Recent studies of obesity have provided new insights into the mechanisms underlying insulin resistance and metabolic dysregulation. Numerous efforts have been made to identify key regulators of obesity-linked adipose tissue inflammation and insulin resistance. We found that angiopoietin-like protein 2 (Angptl2) was secreted by adipose tissue and that its circulating level was closely related to adiposity, systemic insulin resistance, and inflammation in both mice and humans. Angptl2 activated an inflammatory cascade in endothelial cells via integrin signaling and induced chemotaxis of monocytes/macrophages. Constitutive Angptl2 activation in vivo induced inflammation of the vasculature characterized by abundant attachment of leukocytes to the vessel walls and increased permeability. Angptl2 deletion ameliorated adipose tissue inflammation and systemic insulin resistance in diet-induced obese mice. Conversely, Angptl2 overexpression in adipose tissue caused local inflammation and systemic insulin resistance in nonobese mice. Thus, Angptl2 is a key adipocyte-derived inflammatory mediator that links obesity to systemic insulin resistance.
It is possible that SGLT2 inhibitors trigger euglycemic diabetic ketoacidosis in some patients. Possible mechanism of euglycemic DKA induced by SGLT2 inhibitors is illustrated.
HbA1c and fasting plasma glucose (FPG) levels are commonly recognized as diagnostic indices for diabetes and glucose intolerance. However, they are not sufficient for clear detection of glucose intolerance in the early stage unless an oral glucose tolerance test (OGTT) is performed. Moreover, even in case of an OGTT, 2-h postprandial plasma glucose (PG) levels, a criterion for glucose intolerance in OGTTs, may not provide complete information regarding glucose tolerance. Whole glucose excursion after OGTT is considered to represent glucose tolerance well, and the glucose area under the curve (AUC) can be an index of glucose excursion. However, few studies have investigated measurement of the glucose AUC in glucose intolerance screening. In the present study, data from 520 OGTTs were analyzed to define the cutoff value for the glucose AUC for glucose intolerance screening. Our results showed that a cutoff value of 290 mg h/dl for the glucose AUC was highly sensitive and specific (90 and 93 %, respectively) for detecting diabetes, impaired glucose tolerance (IGT), and group at increased risk of diabetes (normal glucose tolerance with 1-h PG levels of C180 mg/dl after glucose load) and showed a better concordance rate than the use of HbA1c, FPG, or 2-h PG levels. Moreover, the cutoff value for the glucose AUC calculated using the diagnostic criteria in the OGTT (305 mg h/dl) was consistent with the value determined from OGTT analysis. These data suggest a possibility that glucose intolerance screening using a glucose AUC cutoff value of 290 mg h/dl could be useful.
Daily glucose fluctuation may have an effect on coronary plaque vulnerability in patients with CAD pre-treated with lipid-lowering therapy. Further investigations should address the rationale for the early detection and control of glucose fluctuation in the era of universal statin use for CAD patients.
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.
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