Jean-François Yale

Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease

Canagliflozin is a sodium glucose co‐transporter 2 inhibitor in development for treatment of type 2 diabetes mellitus (T2DM). This study evaluated the efficacy and safety of canagliflozin in subjects with T2DM and stage 3 chronic kidney disease [CKD; estimated glomerular filtration rate (eGFR) ≥30 and <50 ml/min/1.73 m2].

Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease

This study evaluated the efficacy and safety of canagliflozin, a sodium glucose co‐transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) and within a subset of Stage 3 chronic kidney disease (CKD; estimated glomerular filtration rate [eGFR] ≥30 and <50 ml/min/1.73 m2).

Peroxovanadium compounds: Biological actions and mechanism of insulin-mimesis

When used alone, both vanadate and hydrogen peroxide (H2O2) are weakly insulin-mimetic, while in combination they are strongly synergistic due to the formation of aqueous peroxovanadium species pV(aq). Administration of these pV(aq) species leads to activation of the insulin receptor tyrosine kinase (IRK), autophosphorylation at tyrosine residues and inhibition of phosphotyrosine phosphatases (PTPs). We therefore undertook to synthesize a series of peroxovanadium (pV) compounds containing one or two peroxo anions, an oxo anion and an ancillary ligand in the inner co-ordination sphere of vanadium, whose properties and insulin-mimetic potencies could be assessed. These pV compounds were shown to be the most potent inhibitors of PTPs yet described. Their PTP inhibitory potency correlated with their capacity to stimulate IRK activity. Some pV compounds showed much greater potency as inhibitors of insulin receptor (IR) dephosphorylation than epidermal growth factor receptor (EGFR) dephosphorylation, implying relative specificity as PTP inhibitors. Replacement of vanadium with either molybdenum or tungsten resulted in equally potent inhibition of IR dephosphorylation. However IRK activation was reduced by greater than 80% suggesting that these compounds did not access intracellular PTPs. The insulin-like activity of these pV compounds were demonstrablein vivo. Intra venous (i.v.) administration of bpV(pic) and bpV(phen) resulted in the lowaring of plasma glucose concentrations in normal rats in a dose dependent manner. The greater potency of bpV(pic) compared to bpV(phen) was explicable, in part, by the capacity of the former but not the latter to act on skeletal muscle as well as liver. Finally administration of bpV(phen) and insulin led to a synergism, where tyrosine phosphorylation of the IR β-subunit increased by 20-fold and led to the appearance of four insulin-dependentin vivo substrates. The insulin-mimetic properties of they pV compounds raises the possibility for their use as insulin replacements in the management of diabetes mellitus.

Acarbose in the treatment of elderly patients with type 2 diabetes.

AIMS To study the effect of acarbose, an alpha-glucosidase inhibitor, on glycemic control in elderly patients with type 2 diabetes. METHODS Elderly patients with type 2 diabetes treated with diet alone were randomly treated in a double-blind fashion with placebo (n=99) or acarbose (n=93) for 12 months. RESULTS After 12 months of therapy, there was a statistically significant difference in the change in glycated haemoglobin (HbA(1c)) (-0.6%) in the acarbose group versus placebo, as well as in the incremental post-prandial glucose values (-2.1 mmol h/l) and mean fasting plasma glucose (-0.7 mmol/l). Although there was no effect of acarbose on insulin release, there was a clear effect of acarbose to decrease relative insulin resistance (-0.8) (HOMA method). In addition, acarbose was generally well tolerated and safe in the elderly; most discontinuations were due to gastrointestinal side effects such as flatulence and diarrhea. There were no cases of hypoglycemia reported, and no clinically relevant changes in laboratory abnormalities or vital signs during the study. CONCLUSIONS Acarbose improves the glycemic profile and insulin sensitivity in elderly patients with type 2 diabetes who are inadequately controlled on diet alone.

Consensus Report: The Current Role of Self-Monitoring of Blood Glucose in Non-Insulin-Treated Type 2 Diabetes

The Coalition for Clinical Research—Self-Monitoring of Blood Glucose Scientific Board convened a meeting in San Francisco, CA, July 20–21, 2011, to discuss the current practice of self-monitoring of blood glucose (SMBG) in non-insulin-treated (NIT) type 2 diabetes mellitus (T2DM). Twelve physician panel members from academia, practice, and government attended this meeting. These experts came from the United States, Brazil, Canada, France, Germany, Italy, and the United Kingdom. In addition, three consultants from Australia, Germany, and the United States contributed to the groups final report. This coalition was organized by Diabetes Technology Society. Self-monitoring of blood glucose was studied from eight perspectives related to patients with NIT T2DM: (1) epidemiological studies; (2) randomized controlled trials (RCT)s and meta-analyses; (3) targets, timing, and frequency of SMBG use; (4) incidence and role of SMBG in preventing hypoglycemia with single-drug regimens and combination regimens consisting of antihyperglycemic agents other than secretagogues and insulin; (5) comparison of SMBG with continuous glucose monitoring; (6) technological capabilities and limitations of SMBG; (7) barriers to appropriate use of SMBG; and (8) methods and end points for appropriate future clinical trials. The panel emphasized recent studies, which reflect the current approach for applying this intervention. Among the participants there was consensus that: SMBG is an established practice for patients with NIT T2DM, and to be most effective, it should be performed in a structured format where information obtained from this measurement is used to guide treatment; New, high-quality efficacy data from RCTs have demonstrated efficacy of SMBG in NIT T2DM in trials reported since 2008; Both patients and health care professionals require education on how to respond to the data for SMBG to be effective; and Additional well-defined studies are needed to assess the benefits and costs of SMBG with end points not limited to hemoglobin A1c.

