To compare the effects of insulin degludec (IDeg) and insulin glargine U300 (IGlarU300) on glycaemic stability in subjects with type 1 diabetes. Materials and methods: In this multicentre, crossover trial, 46 individuals with type 1 diabetes and essentially undetectable circulating C-peptide were randomly assigned to either the IDeg-first/IGlarU300-second group or the IGlarU300-first/IDeg-second group, and were treated with the respective basal insulins for 4-week periods. Data were collected in the last week of each treatment period. The primary aim was to examine the potential non-inferiority of IDeg relative to IGlarU300 with regard to dayto-day variability, as evaluated by the standard deviation (SD) of fasting blood glucose (FBG) levels. Intra-day glycaemic variability and other variables were also determined by continuous glucose monitoring (CGM). Results: The SD of FBG for IDeg was non-inferior to that for IGlarU300. The mean of FBG, coefficient of variation of FBG, and various glycaemic variability indexes determined by CGM did not differ between the two insulins. Whereas the administered doses of the insulins also did not differ, the mean glycaemic value was lower for IDeg than IGlarU300; the time above the target range (>180 mg/dL [10.0 mmol/L]) and the time below the target range (<70 mg/dL [3.9 mmol/L]) were shorter and longer, respectively, for IDeg than IGlarU300. Conclusions: Our data suggest that IDeg and IGlarU300 have comparable glucosestabilizing effects in individuals with type 1 diabetes. However, the glucose-lowering effect of IDeg may be greater than that of IGlarU300 when titrated with a unit-based protocol. K E Y W O R D S basal insulin, clinical trial, continuous glucose monitoring, insulin therapy, type 1 diabetes 1 | INTRODUCTION Evidence suggests that, not only hyperglycaemia, but also the fluctuation and variability of glycaemia are related to the development of complications of diabetes. 1-8 Increased glycaemic variability is associated with a risk of hypoglycaemia, 9 which also contributes to the development of various health problems related to diabetes. 10,11 Minimization of glycaemic variability is thus an important issue in the choice of treatment for diabetes.
Homeostatic control of blood glucose is regulated by a complex feedback loop between glucose and insulin, of which failure leads to diabetes mellitus. However, physiological and pathological nature of the feedback loop is not fully understood. We made a mathematical model of the feedback loop between glucose and insulin using time course of blood glucose and insulin during consecutive hyperglycemic and hyperinsulinemic-euglycemic clamps in 113 subjects with variety of glucose tolerance including normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM). We analyzed the correlation of the parameters in the model with the progression of glucose intolerance and the conserved relationship between parameters. The model parameters of insulin sensitivity and insulin secretion significantly declined from NGT to IGT, and from IGT to T2DM, respectively, consistent with previous clinical observations. Importantly, insulin clearance, an insulin degradation rate, significantly declined from NGT, IGT to T2DM along the progression of glucose intolerance in the mathematical model. Insulin clearance was positively correlated with a product of insulin sensitivity and secretion assessed by the clamp analysis or determined with the mathematical model. Insulin clearance was correlated negatively with postprandial glucose at 2h after oral glucose tolerance test. We also inferred a square-law between the rate constant of insulin clearance and a product of rate constants of insulin sensitivity and secretion in the model, which is also conserved among NGT, IGT and T2DM subjects. Insulin clearance shows a conserved relationship with the capacity of glucose disposal among the NGT, IGT and T2DM subjects. The decrease of insulin clearance predicts the progression of glucose intolerance.
Aim
To investigate the relationships between various clinical variables and the metformin‐induced accumulation of fluorodeoxyglucose (FDG) in the intestine, with distinction between the intestinal wall and lumen, in individuals with type 2 diabetes who were receiving metformin treatment and underwent 18F‐labelled FDG ([18F]FDG) positron emission tomography (PET)‐MRI.
Materials and Methods
We evaluated intestinal accumulation of [18F]FDG with both subjective (a five‐point visual scale determined by two experienced radiologists) and objective analyses (measurement of the maximum standardized uptake value [SUVmax]) in 26 individuals with type 2 diabetes who were receiving metformin and underwent [18F]FDG PET‐MRI. [18F]FDG accumulation within the intestinal wall was discriminated from that in the lumen on the basis of SUVmax.
Results
SUVmax for the large intestine was correlated with blood glucose level (BG) and metformin dose, but not with age, body mass index, HbA1c level or estimated glomerular filtration rate (eGFR). SUVmax for the small intestine was not correlated with any of these variables. Visual scale analysis yielded essentially similar results. Metformin dose and eGFR were correlated with SUVmax for the wall and lumen of the large intestine, whereas BG was correlated with that for the wall. Multivariable analysis identified metformin dose as an explanatory factor for SUVmax in the wall and lumen of the large intestine after adjustment for potential confounders including BG and eGFR.
Conclusions
Metformin dose is an independent determinant of [18F]FDG accumulation in the wall and lumen of the large intestine in individuals treated with this drug.
These results suggest pheochromocytoma and paraganglioma impair glucose tolerance primarily through impairment of insulin secretion-in particular, that of the early phase of the insulin secretory response. A prospective study with more patients is warranted to further confirm these results.
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