Diabetes mellitus comprises a group of metabolic disorders characterized by chronic hyperglycemia resulting from impaired insulin secretion, insulin action, or both, leading to dysregulated carbohydrate metabolism. Diabetes is diagnosed based on elevated venous plasma glucose levels or raised glycated hemoglobin (A1C). It is broadly classified into type 1 diabetes, type 2 diabetes, gestational diabetes mellitus, and other specific types due to distinct etiologies such as monogenic diabetes, exocrine pancreatic diseases, and drug-induced diabetes. Diagnostic criteria include fasting plasma glucose (FPG), 2-hour plasma glucose (2-h PG) during a 75-g oral glucose tolerance test (OGTT), random plasma glucose with classic hyperglycemic symptoms, or hyperglycemic crises such as diabetic ketoacidosis or hyperosmolar hyperglycemic state.[1–4] Prediabetes represents an intermediate state of dysglycemia between normoglycemia and diabetes and is defined by impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and/or an A1C of 5.7–6.4%. It is a major risk factor for progression to diabetes, cardiovascular disease, and other cardiometabolic complications and is commonly associated with central obesity, dyslipidemia, and hypertension, necessitating comprehensive cardiovascular risk assessment.[5] IFG is defined by FPG levels of 100–125 mg/dL, while IGT is characterized by 2-h PG levels of 140–199 mg/dL on OGTT. The American Diabetes Association revised the lower threshold for IFG from 110 mg/dL to 100 mg/dL to better align diabetes risk between IFG and IGT populations.[6] Prospective cohort studies demonstrate a continuous, curvilinear association between A1C levels and future diabetes risk. Individuals with A1C levels of 5.5–6.0% have a 5-year diabetes incidence of 9–25%, while those with A1C levels of 6.0–6.5% have a 25–50% risk, with a relative risk approximately 20-fold higher than those with A1C of 5.0%.[5,6] Baseline A1C has also been shown to be a stronger predictor of diabetes and cardiovascular events than fasting glucose, including in high-risk populations and the Diabetes Prevention Program. Individuals with A1C ≥5.7% represent a high-risk group requiring targeted counseling, lifestyle intervention, and close monitoring, particularly those with A1C >6.0% or combined IFG and IGT.[7] Globally, an estimated 537 million adults aged 20–79 years were living with diabetes in 2021, representing a prevalence of 10.5%. This number is projected to rise to 643 million by 2030 and 783 million by 2045. The prevalence of diabetes in India was 9.6% in 2021 and is expected to increase to 10.9% by 2045. Similarly, the prevalence of impaired glucose tolerance and impaired fasting glucose is rising steadily worldwide.[6] Diabetes-related complications contribute significantly to morbidity and mortality and are classified as microvascular and macrovascular. Microvascular complications, including neuropathy, nephropathy, and retinopathy, are more common, while macrovascular complications include cardiovascular disease, stroke, and peripheral arterial disease.[8] Diabetic retinopathy is a neurovascular complication of both type 1 and type 2 diabetes, strongly associated with disease duration and glycemic control. Early pathological changes include retinal microaneurysms and hemorrhages, which serve as key prognostic markers for disease progression. Diabetic retinopathy remains a leading cause of preventable blindness among working-age adults, with individuals with diabetes developing ocular complications such as glaucoma and cataracts earlier and more frequently.[9–11] Additional risk factors for diabetic retinopathy include chronic hyperglycemia, nephropathy, hypertension, and dyslipidemia. Intensive glycemic control has been shown to prevent or delay the onset and progression of retinopathy, reduce the need for ocular interventions, and improve visual outcomes. Early detection through screening is critical, as vision-threatening retinopathy may remain asymptomatic, and timely treatment can prevent or reverse visual loss.[12,13] Risk factors for prediabetes include advancing age, family history of diabetes, physical inactivity, obesity, insulin resistance, metabolic syndrome, gestational diabetes, low birth weight, childhood catch-up obesity, genetic susceptibility, and ethnicity. In Asian Indians, impaired glucose tolerance occurs at a younger age, with reported prevalence of 13.1% below 40 years. Family history is particularly associated with combined IFG and IGT, especially in non-obese individuals. Retinopathy has been reported to be up to four times more prevalent in individuals with impaired glucose tolerance compared to normoglycemic controls. Indian studies report variable prevalence of diabetic retinopathy among newly diagnosed type 2 diabetes patients, ranging from 4.8% to 12.38% across different cohorts.[14–16] The present study aimed at estimating the prevalence of retinopathy in pre-diabetic patients, type of retinopathy and determine its correlation with risk factors.

