Controlled intramolecular antagonism as a regulator of insulin receptor maximal activity.

In the treatment of insulin-dependent diabetes the risk of a fatal insulin overdose is a persistent fear to most patients. In order to potentially reduce the risk of overdose, we report the design, synthesis, and biochemical characterization of a set of insulin analogs designed to be fractionally reduced in maximal agonism at the insulin receptor isoforms. These analogs consist of native insulin that is site-specifically conjugated to a peptide-based insulin receptor antagonist. The structural refinement of the antagonist once conjugated to insulin provided a set of partial agonists exhibiting between 25 and 70% of the maximal agonism of native insulin at the two insulin receptor isoforms, with only slight differences in inherent potency. These rationally-designed partial agonists provide an approach to interrogate whether control of maximal activity can provide glycemic control with reduced hypoglycemic risk.

Development of Pulmonary Hypertension During Treatment with Diazoxide: A Case Series and Literature Review.

Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infancy. The mainstay of medical management for CHI is diazoxide. Diazoxide inhibits insulin release from the pancreas, but also causes smooth muscle relaxation and fluid retention so it is typically given with chlorothiazide. In July 2015, the FDA issued a drug safety communication warning that pulmonary hypertension (PH) had been reported in 11 infants being treated with diazoxide and that the PH resolved with withdrawal of diazoxide. All three of the cases in our hospital were admitted to the neonatal intensive care unit (NICU) for hypoglycemia. All patients received thorough radiologic and laboratory evaluations related to their diagnosis of CHI. All initially improved when diazoxide was initiated. Case 1 and case 3 were discharged from the NICU on diazoxide and chlorothiazide. Case 2 developed pulmonary hypertension while still in the NICU days after an increase in diazoxide dosing. Case 1 presented to the emergency room in respiratory distress shortly after discharge from the NICU with evidence of PH and heart failure. Case 3 presented to the emergency room after 2 weeks at home due to a home blood glucose reading that was low and developed PH and heart failure while an inpatient. Discontinuation of diazoxide led to resolution of all three patients' PH within approximately one week. The experience of our hospital indicates that pulmonary hypertension may be more common than previously thought in infants taking diazoxide. It is unclear if these symptoms develop slowly over time or if there is some other, as yet undescribed, trigger for the pulmonary hypertension. Our hospital's experience adds to the body of evidence and suggests these infants may benefit from more surveillance with echocardiography.

Diabetes Type 4: A Paradigm Shift in the Understanding of Glaucoma, the Brain Specific Diabetes and the Candidature of Insulin as a Therapeutic Agent.

In the present analysis, we aim at probing into many important mechanisms that serve to bridge conceptual gaps to fill up the mosaic of a picture revealing that glaucoma indeed is brain specific diabetes and more appropriately "Diabetes Type 4". Based on this conceptual substance, we weave a novel idea of insulin being a potential remedy for glaucoma. This analysis synthesizes upon the published literature on brain changes in glaucoma, possibility of isolated brain diabetes, insulin signaling glitches in glaucoma pathology, mitochondrial dysfunction and insulin resistance in glaucomatous eyes, insulin mediated regulation of intraocular pressure and its dysregulation in mitochondrial dysfunction. We also look into the role of amyloidopathy and taupathy in glaucoma pathogenesis vis-à-vis insulin signaling. At every step, the discussion reveals that insulin and other allied moieties are a sure promise for glaucoma treatment and management. In this article, we aim at synthesizing a persuasive and all inclusive picture of glaucoma etiopathomechanism centered on "insulin-hypofunctionality" in the central nervous system (i.e. brain specific diabetes). We start with considering the possibility of neurodegenerative diabetes that exists independent of the peripheral diabetes. Once that condition is met, then a metabolic conglomeration of this brain specific diabetes is deliberated upon leading us to understand the development of retinal ganglion cell apoptosis, intraocular pressure elevation, optic cupping and mitochondrial dysfunction. All these are the hallmarks and sufficient conditions to satisfy the diagnostic criteria for glaucoma. Immediate application of this analysis points towards glaucoma therapy centered upon improving what we have termed insulin-hypofunctionality.

Effects of subcutaneous, low-dose glucagon on insulin-induced mild hypoglycaemia in patients with insulin pump treated type 1 diabetes.

