleccionó una revisión sistemática, cinco guías de práctica clínica, una evaluación de tecnologías sanitarias y un ensayo clínico aleatorizado para responder la pregunta PICO formulada. CONCLUSIONES: En pacientes con DM1, el uso de la insulina Lispro en comparación de la insulina NPH, no tuvo diferencias en el riesgo de hipoglicemia severa y la calidad de vida de los pacientes. Las cinco GPC recomiendan preferentemente usar análogos de insulina, como Lispro para pacientes que con alto riesgo de hipoglucemia se definen como aquellos con antecedentes de hipoglucemia grave (que requieren asistencia para su manejo), alteración de la conciencia de la hipoglucemia (IAH) y/o condiciones médicas que los predisponen a la hipoglucemia grave incluida la disfunción renal y hepática. El informe de ETS de Canadá concluye que no hay diferencia en los episodios de hipoglicemia entre la insulina Lispro y la insulina NPH, más que solo un grupo en riesgo de hipoglicemia severa se beneficiaria de la intervención.

Hydrogen Peroxide-Triggered Conversion of Boronic Acid-Appended Insulin into Insulin and Its Application as a Glucose-Responsive Insulin Formulation.

p-Boronophenylmethoxycarbonyl (BPmoc) is a protecting group for amines that is removable by treatment with hydrogen peroxide (H2O2). We prepared BPmoc-modified insulin (BPmoc-Ins) and subcutaneously injected the formulation into diabetic rats. The results demonstrated that BPmoc effectively sealed the blood glucose (Glc)-lowering effects of Ins. Conversely, coinjection of BPmoc-Ins and Glc oxidase (GOx) resulted in reduced blood Glc levels, indicating that Ins was generated from BPmoc-Ins through the following reactions: oxidation of endogenous Glc by GOx; production of H2O2 accompanied by Glc oxidation; removal of BPmoc residues by H2O2. These results show the potential of BPmoc-Ins for a Glc-responsive Ins release system.

RNA m6A reader IMP2/IGF2BP2 promotes pancreatic ß-cell proliferation and insulin secretion by enhancing PDX1 expression.

BACKGROUND: Type 2 diabetes (T2D) is a common metabolic disease. Variants in human IGF2 mRNA binding protein 2 (IMP2/IGF2BP2) are associated with increased risk of T2D. IMP2 contributes to T2D susceptibility primarily through effects on insulin secretion. However, the underlying mechanism is not known. METHODS: To understand the role of IMP2 in insulin secretion and T2D pathophysiology, we generated Imp2 pancreatic ß-cell specific knockout mice (ßIMP2KO) by recombining the Imp2flox allele with Cre recombinase driven by the rat insulin 2 promoter. We further characterized metabolic phenotypes of ßIMP2KO mice and assessed their ß-cell functions. RESULTS: The deletion of IMP2 in pancreatic ß-cells leads to reduced compensatory ß-cell proliferation and function. Mechanically, IMP2 directly binds to Pdx1 mRNA and stimulates its translation in an m6A dependent manner. Moreover, IMP2 orchestrates IGF2-AKT-GSK3ß-PDX1 signaling to stable PDX1 polypeptides. In human EndoC-ßH1 cells, the over-expression of IMP2 is capable to enhance cell proliferation, PDX1 protein level and insulin secretion. CONCLUSION: Our work therefore reveals IMP2 as a critical regulator of pancreatic ß-cell proliferation and function; highlights the importance of posttranscriptional gene expression in T2D pathology.

Oral Coadministration of Zn-Insulin with d-Form Small Intestine-Permeable Cyclic Peptide Enhances Its Blood Glucose-Lowering Effect in Mice.

