Factors Affecting the Absorption of Subcutaneously Administered Insulin:Effect on Variability

Variability in the effect of subcutaneously administered insulin represents a major challenge in insulin therapy where precise dosing is required in order to achieve targeted glucose levels. Since this variability is largely influenced by the absorption of insulin, a deeper understanding of the factors affecting the absorption of insulin from the subcutaneous tissue is necessary in order to improve glycaemic control and the long-term prognosis in people with diabetes. These factors can be related to either the insulin preparation, the injection site/patient, or the injection technique. This review highlights the factors affecting insulin absorption with special attention on the physiological factors at the injection site. In addition, it also provides a detailed description of the insulin absorption process and the various modifications to this process that have been utilized by the different insulin preparations available

Sustained effect of glucagon on body weight and blood glucose:Assessed by continuous glucose monitoring in diabetic rats

<div><p>Insulin is a vital part of diabetes treatment, whereas glucagon is primarily used to treat insulin-induced hypoglycemia. However, glucagon is suggested to have a central role in the regulation of body weight, which would be beneficial for diabetic patients. Since the glucagon effect on blood glucose is known to be transient, it is relevant to investigate the pharmacodynamics of glucagon after repeated dosing. In the present study, we used telemetry to continuously measure blood glucose in streptozotocin induced diabetic Sprague-Dawley rats. This allowed for a more detailed analysis of glucose regulation compared to intermittent blood sampling. In particular, we evaluated the blood glucose-lowering effect of different insulin doses alone, and in combination with a long acting glucagon analog (LAG). We showed how the effect of the LAG accumulated and persisted over time. Furthermore, we found that addition of the LAG decreased body weight without affecting food intake.</p><p>In a subsequent study, we focused on the glucagon effect on body weight and food intake during equal glycemic control. In order to obtain comparable maximum blood glucose lowering effect to insulin alone, the insulin dose had to be increased four times in combination with 1 nmol/kg of the LAG. In this set-up the LAG prevented further increase in body weight despite the four times higher insulin-dose. However, the body composition was changed. The insulin group increased both lean and fat mass, whereas the group receiving four times insulin in combination with the LAG only significantly increased the fat mass. No differences were observed in food intake, suggesting a direct effect on energy expenditure by glucagon. Surprisingly, we observed decreased levels of FGF21 in plasma compared to insulin treatment alone. With the combination of insulin and the LAG the blood glucose-lowering effect of insulin was prolonged, which could potentially be beneficial in diabetes treatment.</p></div

Rodent model choice has major impact on variability of standard preclinical readouts associated with diabetes and obesity research

Laboratory rodents are available as either genetically defined inbred strains or genetically undefined outbred stocks. As outbred rodents are generally thought to display a higher level of phenotypic variation compared to inbred strains, it has been argued that experimental studies should preferentially be performed by using inbred rodents. However, very few studies with adequate sample sizes have in fact compared phenotypic variation between inbred strains and outbred stocks of rodents and moreover, these studies have not reached consistent conclusions. The aim of the present study was to compare the phenotypic variation in commonly used experimental readouts within obesity and diabetes research, for four of the most frequently used mouse strains: inbred C57BL/6 and BALB/c and outbred NMRI and CD-1 mice. The variation for all readouts was examined by calculating the coefficient of variation (CV), i.e., the relative variation, including a 95% confidence interval for the CV. We observed that for the majority of the selected readouts, inbred and outbred mice showed comparable phenotypic variation. The observed variation appeared highly influenced by strain choice and type of readout, which suggests that these collectively would serve as more predictive of the phenotypic variation than the more general classification of mice as inbred or outbred based on genetic heterogeneity