Long-term effects of pioglitazone versus gliclazide on hepatic and humoral coagulation factors in patients with type 2 diabetes.

This study compared the long-term effects of pioglitazone and gliclazide on the production of coagulation factors in patients with type 2 diabetes. Patients (n=283) with glycosylated haemoglobin > 7.5% were randomised to receive either pioglitazone (30-45 mg/day) or gliclazide (80-320 mg/day) for one year. Coagulation factors were measured at baseline and at six and 12 months. While both pioglitazone and gliclazide induced a comparable improvement in glycaemic control, only pioglitazone improved insulin sensitivity. Pioglitazone significantly (p < or = 0.001) decreased circulating levels of von Willebrand factor (-9.7%, -9.4%) and plasminogen activator inhibitor-1 (-16.8 ng/ml, -12.3 ng/ml), and increased levels of antithrombin-III (+1.3 mg/dL, +1.5 mg/dL) after six and 12 months, respectively. The beneficial effects of pioglitazone on glycaemic control, lipid homeostasis, and coagulation and thrombosis, may improve vascular outcomes in patients with type 2 diabetes.

[New frontiers for the therapy of insulin-dependent diabetes mellitus]. / Diabete mellito insulino-dipendente: nuove frontiere terapeutiche.

Introduction of new analogic insulin molecules has favorably impacted control of hyperglycemia with positive effects on onset and severity of chronic complications of the T1DM. However, insulin therapy does not represent a cure for the disease. On the contrary, cell therapy, by substituting diseased tissue with fresh vital cells, whether be they graft of whole pancreas or isolated islets of Langerhans, might provide for a cure for T1DM. However, the restricted availability of cadaveric human donors, coupled with recipient's pharmacologic immunosuppression, strictly hamper the diffusion of this approach. Protecting the isolated islets within microcapsules developed in our laboratory, with no recipient's immunosuppression, may represent a major problem-solving alley. Microcapsules might also offer the opportunity to provide non human tissue as a resource for donor islets thereby circumventing the restrictions in human islet tissue procurement. On another research front, re-activating progenitor cells that may reconstitute original viable and functional beta-cells, within an endocrine pancreas regenerative system, while autoimmunity is being abrogated by engineering the host's immune system, could provide a radical solution to the problem posed by T1DM.

Accelerated functional maturation of isolated neonatal porcine cell clusters: in vitro and in vivo results in NOD mice.

Neonatal porcine cell clusters (NPCCs) might replace human for transplant in patients with type 1 diabetes mellitus (T1DM). However, these islets are not immediately functional, due to their incomplete maturation/ differentiation. We then have addressed: 1) to assess whether in vitro coculture of islets with homologous Sertoli cells (SC) would shorten NPCCs' functional time lag, by accelerating the beta-cell biological maturation/differentiation; 2) to evaluate metabolic outcome of the SC preincubated, and microencapsulated NPCCs, upon graft into spontaneously diabetic NOD mice. The islets, isolated from < 3 day piglets, were examined in terms of morphology/viability/function and final yield. SC effects on the islet maturation pathways, both in vitro and in vivo, upon microencapsulation in alginate/poly-L-ornithine, and intraperitoneal graft into spontaneously diabetic NOD mice were determined. Double fluorescence immunolabeling showed increase in beta-cell mass for SC+ neonatal porcine islets versus islets alone. In vitro insulin release in response to glucose, as well as mRNA insulin expression, were significantly higher for SC+ neonatal porcine islets compared with control, thereby confirming SC-induced increase in viable and functional beta-cell mass. Graft of microencapsulated SC+ neonatal porcine islets versus encapsulated islets alone resulted in significantly longer remission of hyperglycemia in NOD mice. We have preliminarily shown that the in vitro NPCCs' maturation time lag can dramatically be curtailed by coincubating these islets with SC. Graft of microencapsulated neonatal porcine islets, precultured in Sertoli cells, has been proven successful in correcting hyperglycemia in stringent animal model of spontaneous diabetes.

Grafts of microencapsulated pancreatic islet cells for the therapy of diabetes mellitus in non-immunosuppressed animals.

Pancreatic-islet-cell transplantation may reverse hyperglycaemia in diabetic recipients that undertake general pharmacological immunosuppression. A major challenge that remains is the need to avoid immunosuppression associated with the use of allogeneic or heterologous islet cells. In the present study we demonstrate the use of microencapsulation of cells using artificial biocompatible and permselective membranes prepared with alginic acid derivatives and polyamino acids. While characterization of the microcapsule constituent polymers continues to progress, other technical issues such as definition of the immunobarrier capacity, biocompatibility, size, shape and graft site have come into sharper focus. Assessment of microcapsules properties, in order to establish possible guidelines for fabrication of reproducible membranes, and results from both in vitro functional testing, and in vivo encapsulated-islet-transplant outcome in several animal models of diabetes are reported.

