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Borgono C.A.,University of Toronto | Zinman B.,Leadership Sinai Center for Diabetes
Endocrinology and Metabolism Clinics of North America | Year: 2012

This article highlights selected milestones in insulin discovery and its continued development as a pivotal therapy for diabetes. The last 90 years have witnessed tremendous progress in insulin therapy, from the initial crude, yet life-saving, animal insulin extracts to novel human insulin analogues. Although the complete physiologic replacement of insulin is inherently difficult to achieve with open-loop subcutaneously administered insulin, the continued development of improved injectable insulin formulations with superior pharmacokinetics and pharmacodynamics will enhance glucose control, and represents important clinical advances in the treatment of both type 1 and type 2 diabetes. © 2012 Elsevier Inc.

Lorenzo C.,University of Texas Health Science Center at San Antonio | Hanley A.J.,University of Toronto | Hanley A.J.,Leadership Sinai Center for Diabetes | Haffner S.M.,University of Texas Health Science Center at San Antonio
Diabetologia | Year: 2014

Aims/hypothesis: White cell count has been shown to predict incident type 2 diabetes, but differential white cell count has received scant attention. We examined the risk of developing diabetes associated with differential white cell count and neutrophil:lymphocyte ratio and the effect of insulin sensitivity and subclinical inflammation on white cell associations. Methods: Incident diabetes was ascertained in 866 participants aged 40-69 years in the Insulin Resistance Atherosclerosis Study after a 5 year follow-up period. The insulin sensitivity index (SI) was measured by the frequently sampled IVGTT. Results: C-reactive protein was directly and independently associated with neutrophil (p < 0.001) and monocyte counts (p < 0.01) and neutrophil:lymphocyte ratio (p < 0.001), whereas SI was inversely and independently related to lymphocyte count (p < 0.05). There were 138 (15.9%) incident cases of diabetes. Demographically adjusted ORs for incident diabetes, comparing the top and bottom tertiles of white cell (1.80 [95% CI 1.10, 2.92]), neutrophil (1.67 [1.04, 2.71]) and lymphocyte counts (2.30 [1.41, 3.76]), were statistically significant. No association was demonstrated for monocyte count (1.18 [0.73, 1.90]) or neutrophil:lymphocyte ratio (0.89 [0.55, 1.45]). White cell and neutrophil associations were no longer significant after further adjusting for family history of diabetes, fasting glucose and smoking, but the OR comparing the top and bottom tertiles of lymphocyte count remained significant (1.96 [1.13, 3.37]). This last relationship was better explained by SI rather than C-reactive protein. Conclusions/interpretation: A lymphocyte association with incident diabetes, which was the strongest association among the major white cell types, was partially explained by insulin sensitivity rather than subclinical inflammation. © 2013 Springer-Verlag Berlin Heidelberg.

Lorenzo C.,University of Texas Health Science Center at San Antonio | Hanley A.J.,University of Toronto | Hanley A.J.,Leadership Sinai Center for Diabetes | Rewers M.J.,Aurora University | Haffner S.M.,University of Texas Health Science Center at San Antonio
Diabetologia | Year: 2013

Aims/hypothesis: Markers of liver injury, such as alanine aminotransferase (ALT), have been associated with atherogenic lipoprotein changes. We examined the extent to which this association was explained by insulin resistance, adiposity, glucose tolerance and chronic inflammation. Methods: In this analysis we included 824 non-diabetic participants (age 40-69 years) in the Insulin Resistance Atherosclerosis Study. No participants reported excessive alcohol intake or treatment with lipid-lowering medications. Lipoproteins and apolipoproteins were measured by conventional methods and lipoprotein heterogeneity by nuclear magnetic resonance (NMR) spectroscopy. Results: ALT had a positive relationship with triacylglycerols, LDL-to-HDL-cholesterol ratio and apolipoprotein B (ApoB) after adjusting for demographic variables (p < 0.001 for all three relationships). ALT was also associated with the following NMR lipoproteins: positively with large VLDL (p < 0.001), intermediate-density lipoprotein (IDL) (p < 0.001) and small LDL subclass particles (p < 0.001), and VLDL particle size (p < 0.001); and negatively with large LDL subclass particles (p < 0.05) and LDL (p < 0.001) and HDL particle sizes (p < 0.01). ALT remained associated with IDL and small LDL subclass particles and ApoB after adjusting for glucose tolerance, adiposity, directly measured insulin sensitivity and C-reactive protein. Conclusions/interpretation: ALT is associated with a wide range of atherogenic lipoprotein changes, which are partially explained by insulin resistance, adiposity, glucose tolerance and chronic inflammation. Because of the significant variability in the relationship between ALT and liver fat, further studies are needed to assess the extent of the lipoprotein changes using a direct measure of liver fat. © 2013 Springer-Verlag Berlin Heidelberg.

Zinman B.,Samuel Lunenfeld Research Institute | Zinman B.,Leadership Sinai Center for Diabetes
Diabetes, Obesity and Metabolism | Year: 2013

Basal insulin analog therapy is the most common method of introducing insulin replacement therapy for the majority of patients with type 2 diabetes mellitus. Long-acting insulin analogs provide relatively peakless and more physiologic insulin replacement therapy than neutral protaminated Hagedorn insulin. Recently 2 new basal insulin analogs have been developed with superior pharmacokinetic and pharmacodynamics properties; insulin degludec and a pegylated insulin lispro. These agents are generally well tolerated and have been evaluated in both type 1 and type 2 diabetes. In this article we review the results of clinical trials assessing the efficacy, safety and tolerability of these newer longer-acting insulin analogs. In general rates of hypoglycaemia in these trials were low, glucose control was comparable to currently available basal insulin analogs, and rates of nocturnal hypoglycaemia were significantly and substantially lower. While further study will be required, advances in basal insulin replacement may offer important advantages over existing options for starting insulin strategies. © 2013 Blackwell Publishing Ltd.

Kramer C.K.,Leadership Sinai Center for Diabetes | Kramer C.K.,University of Toronto
Canadian Journal of Cardiology | Year: 2015

Overweight/obesity has been associated with increased risk for several conditions, including hypertension, hypercholesterolemia, diabetes mellitus, heart disease, and stroke. The morbidity associated with overweight and obesity translates into excess mortality risk, which is observed even when increased weight is not associated with metabolic abnormalities. The achievement of moderate weight loss, regardless of the treatment strategy, is associated with favorable clinical outcomes, including significant reduction in the incidence of type 2 diabetes and blood pressure levels. These data suggest that weight loss might be a useful therapeutic objective in the prevention and management of comorbidities associated with overweight/obesity. © 2015 Canadian Cardiovascular Society.

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