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Insulin Resistance Syndrome in the Elderly: Assessment of Functional, Biochemical, Metabolic, and Inflammatory Status

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Insulin Resistance Syndrome in the Elderly: Assessment of Functional, Biochemical, Metabolic, and Inflammatory Status Diabetes Care In Press, published online May 29, 2007 Insulin Resistance Syndrome in the Elderly: Assessment of Functional, Biochemical, Metabolic, and Inflammatory Status Received for publication 3 April 2007 and accepted in revised form 21 May 2007. William A. Banks MD1,2, Lisa M. Willoughby PhD3, David R. Thomas MD2, John E. Morley MB,BCh1,2 GRECC, Veterans Affairs Medical Center-St. Louis1 Saint Louis University School of Medicine, Division of Geriatrics, Department of Internal Medicine2 Saint Louis University School of Medicine, Center for Outcomes Research, Department of Internal Medicine3 Running Title: Insulin Resistance Syndrome in the Elderly Correspondence and Reprint Requests to: William A. Banks, MD 915 N. Grand Blvd St. Louis, MO 63106 email: [email protected] Page 1 Copyright American Diabetes Association, Inc., 2007 Abstract Objective: Hyperinsulinemic euglycemia, or the Insulin Resistance Syndrome (IRS), is associated with increased morbidity and mortality. Although thought to be associated with proinflammatory states, little work has been done in this area. Here, we determined the impact of IRS on functional, biochemical, metabolic, and inflammatory status in a high risk population: elderly women in nursing homes. Research Design and Methods: Functional, biochemical, metabolic, and inflammatory parameters were measured in 100 consecutive ambulatory, elderly, nursing home females. Diabetics and residents with FBS >110 mg/dl were excluded. Remaining residents were classified as insulin resistant (IR: insulin>100 pM) or non-insulin resistant (NIR). Results: 16 residents had IR and 53 NIR. No differences in functional status, BMI, renal function, C-reactive protein, or immune cell levels were found. FBS was higher in IR (94.1 ± 8.1 (SD) vs 87.9 ± 8.2, P<0.05), indicating a very mild glucose intolerance. Serum C-peptide (P<0.05), amylin (P<0.01), and leptin (P<0.01), but not adiponectin nor resistin, were higher in IR. Higher leptin/BMI and insulin/C-peptide ratios suggested an increased percent body fat mass and altered clearance of insulin, respectively. 11 of 13 cytokines had arithmetic elevations, but only tumor necrosis factor-alpha (TNF) reached statistical significance (P<0.01). TNF and insulin levels were highly correlated. Conclusions: IRS in the healthiest of long-term care residents is relatively rare, but associated with mild glucose intolerance, increased percent body fat, altered insulin clearance, and a proinflammatory status as evidenced by an elevated TNF. Page 2 Insulin resistance syndrome (IRS) is Research Design and Methods characterized by a decreased tissue sensitivity Patient Population: Studies were approved by to the action of insulin, leading to a the local IRB and consent forms obtained on compensatory increase in insulin secretion all participants. 100 elderly ambulatory (1). It is thought that most adults with IRS females aged 65 years or older were recruited maintain normal glucose levels and will never from eight long-term care facilities in the St. develop overt type 2 diabetes, but are Louis metropolitan area. Exclusion criteria nonetheless at increased risk for for the study were non-ambulatory status or cardiovascular disease. Whereas diabetes those with a contraindication for exercise. A mellitus is defined on the basis of serum fasting morning blood sample was drawn and glucose levels regardless of insulin status, IRS measured for glucose, electrolytes, blood urea is defined on the basis of serum insulin levels nitrogen, creatinine, blood urea regardless of glucose status. The population nitrogen/anion gap ratio, anion gap, c-reactive of IRS that clearly does not overlap with protein, pre-albumin, albumin, transferrin, diabetes mellitus is that with euglycemic white blood cells (further assessed as hyperinsulinemia. Residents with IRS, percentages of neutrophils, lymphocytes, despite euglycemia, are at increased risk for eosinophils, and segments), platelets, red cell hypertension, stroke, polycystic ovary indices, and hemoglobin. Blood samples syndrome, and nonalcoholic steatohepatitis were also measured blinded with multiplex (2). kits (Millipore, St. Charles, MO) for insulin, Because measuring serum insulin is C-peptide, leptin, total amylin, adiponectin, not part of routine clinical practice, resistin, interleukin (IL)-1 alpha, IL-1ß, IL-1 diagnosing IRS is difficult. As such, receptor antagonist, IL-2, IL-4, IL-6, IL-8, IL- diagnosis is often made based on the presence 10, interferon-gamma, tumor necrosis factor- of secondary criteria, such as hypertension, alpha (TNF), eotaxin, macrophage history of glucose intolerance, or