Oral delivery of insulin remains a challenge owing to its poor permeability across the small intestine and enzymatic digestion in the gastrointestinal tract. In a previous study, we identified a small intestine-permeable cyclic peptide, C-DNPGNET-C (C-C disulfide bond, cyclic DNP peptide), which facilitated the permeation of macromolecules. Here, we showed that intraintestinal and oral coadministration of insulin with the cyclic DNP derivative significantly reduced blood glucose levels by increasing the portal plasma insulin concentration following permeation across the small intestine of mice. We also found that protecting the cyclic DNP derivative from enzymatic digestion in the small intestine of mice using d-amino acids and by the cyclization of DNP peptide was essential to enhance cyclic DNP derivative-induced insulin absorption across the small intestine. Furthermore, intraintestinal and oral coadministration of insulin hexamer stabilized by zinc ions (Zn-insulin) with cyclic D-DNP derivative was more effective in facilitating insulin absorption and inducing hypoglycemic effects in mice than the coadministration of insulin with the cyclic D-DNP derivative. Moreover, Zn-insulin was more resistant to degradation in the small intestine of mice compared to insulin. Intraintestinal and oral coadministration of Zn-insulin with cyclic DNP derivative also reduced blood glucose levels in a streptozotocin-induced diabetes mellitus mouse model. A single intraintestinal administration of the cyclic D-DNP derivative did not induce any cytotoxicity, either locally in the small intestine or systemically. In summary, we demonstrated that coadministration of Zn-insulin with cyclic D-DNP derivative could enhance oral insulin absorption across the small intestine in mice.

In Vitro and in Vivo Comparative Study of Oral Nanoparticles and Gut Iontophoresis as Oral Delivery Systems for Insulin.

Multiple daily injections of insulin for diabetes cause many hazards for diabetic patients. Oral noninvasive insulin delivery could be more convenient and less painful than parenteral route. In past decades transdermal iontophoresis had been studied for insulin delivery across the skin with or without chemical permeation enhancers. However, the results of these studies were not efficacious and serum insulin levels were not therapeutically effective. In the present study an advanced technology "gut iontophoresis" for insulin delivery across the gut wall was compared with traditional oral insulin delivery in the form of nanoparticles. In vitro application of electric current to the intestinal membrane could enhance the flux of insulin nanoparticles (3.4 fold enhancement of insulin transport) from the donor to the receptor compartment in the Franz cell. In vivo iontophoresis of insulin nanoparticles through the gut wall would produce intense hypoglycemia (57% glycemia drop in 3 h) without damage of the intestinal tissues. Cell viability assay indicated that 50-500 µg/mL nanoparticles had no toxic effect on Caco-2 cells. Nanoparticles gut iontophoresis could be a promising non-invasive technique for oral insulin delivery.

Smart microneedle patches for rapid, and painless transdermal insulin delivery.

Insulin administration at mealtimes for the control of postprandial glucose is a major part of basal-bolus insulin therapy; however, painful subcutaneous (SC) injections lead to poor patient compliance. The microneedle (MN) patch, which allows painless transdermal drug delivery, is a promising substitute; however, it remains a big challenge to deliver insulin as rapidly as by SC injection. Here a novel MN patch is designed in which the MNs are coated with insulin/poly-l-glutamic acid (PGA) layer-by-layer (LBL) films at pH 3.0. This coating is pH-sensitive because the net charge of insulin turns from positive to negative when the pH increases from 3.0 to 7.4. As a result, when transferred to pH 7.4 media, e.g., when inserted into skin, the coating dissociates instantly and releases insulin rapidly. A brief epidermal application (<1 min) of the coated MNs is enough for complete film dissociation. More importantly, the coated MN patch exhibits a pharmacokinetic and a pharmacodynamic profile comparable to that of insulin administrated by SC injection, suggesting the coated MN patch can deliver insulin as rapidly as the SC injection. In addition, the patch exhibits excellent biocompatibility and storage stability. The new MN patch is expected to become a painless, convenient method for the control of postprandial glucose.

Diabetic Ketoacidosis and Related Events With Sotagliflozin Added to Insulin in Adults With Type 1 Diabetes: A Pooled Analysis of the inTandem 1 and 2 Studies.