This hospital-based prospective observational study was conducted in the Department of Ophthalmology at Maharishi Markandeshwar Medical College and Hospital, Kumarhatti, Solan, a tertiary care center serving patients from across the state. The study was carried out over an 18-month period from April 2023 to March 2024 after obtaining approval from the Institutional Ethics Committee. A total of 75 prediabetic patients were enrolled. Adult patients aged 18–85 years with prediabetes attending the Medicine or Ophthalmology outpatient departments or admitted to the Medicine wards were included using convenient sampling. Prediabetes was defined according to the American Diabetes Association criteria as impaired fasting glucose (fasting plasma glucose 100–125 mg/dL), impaired glucose tolerance (2-hour plasma glucose 140–199 mg/dL on a 75-g oral glucose tolerance test), and/or HbA1C levels between 5.7% and 6.4%. Patients with known diabetes mellitus, opaque ocular media, fundus images that were not adequately interpretable, or those unwilling to participate were excluded. Data collection was distributed throughout the week to minimize temporal bias. After obtaining written informed consent, demographic details, anthropometric measurements, and clinical parameters including body mass index and blood pressure were recorded using a predesigned proforma. All participants underwent biochemical investigations including fasting and post-prandial blood glucose levels, HbA1C, renal function tests, lipid profile, and complete hemogram. Hypertension was defined as blood pressure ≥140/90 mmHg (JNC-VII criteria), obesity as BMI ≥25 kg/m² (JAPI criteria), and dyslipidemia according to NCEP-ATP III guidelines. A comprehensive ophthalmological evaluation was performed for all participants. Visual acuity was assessed using a Snellen chart at a distance of six meters. Pupillary dilation was achieved with 5% phenylephrine hydrochloride and 0.8% tropicamide, following which fundus examination was conducted using direct and indirect ophthalmoscopy. Slit-lamp biomicroscopy with a +90D lens was used for detailed fundus evaluation. Fundus photography was performed for both anterior and posterior segments, including assessment of the retina, macula, optic nerve head, and vitreous. Optical coherence tomography and fundus fluorescein angiography were performed where clinically indicated. Diabetic retinopathy was graded using the Early Treatment Diabetic Retinopathy Study (ETDRS) modified Airlie House classification. Data were entered into Microsoft Excel and analyzed statistically. Categorical variables were expressed as frequencies and percentages, while continuous variables were summarized as mean with standard deviation or median with interquartile range based on data distribution. Associations between categorical variables were assessed using the Chi-square test, and comparisons of continuous variables were performed using the Student’s t-test where applicable. A p-value <0.05 was considered statistically significant. The study was conducted in accordance with ethical standards. Written informed consent was obtained from all participants in a language they understood, confidentiality of data was maintained, and participation was entirely voluntary. The study posed no additional risk or financial burden to the participants or the institution.

The study included 75 prediabetic participants, of whom 8 (10.7%) had evidence of retinopathy and 67 (89.3%) did not. The distribution of retinopathy across age groups showed a statistically significant association with age (p = 0.028). The mean age of participants with retinopathy was higher (54.71 ± 15.39 years) compared to those without retinopathy (50.28 ± 13.73 years). Retinopathy was observed across all age categories, with proportions ranging from 7.7% in the 36–45 year age group to 16.7% in the 66–75 year age group. Among males, 5 out of 55 participants (9.1%) had retinopathy, while 3 out of 20 females (15.0%) were affected; however, this difference was not statistically significant (p = 0.347). Retinopathy was present in 11.1% of participants with a history of smoking and in 10.4% of non-smokers, with no significant association observed (p = 0.497). Similarly, participants with a family history of diabetes mellitus had a retinopathy prevalence of 10.3%, compared to 11.1% among those without such a history, and this difference was not statistically significant (p = 0.319). With respect to body mass index, retinopathy was not observed among underweight participants. Retinopathy prevalence was 11.6% in individuals with normal BMI, 9.1% in overweight participants, and 12.5% among obese participants. The mean BMI was comparable between participants with and without retinopathy (23.56 ± 8.32 kg/m² vs. 22.95 ± 6.38 kg/m²), and no statistically significant association was found (p = 0.347). Participants with retinopathy had significantly higher mean