Is Peripheral Neuropathy Associated With Retinopathy and Albuminuria in Individuals With Impaired Glucose Metabolism?: The 1999–2000 AusDiab

The Australian, Diabetes, Obesity, and Lifestyle Study (AusDiab) is a population-based survey of Australian adults aged ≥25 years (11). Glucose tolerance status was determined by a 75-g oral glucose tolerance test (12). The prevalence of diabetes in the AusDiab was 7.4%, while 16.4% had IGT or IFG (13). All participants with diabetes, IGT, IFG, and a random sample of normal control subjects were invited for complications testing (6). This analysis is based on the 1,154 individuals with IGT or IFG who attended the complications screening.

Neuropathy was classified by 1) the modified neuropathy symptom score (NSS), 2) the modified neuropathy disability score (NDS), 3) the pressure perception score (PPS), and 4) a postural systolic blood pressure drop score of ≥20 mmHg. The NSS measured symptoms such as burning and numbness. The NDS examined ankle reflexes, vibration perception on the great toe, pin-prick perception on the dorsal surface of the great toe, and temperature perception on the dorsal surface of the metatarsals. The PPS assessed pressure perception on the plantar surface of both feet, at the great toe and the first and fifth metatarsal heads using a 10-g monofilament. Postural hypotension was determined by subtracting standing (taken after standing for 60 s) from supine systolic blood pressure. An NSS >4, an NDS >5, a PPS <6 (each site scored as 1 if normal and 0 if abnormal), and a fall in systolic blood pressure of ≥20 mmHg were considered abnormal. An overall abnormal neuropathy score was defined as abnormal if two or more of the four scales were abnormal (6,14–16).

Nonmydriatic retinal photographs (macula centered and nasal-to-disc) of each eye were taken (Canon CR6–45NM) (7) and graded according to a simplified version of the Wisconsin grading system (17). The presence of retinopathy (at least one definite retinal hemorrhage and/or microaneurysm) was determined for each eye, and individual classification was based on grading of the worst eye. Random regrading showed a high level of intrarater agreement (κ = 0.73).

A spot morning urine specimen was used to determine urinary albumin and creatinine levels (Olympus AU600 analyzer). Albuminuria was defined as presence of microalbuminuria (an albumin-to-creatinine ratio of 2.5–25 mg/mmol in men and 3.5–25 mg/mmol in women) or macroalbuminuria (albumin-to-creatinine ratio of ≥25 mg/mmol). Participants also had other laboratory measures and answered questionnaires on health status. Ethics committee approval and informed consent were obtained (11).

The proportions of participants with concomitant complications were assessed. Multiple logistic regressions were used to estimate the odds of neuropathy associated with retinopathy and albuminuria, while controlling for potential confounders. Analyses were performed with SPSS (SPSS 11.5; Chicago, IL).

Of 1,154 subjects with IGT or IFG, 1,150 had complete data regarding their neuropathy status, 1,027 had gradable eye photos, and 1,104 had data on their urinary albumin-to-creatinine ratio.

In individuals with IGT or IFG, 21.7% had at least one microvascular complication. In those who were classified as abnormal on the overall neuropathy score, 20.4% were classified as having retinopathy and 28.8% had albuminuria (microalbuminuria or macroalbuminuria). Older age, higher systolic blood pressure, hypertension (≥140/90 mmHg or taking antihypertensive medication), lower total cholesterol, lower LDL cholesterol, use of lipid-lowering medication, and abnormal albumin-to-creatinine excretion rate were all significantly associated with an abnormal overall neuropathy score (P < 0.05). The associations between each of the neuropathy scales with both retinopathy and albuminuria are outlined in Table 1. The overall neuropathy score was independently associated with both retinopathy and albuminuria after adjusting for the effects of age, sex, hypertension, lipid-lowering medication use, and total cholesterol (model 1). The association between neuropathy and retinopathy persisted despite further adjustment for albuminuria (model 2); however, the relationship between neuropathy and albuminuria was no longer significant after adjustment for retinopathy. The inclusion of fasting blood glucose, postload glucose, or HbA_1c in the model did not alter the strength of the association between the overall neuropathy score and retinopathy or the overall neuropathy score and albuminuria (data not shown).

Finally, in a subsidiary analysis where abnormal postural hypotension was defined as a drop of 30 mmHg or higher (6), the results were largely similar, with a multivariate adjusted odds ratio associated with an abnormal hypotension score of 4.1 (95% CI 0.8–21.2; adjusting for variables in model 1) for retinopathy and 4.5 (1.2–17.4) for albuminuria.

In this study, we have demonstrated associations between three microvascular complications in a population-derived sample of individuals with IGT or IFG. Compared with those without neuropathy, individuals with neuropathy were nearly four times more likely to have retinopathy and two times more likely to have albuminuria, independent of age, sex, hypertension, lipid-lowering medication use, and total cholesterol.

These results extend upon the findings of other population-based studies that have found a relationship between neuropathy and other microvascular complications in people with diabetes (9,10). Our study suggests that neuropathy is associated with other microvascular complications among those without diabetes. It is difficult to distinguish whether these complications are associated with small- or large-fiber neuropathy deficits because although there was a lack of association of retinopathy and albuminuria with the NSS, there was a stronger association with postural hypotension. Prospective studies are required to examine the temporal relationships between risk factors and the development of these microvascular complications among people with normal and impaired glucose metabolism.

We are most grateful to the following for their support of the study: the Commonwealth Department of Health and Ageing, Abbott Australasia, Alphapharm, Aventis, AstraZeneca, Bristol-Myers Squibb, Eli Lilly (Aust), GlaxoSmithKline, Janssen-Cilag (Aust), Merck Lipha, Merck Sharp & Dohme (Aust), Novartis (Aust), Novo Nordisk, Pharmacia and Upjohn, Pfizer, Roche Diagnostics, Sanofi Synthelabo (Aust), Servier Laboratories (Aust), Bio-Rad Laboratories, HITECH Pathology, the Australian Kidney Foundation, Diabetes Australia, Diabetes Australia (Northern Territory), Queensland Health, South Australian Department of Human Services, Tasmanian Department of Health and Human Services, Territory Health Services, Victorian Department of Human Services and Health Department of Western Australia. Also, for their contribution to the field activities of AusDiab, we are grateful to Annie Allman, Marita Dalton, David Dunstan, Adam Meehan, Claire Reid, Alison Stewart, and Fay Wilson. Additional support was provided by the National Health and Medical Research Council, Australia (grant no. 350448), the Science Technology Innovation Grant, Victoria, and the Sylvia and Charles Viertel Clinical Investigator Award (to T.Y.W.).