OBJECTIVE: To evaluate the incidence and risk factors for diabetic ketoacidosis (DKA) and related adverse events (AEs) in adults with type 1 diabetes treated with sotagliflozin adjunctive to insulin. RESEARCH DESIGN AND METHODS: Data from two identically designed, 52-week, randomized studies were pooled and analyzed for DKA, changes in ß-hydroxybutyrate (BHB), and percentage of patients with BHB >0.6 and >1.5 mmol/L. The patients were administered placebo, sotagliflozin 200 mg, or sotagliflozin 400 mg once daily. RESULTS: A total of 191 ketosis-related AEs were reported, and 98 underwent adjudication. Of these, 37 events (36 patients) were adjudicated as DKA, with an exposure-adjusted incidence rate of 0.2, 3.1, and 4.2 events per 100 patient-years for placebo, sotagliflozin 200 mg, and sotagliflozin 400 mg, respectively. No patient died of a DKA event. From a baseline BHB of ∼0.13 mmol/L, sotagliflozin treatment led to a small median increase over 52 weeks (≤0.05 mmol/L at all time points). Of sotagliflozin-treated patients, approximately 47% and 7% had ≥1 BHB measurement >0.6 mmol/L and >1.5 mmol/L, respectively (vs. 20% and 2%, respectively, of placebo-treated patients). Subsequent to the implementation of a risk mitigation plan, annualized DKA incidence was lower versus preimplementation in both the sotagliflozin 200 and 400 mg groups. CONCLUSIONS: In patients with type 1 diabetes, confirmed DKA incidence increased when sotagliflozin was added to insulin compared with insulin alone. A lower incidence of DKA was observed following the implementation of an enhanced risk mitigation plan, suggesting that this risk can be managed with patient education.

Effect of Afrezza on Glucose Dynamics During HCL Treatment.

OBJECTIVE: A major obstacle in optimizing the performance of closed-loop automated insulin delivery systems has been the delay in insulin absorption and action that results from the subcutaneous (SC) route of insulin delivery leading to exaggerated postmeal hyperglycemic excursions. We aimed to investigate the effect of Afrezza inhaled insulin with ultrafast-in and -out action profile on improving postprandial blood glucose control during hybrid closed-loop (HCL) treatment in young adults with type 1 diabetes. RESEARCH DESIGN AND METHODS: We conducted an inpatient, three-way, randomized crossover standardized meal study to assess the efficacy and safety of Afrezza at a low (AL) and a high (AH) dose as compared with a standard SC rapid-acting insulin (aspart) premeal bolus during Diabetes Assistant (DiAs) HCL treatment. Participants received two sequential meals on three study days, and premeal insulin bolus was determined based on home insulin-to-carbohydrate ratio for each meal (rounded up to the closest available Afrezza cartridge dose for AH and down for AL). The primary efficacy outcome was the peak postprandial plasma glucose (PPG) level calculated by pooling data for up to 4 h after the start of each meal. Secondary outcomes included hyperglycemic, hypoglycemic, and euglycemic venous glucose metrics. RESULTS: The mean ± SD PPG for the rapid-acting insulin control arm and AH was similar (185 ± 50 mg/dL vs. 195 ± 46 mg/dL, respectively; P = 0.45), while it was higher for meals using AL (208 ± 54 mg/dL, P = 0.04). The AH achieved significantly lower early PPG level than the control arm (30 min; P < 0.001), and improvement in PPG waned at later time points (120 and 180 min; P = 0.02) coinciding with the end of Afrezza glucodynamic action. CONCLUSIONS: Afrezza (AH) premeal bolus reduced the early glycemic excursion and improved PPG during HCL compared with aspart premeal bolus. The improvement in PPG was not sustained after the end of Afrezza glucodynamic action at 120 min.

