Clinical evidence links arterial calcification and cardiovascular risk. Finite-element modelling of the stress distribution within atherosclerotic plaques has suggested that subcellular microcalcifications in the fibrous cap may promote material failure of the plaque, but that large calcifications can stabilize it. Yet the physicochemical mechanisms underlying such mineral formation and growth in atheromata remain unknown. Here, by using three-dimensional collagen hydrogels that mimic structural features of the atherosclerotic fibrous cap, and high-resolution microscopic and spectroscopic analyses of both the hydrogels and of calcified human plaques, we demonstrate that calcific mineral formation and maturation results from a series of events involving the aggregation of calcifying extracellular vesicles, and the formation of microcalcifications and ultimately large calcification zones. We also show that calcification morphology and the plaque’s collagen content – two determinants of atherosclerotic plaque stability - are interlinked.

National Institutes of Health and National Institute of Diabetes Digestive Diseases and Kidney and the Helmsley Charitable Trust.

OBJECTIVEEven under closed-loop (CL) conditions, meal-related blood glucose (BG) excursions frequently exceed target levels as a result of delays in absorption of insulin from the subcutaneous site of infusion. We hypothesized that delaying gastric emptying with preprandial injections of pramlintide would improve postprandial glycemia by allowing a better match between carbohydrate and insulin absorptions.RESEARCH DESIGN AND METHODSEight subjects (4 female; age, 15–28 years; A1C, 7.5 ± 0.7%) were studied for 48 h on a CL insulin-delivery system with a proportional integral derivative algorithm with insulin feedback: 24 h on CL control alone (CL) and 24 h on CL control plus 30-μg premeal injections of pramlintide (CLP). Target glucose was set at 120 mg/dL; timing and contents of meals were identical on both study days. No premeal manual boluses were given. Differences in reference BG excursions, defined as the incremental glucose rise from premeal to peak, were compared between conditions for each meal.RESULTSCLP was associated with overall delayed time to peak BG (2.5 ± 0.9 vs. 1.5 ± 0.5 h; P < 0.0001) and reduced magnitude of glycemic excursion (88 ± 42 vs. 113 ± 32 mg/dL; P = 0.006) compared with CL alone. Pramlintide effects on glycemic excursions were particularly evident at lunch and dinner, in association with higher premeal insulin concentrations at those mealtimes.CONCLUSIONSPramlintide delayed the time to peak postprandial BG and reduced the magnitude of prandial BG excursions. Beneficial effects of pramlintide on CL may in part be related to higher premeal insulin levels at lunch and dinner compared with breakfast.

Addition of IFB to the PID controller markedly reduced the occurrence of hypoglycemia without increasing meal-related glucose excursions. Higher average BG levels may be attributable to differences in the determination of system gain (Kp) in this study. The prevention of postprandial hypoglycemia suggests that the PID + IFB algorithm may allow for lower target glucose selection and improved overall glycemic control.