One-year glycemic control with a sulfonylurea plus pioglitazone versus a sulfonylurea plus metformin in patients with type 2 diabetes.

OBJECTIVE: The goal was to assess the 1-year efficacy and safety of the addition of pioglitazone or metformin to existing sulfonylurea (SU) therapy in patients with inadequately controlled type 2 diabetes. RESEARCH DESIGN AND METHODS: In this multicenter, double-blind study, patients were randomized to receive either pioglitazone 15 mg (n = 319) or metformin 850 mg (n = 320) and up to 45 mg/day and 2,550 mg/day, respectively. The primary efficacy endpoint was HbA(1c) at week 52. Fasting plasma glucose, insulin, and lipid profiles were also measured. RESULTS: HbA(1c) was reduced by 1.20% in the SU plus pioglitazone group and 1.36% in the SU plus metformin group, and fasting plasma glucose was reduced by 2.2 and 2.3 mmol/l in the respective groups. Fasting insulin levels were also reduced (pioglitazone arm -1.3 micro IU/ml; metformin arm -0.8 micro IU/ml). There were no significant between-treatment differences in these three parameters. Pioglitazone addition to SU significantly reduced triglycerides (-16 vs. -9%; P = 0.008) and increased HDL cholesterol (14 vs. 8%; P < 0.001) compared with metformin addition. LDL cholesterol was increased 2% by the addition of pioglitazone and decreased 5% by the addition of metformin to SU (P < 0.001). Urinary albumin-to-creatinine ratio was reduced by 15% in the SU plus pioglitazone group and increased 2% in the SU plus metformin group (P = 0.017). Both combinations were well tolerated with no evidence of hepatic or cardiac toxicity in either group. CONCLUSIONS: Clinically equivalent improvements in glycemic control were observed for both combinations. Compared with metformin plus SU, addition of pioglitazone to SU resulted in a reduction of the urinary albumin-to-creatinine ratio, a small but significant rise in LDL cholesterol, and significantly greater improvements in triglyceride levels and HDL cholesterol levels. Metformin plus SU was associated with a significant reduction in LDL cholesterol. SU plus pioglitazone is an effective and well-tolerated combination regimen that may provide additional beneficial effects for patients with type 2 diabetes.

The artificial pancreas.

In type 1 diabetes an absolute deficiency of insulin secretion requires exogenous insulin supply to guarantee the patient's life avoiding ketoacidotic coma and to prevent the chronic complications of diabetes. In order to obtain a more physiological replacement therapy different approaches have been pursued since the early 70s to create an artificial wearable pancreas able to deliver insulin according to the blood glucose values as determined by continuous monitoring. Four components are considered essential for the realisation of an artificial pancreas: the sampling system, the glucose sensor, the mathematical models and the related algorithms for the calculation of the insulin doses and the infusion system for the insulin delivery. At present the still unsolved issues are mainly represented by the availability of reliable continuous glucose monitor and control algorithms, while the new technologies allow for the miniaturisation of the system.

Mitogenic effects of Brazilian arthropod venom on isolated islet beta cells: in vitro morphologic ultrastructural and functional studies.

BACKGROUND: One of the major pitfalls associated with use of isolated adult islets of Langerhans' cells is their minimal mitotic capacity. Consequently, maintenance of a steady viable islet cell mass is very difficult. To explore how to enhance beta-cell mitogenesis, we have examined the effects of venom fractions extracted from a Brazilian scorpion on morphologic and functional beta-cell patterns. The venom was previously known to induce nesidioblastosis-like effects with chronic hypoglycemia and pancreatitis in animal models. METHODS: Venom fractions purified from Tityus bahiensis were incubated with batches of isolated rat islets, while a morphologic examination, glucose-stimulated insulin release, insulin content, and insulin messenger ribonucleic acid (mRNA) were carried out early during incubation. On fixation and double fluorescence immunolabeling (rhodamine for anti-insulin monoclonal antibodies; fluorescein for anti-5-bromodeoxyuridine), the preparations were imaged by confocal laser microscopy (CLM) for morphometric quantification of the mitoses. Insulin recovery and mRNA were also assessed at 21 days of culture. RESULTS: Under CLM examination, the beta-cell mitotic rate significantly rose from 1 to 12.8% for the venom-exposed islets. At day 7, insulin release and content were significantly lower for the venom-exposed than the control islets. However, at day 21 of culture, insulin release in response to static incubation with glucose and insulin mRNA from the venom-exposed islets was higher than controls (p < .05). CONCLUSIONS: Incubation with the scorpion venom induced a rapid and significant increase in the beta-cell proliferation not associated with a short-term increase in insulin secretion. The latter fully resumed and overcame controls later in culture, possibly after completion of the beta-cell expansion process.