Insulina basal análoga versus insulina basal humana para el manejo de diabetes en pacientes con tuberculosis / Basal insulin analog versus basal human insulin for the diabetes management in tuberculosis patients

INTRODUCCIÓN: Este documento técnico se realiza a solicitud de la Dirección General de Intervenciones Estratégicas en Salud Pública - MINSA. A. Cuadro clínico: La tuberculosis (TB) es infección causada por la bacteria Mycobacterium tuberculosis. Cada año, 10 millones de personas tienen un nuevo diagnóstico de TB. A pesar de ser una enfermedad prevenible y curable, 1.5 millones de personas mueren de TB cada año, lo que la convierte en la principal causa de muerte infecciosa del mundo. La diabetes (DM) no sólo aumenta el riesgo de TB, sino que aumenta la probabilidad de fracaso al tratamiento de TB, con un aumento significativamente en la mortalidad y en el riesgo a desarrollar tuberculosis recurrente. Del mismo modo, la tuberculosis puede complicar el manejo de la diabetes y empeorar el control glucémico. Ambas condiciones tienen un impacto económico y de salud sustancial tanto en las personas como en sus familias. B. Tecnología sanitária: Las insulinas basales se dividen en insulinas humanas e insulina análogas humana La insulina NPH (protamina neutra de Hagedorn), también conocida como insulina isofana o insulina humana, es una molécula insoluble de acción intermedia. Es la insulina basal más usada, ayuda a incrementar la recaptación de glucosa en el hígado, tejido adiposo y músculos, también promoviendo la síntesis de glucógeno hepático y el metabolismo de ácidos grasos para la síntesis de lipoproteínas. Las insulinas análogas se diseñaron para tratar de imitar fisiológicamente la secreción oscilatoria de insulina de las células beta del páncreas. El mecanismo de acción es el mismo que el de la insulina humana, inhibir la producción hepática de glucosa, estimula la captación de glucosa en tejidos periféricos y adicionalmente inhibe la lipólisis y proteólisis. OBJETIVO: Evaluar la evidencia disponible acerca del uso de insulina basal humana versus insulina basal análoga para el manejo de diabetes en pacientes con tuberculosis. Además, compilaremos la evidencia y experiencia de su uso, así como otros documentos de políticas de cobertura. METODOLOGÍA: Se realizó una búsqueda en las principales bases de datos bibliográficas: MEDLINE, LILACS, COCHRANE y EMBASE, así como en buscadores genéricos de Internet incluyendo Google Scholar y TRIPDATABASE. Adicionalmente, se hizo una búsqueda dentro de la información generada por las principales instituciones internacionales de infectología y endocrinología, así como agencias de tecnologías sanitarias que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS), guías de práctica clínica (GPC) y evaluaciones económicas de la región. RESULTADOS: No se encontraron estudios que evaluaran comparativamente tratamientos basados en insulina. Adicionalmente se incluyeron dos GPC. Ante la escasez de información acerca de nuestra pregunta de interés incluimos cuatro revisiones narrativas. No se encontraron ETS o evaluaciones económicas de la región. En el año 2018 The Union (International Union Against Tuberculosis and Lung Disease) y la GPC para prevención, tratamiento y diagnóstico de tuberculosis publicada por el Ministerio de Salud Pública de Ecuador en 2018 coinciden en recomendar terapias basadas en insulina para el control de la DM al diagnóstico, sin embargo, no mencionan alguna preferencia basada en el tipo de insulina. Se identificaron cuatro revisiones narrativas que tienen como objetivo guiar a la práctica clínica. Estos documentos (R. van Crevel 2018, Rusalmi 2010, Riza et al. 2014 y Niazi et al 2012) contemplan a la insulina como una opción de tratamiento sin realizar una clara comparación entre los diferentes tipos de insulinas. CONCLUSIONES: La evidencia con respecto al uso de tratamientos basados en insulina, específicamente comparando insulina basal versus análoga, es escasa. Se seleccionaron dos GPC que, si bien recomendaban el uso de esquemas basados en insulina, no hacían una diferenciación de una tecnología por sobre la otra. No se identificaron evaluaciones de tecnología sanitaria ni evaluaciones económicas de la región.(AU)

Hollow fiber-combined glucose-responsive gel technology as an in vivo electronics-free insulin delivery system.

