Substantial inter-individual variations in insulin secretion and sensitivity across the glucometabolic spectrum

Abstract

Impaired insulin secretion and action are important for development of type 2 diabetes (T2D) and metabolic syndrome (MetS). Despite recognized heterogeneity of these glucometabolic disorders, few data are available of biological variation in insulin secretion and action among individuals with T2D and MetS. The aim of this study was to explore the inter-individual variations using gold standard methods in a cross-sectional study of two independent cohorts of phenotypically well-characterized subjects. Cohort I included 486 subjects with MetS, and cohort II 62 subjects with established T2D. First phase insulin secretion was defined as the incremental area under the curve 0-8 min (iAUC 0-8 min) during an intravenous glucose tolerance test (IVGTT). Insulin sensitivity was measured as the insulin sensitivity index (S I) modelled from IVGTT in cohort I, and in II as total glucose disposal (TGD) estimated from a euglycaemic-hyperinsulinaemic clamp. Variation is given as total range and, fold-variation between 5%-and 95%-percentile. The iAUC 0-8 min ranged from À60 to 3397 mUL À1 min À1 among subjects with MetS and from À263 to 1194 mUL À1 min À1 in subjects with T2D, representing a more than 10-fold variation. Insulin sensitivity ranged from S I 0.19 to 15.29 (mU/L) À1 min À1 among subjects with MetS and TGD 12.9-101.6 lmolkgFFM À1 min À1 in subjects with T2D, representing a 6.8 and 5.5fold variation, respectively. The other components of MetS; BMI, waist-hip ratio, HDL-cholesterol, triglycerides and blood pressure (BP), showed a 1.4-4.7-fold variation. In conclusion, our data demonstrated extensive inter-individual variations in insulin secretion and sensitivity. These variations may be essential to take into account when planning clinical research and treatment in subjects with T2D and MetS.

Comparison of measures of insulin sensitivity in early-lactation dairy goats

“…However, these results should be interpreted with caution because in Zamuner et al (2020a) we found no difference in peripheral tissue response to insulin between goats of different basal insulin levels (5.6 vs. 12.9 mU/L, P = 0.008). Therefore, the observed large interindividual variations in insulin production and secretion could be attributed to genetic differences, as has been demonstrated in humans (Hansen et al, 2020), or to differences in milk production and energy status (Zamuner et al, 2020a). Nevertheless, the reasons for the present findings remain speculative.…”

Bioengineered Pancreas–Liver Crosstalk in a Microfluidic Coculture Chip Identifies Human Metabolic Response Signatures in Prediabetic Hyperglycemia

“…Furthermore, by using material from different donors, for instance, with and without T2DM, NAFLD or metabolic syndrome, the established model provides an appealing system to parse the molecular basis for interindividual differences in insulin sensitivity and secretion across the glucometabolic spectrum, which are known to be extensive. [110] Combined, we have developed a versatile modular chip platform with pneumatic actuation that allows for controlled reciprocal mass transfer between different tissue models at physiologically relevant compartment-specific flow rates. By establishing an integrated coculture of healthy organotypic primary human liver spheroids and intact primary human islets, we demonstrate functional tissue crosstalk.…”

“…Furthermore, by using material from different donors, for instance, with and without T2DM, NAFLD or metabolic syndrome, the established model provides an appealing system to parse the molecular basis for interindividual differences in insulin sensitivity and secretion across the glucometabolic spectrum, which are known to be extensive. [ 110 ]…”

Use of c-peptide as a measure of cephalic phase insulin release in humans

“…First, it is well documented that there are individual differences in beta cell function (45,46), which contribute to differences in the degree of insulin and c-peptide secretion (recall that insulin and c-peptide are co-secreted in equimolar amounts). While this difference is most pronounced in conditions such as metabolic syndrome and type 2 diabetes (47), individual differences in the secretory capacity of the beta cell in healthy individuals have been reported as well (48,49). Another important consideration is that at least 70% of total secreted insulin and c-peptide is released in a pulsatile manner (50) with a typical period of about 5 minutes (51,52).…”