Insulin sensitivity in tissues such as a skeletal muscle and fat is closely correlated with insulin action in the vasculature, but the mechanism underlying this is unclear. We investigated the effect of dexamethasone on insulin-stimulated glucose disposal and vasodilation in healthy males to test the hypothesis that a reduction in glucose disposal would be accompanied by a reduction in insulin action in the vasculature. We performed a double-blind, placebo-controlled, cross-over trial comparing insulin sensitivity (measured by the euglycemic hyperinsulinemic clamp) and vascular insulin action (measured by small vessel wire myography) in young healthy males allocated to placebo or 1 mg dexamethasone twice daily for 6 d, each in random order. Six days of dexamethasone therapy was associated with a 30% (95% confidence interval, 19.1-40.0%) fall in insulin sensitivity. Despite this, there was no difference in insulin-mediated vasodilation between phases. Dexamethasone had no effect on circulating markers of endothelial function, such as D-dimer, von Willebrand factor, and tissue plasminogen activator. By short-term exposure to high dose dexamethasone we were able to differentially affect the metabolic and vascular actions of insulin. This implies that, using this model, there is physiological uncoupling of the effects of insulin in different tissues.
Insulin pump therapy, also known as continuous subcutaneous insulin infusion (CSII), is an important and evolving form of insulin delivery, which is mainly used for people with type 1 diabetes. However, even with modern insulin pumps, errors of insulin infusion can occur due to pump failure, insulin infusion set (IIS) blockage, infusion site problems, insulin stability issues, user error, or a combination of these. Users are therefore exposed to significant and potentially fatal hazards: interruption of insulin infusion can result in hyperglycemia and ketoacidosis; conversely, delivery of excessive insulin can cause severe hypoglycemia. Nevertheless, the available evidence on the safety and efficacy of CSII remains limited. The European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA) have therefore joined forces to review the systems in place for evaluating the safety of pumps from a clinical perspective. We found that useful information held by the manufacturing companies is not currently shared in a sufficiently transparent manner. Public availability of adverse event (AE) reports on the US Food and Drug Administration's Manufacturer and User Facility Device Experience (MAUDE) database is potentially a rich source of safety information but is insufficiently utilized due to the current configuration of the system; the comparable database in Europe (European Databank on Medical Devices [EUDAMED]) is not publicly accessible. Many AEs appear to be attributable to human factors and/or user error, but the extent to which manufacturing companies are required by regulators to consider the interactions of users with the technical features of their products is limited. The clinical studies required by regulators prior to marketing are small and over-reliant on bench testing in relation to "predicate" products. Once a pump is available on the market, insufficient data are made publicly available on its long-term use in a real-world setting; such data could provide vital information to help health care teams to educate and support users and thereby prevent AEs. As well as requiring more from the manufacturing companies, we call for public funding of more research addressing clinically important questions in relation to pump therapy: both observational studies and clinical trials. At present, there are significant differences in the regulatory systems between the US and European Union at both pre- and postmarketing stages; improvements in the European system are more urgently required. This statement concludes with a series of recommended specific actions for "meknovigilance" (i.e., a standardized safety approach to technology) that could be implemented to address the shortcomings we highlight.
The objective of this cross-sectional study was to explore the relationship of detectable C-peptide secretion in type 1 diabetes to clinical features and to the genetic architecture of diabetes. C-peptide was measured in an untimed serum sample in the SDRNT1BIO cohort of 6076 Scottish people with clinically diagnosed type 1 diabetes or latent autoimmune diabetes of adulthood. Risk scores at loci previously associated with type 1 and type 2 diabetes were calculated from publicly available summary statistics. Prevalence of detectable C-peptide varied from 19% in those with onset before age 15 and duration greater than 15 years to 92% in those with onset after age 35 and duration less than 5 years. Twenty-nine percent of variance in C-peptide levels was accounted for by associations with male gender, late age at onset and short duration. The SNP heritability of residual C-peptide secretion adjusted for gender, age at onset and duration was estimated as 26%. Genotypic risk score for type 1 diabetes was inversely associated with detectable C-peptide secretion: the most strongly associated loci were the HLA and INS gene regions. A risk score for type 1 diabetes based on the HLA DR3 and DQ8-DR4 serotypes was strongly associated with early age at onset and inversely associated with C-peptide persistence. For C-peptide but not age at onset, there were strong associations with risk scores for type 1 and type 2 diabetes that were based on SNPs in the HLA region but not accounted for by HLA serotype. Persistence of C-peptide secretion varies widely in people clinically diagnosed as type 1 diabetes. C-peptide persistence is influenced by variants in the HLA region that are different from those determining risk of early-onset type 1 diabetes. Known risk loci for diabetes account for only a small proportion of the genetic effects on C-peptide persistence.
