Insulin therapy for type 2 diabetes - are we there yet? The d-Nav® story.

Insulin replacement therapy is mostly used by patients with type 2 diabetes who become insulin deficient and have failed other therapeutic options. They comprise about a quarter of those with diabetes, endures the majority of the complications and consumes the majority of the resources. Adequate insulin replacement therapy can prevent complications and reduce expenses, as long as therapy goals are achieved and maintained. Sadly, these therapy goals are seldom achieved and outcomes have not improved for decades despite advances in pharmacotherapy and technology. There is a growing recognition that the low success rate of insulin therapy results from intra-individual and inter-individual variations in insulin requirements. Total insulin requirements per day vary considerably between patients and constantly change without achieving a steady state. Thus, the key element in effective insulin therapy is unremitting and frequent dosage adjustments that can overcome those dynamics. In practice, insulin adjustments are done sporadically during outpatient clinic. Due to time constraints, providers are not able to deliver appropriate insulin dosage optimization. The d-Nav® Insulin Guidance Service has been developed to provide appropriate insulinization in insulin users without increasing the burden on healthcare systems. It relies on dedicated clinicians and a spectrum of technological solutions. Patients are provided with a handheld device called d-Nav® which advises them what dose of insulin to administer during each injection and automatically adjust insulin dosage when needed. The d-Nav care specialists periodically follow-up with users through telephone calls and in-person consultations to bestow user confidence, correct usage errors, triage, and identify uncharacteristic clinical courses. The following review provide details about the service and its clinical outcomes.

Dynamics in insulin requirements and treatment safety.

AIMS: The majority of insulin users have elevated HbA1c. There is growing recognition that the low success rates are due to variations in insulin requirements. Thus, frequent dosage adjustments are needed. In practice, adjustments occur sporadically due to limited provider availability. We investigated intra-individual dynamics of insulin requirements using data from a service evaluation of the d-Nav® Insulin Guidance Service. This service facilitates automated insulin dosage adjustments, as often as needed, to achieve and maintain optimal glycemic balance. METHODS: Data were collected from subjects who have been using the service for more than a year. Events of considerable and persistent decrease in insulin requirements were identified by drops in total daily insulin ≥25%. RESULTS: Overall, 62 patients were studied over an average period of 2.1±0.5 (mean±standard deviation) years. Stability in HbA1c was attained after ~3 quarters at 7.4%±0.2% (57.4mmol/mol±1mmol/mol). Events were identified in 56.5% of the patients. On average, each affected patient had 0.8±0.4 events per year, lasting 9.7±6.6weeks, while total daily insulin dosage decreased by 41.4±13.4%. CONCLUSIONS: Our findings may call attention to a major contributing factor to hypoglycemia among insulin users. In reality, insulin dosage is seldom adjusted and thus transient periods of decrease in insulin requirements and overtreatment are usually overlooked.

Histological insights into the pathogenesis of post-Roux-en-Y hyperinsulinaemic hypoglycaemia.

BACKGROUND: ß-cell hyperplasia has been implicated in the aetiology of post Roux-en-Y gastric bypass hyperinsulinaemic hypoglycaemia, but the pathogenesis of this condition is still unclear. CASE REPORT: We report a case of a 52-year-old man with post-Roux-en-Y gastric bypass hyperinsulinaemic hypoglycaemia who underwent distal pancreatectomy to alleviate his symptoms. Pancreatic histopathology showed chronic pancreatitis with a corresponding loss of exocrine tissue and islet retention. Amyloid deposition was found in pancreatic islets. These features are more typically associated with Type 2 diabetes. DISCUSSION: This case highlights the potential multifactorial pathogenesis of symptomatic hypoglycaemia after Roux-en-Y gastric bypass.

Specific induction of tumor neovasculature death by modified murine PPE-1 promoter armed with HSV-TK.