systolic blood pressure (143.29 ± 12.76 mmHg) compared to those without retinopathy (131.73 ± 15.36 mmHg), with this difference reaching statistical significance (p = 0.047). Similarly, mean diastolic blood pressure was significantly higher among participants with retinopathy (98.28 ± 10.84 mmHg) than those without retinopathy (87.46 ± 9.75 mmHg) (p = 0.034). (Table 1) Table 1: Association of Sociodemographic and Clinical Variables with Retinopathy Status (n = 75) Variable Category Retinopathy Present (n = 8) Retinopathy Absent (n = 67) Total (n = 75) p-value Age (years) Mean ± SD 54.71 ± 15.39 50.28 ± 13.73 52.45 ± 14.35 0.028 Sex Male 5 (9.1) 50 (90.9) 55 (100) Female 3 (15.0) 17 (85.0) 20 (100) 0.347 History of Smoking Present 3 (11.1) 24 (88.9) 27 (100) Absent 5 (10.4) 43 (89.6) 48 (100) 0.497 Family History of Diabetes Mellitus Present 4 (10.3) 35 (89.7) 39 (100) Absent 4 (11.1) 32 (88.9) 36 (100) 0.319 Body Mass Index (kg/m²) Mean ± SD 23.56 ± 8.32 22.95 ± 6.38 23.12 ± 6.94 0.347 Systolic BP (mmHg) Mean ± SD 143.29 ± 12.76 131.73 ± 15.36 133.84 ± 15.92 0.047 Diastolic BP (mmHg) Mean ± SD 98.28 ± 10.84 87.46 ± 9.75 85.38 ± 10.93 0.034 Biochemical parameters were compared between participants with and without retinopathy. Participants with retinopathy had higher mean fasting blood sugar (121.73 ± 18.45 mg/dL) and post-prandial blood sugar levels (183.92 ± 27.73 mg/dL) compared to those without retinopathy (107.28 ± 17.82 mg/dL and 168.91 ± 22.57 mg/dL, respectively). Mean HbA1C levels were also higher among participants with retinopathy (6.37 ± 0.81%) than among those without retinopathy (6.18 ± 0.98%), and this difference was statistically significant (p = 0.013). Renal function status showed a significant association with retinopathy (p < 0.001). Retinopathy was present in 58.3% of participants with deranged renal function compared to 1.6% of those with normal renal function. Serum lipid abnormalities were significantly associated with retinopathy. Retinopathy was observed in 33.3% of participants with deranged total cholesterol compared to 3.5% among those with normal levels (p = 0.031). Similarly, 31.8% of participants with elevated triglyceride levels had retinopathy, whereas only 1.8% of those with normal triglyceride levels were affected (p = 0.027). Participants with deranged LDL cholesterol demonstrated a markedly higher prevalence of retinopathy (63.6%) compared to those with normal LDL levels (1.6%), with this association reaching statistical significance (p = 0.008). Likewise, retinopathy was present in 42.9% of participants with low HDL cholesterol compared to 3.3% among those with normal HDL levels (p = 0.017). (Table 2) Table 2: Association of Biochemical Parameters with Retinopathy Status (n = 75) Variable Category Retinopathy Present (n = 8) Retinopathy Absent (n = 67) Total (n = 75) p-value Fasting Blood Sugar (mg/dL) Mean ± SD 121.73 ± 18.45 107.28 ± 17.82 110.14 ± 18.09 Post-Prandial Blood Sugar (mg/dL) Mean ± SD 183.92 ± 27.73 168.91 ± 22.57 172.77 ± 23.49 HbA1C (%) Mean ± SD 6.37 ± 0.81 6.18 ± 0.98 6.22 ± 0.93 0.013 Renal Function Normal 1 (1.6) 62 (98.4) 63 (100) Deranged 7 (58.3) 5 (41.7) 12 (100) <0.001 Serum Total Cholesterol Normal 2 (3.5) 55 (96.5) 57 (100) Deranged 6 (33.3) 12 (66.7) 18 (100) 0.031 Serum Triglycerides Normal 1 (1.8) 53 (98.2) 54 (100) Deranged 7 (31.8) 15 (68.2) 22 (100) 0.027 Serum LDL-C Normal 1 (1.6) 63 (98.4) 64 (100) Deranged 7 (63.6) 4 (36.4) 11 (100) 0.008 Serum HDL-C Normal 2 (3.3) 59 (96.7) 61 (100) Deranged 6 (42.9) 8 (57.1) 14 (100) 0.017

Diabetic retinopathy is traditionally regarded as a complication of established diabetes; however, emerging evidence suggests that retinal microvascular changes may occur during the prediabetic stage. Chronic low-grade hyperglycemia in prediabetes can induce endothelial dysfunction, capillary leakage, microaneurysm formation, and subclinical inflammation, particularly in the presence of coexisting cardiometabolic risk factors such as hypertension, dyslipidemia, and insulin resistance. These early vascular alterations underscore the importance of screening and metabolic optimization even before the onset of overt diabetes.[17–19] In the present hospital-based prospective study of 75 prediabetic individuals, retinopathy was detected in 10.7% of participants. Advancing age showed a statistically significant association with retinopathy, consistent with the cumulative effect of metabolic and vascular insults over time. Similar age-related associations have been reported across multiple population-based studies, which have demonstrated increasing retinopathy prevalence with advancing age even among non-diabetic and prediabetic populations. Blood pressure emerged as a key determinant of retinopathy in the present study, with both systolic and diastolic blood pressures significantly higher among individuals with retinopathy. Hypertension contributes to retinal