Accumulating evidence demonstrates that not only sustained elevation of blood glucose levels but also the glucose fluctuation represents key determinants for diabetic complications and mortality. Current closed-loop insulin therapy option is limited to the use of electronics-based systems, although it poses some technical issues with high cost. Here we demonstrate an electronics-free, synthetic boronate gel-based insulin-diffusion-control device technology that can cope with glucose fluctuations and potentially address the electronics-derived issues. The gel was combined with hemodialysis hollow fibers and scaled suitable for rats, serving as a subcutaneously implantable, insulin-diffusion-active site in a manner dependent on the subcutaneous glucose. Continuous glucose monitoring tests revealed that our device not only normalizes average glucose level of rats, but also markedly ameliorates the fluctuations over timescale of a day without inducing hypoglycemia. With inherent stability, diffusion-dependent scalability, and week-long & acute glucose-responsiveness, our technology may offer a low-cost alternative to current electronics-based approaches.

Electrothermal patches driving the transdermal delivery of insulin.

Transdermal patches have become a widely used approach for painless delivery of drugs. One major current limitation of these systems remains the restricted skin permeation of proteins and peptides as exemplified by insulin, necessitating different considerations for their successful transdermal delivery. We present a novel patch design based on the integration of nano-engineered heating elements on polyimide substrates for electrothermal transdermal therapy. The results reveal that tuning of the electrical resistivity of an array of gold nanoholes, patterned on polyimide, facilitates a fast-responding electrothermal skin patch, while post-coating with reduced graphene oxide offers capabilities for drug encapsulation, like insulin. Application of insulin-loaded patches to the skin of mice resulted in blood glucose regulation within minutes. While demonstrated for insulin, the skin patches might be well adapted to other low and high molecular weight therapeutic drugs, enabling on-demand electrothermal transdermal delivery.

A Novel Dual-Hormone Insulin-and-Pramlintide Artificial Pancreas for Type 1 Diabetes: A Randomized Controlled Crossover Trial.

OBJECTIVE: The rapid insulin-alone artificial pancreas improves glycemia in type 1 diabetes but daytime control remains suboptimal. We propose two novel dual-hormone artificial pancreas systems. RESEARCH DESIGN AND METHODS: We conducted a randomized crossover trial comparing a rapid insulin-alone artificial pancreas with rapid insulin-and-pramlintide and with regular insulin-and-pramlintide artificial pancreas systems in adults with type 1 diabetes. Participants were assigned to the interventions in random order during three 24-h inpatient visits. Each visit was preceded by an outpatient hormonal open-loop run-in period of 10-14 days. The dual-hormone artificial pancreas delivered pramlintide in a basal-bolus manner, using a novel dosing algorithm, with a fixed ratio relative to insulin. The primary outcome was time in the range 3.9-10.0 mmol/L. RESULTS: Compared with the rapid insulin-alone artificial pancreas system, the rapid insulin-and-pramlintide system increased the time in range from 74% (SD 18%) to 84% (13%) (P = 0.0014), whereas the regular insulin-and-pramlintide system did not change the time in range (69% [19%]; P = 0.22). The increased time in range with the rapid insulin-and-pramlintide system was due to improved daytime control (daytime time in range increased from 63% [23%] to 78% [16%], P = 0.0004). There were 11 (1 per 2.5 days) hypoglycemic events (<3.3 mmol/L with symptoms or <3.0 mmol/L irrespective of symptoms) with the rapid insulin-alone system, compared with 12 (1 per 2.3 days) and 18 (1 per 1.4 days) with the rapid and regular insulin-and-pramlintide systems, respectively. Gastrointestinal symptoms were reported after 0% (0 of 112) of meals with the rapid insulin-alone system, compared with 6% (6 of 108) and 11% (11 of 104) with the rapid and regular insulin-and-pramlintide systems, respectively; none of the symptoms were severe. CONCLUSIONS: A novel rapid insulin-and-pramlintide artificial pancreas improves glucose control compared with a rapid insulin-alone artificial pancreas (ClinicalTrials.gov number NCT02814123).