BACKGROUND: One strategy to increase tissue specificity of gene therapy is to use promoters or enhancers. OBJECTIVES: (1) To enhance the selectivity of a murine preproendothelin-1 (PPE-1) promoter in tumor angiogenesis by using a positive endothelial transcription-binding element. (2) To test the specificity and efficiency of the modified PPE-1 promoter [PPE-1(3X)] in vitro and in vivo by using reporter genes, and the therapeutic gene herpes simplex virus-thymidine kinase (HSV-TK) in a mouse model of Lewis lung carcinoma (LLC). RESULTS: The modified PPE-1 promoter specifically induced expression in the tumor angiogenic vascular bed with a 35-fold higher expression compared to the normal vasculare bed of the lung. Thus, when the HSV-TK gene controlled by the modified PPE-1 promoter was used systemically, it induced tumor-specific necrosis, apoptosis and mononuclear infiltrates, leading to massive destruction of the neovasculature of the pulmonary metastasis, which suppressed metastasis development. CONCLUSIONS: These results show that an adenoviral vector armed with HSV-TK controlled by the endothelial-selective murine PPE-1(3X) promoter is efficient and safe to target tumor neovasculature.

Antiangiogenic systemic gene therapy combined with doxorubicin administration induced caspase 8 and 9-mediated apoptosis in endothelial cells and an anti-metastasis effect.

Ad-PPE-Fas-c is an adenovector that expresses Fas-c under the control of the modified pre-proendothelin-1 (PPE-1) promoter. Fas-c is a chimeric death receptor containing the extracellular portion of tumour necrosis factor 1 receptor (TNFR1) and the transmembrane and intracellular portion of Fas. We recently demonstrated that Ad-PPE-Fas-c induced Fas-receptor-mediated endothelial cell apoptosis. Previously, doxorubicin was shown to enhance Fas-receptor clustering and the induction of its cascade. Therefore, the goal of this work was to test whether doxorubicin augments the capacity of Ad-PPE-Fas-c to induce endothelial cell apoptosis and to elucidate whether either the death-receptor-mediated apoptotic cascade or the mitochondria-associated apoptotic cascade is involved in the combined treatment effect. We found that a combined treatment of Ad-PPE-Fas-c and doxorubicin synergistically induced a reduction in endothelial cell viability and apoptosis. z-IETD-FMK, a caspase-8 inhibitor, and z-LEHD-FMK, a caspase-9 inhibitor, significantly decreased apoptosis induced by the combined treatment. Systemically administered combined therapy significantly reduced the lung metastases burden (70%) in mice as compared to each treatment alone. Thus, a combined treatment of Ad-PPE-Fas-c gene therapy and chemotherapy may be effective in the treatment of metastatic diseases and both the Fas cascade and the mitochondria-associated cascade are essential for this effect.

Intravitreal gas injection for hypotony after cataract surgery.

PURPOSE: To evaluate the efficacy and safety of intravitreal perfluoropropane gas injection to treat hypotony after cataract surgery. SETTING: The ophthalmology department of a major tertiary medical center. METHODS: After uneventful cataract extraction, 5 patients with hypotony due to iridocyclitis, choroidal detachment, and serous retinal detachment were treated with an intravitreal injection of 1.0 cc of perfluoropropane gas. RESULTS: The hypotony, choroidal detachment, and exudative retinal detachment resolved in all 5 patients, and visual acuity improved. No complications were observed. CONCLUSION: Intravitreal gas injection can be used to treat hypotony after cataract surgery in selected patients.

[Frequency of the Gaucher mutation among recent Russian immigrants].

Gaucher's disease is frequent in the Ashkenazi Jewish population of Israel, with a gene frequency by molecular analysis of approximately 0.032, corresponding to a birth rate of 1:850. The recent immigration from the former Soviet Union brought more than 400,000 Jews, mostly of Ashkenazi descent. However, only a few cases of Gaucher's disease have been diagnosed. Possible explanations are lack of awareness of the signs of Gaucher's disease among Russian health workers and family practitioners in Israel, and a significantly lesser frequency of the Gaucher gene among Russian immigrants than among other Ashkenazi Jews in Israel and the US. We studied the frequency of the 1226G (N370S) mutation in a cohort of 202 recent immigrants from the former Soviet Union. We found 10 carriers (4.95%), indicating a decreased frequency of the Gaucher gene, but by extension, the probability of unidentified cases in need of treatment. Family practitioners should be aware of the possibility that heretofore misdiagnosed symptoms may be those of Gaucher's disease.