AIM: To investigate the dose-response relationship of subcutaneous (s.c.) glucagon administration on plasma glucose and on counter-regulatory hormone responses during s.c. insulin-induced mild hypoglycaemia in patients with type 1 diabetes treated with insulin pumps. METHODS: Eight insulin pump-treated patients completed a blinded, randomized, placebo-controlled study. Hypoglycaemia was induced in the fasting state by an s.c. insulin bolus and, when plasma glucose reached 3.4 mmol/l [95% confidence interval (CI) 3.2-3.5], an s.c. bolus of either 100, 200, 300 µg glucagon or saline was administered. Plasma glucose, counter-regulatory hormones, haemodynamic variables and side effects were measured throughout each study day. Peak plasma glucose level was the primary endpoint. RESULTS: Plasma glucose level increased significantly by a mean (95% CI) of 2.3 (1.7-3.0), 4.2 (3.5-4.8) and 5.0 (4.3-5.6) mmol/l to 6.1 (4.9-7.4), 7.9 (6.4-9.3) and 8.7 (7.8-9.5) vs 3.6 (3.4-3.9) mmol/l (p < 0.001) after the three different glucagon doses as compared with saline, and the increase was neither correlated with weight nor insulin levels. Area under the plasma glucose curve, peak plasma glucose, time to peak plasma glucose and duration of plasma glucose level above baseline were significantly enhanced with increasing glucagon doses; however, these were not significantly different between 200 and 300 µg glucagon. Free fatty acids and heart rates were significantly lower initially after glucagon than after saline injection. Other haemodynamic variables, counter-regulatory hormones and side effects did not differ between interventions. CONCLUSIONS: An s.c. low-dose glucagon bolus effectively restores plasma glucose after insulin overdosing. Further research is needed to investigate whether low-dose glucagon may be an alternative treatment to oral carbohydrate intake for mild hypoglycaemia in patients with type 1 diabetes.

Severe hypoglycemia is associated with antidiabetic oral treatment compared with insulin analogs in nursing home patients with type 2 diabetes and dementia: results from the DIMORA study.

OBJECTIVES: Severe hypoglycemia is associated with cognitive decline and dementia in older persons with type 2 diabetes. The role of antidiabetic treatments on severe hypoglycemia is unknown in dementia. The aims were to determine the prevalence of severe hypoglycemic events and investigate associations among severe hypoglycemic and specific antidiabetic treatments (classes of oral agents and types of insulin analogs) in a large sample of nursing home patients with diabetes according to dementia status. DESIGN: Cross-sectional observational study. SETTING: A total of 150 nursing homes across Italy. PARTICIPANTS: A total of 2258 patients with type 2 diabetes (dementia = 1138, no dementia = 1120). MEASUREMENTS: Diagnosis of dementia before nursing home admission. Data were collected regarding functional status, glycemic control, antidiabetic treatments, comorbidities, and biochemical and clinical measurements. Logistic regression models with severe hypoglycemia as the dependent variable were used to test associations with antidiabetic agents. RESULTS: Patients had a mean age (SD) of 82 (8) years, body mass index (BMI) of 25.4 (4.8), fasting plasma glucose (FPG) of 7.5 (3.0) mmol/L, postprandial glucose (PPG) of 10.3 (3.6) mmol/L, HbA1c of 7.1% (54 mmol/L), and impairments in activities of daily living (ADLs) of 3.7 (2.1). Severe hypoglycemia was more prevalent in patients with dementia (18%) compared with patients without dementia (8%). Patients with dementia were older, showed greater ADL impairments, greater number of comorbidities, lower FPG, and higher PPG compared with those without dementia. Adjusted logistic regression models in patients with dementia showed that rapid- and long-acting insulin analogs were associated with reduced odds ratio (OR) (OR 0.333; 95% confidence interval [CI] 0.184-0.602; OR 0.248, 95% CI 0.070-0.882, respectively), whereas sulphonylureas and combined metformin + sulphonylurea were associated with increased ORs (OR 8.805, 95% CI 4.260-18.201; OR 6.639; 95% CI 3.273-14.710, respectively) of experiencing severe hypoglycemia. No correlations were found in patients without dementia. CONCLUSION: In older nursing home patients with type 2 diabetes, severe hypoglycemia was significantly higher in dementia. Our findings suggest that sulphonylureas should be used with caution, whereas rapid- and long-acting insulin analogs seem safer.