Randomized Controlled Trial of Mobile Closed-Loop Control.

OBJECTIVE: Assess the efficacy of inControl AP, a mobile closed-loop control (CLC) system. RESEARCH DESIGN AND METHODS: This protocol, NCT02985866, is a 3-month parallel-group, multicenter, randomized unblinded trial designed to compare mobile CLC with sensor-augmented pump (SAP) therapy. Eligibility criteria were type 1 diabetes for at least 1 year, use of insulin pumps for at least 6 months, age ≥14 years, and baseline HbA1c <10.5% (91 mmol/mol). The study was designed to assess two coprimary outcomes: superiority of CLC over SAP in continuous glucose monitor (CGM)-measured time below 3.9 mmol/L and noninferiority in CGM-measured time above 10 mmol/L. RESULTS: Between November 2017 and May 2018, 127 participants were randomly assigned 1:1 to CLC (n = 65) versus SAP (n = 62); 125 participants completed the study. CGM time below 3.9 mmol/L was 5.0% at baseline and 2.4% during follow-up in the CLC group vs. 4.7% and 4.0%, respectively, in the SAP group (mean difference -1.7% [95% CI -2.4, -1.0]; P < 0.0001 for superiority). CGM time above 10 mmol/L was 40% at baseline and 34% during follow-up in the CLC group vs. 43% and 39%, respectively, in the SAP group (mean difference -3.0% [95% CI -6.1, 0.1]; P < 0.0001 for noninferiority). One severe hypoglycemic event occurred in the CLC group, which was unrelated to the study device. CONCLUSIONS: In meeting its coprimary end points, superiority of CLC over SAP in CGM-measured time below 3.9 mmol/L and noninferiority in CGM-measured time above 10 mmol/L, the study has demonstrated that mobile CLC is feasible and could offer certain usability advantages over embedded systems, provided the connectivity between system components is stable.

Glucose and Counterregulatory Responses to Exercise in Adults With Type 1 Diabetes and Impaired Awareness of Hypoglycemia Using Closed-Loop Insulin Delivery: A Randomized Crossover Study.

OBJECTIVE: To evaluate exercise-related glucose and counterregulatory responses (CRR) in adults with type 1 diabetes with impaired awareness of hypoglycemia (IAH) using hybrid closed-loop (HCL) insulin delivery to maintain glucose homeostasis. RESEARCH DESIGN AND METHODS: Twelve participants undertook 45-min high-intensity intermittent exercise (HIIE) and moderate-intensity exercise (MIE) in random order. The primary outcome was continuous glucose monitoring (CGM) time in range (70-180 mg/dL) for 24-h post-exercise commencement. RESULTS: CGM time in range was similar for HIIE and MIE (median 79.5% [interquartile range 73.2, 87.6] vs. 76.1% [70.3, 83.9], P = 0.37), and time with levels <54mg/dL post-exercise commencement was 0%. HIIE induced greater increases in cortisol (P = 0.002), noradrenaline (P = 0.005), and lactate (P = 0.002), with no differences in adrenaline, dopamine, growth hormone, or glucagon responses. CONCLUSIONS: IAH adults using HCL undertaking HIIE and MIE exhibit heterogeneity in CRR. Novel findings were a preserved cortisol response and variable catecholamine responses to HIIE.

Determinants of longitudinal change in insulin clearance: the Prospective Metabolism and Islet Cell Evaluation cohort.