Effects of Cyclosporine on Glucose Tolerance in the Rat

In a study of prevention of spontaneous diabetes in BB rats by therapeutic doses of cyclosporine (10 mg/kg/ day), the male control non-diabetes-prone rats showed glucose intolerance after a 0.25 g/kg glucose load by gavage, at 90 and 130 days of treatment. Non-BB male Wistar rats treated similarly showed glucose intolerance at 1 wk of treatment, with progressive worsening for 5 wk, then sustained up to 12 wk of treatment. Fasting euglycemia was maintained, but both pre- and postchallenge plasma insulin levels were significantly lower with cyclosporine at several time points. Total pancreatic insulin was decreased to one-third that of control after 5 wk. After withdrawal of cyclosporine, glucose tolerance returned to normal in 2 wk. Sprague-Dawley rats responded similarly and in both strains, an increase in the cyclosporine dose to 15 mg/kg/day augmented the glucose intolerance. These results demonstrate that therapeutic doses of this agent induce reversible glucose intolerance due, in part, to inhibition of insulin secretion and also possibly inhibition of synthesis, though a peripheral effect is not excluded. This hyperglycemic effect of cyclosporine has implications for its potential use in type I diabetes mellitus, transplantation, and other autoimmune disease.

Treatment gaps in the management of cardiovascular risk factors in patients with type 2 diabetes in Canada

OBJECTIVES To evaluate vascular protection treatment patterns and attainment of the 2003 Canadian Diabetes Associations recommended targets in ambulatory patients with type 2 diabetes. METHODS Between 2005 and 2006, 3002 outpatients with type 2 diabetes were enrolled by 229 primary health care settings across Canada. Baseline characteristics, therapeutic regimens and treatment success - defined as the achievement of a blood pressure (BP) of 13080 mmHg or lower, glycosylated hemoglobin (A1C) of 7% or lower, low-density lipoprotein cholesterol (LDL-C) lower than 2.5 mmolL and total cholesterolhigh-density lipoprotein cholesterol ratio lower than 4.0 - are reported. RESULTS Overall, 46% of individuals had a BP that was above the Canadian Diabetes Associations recommended target. Of these, 11% were untreated, 28% were receiving monotherapy, 38% were not receiving an angiotensin-converting enzyme inhibitor and 16% were not receiving either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Optimal A1C levels were achieved in 53% of patients. Of those who did not attain A1C targets, 3% were not on glucose- lowering pharmacotherapy and 27% were receiving monotherapy. A total of 74% of patients were treated with statins. Overall, 64% and 62%, respectively, met the target LDL-C and the target total cholesterolhigh-density lipoprotein cholesterol ratio. Statins were not prescribed to 43% of patients with LDL-C above target. Antiplatelet therapy was implemented in 81% of patients. In total, 21% achieved the combined targets for BP, A1C and LDL-C. INTERPRETATION A substantial proportion of patients did not achieve guideline-recommended targets and were not receiving evidence- based therapy for vascular protection two years after publication of the Canadian guidelines. More research is warranted, and novel and effective strategies must be tested and implemented to correct this ongoing treatment gap.

Diabetes prevention in BB rats by inhibition of endogenous insulin secretion

Chronic prophylactic exogenous insulin treatment commenced in young diabetes susceptible BB rats has been shown to prevent type I diabetes. This study was undertaken to examine whether this diabetes protection resulted from inhibition of beta-cell insulin secretion by exogenous insulin administration or from either a metabolic (chronic hypoglycemia) or immune effect of this treatment. We compared the effects of prophylactic exogenous insulin treatment with those of an insulin secretion inhibitor, diazoxide, an oral hypoglycemic agent, glyburide, and, water alone as controls in randomly divided BB diabetes-prone littermates treated from age 30 to 150 days. These experiments confirmed that exogenous insulin can prevent type I diabetes in the BB rat. Diazoxide, which inhibits endogenous insulin secretion while causing hyperglycemia (rather than hypoglycemia with insulin), also offered protection from diabetes. In contrast, the oral hypoglycemic agent glyburide, which increased insulin secretion, but decreased plasma glucose during the early part of the experiment, did not affect the incidence of diabetes. The lymphocyte subpopulations were unaffected by these treatments. These data support the hypothesis that decreased beta-cell activity is responsible for the protection against the immune beta-cell destruction.

Study of Once Daily Levemir (SOLVE™): Insights into the timing of insulin initiation in people with poorly controlled type 2 diabetes in routine clinical practice

Aims: The aim of this analysis is to determine the timing of insulin initiation in routine clinical practice, especially in relation to glycaemic control and use of oral antidiabetic drugs (OADs).

Protection of islets of Langerhans from antibodies by microencapsulation with alginate poly-l-lysine membranes.

Microencapsulation of islets has been proposed to prevent their immune destruction following transplantation. An indirect immunofluorescence technique has been developed and used to study the permeability of the alginate-poly-L-lysine microcapsules to antibodies. Wistar rat islets were incubated with the R2D6 monoclonal mouse IgM antibody against rat islets, microen-capsulated, and incubated with fluorescein-labeled goat IgG antibodies against mouse IgG and IgM. For the negative controls, the first antibody was omitted or both antibodies were omitted. The positive controls included islets incubated with both antibodies before they were encapsulated. Our study demonstrated that the alginate-poly-L-lysine membranes are not permeable to IgG when poly-L-lysine of molecular weights ranging from 21,000 to 390,000 are used. This simple immunofluorescence technique demonstrated the nonpermeability of the microcapsules to IgG, and could be useful for the initial evaluation of new types of membranes.