Persistent hyperinsulinaemic hypoglycaemia in infancy.

Persistent hyperinsulinaemic hypoglycaemia in infancy (PHHI) is a heterogeneous condition characterised by unregulated insulin secretion in response to a low blood glucose level. It is the most common cause of severe and persistent hypoglycaemia in neonates. It is extremely important to recognise this condition early and institute appropriate management to prevent significant brain injury leading to complications like epilepsy, cerebral palsy and neurological impairment. Histologically, PHHI is divided mainly into three types-diffuse, focal and atypical disease. Fluorine-18-l-3,4-dihydroxyphenylalanine positron emission tomography (18F-DOPA-PET/CT) scan allows differentiation between diffuse and focal diseases. The diffuse form is inherited in an autosomal recessive (or dominant) manner whereas the focal form is sporadic in inheritance and is localised to a small region of the pancreas. The molecular basis of PHHI involves defects in key genes (ABCC8, KCNJ11, GCK, SLC16A1, HADH, UCP2, HNF4A and GLUD1) that regulate insulin secretion. Focal lesions are cured by lesionectomy whereas diffuse disease (unresponsive to medical therapy) will require a near-total pancreatectomy with a risk of developing diabetes mellitus and pancreatic exocrine insufficiency. Open surgery is the traditional approach to pancreatic resection. However, recent advances in laparoscopic surgery have led to laparoscopic near-total pancreatectomy for diffuse lesions and laparoscopic distal pancreatectomy for focal lesions distal to the head of the pancreas.

Efecto del tratamiento optimizado con insulina en la reactividad plaquetaria tras el alta de pacientes hiperglucémicos con síndrome coronario agudo / Effect of an optimized treatment with insulin on platelet reactivity after discharge in patients with an acute coronary syndrome and hyperglycemia

Introducción y objetivos. El control intensivo con insulina de la glucemia de pacientes con un síndrome coronario agudo reduce la reactividad plaquetaria durante la fase hospitalaria en comparación con un tratamiento convencional. Sin embargo, se desconoce el efecto en la reactividad plaquetaria con un control estricto de la glucemia a largo plazo. Métodos. Ensayo prospectivo y aleatorizado que evaluó el efecto de un tratamiento optimizado para el control de la glucemia (objetivo, 80-120 mg/dl) con insulina comparado con un tratamiento convencional (objetivo, < 180 mg/dl) en la reactividad plaquetaria al alta hospitalaria de pacientes con un síndrome coronario agudo e hiperglucemia. El objetivo primario es la valoración de la agregación plaquetaria tras estímulo con adenosina difosfato 20 mM a los 12 meses de seguimiento. Resultados. Se incluyó a 104 pacientes (53 al tratamiento optimizado y 51 al convencional). No se encontraron diferencias en las características basales de ambos grupos, incluida la función plaquetaria. A los 12 meses de seguimiento, las cifras de glucemia eran significativamente menores en el grupo de tratamiento optimizado (104 frente a 119 mg/dl; p < 0,001). Sin embargo, la agregación plaquetaria tras estímulo con adenosina difosfato 20 mM no mostró diferencias significativas entre los grupos (tratamiento optimizado frente a convencional, 54,2 ± 14,3% frente a 55,1 ± 18,3%; p = 0,81). Tampoco se objetivaron diferencias significativas con los otros tests de función plaquetaria evaluados. Conclusiones. El control optimizado de la glucemia con insulina a largo plazo en pacientes que han sufrido un síndrome coronario agudo no reduce la reactividad plaquetaria en comparación con un tratamiento convencional (AU)