elevated inflammatory protein-1 alpha, and RANTES. BMI (2). As these are also associated with Any multiplex levels above the detection limit diabetes mellitus and likely are sequella were diluted and assayed again. Any developing from IRS, such a diagnostic multiplex levels below the detection limit approach makes it difficult to ascertain were assigned the value of 1.0. Residents incidence of IRS or to study early were weighed, their height measured, and pathological events that may be unique to it. their body mass index calculated as weight (in These difficulties are magnified in the elderly kg) divided by the square of height (in m). as many of the secondary criteria are Mini-mental status examination (3), mini- independently associated with aging. nutritional assessment (4), activities of daily Here, we studied a population of living (5), the geriatric depression scale (6), elderly, ambulatory women living in long- functional independence measure (7) the term care facilities in a midwestern comorbidity scale of Charlson (8;9), the timed metropolitan area. We assessed in the get up and go test (10), the timed six meter euglycemic subset their functional, walk (11), the six minute walk (12), smoking biochemical, metabolic, and inflammatory history, and alcohol consumption history were parameters as a function of endogenous serum assessed at the time of enrollment. insulin levels. Residents on any form of medication Page 3 for the treatment of diabetes mellitus or with a was slightly elevated in the NIR group fasting blood sugar of 110 mg/dl or greater (P<0.05), but no differences in the other were excluded from further analysis. One general chemistries. Renal function as resident with abnormally high values for C- measured by creatinine or the BUN/creatinine peptide (>4500 pM), insulin (2280 pM), and ratio was similar between the two groups. total amylin (>4500 pM) was excluded from C-peptide (P<0.05), amylin (P<0.001), the study. The 69 remaining nondiabetic, and leptin (P<0.01) were all elevated in the IR euglycemic residents were classified as group (Table 2). Adiponectin showed a insulin resistant (IR; fasting serum insulin statistical trend (P=0.08) towards being lower >100 pM, n = 16) or non-insulin resistant in the IR group. (NIR, fasting serum insulin <100 pM, n = 53). The proinflammatory cytokine TNF Two inflammatory scores were was about 50% higher (P<0.01; Table 2); calculated by first determining the median although the other cytokines except for MIP- values for a parameter and then calculating 1α and RANTES were arithmetically higher the number of subjects who had values higher in the IR group, none reached statistical than the median. The first inflammatory significance. C-reactive protein, immune cell score included the parameters of C-reactive measures, and neither of the proinflammatory protein, TNF, IL-6, and IL-1ß and values indices were significantly different between ranged from 0-4. The second inflammatory the IR and NIR groups. score excluded C-reactive protein for a Ratios of leptin/BMI (P<0.01), measure based entirely on cytokine measures. insulin/c-peptide (P<0.001), insulin/BMI (P<0.001), and insulin/TNF (P<0.001) were Analysis of data: Means are reported with significantly higher in the IR group (Table 3). their standard deviations and n. Results were The ratios for insulin/leptin, TNF/BMI, and analyzed using the SPSS v14 package. IR insulin/amylin were not different between the and NIR subjects were compared using Chi- two groups. square tests for categorical variables and Significant positive correlations were Mann-Whitney-U tests for continuous found between BMI and leptin (P<0.001, r = variables. Rank-order correlations 0.68), TNF and insulin (P<0.01, r = 0.36), (Spearman’s r) were used to investigate leptin and insulin (P<0.01, r = 0.31), and associations. Statistical significance was insulin and the leptin/BMI ratio (P<0.01, r = determined at the 0.05 level and statistical 0.34). Figure 1 shows the relation between trend defined as 0.05<P<0.10. TNF and log insulin (Y = 9.21x + 5.36, r = 0.533, n = 69, p<<0.01). Adiponectin and Results leptin were inversely correlated (P<0.001, r = The mean insulin levels were 280 ± - 0.50). There were trends for associations 313 pM (IR group, n = 16) and 58.4 ± 18.51 between C-reactive protein vs TNF (P=0.07) pM (NIR group, n = 53). Table 1 compares and insulin vs BMI (P=0.06). TNF and leptin resident characteristics. There were no did not correlate. differences in age, morphometric measures, or functional, nutritional, or mental status, Discussion although there was a statistical trend (P=.09) IRS is increasingly recognized as a towards an elevated BMI in the insulin harbinger of classical disease states, including resistant group. Table 2 shows that glucose diabetes mellitus and metabolic syndrome X. Page 4 It has been postulated that insulin resistance, associated with in-patient
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