High HOMA2-B: A novel risk factor for diabetic peripheral neuropathy beyond metabolic syndrome components in type 2 diabetes

Currently, there are no effective pharmacological treatments for diabetic neuropathy. It is widely recognized that a comprehensive therapeutic approach should include both the management of risk factors and the implementation of strict, early blood glucose control.

The European Diabetes (EURODIAB) Prospective Study identified several independent risk factors for diabetic neuropathy. Tesfaye et al.¹ examined modifiable risk factors contributing to the development of diabetic neuropathy in 1,172 patients with type 1 diabetes mellitus, in EURODIAB Prospective Complications Study. Their analysis demonstrated that the total incidence of neuropathy was closely linked to glycosylated hemoglobin levels and the duration of diabetes. After adjustment for these factors, the study found that elevated total and low-density lipoprotein (LDL) cholesterol levels, higher triglycerides, increased body mass index (BMI), elevated von Willebrand factor, greater urinary albumin excretion, hypertension, and smoking were all significantly associated with the risk of neuropathy. These findings suggest that rigorous management of risk factors, including hypertension, dyslipidemia, obesity, and smoking, may be vital for the effective treatment of diabetic neuropathy.

Conversely, increasing evidence supports a link between the degree of obesity and the risk of developing diabetic neuropathy in type 2 diabetes, with components of metabolic syndrome also recognized as significant risk factors for diabetic neuropathy². Christensen et al.³ examined the relationship between metabolic and lifestyle factors and the onset of possible diabetic neuropathy and neuropathic pain in patients with early-stage type 2 diabetes. Their study revealed that central obesity, measured by waist circumference, waist-to-hip ratio, and waist-to-height ratio, was strongly associated with diabetic neuropathy. Additionally, other key metabolic factors, including hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol, high-sensitivity C-reactive protein (hs-CRP), C-peptide, and HbA1c, were linked to diabetic neuropathy. Antihypertensive medication use, smoking, and physical inactivity were also found to be associated with diabetic neuropathy, while smoking, excessive alcohol consumption, and a failure to increase physical activity following a diabetes diagnosis were related to neuropathic pain. The study concluded that potential diabetic neuropathy is correlated with metabolic syndrome factors, insulin resistance, inflammation, and modifiable lifestyle behaviors in early-stage type 2 diabetes. Therefore, addressing metabolic and lifestyle risk factors is essential for the effective management of diabetic neuropathy.

Patients newly diagnosed with type 2 diabetes mellitus can be stratified into three distinct pathophysiological categories based on the homeostasis model assessment-2 (HOMA2) indices of fasting β-cell function (HOMA2-B) and insulin sensitivity (HOMA2-S): hyperinsulinemic type 2 diabetes mellitus (characterized by elevated HOMA2-B and reduced HOMA2-S), classical type 2 diabetes mellitus (reduced HOMA2-B and reduced HOMA2-S), and insulinopenic type 2 diabetes mellitus (reduced HOMA2-B and elevated HOMA2-S). In their analysis of 4,388 Danish patients with newly diagnosed type 2 diabetes mellitus, Stidsen et al.⁴ assessed both HOMA2-B and HOMA2-S and found that individuals with hyperinsulinemic type 2 diabetes mellitus presented with more severe metabolic syndrome components and a higher incidence of cardiovascular disease than the other subgroups of type 2 diabetes mellitus.

Hyperinsulinemia has been suggested to adversely affect dorsal root ganglions by impeding neurite regeneration and heightening their susceptibility to oxidative stress and chronic low-grade inflammation. Elevated insulin resistance levels have been correlated with a rising prevalence of diabetic neuropathy in patients with long-standing diabetes. However, only a limited number of studies have explored the associations between hyperinsulinemia and diabetic neuropathy, while controlling for other components of metabolic syndrome.

To enhance our comprehension of the relationship between hyperinsulinemia, insulin resistance, and diabetic neuropathy, Kristensen et al.⁵ conducted a study involving 4,338 Danish individuals recently diagnosed with type 2 diabetes mellitus, utilizing comprehensive phenotypic data collected during routine clinical evaluations. After a median follow-up duration of 3 years, participants completed the Michigan Neuropathy Screening Instrument questionnaire (MNSIq) to evaluate the presence of diabetic neuropathy, defined as a score exceeding 4. Among the 3,397 (77%) individuals who submitted the MNSIq, 900 (27%) were categorized as hyperinsulinemic, 2,150 (63%) as classical, and 347 (10%) as insulinopenic type 2 diabetes patients.

