Conclusiones:
"Insulin resistance in muscle, adipose tissue, liver, and vascular endothelium is a prominent feature and an integral part of T1D pathophysiology, develops early during its progression, and is sustained after clinical diagnosis. Contributing factors for insulin resistance in T1D include peripheral insulin administration, weight gain, physical inactivity, and sleep disturbances operating through glucotoxicity, lipotoxicity, hyperinsulinemia, hyperglucagonemia, low-grade inflammation, and impaired mitochondrial function and oxidative stress. Results are sometimes equivocal owing to cohort selection, differences in glycemic control, physical fitness level, and diabetes duration, all playing important roles. Of note, the expected involvement of these risk factors and mechanisms does not always explain the presence of insulin resistance in T1D suggesting a unique phenotype different from T2D. The reciprocal relationship between insulin resistance and impaired endothelial function provides the ground for the development of diabetes-related complications. Concerning the contribution of insulin resistance to chronic complications, it should be noted that the various studies have differently taken confounders into account.
The pathophysiology of T1D is likely multifactorial. In some cases, it may be primarily driven by autoimmunity, whereas in other cases other factors may initiate the destruction of β-cells and hyperglycemia, with autoimmunity to follow. Within this context, the causality in the interplay between insulin resistance and autoimmunity is still unclear.
In clinical practice, individualized physical activity and CSII compared to multiple insulin injections insulin treatment have been shown to improve insulin sensitivity and glycemic control and reduce insulin dose. Several agents improving insulin resistance directly or indirectly, such as metformin, GLP-1RAs, SGLT-2i, and pramlintide have been examined, but are not widely used in routine clinical care at present along with insulin due to limited efficacy, side effects, and a limited number of real-world outcome trials in people with T1D.
Although insulin resistance seems to be an important issue for the clinical care of T1D, its gold-standard assessment is not recommended for clinical routing because the euglycemic–hyperinsulinemic clamp is costly, personnel-intensive, and time-consuming. Nevertheless, the HOMA-IR can serve as a rather simple alternative at least in the preclinical stages and possibly in recent-onset T1D. In preclinical T1D, postprandial insulin sensitivity indexes obtained from OGTT, or mixed meals can also be applied. In overt T1D, eGDR remains the only surrogate index of insulin resistance, which, however, should be interpreted with caution due to limitations (see “Contribution of Individual Tissues to Insulin Resistance”).
Regarding the role of insulin resistance in the pathophysiology and treatment of T1D, several issues remain to be considered by the scientific and clinical community.
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In individuals genetically susceptible to T1D before autoimmune seroconversion, research is needed with euglycemic–hyperinsulinemic clamps to investigate whether insulin resistance contributes and to what extent to initiating autoimmunity.
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Although exercise training and increased physical activity improve insulin sensitivity in people with T1D, the fear of hypoglycemia remains a significant barrier to meeting current guidelines. Active research on simple interventions, such as interrupting prolonged sitting with frequent short bouts of light-intensity activities, is urgently needed to encourage sedentary people with T1D who are unwilling to be involved in structured programs to incorporate physical activity into their everyday schedule.
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Iatrogenic hyperinsulinemia significantly contributes to inducing insulin resistance in T1D. Optimizing subcutaneous insulin treatment to approach physiological insulin supplementation remains an important goal.
- Real-world studies are necessary on the metabolic benefits and side effects of daily GLP-1/once-weekly GLP-1/dual GLP-1/GIP receptor agonists, and SGLT-2i in T1D, and their protective effects on CVD and chronic kidney disease progression. Measurements of residual C-peptide before treatment initiation with these agents may be useful to reduce the risk of adverse events. Furthermore, studies directly measuring insulin sensitivity with euglycemic–hyperinsulinemic clamps before and after treatment with these agents are needed."
Maria Apostolopoulou, Vaia Lambadiari, Michael Roden, George D Dimitriadis, Insulin Resistance in Type 1 Diabetes: Pathophysiological, Clinical, and Therapeutic Relevance, Endocrine Reviews, Volume 46, Issue 3, June 2025, Pages 317–348, https://doi.org/10.1210/endrev/bnae032