Validation of a counseling strategy to promote the adoption and the maintenance of physical activity by type 2 diabetic subjects.

OBJECTIVE: There is enough evidence that physical activity is an effective therapeutic tool in the management of type 2 diabetes. The present study was designed to validate a counseling strategy that could be used by physicians in their daily outpatient practice to promote the adoption and maintenance of physical activity by type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: The long-term (2-year) efficacy of the behavioral approach (n = 182) was compared with usual care treatment (n = 158) in two matched, randomized groups of patients with type 2 diabetes who had been referred to our Outpatient Diabetes Center. The outcome of the intervention was consistent patient achievement of an energy expenditure of >10 metabolic equivalents (METs)-h/week through voluntary physical activity. RESULTS: After 2 years, 69% of the patients in the intervention group (27.1 +/- 2.0 METs x h/week) and 18% of the control group (4.1 +/- 0.8 METs x h/week) achieved the target (P < 0.001) with significant (P < 0.001) improvements in BMI (intervention group 28.9 +/- 0.2 versus control group 30.4 +/- 0.3 kg/m(2)) and HbA(1c) (intervention group 7.0 +/- 0.1 versus control group 7.6 +/- 0.1%). CONCLUSIONS: This randomized, controlled study shows that physicians can motivate most patients with type 2 diabetes to exercise long-term and emphasizes the value of individual behavioral approaches in daily practice.

Administration of neutral protamine Hagedorn insulin at bedtime versus with dinner in type 1 diabetes mellitus to avoid nocturnal hypoglycemia and improve control. A randomized, controlled trial.

BACKGROUND: Intensive insulin treatment of type 1 diabetes mellitus increases the risk for nocturnal hypoglycemia. OBJECTIVE: To demonstrate that splitting the evening insulin regimen reduces the risk for nocturnal hypoglycemia in intensive treatment of type 1 diabetes mellitus. DESIGN: Randomized, open, two-treatment crossover trial in two 4-month periods. SETTING: University research center in Italy. PATIENTS: 22 C-peptide-negative persons with type 1 diabetes mellitus (mean age [+/-SD], 29 +/- 3 years). INTERVENTIONS: Each patient was randomly assigned to one of two insulin regimens for 4 months and then switched to the other regimen for another 4 months. The two treatment regimens were 1) mixed treatment--a mixture of human regular and neutral protamine Hagedorn (NPH) insulin administered before dinner and 2) split treatment--human regular insulin administered at dinner and NPH insulin administered at bedtime. MEASUREMENTS: Frequency of nocturnal hypoglycemia. Secondary end points were levels of fasting blood glucose and hemoglobin A1c and responses to experimental hypoglycemia. RESULTS: During the split-regimen treatment period, patients had fewer episodes of nocturnal hypoglycemia (mean [+/-SE], 0.10 +/- 0.02 episode/patient-day vs. 0.28 +/- 0.04 episode/patient-day; P = 0.002), a lower fasting blood glucose level (mean [+/-SE], 7.6 +/- 0.2 mmol/L vs. 8.3 +/- 0.5 mmol/L [137 +/- 4 mg/dL vs. 160 +/- 8 mg/dL]; P = 0.030), less variable fasting blood glucose levels (SD range, 2.0 +/- 0.4 vs. 3.5 +/- 0.6; P = 0.001), and lower hemoglobin A1c value (mean [+/-SE], 7.0% +/- 0.11% vs. 7.5% +/- 0.15%; P = 0.004) than during the mixed regimen. Responses to experimental hypoglycemia were better preserved with the split regimen than with the mixed regimen. CONCLUSION: When the goal of insulin therapy in type 1 diabetes mellitus is near-normoglycemia, splitting the evening insulin treatment regimen into short-acting insulin at dinner and NPH insulin at bedtime reduces the risks for nocturnal hypoglycemia and hypoglycemia unawareness and decreases the hemoglobin A1c value compared with mixing short-acting insulin and NPH insulin at dinner.

La neuropatía diabética / Diabetic neuropathy

La neuropatía diabética es un desorden del sistema nervioso periférico del que se ven afectados los pacientes diabéticos en ausencia de otras causas de neuropatía. Se compromete tanto el componente somático como el autonómico y puede ser responsable de cuadros clínicos complejos y graves o, también, de alteraciones demostrables exclusivamente con la ayuda de metodologías instrumentales. Existen diferentes formas clínicas de neuropatía diabética que se distinguen en base a criterios topográficos y de simetría y que se diferencian por la patogénesis, evolución y pronóstico. En la patogénesis los factores en juego son múltiples pero la hiperglicemia es la condición necesaria para el desarrollo de dicha neuropatía. El tratamiento de la neuropatía diabética se basa en la optimización del control metabólico y en algunas esperanzas farmacogénicas