Introduction and objectives. Intensive glucose control with insulin in patients with an acute coronary syndrome reduces platelet reactivity during hospitalization, compared to conventional control. However, the effect of strict, long-term glucose control on platelet reactivity in these patients remains uncertain. Methods. This is a prospective, randomized trial evaluating the effects of optimized glucose control (target glucose, 80-120 mg/dL) with insulin, compared with conventional control (target glucose, <180 mg/dL), on platelet reactivity after hospital discharge in patients with an acute coronary syndrome and hyperglycemia. The primary endpoint was assessment of platelet aggregation after stimulation with adenosine diphosphate 20 mM at 12-month follow-up. Results. One hundred four patients were randomized to optimized management (n=53) or conventional management (n=51). There were no differences between groups in baseline characteristics or platelet function. After 12 months of follow-up, blood glucose levels were significantly lower in the optimized treatment group (104 vs 119 mg/dL; P<.001). However, platelet aggregation following adenosine diphosphate 20 mM stimulation showed no differences between the groups (54.2% [14.3%] vs 55.1% [18.3%] respectively; P=.81). There were no significant differences for other platelet function tests. Conclusions. Long-term optimized glucose control with insulin in patients with an acute coronary syndrome did not result in a reduction in platelet reactivity compared to conventional control (AU)

Congenital hyperinsulinism in an infant with paternal uniparental disomy on chromosome 11p15: few clinical features suggestive of Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is the most common congenital overgrowth syndrome involving tumor predisposition. BWS is caused by various epigenetic or genetic alterations that disrupt the imprinted genes on chromosome 11p15.5 and the clinical findings of BWS are highly variable. Hyperinsulinemic hypoglycemia is reported in about half of all babies with BWS. We identified an infant with diazoxide-unresponsive congenital hyperinsulinism (HI) without any apparent clinical features suggestive of BWS, but diagnosed BWS by molecular testing. The patient developed severe hyperinsulinemic hypoglycemia within a few hours after birth, with macrosomia and mild hydronephrosis. We excluded mutations in the K(ATP) channel genes on chromosome 11p15.1, but found a rare homozygous single nucleotide polymorphism (SNP) of ABCC8. Parental SNP pattern suggested paternal uniparetal disomy in this region. By microsatellite marker analysis on chromosome 11p15, we could diagnose BWS due to the mosaic of paternal uniparental disomy. Our case suggests that some HI of unknown genetic etiology could involve undiagnosed BWS with no apparent clinical features, which might be diagnosed only by molecular testing.

Riesgos y beneficios del tratamiento de la hiperglucemia en el paciente hospitalizado no crítico / Risk and benefits of hyperglycemia treatment in the non-critical hospitalized patient

La prevalencia de hiperglucemia en los pacientes hospitalizados no críticos es alta, presentándose hasta en un tercio de los pacientes no diagnosticados previamente de diabetes. La hiperglucemia aumenta la morbimortalidad intrahospitalaria, siendo el impacto mayor en los pacientes no diabéticos conocidos. El beneficio del tratamiento intensivo de la hiperglucemia en pacientes hospitalizados no críticos está poco establecido, el único beneficio demostrado es la disminución del riesgo de infecciones. La recomendación actual es mantener una glucemia basal <140 mg/dl y utilizar la terapia bolo-basal para el control de la hiperglucemia durante el ingreso. Aunque el miedo a la hipoglucemia es una de las causas fundamentales del insuficiente control glucémico, la evidencia que tenemos de su repercusión en la morbimortalidad hospitalaria es muy limitada. La hipoglucemia al ingreso y la espontánea sí está asociada a un aumento de mortalidad intrahospitalaria. El mayor riesgo de hipoglucemia iatrogénica se produce al alta hospitalaria, por lo cual se debe planificar esta de forma adecuada

The prevalence of hyperglycemia in non-critical hospitalized patients is high, occurring in up to one third of patients not previously diagnosed with diabetes. Hyperglycemia increases hospital morbidity and mortality, the impact being greater in patients not known to be diabetics. The effect of intensive treatment of hyperglycemia in non-critical hospitalized patients is unclear, the only proven benefit is the reduction in the risk of infection. The current recommendation is to keep blood glucose levels <140mg/dL, and to use the basal-bolus insulin therapy for the glycemic control during hospitalization. Although the fear of inducing hypoglycemia is one of the main causes of poor glycemic control, the evidence of its impact on hospital morbidity and mortality is very limited. Only spontaneous hypoglycemia at admission and is associated with increased hospital mortality. There is an increased risk of iatrogenic hypoglycemia at discharge, so this should be carefully monitored

En relación con el número extraordinario monográfico sobre insulina aspártica / As regards the Special Issue on insulin aspart

No disponible

Xylitol toxicosis in dogs.

