Insulin resistance (IR) is a dysmetabolic condition resulting in a reduced response to insulin from peripheral target tissues. Therefore, tissues require higher concentrations of insulin to achieve a physiological response, leading to compensatory hyperinsulinemia, which is the typical diagnostic hallmark of IR (1).

The direct metabolic consequences of IR include hyperglycemia and obesity, which may lead to inflammation, hypertension, endothelial dysfunction, cardiovascular diseases, metabolic syndrome, non-alcoholic steatosis, and type 2 diabetes mellitus (2–5).

Aside from genetic susceptibility, IR and obesity typically stem from an unhealthy lifestyle, examples of which include a nutritional imbalance with weight gain and an excess buildup of adipose tissue, insufficient physical activity, increased sodium intake, and glucose toxicity and lipotoxicity from excessive circulating free fatty acids (6). In addition, several studies suggest the impairment of gut microbiota, as an environmental factor, may be related to the progression of IR, obesity, and metabolic disturbances (7, 8).

Therefore, lifestyle intervention is crucial for both the treatment and prevention of IR in at-risk patients, as compelling evidence has demonstrated that a moderate and well-tailored weight loss—by as little as 5%–10%—can lead to several health benefits, including a reduction of blood pressure and positive changes in insulin sensitivity and inflammatory biomarkers (9).

In this context, the hypocaloric regimen defined as the Mediterranean diet can improve IR in obese individuals when compared to other dietary approaches, especially in terms of insulin levels, homeostasis model assessment index for IR (HOMA-IR), and inflammation (10–12).

When lifestyle modifications alone are not sufficient to achieve clinically relevant weight loss and metabolic recovery, supplementation with natural compounds may be of great help, accelerating the recovery process and avoiding, or at least postponing, pharmacological interventions and/or surgical approaches.

Among natural molecules with insulin-sensitizing properties, inositols have proven effective in normalizing IR and hyperinsulinemia in dysmetabolic patients, mainly in overweight and obese women, or in women with polycystic ovary syndrome (PCOS) (13–17). D-chiro-inositol (DCI)—the second-most represented isomer of the inositol family—regulates insulin secretion, the mitochondrial respiratory chain, and glycogen storage. The first evidence of the importance of DCI in these processes derives from the observation of a higher DCI content in the body areas deputed to glycogen storage, mainly adipose cells, muscles, and the liver (18). As such, physicians use this molecule to treat insulin dysfunctions in a panel of conditions characterized by metabolic abnormalities (18). Moreover, some studies have suggested that a deficiency of DCI and its high urinary clearance correlate with IR and hyperinsulinemia, leading to the onset of diabetes and metabolic disorders, as observed in patients with PCOS (17, 19–22). There is plenty of clinical evidence on the effectiveness of DCI as an insulin sensitizer, and as a relevant molecule in the field of endocrinology and nutrition (16, 19, 22, 23).

On these premises, the present study aims to evaluate metabolic changes experienced by insulin-resistant overweight/obese women on a hypocaloric Mediterranean diet supplemented with DCI for a period of 4 months.

Obesity is a chronic condition that is associated with several metabolic and non-metabolic comorbidities, impacting life quality and expectancy and increasing public health costs worldwide (27–30). Among the drivers of excess weight and related complications, IR stands out as a primary contributing factor (31–33). Indeed, IR and prediabetes are on the increase worldwide, with alarming predictions for the next 15–20 years (34). Clearly, these data underscore the pressing need for lifestyle adjustments to tackle weight gain and associated disorders.

The recommended first-line approach for weight loss relies on adequate physical activity and healthy eating habits (35). In this context, the Mediterranean diet is associated with several benefits in terms of reducing IR, and lowering the risk of developing diabetes, metabolic syndrome, and cardiovascular diseases (36, 37).

Furthermore, nutraceutical interventions are currently employed on a large-scale basis as potential treatments for weight management and insulin sensitivity improvement (38, 39).

Consequently, inositols have attracted much attention, as several studies have confirmed their effectiveness in improving IR and excess weight-associated complications in patients with PCOS, metabolic syndrome, and diabetes (40).

Aside from increasing insulin sensitivity, inositols, and notably DCI, have been proven to be able to correct the imbalance between energy intake and energy output (41), leading to a reduction in oxidative stress (42), inflammation (43), and BMI (16, 44).

As such, this study intended to examine the benefits, in terms of metabolic and hormonal rebalance, of supplementing insulin-resistant overweight/obese women with DCI in combination with a hypocaloric Mediterranean diet.

In agreement with the results of the Nestler research group (25, 26), we opted for a treatment with high-dose DCI (45), as prior data has demonstrated that DCI improves metabolic and reproductive function in certain patients.

Our findings highlight once more that DCI supplementation causes a significant improvement in insulin sensitivity, delineated by a reduction in the HOMA index, along with a decrease in blood glucose and fasting insulin levels across both groups. Moreover, although the BMI was already significantly different at T0, the patients demonstrated significant body weight and BMI reductions in both the diet and DCI-supplemented groups. In contrast, our study, for the first time, questions the usefulness of high doses of this inositol to correct metabolic disturbances and the associated gynecological issues in a population different from healthy volunteers.

In detail, the administration of high-dose DCI resulted in alarming effects on hormonal profiles and menstrual cycle fluctuations. The control group exhibited a decline in total testosterone and androstenedione, likely due to the lowering of insulin levels and insulin-dependent production of ovarian androgens. In contrast, the treatment group experienced a noteworthy increase in the abovementioned androgens. Naturally, the FAI was also increased by treatment with high-dose DCI, whereas it was reduced in the diet-only group in agreement with the evidence in the literature (46). The increase in the FAI signifies that the women treated with high-dose DCI may have progressed toward a more hyperandrogenic phenotype, and this likely accounts for the menstrual irregularities observed in the treated group.

Due to the above-reported metabolic and hormonal concerns in the treatment group, the trial was stopped due to ethical considerations.

We speculate that these results are attributable to the endocrine role of DCI, which participates in steroidogenesis, downmodulating the conversion of androgens to estrogens via the aromatase enzyme. Indeed, as initially demonstrated by Sacchi using in vitro experiments (47) and later confirmed in vivo by Bevilacqua (48), DCI inhibits aromatase gene expression, promoting androgen accumulation at the expense of estrogens. In this regard, the literature agrees that DCI administration should be avoided in hyperandrogenic women with PCOS, who may experience a worsening of their symptoms.

Furthermore, a recent study (49) encouraged a more careful evaluation of doses, timing, and patient features in the case of a treatment with DCI, in order to achieve the desired therapeutic effect without exacerbating pathological conditions, such as PCOS-related hyperandrogenism (18).

Our study is not intended to confirm or explain the molecular mechanism underlying the clinical effects of DCI. Therefore, it is imperative that further research unravels the intricate interplay between DCI, insulin sensitivity, and hormonal regulation. Moreover, the importance of long-term studies cannot be overstated, as they are crucial for evaluating the sustainability of therapeutical effects and their broader clinical implications.

Overall, this study emphasizes how proper nutritional habits positively impact insulin sensitivity and excess weight. Undoubtedly, the joint use of combinational approaches may contribute to metabolic recovery; however, our study does not indicate any additional benefits of high-dose D-chiro-inositol supplementation compared to diet alone.

Moreover, our results indicate that it is crucial for clinicians to be aware of all known mechanisms of action of food supplements, in addition to dose- and time-related effects. It is hoped that this study may guide clinicians towards the prescription of tailored therapeutical strategies that address the patients’ individual needs.