Objective: To evaluate multiple determinants of the longitudinal change in insulin clearance (IC) in subjects at high risk for type 2 diabetes (T2D). Research design and methods: Adults (n=492) at risk for T2D in the Prospective Metabolism and Islet Cell Evaluation cohort, a longitudinal observational cohort, had four visits over 9 years. Values from oral glucose tolerance tests collected at each assessment were used to calculate the ratios of both fasting C peptide-to-insulin (ICFASTING) and areas under the curve of C peptide-to-insulin (ICAUC). Generalized estimating equations (GEE) evaluated multiple determinants of longitudinal changes in IC. Results: IC declined by 20% over the 9-year follow-up period (p<0.05). Primary GEE results indicated that non-European ethnicity, as well as increases in baseline measures of waist circumference, white cell count, and alanine aminotransferase, was associated with declines in ICFASTING and ICAUC over time (all p<0.05). There were no significant associations of IC with sex, age, physical activity, smoking, or family history of T2D. Both baseline and longitudinal IC were associated with incident dysglycemia. Conclusions: Our findings suggest that non-European ethnicity and components of the metabolic syndrome, including central obesity, non-alcoholic fatty liver disease, and subclinical inflammation, may be related to longitudinal declines in IC.

Peripherally delivered hepatopreferential insulin analog insulin-406 mimics the hypoglycaemia-sparing effect of portal vein human insulin infusion in dogs.

AIMS: We previously quantified the hypoglycaemia-sparing effect of portal vs peripheral human insulin delivery. The current investigation aimed to determine whether a bioequivalent peripheral vein infusion of a hepatopreferential insulin analog, insulin-406, could similarly protect against hypoglycaemia. MATERIALS AND METHODS: Dogs received human insulin infusions into either the hepatic portal vein (PoHI, n = 7) or a peripheral vein (PeHI, n = 7) for 180 minutes at four-fold the basal secretion rate (6.6 pmol/kg/min) in a previous study. Insulin-406 (Pe406, n = 7) was peripherally infused at 6.0 pmol/kg/min, a rate determined to decrease plasma glucose by the same amount as with PoHI infusion during the first 60 minutes. Glucagon was fixed at basal concentrations, mimicking the diminished α-cell response seen in type 1 diabetes. RESULTS: Glucose dropped quickly with PeHI infusion, reaching 41 ± 3 mg/dL at 60 minutes, but more slowly with PoHI and Pe406 infusion (67 ± 2 and 72 ± 4 mg/dL, respectively; P < 0.01 vs PeHI for both). The hypoglycaemic nadir (c. 40 mg/dL) occurred at 60 minutes with PeHI infusion vs 120 minutes with PoHI and Pe406 infusion. ΔAUCepinephrine during the 180-minute insulin infusion period was two-fold higher with PeHI infusion compared with PoHI and Pe406 infusion. Glucose production (mg/kg/min) was least suppressed with PeHI infusion (Δ = 0.79 ± 0.33) and equally suppressed with PoHI and Pe406 infusion (Δ = 1.16 ± 0.21 and 1.18 ± 0.17, respectively; P = NS). Peak glucose utilization (mg/kg/min) was highest with PeHI infusion (4.94 ± 0.17) and less with PoHI and Pe406 infusion (3.58 ± 0.58 and 3.26 ± 0.08, respectively; P < 0.05 vs Pe for both). CONCLUSIONS: Peripheral infusion of hepatopreferential insulin can achieve a metabolic profile that closely mimics portal insulin delivery, which reduces the risk of hypoglycaemia compared with peripheral insulin infusion.

Concentrated insulins in current clinical practice.