The sugar alcohol xylitol is a popular sweetener used in gums, candies, and baked goods. While xylitol has a wide margin of safety in people and most mammalian species, when ingested by dogs it is believed to stimulate excessive insulin secretion leading to severe hypoglycemia, potentially followed by acute hepatic failure and coagulopathies. Additional clinical findings may include thrombocytopenia, hypokalemia, and hyperphosphatemia. The prognosis for recovery in dogs that develop uncomplicated hypoglycemia is generally good with prompt and aggressive veterinary care.

Evaluation of an intensive insulin transition protocol in the intensive care unit setting: a before and after study / Evaluación de un protocolo de transición de insulina intensiva en una unidad de cuidados intensivos: estudio antes-después

The benefits of controlling blood glucose levels in intensive care units (ICUs) are well documented. Objective: This study determined the effectiveness and safety of a standardized transition order set for converting a continuous insulin infusion to a subcutaneous insulin regimen in non-cardiovascular surgery ICUs patient population. Methods: A retrospective study was conducted. Patients presenting with diabetic ketoacidosis or hyperosmolar hyperglycemic syndrome were excluded. One hundred patients were included prior to and 100 patients were included after initiating the transition order set. Blood glucose control was reviewed for up to 72 hours following the transition. Results: A total of 115 patients were included in data analysis: 85 prior to and 30 after transition protocol. All patients transitioned using the protocol were transitioned to basal insulin, compared to only 40% of the prior to protocol group. Patients transitioned correctly per the transition order set, «per protocol», had 54% of blood sugars within the desired range, no increase in hypoglycemic events, and on average 5.56 hyperglycemic events (blood glucose >180 mg/dL) per person during the 72 hours compared to 6.68 and 9.00 for the prior to protocol group and the «off protocol» group (transitioned different than the protocol recommended), respectively (p= 0.05). There were significant differences in blood sugar control at 48 and 72 hours between the «per protocol» and «off protocol» groups (p= 0.01) and a 40% reduction in sliding scale or correctional insulin coverage. Conclusion: The addition of basal insulin to transition regimens resulted in fewer hyperglycemic events with no increase in hypoglycemic events. Patients transitioned «per protocol» had better glucose control demonstrated by: less hyperglycemic events, lower mean blood glucose levels at 48 and 72 hours, and lower need for correctional insulin. These findings showed benefits of glycemic control in the ICU by following a standardized transition protocol (AU)

Los beneficios de controlar la glucemia en las unidades de cuidados intensivos (UCI) están ben documentados. Objetivo: Este estudio determinó la efectividad y seguridad de un orden de transición estandarizado para convertir un régimen de insulina de infusión continua a un régimen de insulina subcutánea en una población de pacientes de UCI de cirugía no vascular. Métodos: Se realizó un estudio retrospectivo. Se excluyó a los pacientes que presentaban cetoacidosis diabética o síndrome hiperglucémico hiperosmolar. Se incluyo a 100 pacientes antes y después de iniciar el sistema de transición. Se revisó la glucemia hasta 72 horas después de la transición. Resultados: Un total de 115 pacientes fueron incluidos para el análisis de datos: 85 antes y 35 después del protocolo de transición. Todos los pacientes que transitaron usando el protocolo pasaron a insulina basal, comparados con sólo el 40% del grupo de antes del protocolo. El 54% de los pacientes que transitaron correctamente con el protocolol, «por protocolo» tuvieron la glucemia en el rango deseado, sin aumento de eventos hipoglucémicos, y con un 5,56% de eventos hiperglucémicos (glucemia>180 mg/dL) durante las 72 horas de vigilancia, comparados con el 6,68% y 9,00% respectivamente para el grupo anterior al protocolo y el grupo «fuera de protocolo» (que transitó diferente a lo recomendado por el protocolo) (p=0,05). Hubo diferencia significativas en el control glucémico a las 48 y 72 horas entre los grupos «por protocolo» y «fuera de protocolo» (p=0,01) y un 40% de reducción en la escala descendente o cobertura de insulina de corrección. Conclusión: La adición de insulina basal a los regímenes de transición provocó menores eventos hiperglicémicos sin aumento de eventos hipoglicémicos. Los pacientes que transitaron «por protocolo» tuvieron mejor control glucémico, demostrado por: menores eventos hiperglucémicos, menores niveles medios de glucemia a las 48 y 72 horas, y menor necesidad de corrección de insulina. Estos hallazgos demostraron los beneficios de un control glucémico en la UCI siguiendo un protocolo estandarizado de transición (AU)

Role of insulin and testosterone in prostatic growth: who is doing what?