microvascular damage by increasing shear stress, promoting endothelial dysfunction, and accelerating capillary basement membrane thickening. Numerous epidemiological studies, including large cohort and population-based investigations, have consistently demonstrated blood pressure as an independent risk factor for retinopathy across the glycemic spectrum, including prediabetes. Renal dysfunction showed a strong association with retinopathy in this study, reflecting shared microvascular pathology between the kidney and retina. The coexistence of retinal changes and renal impairment has been well documented, with studies reporting associations between retinopathy, albuminuria, and declining renal function even in early dysglycemic states. These findings highlight renal dysfunction as a marker of systemic microvascular injury. Lipid abnormalities were significantly associated with retinopathy in the present study. Elevated total cholesterol, triglycerides, and LDL cholesterol, along with reduced HDL cholesterol, were more frequent among participants with retinopathy. Dyslipidemia contributes to retinal damage through lipid exudation, oxidative stress, and inflammatory mechanisms, facilitating microvascular injury. Several epidemiological and cohort studies have reported similar associations, reinforcing the role of lipid metabolism in the pathogenesis of retinal changes in prediabetes. No significant association was observed between retinopathy and sex, body mass index, smoking status, or family history of diabetes in the present study. While some studies have reported associations with obesity and smoking, others—including large population-based cohorts—have failed to demonstrate consistent independent relationships, suggesting that the impact of these factors may vary across populations and study designs. The findings of the present study are supported by several large-scale epidemiological investigations, including studies from diverse populations such as Pima Indians, Latinos, Chinese, Europeans, and participants of the Diabetes Prevention Program. These studies collectively demonstrate that retinopathy can occur in individuals with impaired glucose regulation and prediabetes, often in association with elevated blood pressure, dysglycemia, renal impairment, and lipid abnormalities. HbA1C has consistently emerged as a strong predictor of retinopathy across glycemic stages, from prediabetes to established type 2 diabetes.[7,9,20] The principal limitations of the present study include the absence of a normoglycemic control group and a relatively small sample size, which may limit generalizability. Additionally, the cross-sectional nature of the analysis precludes causal inference. Nevertheless, the study provides clinically relevant evidence that retinal changes are not uncommon in prediabetic individuals and are closely linked to modifiable cardiometabolic risk factors. In conclusion, retinopathy in prediabetes was significantly associated with advancing age, elevated systolic and diastolic blood pressure, renal dysfunction, and dyslipidemia, while no significant associations were observed with sex, body mass index, smoking, or family history of diabetes. These findings support the need for early ophthalmic screening and aggressive management of cardiovascular risk factors in prediabetic individuals to prevent progression of retinal microvascular disease.

Our investigation revealed that retinopathy was associated with increasing age, elevated systolic blood pressure, elevated diastolic blood pressure, impaired renal function, increased serum total cholesterol, elevated serum triglycerides, heightened serum LDL, and decreased serum HDL. Nonetheless, our analysis revealed no significant correlation between retinopathy and the patient's sex, BMI, smoking habits, or family history of diabetes. The primary limitation of our study was the absence of control groups. Furthermore, our sample size was constrained. Additional research is necessary on this subject with an expanded sample size and appropriate controls. In persons predisposed to diabetes due to prediabetes and overweight/obesity, diabetic retinopathy (DR) initiates early in the progression of dysglycemia and manifests early in the diabetes trajectory. Glycemic indicators, particularly HbA1c, are significant independent risk factors for diabetic retinopathy over the whole range of glycemia, even prior to the diagnosis of diabetes. Given that therapies mitigating diabetes onset have demonstrated a reduction in the eventual emergence of chronic diabetes-related retinopathy, it becomes prudent to test for retinal alterations in individuals with prediabetes. Further research is necessary to determine whether therapies aimed at reducing plasma glucose or other metabolic abnormalities during the prediabetes phase would influence the trajectory of long-term problems.

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