Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Feb;59(2):207-215.
doi: 10.1007/s00592-021-01785-9. Epub 2021 Sep 24.

The pathophysiology of glucose intolerance in newly diagnosed, untreated T2DM

Gareth J Dunseath  1 , Stephen D Luzio  2 , Rajesh Peter  2 , David R Owens  2
Affiliations

The pathophysiology of glucose intolerance in newly diagnosed, untreated T2DM

Gareth J Dunseath et al. Acta Diabetol. 2022 Feb.

Abstract

Aims: The two predominant pathophysiological defects resulting in glucose intolerance are beta-cell dysfunction and insulin insensitivity. This study aimed to re-examine beta-cell function and insulin sensitivity across a continuum from normal glucose tolerance (NGT) to early type 2 diabetes (T2DM) employing highly specific insulin, C-peptide and intact proinsulin assays.

Materials and methods: A total of 104 persons with NGT, 85 with impaired glucose tolerance (IGT) and 554 with newly diagnosed T2DM were investigated. Following an overnight fast, all underwent a 4-h standardised mixed meal tolerance test (MTT), and on a second day, a sub-group underwent a frequently sampled insulin-modified intravenous glucose tolerance test (FSIVGTT) over a 3-h period. The participants were stratified according to fasting glucose and BMI for analysis.

Results: The MTT revealed that increasing FPG was accompanied by progressively elevated and delayed postprandial glucose peaks. In parallel, following an initial compensatory increase in fasting and postprandial insulin responses there followed a progressive demise in overall beta-cell secretory capacity. FSIVGTT demonstrated a major reduction in the early insulin response to IV glucose in persons with IGT accompanied by a dramatic fall in insulin sensitivity. Beyond pre-diabetes, ever-increasing fasting and postprandial hyperglycaemia resulted predominantly from a progressively decreasing beta-cell secretory function.

Conclusion: This study utilising improved assay technology re-affirms that beta-cell dysfunction is evident throughout the spectrum of glucose intolerance, whereas the predominant fall in insulin sensitivity occurs early in its evolution.

Keywords: Beta-cell function; Glucose intolerance; Insulin sensitivity; Type 2 diabetes mellitus.

PubMed Disclaimer

Conflict of interest statement

GJD, SDL, RP and DRO have no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1
Summary of study procedures
Fig. 2
Fig. 2
Mean (SEM) plasma a glucose, b insulin, c C-peptide and d intact proinsulin responses during the MTT and e glucose, f glucose (0–10 min post-glucose bolus), g insulin and h acute insulin response during the FSIVGTT in subjects with NGT, IGT and T2DM stratified by tertiles of FPG. Dotted line = NGT, dashed line = IGT, solid line = T2DM; open circle = T2DM-GT1, grey circle = T2DM-GT2, solid circle = T2DM-GT3
Fig. 3
Fig. 3
Relationship between fasting glucose and a insulin sensitivity and b beta-cell function (disposition index). Open square = NGT, solid triangle = IGT, open circle = T2DM-GT1, grey circle = T2DM-GT2, solid circle = T2DM-GT3
See this image and copyright information in PMC

References

    1. Kahn SE, Prigeon RL, McCulloch DK, et al. Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. evidence for a hyperbolic function. Diabetes. 1993;42(11):1663–1672. doi: 10.2337/diab.42.11.1663. - DOI - PubMed
    1. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet. 2014;383(9922):1068–1083. doi: 10.1016/S0140-6736(13)62154-6. - DOI - PMC - PubMed
    1. Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest. 1999;104(6):787–794. doi: 10.1172/JCI7231. - DOI - PMC - PubMed
    1. Defronzo RA. Banting lecture. from the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773–795. doi: 10.2337/db09-9028. - DOI - PMC - PubMed
    1. Tabak AG, Jokela M, Akbaraly TN, Brunner EJ, Kivimaki M, Witte DR. Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study. Lancet. 2009;373(9682):2215–2221. doi: 10.1016/S0140-6736(09)60619-X. - DOI - PMC - PubMed