Previous studies have demonstrated increased incidence of benign prostatic hyperplasia in insulin-resistant individuals. In addition to androgens, prostatic growth is sensitive to the peptide growth factors including insulin. Experimental studies employing intervention of selective ß-cell toxin streptozotocin and castration suggest that depletion of either insulin or testosterone results in the severe prostatic atrophy (>80%). Exogenous testosterone and diet-induced experimental hyperinsulinemia induces prostatic enlargement in rats. Further, hyperinsulinemia sensitizes prostate towards the growth promoting effect of testosterone, and testosterone augments prostatic growth even in the hypoinsulinemic rats. However, in castrated rats diet-induced hyperinsulinemia fails to promote prostatic growth. Based on these evidences it is hypothesized that in the presence of testosterone insulin plays an important role in the prostatic growth. The epidemiological reports witnessing increased incidences of prostatic enlargement in men with metabolic syndrome, which are known to have increased level of insulin, provides a validating clue to the hypothesis. Further, the hypothesis suggests that targeting insulin signaling pathway could be a new objective for the treatment of prostatic enlargement.

Infertility and pregnancy in women with polycystic ovary syndrome.

Management of polycystic ovary syndrome (PCOS) usually spans a woman's reproductive years. While treatment of androgenic symptoms is often a primary concern, periodically, the regimen has to be modified because of a desire for pregnancy. At this time the couple should be evaluated for factors that may contribute to infertility and this should include semen analysis. However, for many, anovulation is likely to be the cause of infertility and ovulation induction is generally required. The premise on which ovulation induction in PCOS is based is two-fold: increasing ovarian exposure to follicle stimulating hormone (FSH) and/or correcting hormonal derangements. Potential differences in pathogenesis, evidenced clinically by phenotypic diversity, would suggest that treatment should be individualized. After a brief overview of factors relating to infertility, this paper outlines treatments available for ovulation induction in women with PCOS and provides a critical appraisal of management options. These options include the use of clomiphene citrate, insulin sensitizers, and the combination. Protocols for ovulation induction with FSH injections are outlined and the relative risks of multiple gestation and severe ovarian hyperstimulation syndrome of these various protocols discussed. The use of aromatase inhibitors and the occasional use of glucocorticoids are briefly reviewed, and indications for in vitro fertilization and laparoscopic ovarian diathermy outlined. Pregnancy outcome in this patient population is also discussed.

[Insulin and insulin-like growth factor pathway, a new targeted therapy in oncology]. / La vía de la insulina y el factor de crecimiento similar a la insulina, una nueva diana terapéutica en oncología.

The molecular biology of cancer has made it possible to identify new targets for attacking tumourous cells. One of these recently proposed targets is the insulin and insulin-like growth factor signaling pathway. This review describes its biological function, laboratory data, population studies that warn of its role in cancer, and the key elements of this signaling pathway: the ligands (insulin, IGF1, IGF2), its receptors and the cascade of intracellular signals that trigger its activation. Also reviewed are the different strategies under investigation for blocking it, some of which are already in phase III advanced studies. The preliminary data indicate that the medicines designed for blocking this pathway might be a new therapeutic weapon for oncology patients in the near future.

Weight loss in obese men by caloric restriction and high-dose diazoxide-mediated insulin suppression.