Initially, they assessed the prevalence of diabetic neuropathy in hyperinsulinemic and insulinopenic patients in comparison with classical patients, both overall and independent of the components of metabolic syndrome. The prevalence of diabetic neuropathy was observed to be 23% in hyperinsulinemic patients, 16% in classical patients, and 14% in insulinopenic patients (Figure 1). Therefore, the hyperinsulinemic subgroup demonstrated the highest incidence of diabetic neuropathy.

The prevalence ratio (PR) of diabetic neuropathy was adjusted for demographic variables, including age and sex, as well as the duration of diabetes and treatment regimen. Lifestyle factors, such as physical activity, smoking, and alcohol consumption, along with components of metabolic syndrome—including waist circumference, triglycerides, HDL cholesterol, hypertension, and HbA1c—were also considered. Adjustments were made alternately for HOMA2-B while evaluating HOMA2-S and for HOMA2-S while assessing HOMA2-B.

The adjusted PR of diabetic neuropathy was found to be 1.35 (95% confidence interval [CI] 1.15–1.57) for hyperinsulinemic patients with type 2 diabetes mellitus in comparison with those with classical type 2 diabetes mellitus. In contrast, only a marginal difference in the adjusted PR was noted for insulinopenic patients, recorded at 1.04 (95% CI 0.77–1.38).

Second, the researchers examined the relationship between estimated fasting HOMA2 indices of β-cell function and insulin sensitivity in relation to diabetic neuropathy, with the objective of differentiating the effects of elevated β-cell function (hyperinsulinemia) from those of reduced insulin sensitivity. Spline analyses revealed a linear correlation between higher prevalence of diabetic polyneuropathy (DPN) and increasing HOMA2-B, independent of both metabolic syndrome components and HOMA2-S (Figure 2). Conversely, the association between HOMA2-S and DPN prevalence was not observed following adjustments for metabolic syndrome components and HOMA2-B. They concluded that hyperinsulinemia, characterized by increased HOMA2-B levels, is likely a critical risk factor for diabetic neuropathy that transcends the components of metabolic syndrome and insulin resistance.

Hyperinsulinemia has been recognized as a significant risk factor for diabetic complications and atherosclerosis in patients with diabetes. These findings, for the first time, indicate that hyperinsulinemia, as determined by elevated HOMA2-B levels, may represent a novel risk factor for diabetic neuropathy that is independent of the components of metabolic syndrome and HOMA2-S. Several points regarding this study warrant attention: (1) The study does not explain why only HOMA2-B, and not HOMA2-S, correlates with the prevalence of diabetic neuropathy. (2) The research focused exclusively on patients newly diagnosed with type 2 diabetes mellitus, and the authors did not include individuals with a history of long-standing diabetes. Given that the majority of type2 diabetes patients in clinical practice are typically those with prolonged disease duration, further investigation into this population is necessary. (3) The prevalence of hyperinsulinemic type2 diabetes patients is relatively high in Europe and the United States; however, the incidence of obese diabetic patients, specifically hyperinsulinemic type2 diabetes patients, may be lower in Asia. Consequently, it is essential to verify whether these findings are applicable to the Asian population through clinical studies.

Numerous studies have reported an association between metabolic syndrome, specifically insulin resistance, and diabetic neuropathy. Notably, this study highlights that the prevalence of diabetic neuropathy correlates with elevated HOMA2-B values, whereas no such relationship was observed with HOMA-R. Given the findings indicating that HOMA2-B serves as a risk factor for diabetic neuropathy in patients with new-onset type 2 diabetes mellitus, it is imperative that individuals with high HOMA2-B levels, who are at an increased risk for developing diabetic neuropathy, receive comprehensive treatment aimed at preventing its onset. Furthermore, if deemed necessary, these patients may require antidiabetic medications that do not promote insulin secretion. It is anticipated that these hypotheses will be validated in forthcoming clinical trials, thereby facilitating the integration of HOMA2-B into routine clinical practice for the management of diabetic neuropathy.

Koichi Kato received lecture fees from Daiichi Sankyo.

Approval of the research protocol: N/A.

Informed Consent: N/A.

Registry and the Registration No. of the study/trial: N/A.

Animal studies: N/A.