New concentrated insulins (exceeding 100 units/mL) and dedicated devices have recently become available, offering new treatment options for people with diabetes, for basal and prandial insulin supplementation. The concentrated insulin formulations range from 2-fold concentration (insulin lispro 200 units/mL) with rapid-acting prandial action to 5-fold concentration (human regular insulin, 500 units/mL) with basal and short-acting prandial actions. Long-acting basal insulins include degludec 200 units/mL and glargine 300 units/mL. Concentrated insulins have been developed with the goal of easing insulin therapy by reducing the volume and number of injections and in some cases making use of altered pharmacokinetic and pharmacodynamic properties. This review summarizes the unique characteristics of each concentrated insulin to help healthcare providers and people with diabetes understand how to best use them.

Enterically delivered insulin tregopil exhibits rapid absorption characteristics and a pharmacodynamic effect similar to human insulin in conscious dogs.

AIMS: Current therapy fails to emulate rapid (first-phase) insulin release in relation to a meal, a key defect in types 1 and 2 diabetes. We aimed to quantify the pharmacokinetic (PK) and pharmacodynamic (PD) profile of insulin tregopil, an enterically-absorbed insulin analog that restores the normal distribution of insulin between the hepatic portal and peripheral circulations. MATERIALS AND METHODS: The PK and PD profiles of insulin tregopil were studied in overnight-fasted, catheterized, conscious canines using four approaches: (1) equimolar intraportal infusions of tregopil vs human insulin; (2) escalating doses of oral tregopil; (3) identical, consecutive enteric doses of tregopil; and (4) comparison of oral tregopil to inhaled and subcutaneous human insulin administration. RESULTS: Equimolar intraportal infusions of tregopil and human insulin resulted in very similar PK profiles and PD profiles were nearly identical. Enteric delivery of tregopil brought about rapid absorption with tmax = 20 minutes in most cases. Median tmax was 20 minutes for oral tregopil and inhaled insulin and 88 minutes for subcutaneous human insulin. The time required for arterial plasma insulin levels to return to baseline was approximately 90, 210 and 360 minutes for oral tregopil, inhaled insulin and subcutaneous insulin, respectively. CONCLUSIONS: Enterically delivered tregopil is rapidly absorbed and restores a portal-to-peripheral vascular distribution. These characteristics should improve postprandial hyperglycaemia in types 1 and 2 diabetes.

Control of Postprandial Hyperglycemia in Type 1 Diabetes by 24-Hour Fixed-Dose Coadministration of Pramlintide and Regular Human Insulin: A Randomized, Two-Way Crossover Study.

OBJECTIVE: Healthy pancreatic ß-cells secrete the hormones insulin and amylin in a fixed ratio. Both hormones are lacking in type 1 diabetes, and postprandial glucose control using insulin therapy alone is difficult. This study tested the pharmacodynamic effects of the amylin analog pramlintide and insulin delivered in a fixed ratio over a 24-h period. RESEARCH DESIGN AND METHODS: Patients with type 1 diabetes were stabilized on insulin pump therapy with insulin lispro before a randomized, single-masked, two-way crossover, 24-h inpatient study in which regular human insulin was administered with pramlintide or placebo using separate infusion pumps in a fixed ratio (9 µg/unit). Meal content and timing and patient-specific insulin doses were the same with each treatment. The primary outcome measure was change in mean glucose by continuous glucose monitoring (CGM). Profiles of laboratory-measured glucose, insulin, glucagon, and triglycerides were also compared. RESULTS: Mean 24-h glucose measured by CGM was lower with pramlintide versus placebo (8.5 vs. 9.7 mmol/L, respectively; P = 0.012) due to a marked reduction of postprandial increments. Glycemic variability was reduced, and postprandial glucagon and triglycerides were also lower with pramlintide versus placebo. Gastrointestinal side effects were more frequent during use of pramlintide; no major hypoglycemic events occurred with pramlintide or placebo. CONCLUSIONS: Coadministration of fixed-ratio pramlintide and regular human insulin for 24 h improved postprandial hyperglycemia and glycemic variability in patients with type 1 diabetes. Longer studies including dose titration under daily conditions are needed to determine whether this regimen could provide long-term improvement of glycemic control.