OBJECTIVE: To examine the concept whether high-dose diazoxide (DZX)-mediated insulin suppression, in combination with moderate caloric restriction and increased physical activity, can establish a weight loss of at least 15% in obese hyperinsulinaemic men. DESIGN: Open, uncontrolled, 6-month pilot study. Energy intake was reduced by 30%, and walking for at least 30 min a day was strongly recommended. DZX treatment was started at 50 mg t.i.d. and increased by 50 mg per dose every 4 weeks to a maximum of 300 mg t.i.d., unless hyperglycaemia or other side-effects occurred. SUBJECTS AND METHODS: Eighteen obese hyperinsulinaemic men with a body mass index of 30-35 kg/m(2). Measurements included body weight, body composition, blood pressure, glycaemic control, insulin response, adiponectin and serum lipids. RESULTS: Body weight decreased by 9.4 kg (95% CI: 5.6-13.2 kg, p < 0.001), waist circumference reduced by 9.2 cm (95% CI: 5.3-12.9 cm, p < 0.001) and total body fat mass decreased by 23.3% (95% CI: 13.7-32.9%, p < 0.001), without a concomitant change in soft tissue lean body mass or bone mass. Fat loss was inversely related to fasting insulin levels achieved at 6 months (r = -0.76, p < 0.002). Diastolic blood pressure decreased by 10.9 mmHg (95% CI: 6.5-15.4 mmHg, p < 0.002). Fasting and postmeal peak insulin levels were reduced by about 65% (p < 0.001) and decreased to the normal range for non-obese men. Fasting and postmeal peak glucose levels increased by 0.8 +/- 0.3 mmol/l (p = 0.01) and 1.4 +/- 0.7 mmol/l (p = 0.06) respectively. Haemoglobin A1c rose by 0.5% to 5.9 +/- 0.2%. CONCLUSION: High-dose DZX-mediated insulin suppression, in combination with moderate caloric restriction and lifestyle advice, is associated with a clinically relevant degree of weight reduction. A more extensive exploration is warranted to optimize this mode of treatment and to further clarify its risks and benefits.

Reprogramming adipose tissue derived mesenchymal stem cells into insulin-producing cells

b-cell replacement is currently considered the most promising treatmentfor type 1 diabetes. However it is strongly limited by the scarcityof transplantable material, i.e. islets of Langerhans from cadavericdonors. In this context, stem cells are an alternative source dueto their potential to duplicate and differentiate into certain lineagesunder specific culture conditions. Both embryonic and adult stemcells can differentiate into insulin-producing cells, however existingprotocols still require substantial improvements. Concerning embryonicstem cells, there are also certain ethical limitations that constrainits possible clinical use. Adult stem cells, on the other hand, donot present these problems. In addition, as seen with adipose tissuederivedmesenchymal stem cells, they can be easily isolated andtransplanted again, once reprogrammed, to the donor without theneed of immunosuppresors. Theoretically, the differentiation of mesenchymalstem cells, either from adipose tissue or bone marrow, toinsulin-producing cells can be achieved by various strategies, whichcan be grouped, according to the existing information, into coaxialand directional protocols

Valoración del sistema telemático Medical Guard Diabetes® en pacientes con diabetes tipo 1 / Evaluation of the telematic system Medical Guard Diabetes™ in patients with type 1 diabetes

El control de la diabetes tipo 1 requiere la interacción entre lospacientes y el equipo de salud. En esta línea, los sistemas telemáticospodrían ser de utilidad. El objetivo de este trabajo fue evaluarla eficacia y seguridad del sistema telemático Medical Guard Diabetes® (MGD), que fue modificado para poder enviar glucemias yotros datos. Se incluyeron 20 pacientes con diabetes tipo 1 y malcontrol metabólico, que fueron aleatorizados a control presencialmensual (CP) o envío de información (glucemias, dosis de insulina,raciones de carbohidratos) con MGD (MG) y respuesta mensualmediante SMS (short message system). La intervención duró 6meses. Se evaluaron la hemoglobina glucosilada (HbA1c), el númerode hipoglucemias, los conocimientos sobre la diabetes, la calidadde vida y el coste de la intervención. Las características basalesde ambos grupos fueron similares. Un paciente del grupo MGabandonó el estudio. Sólo los pacientes del grupo MG presentaronuna disminución significativa en el número de hipoglucemias alfinal del estudio respecto del inicio (p= 0,027). En el grupo CP, lavariación de la HbA1c durante el seguimiento fue del –0,66% (p=0,102), y en el grupo MG fue del 0,16% (p= 0,666). En ambosgrupos se observó una mejoría en los test de conocimientos (CP:p= 0,025; MG: p= 0,023) al final de la intervención. No hubodiferencias en los tests de calidad de vida. La duración de las visitasfue menor en el grupo MG (p= 0,025), al igual que los costes totalesde la intervención (CP= 119,20 euros frente a MG= 82,70euros). En conclusión, el sistema MGD es eficaz y seguro para elenvío de datos, y la visita telemática resulta menos costosa que lasconvencionales