Interrogation of peripheral vascular function is increasingly recognized as a noninvasive surrogate marker for coronary vascular function and carries with it important prognostic information regarding future cardiovascular risk. Laser Doppler imaging (LDI) is a completely noninvasive method for looking at peripheral microvascular function. We sought to look at reproducibility and repeatability of LDI-derived assessment of peripheral microvascular function between arms and 8 weeks apart. We used LDI in conjunction with iontophoretic application of ACh and SNP to look at endothelium-dependent and -independent microvascular function, respectively, in a mixture of women with cardiac syndrome X and healthy volunteers. We looked at variation between arms (n = 40) and variation at 8 weeks apart (n = 22). When measurements were corrected for skin resistance, there was nonsignificant variation between arms for ACh (2.7%) and SNP (3.8%) and nonsignificant temporal variation for ACh (3.5%) and SNP (4.7%). Construction of Bland-Altman plots reinforce that measurements have good repeatability. Elimination of the baseline perfusion response had deleterious effects on repeatability. LDI can be used to assess peripheral vascular response with good repeatability as long as measurements are corrected for skin resistance, which affects drug delivery. This has important implications for the future use of LDI.
Current drug labels for thiazolidinediones (TZDs) warn of increased fractures, predominantly for distal fractures in women. We examined whether exposure to TZDs affects hip fracture in women and men and compared the risk to that found with other drugs used in diabetes.Using a nationwide database of prescriptions, hospital admissions and deaths in those with type 2 diabetes in Scotland we calculated TZD exposure among 206,672 individuals. Discrete-time failure analysis was used to model the effect of cumulative drug exposure on hip fracture during 1999-2008.There were 176 hip fractures among 37,479 exposed individuals. Hip fracture risk increased with cumulative exposure to TZD: OR per year of exposure 1.18 (95% CI 1.09, 1.28; p = 3 × 10(-5)), adjusted for age, sex and calendar month. Hip fracture increased with cumulative exposure in both men (OR 1.20; 95% CI 1.03, 1.41) and women (OR 1.18; 95% CI 1.07, 1.29) and risks were similar for pioglitazone (OR 1.18) and rosiglitazone (OR 1.16). The association was similar when adjusted for exposure to other drugs for diabetes and for other potential confounders. There was no association of hip fracture with cumulative exposure to sulfonylureas, metformin or insulin in this analysis. The 90-day mortality associated with hip fractures was similar in ever-users of TZD (15%) and in never-users (13%).Hip fracture is a severe adverse effect with TZDs, affecting both sexes; labels should be changed to warn of this. The excess mortality is at least as much as expected from the reported association of pioglitazone with bladder cancer.
Purpose of review We provide an overview of recent publications that extend clinically relevant knowledge relating to metformin's effects on lipids and atherosclerotic vascular disease and/or provide insights into the drug's mechanisms of action on the heart and vasculature. Recent findings We focus on original research in humans or in human tissues. Several recently completed randomized clinical trials have reported effects of metformin on surrogate measures of atherosclerotic vascular disease, including carotid–intima media thickness, vascular reactivity and calcification in people with Type 1 (T1D) and Type 2 (T2D) diabetes as well as nondiabetic dysglycaemia. In addition, observational studies have provided novel insights into the mechanisms of metformin's effects on carotid plaque, monocytes/macrophages, vascular smooth muscle and endothelial cells, including via 5’-adenosine monophosphate-activated protein kinase (AMPK) activation. Summary Recent trials based on surrogate outcome measures have provided further data suggesting protective effects of metformin against vascular disease in youth and adults with Type 1 diabetes, as well as in adults with prediabetes and Type 2 diabetes. In parallel, human tissue and cell studies have provided new insights into pleiotropic effects of metformin and suggest novel drug targets. As metformin is an inexpensive agent with an established safety profile, larger scale clinical trials based on hard clinical outcomes [cardiovascular disease (CVD) events] are now indicated.
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