The control of type 1 diabetes requires interaction between patientsand the healthcare team. To achieve this, telematic systemsmay be useful. The aim of this study was to assess the efficacy andsafety of the telematic system Medical Guard Diabetes® (MGD),which was modified for sending glycaemia and other data. In thisstudy, 20 type 1 diabetic patients with poor metabolic control wererandomized to either carry out hospital appointments (CP) or tosend information (glycaemia, insulin, carbohydrate intake) with theMGD (MG) and monthly contact by SMS. The study period was 6months evaluating HbA1c, number of hypoglycaemias, patientknowledge on diabetes, quality of life and costs. Both groups werecomparable at baseline. One patient in the MG group left the study.On comparing basal and final values only the MG group showed asignificant decrease in the number of hypoglycaemias (p= 0.027).During the follow-up, the change in HbA1c was –0.66% (p= 0.102)in the CP group and 0.16% (p= 0.666) in the MG group. Bothgroups showed an improvement in the knowledge test at the endof study (CP: p= 0.025; MG: p= 0.023). There was no significantdifference in the quality of life tests. The length of the visits wasshorter in the MG group (p= 0.025) as was the intervention totalcost (CP=119.20 € vs. MG= 82.70 €). In conclusion, the MGDsystem is effective and safe for sending information and thetelematic appointment is less expensive than hospital appointments

Estrategias de insulinización en la diabetes mellitus tipo 2 / Insulin strategies in type 2 diabetes

La diabetes tipo 2 se caracteriza por una resistencia a la insulina y un deterioro progresivo de la función beta pancreática. Cuando dicha función se altera, muchos pacientes con diabetes mellitus tipo 2 necesitarán tratamiento con insulina. Diversos estudios clínicos han demostrado que un control estricto de la glucemia previene la aparición y progresión de las complicaciones microvasculares asociadas a la diabetes. La insulina es el fármaco existente más potente para conseguir un control óptimo de la glucemia solamente limitada por la hipoglucemia. Sin embargo, con frecuencia no se usa precozmente ni de forma lo suficientemente agresiva para alcanzar los objetivos terapéuticos necesarios en la prevención de las complicaciones crónicas de los pacientes. Recientemente, se han desarrollado nuevos análogos de insulina de acción prolongada y rápida que reproducen mejor el perfil fisiológico de la secreción de insulina en comparación con las insulinas humanas. Estas insulinas ofrecen mayor flexibilidady adaptabilidad, lo que propicia una mejora de la calidad de vida delos pacientes. La terapia con insulina debe iniciarse o intensificarse tan pronto como otros tratamientos no sean efectivos para alcanzarlas metas de control glucémico. En este manuscrito se revisan las diferentes estrategias disponibles para iniciar o intensificar el tratamiento con insulina en pacientes con diabetes tipo 2, como la adición de análogos de acción prolongada al tratamiento previo con hipoglucemiantes orales, las insulinas premezcladas o la terapia basal-bolus (AU)

Type 2 diabetes is characterized by insulin resistance and progressive beta-cell deterioration of pancreatic function. As beta-cell function declines, many patients with type 2 diabetes will require insulintherapy. Several clinical studies have shown that tight control of blood glucose levels prevents the development and progression of microvascular complications caused by diabetes. Insulin is the mostpotent drug currently available to achieve tight glycemic control only limited by hypoglycemia. However, it is not often used early or aggressively enough for patients to achieve the glycemic targets required to prevent chronic complications. Recently, new long-acting insulin analogues and rapid-acting insulin analogues were developed to better reproduce the physiological time-action profiles of insulin secretion compared with human insulin formulations. They offer more flexibility and convenience, there by improving patient’s quality of life. Insulin therapy should be initiated or intensify as soon as other diabetes therapies are no longer effective in achieving and sustaining glycemic targets. This article reviews the different treatment strategies available to initiate or intensify insulin therapy in people with type 2 diabetes such as addition of basal insulin analogues to priororal hypoglycemic agents, premixed insulin analogues or basal-bolustherapy (AU)