Rise in Insulin Resistance

Aging is associated with body composition changes that result in increased insulin resistance.¹² Increased visceral fat is associated with increased rates of lipolysis causing high levels of free fatty acids, which may have a role in reducing peripheral insulin sensitivity.¹³ Reduction of muscle mass or sarcopenia occurs with aging through physical inactivity and, because the muscle is the main site of glucose consumption, the loss of muscle mass increases insulin resistance.¹² Accumulation of lipids within the muscles is another factor reducing insulin sensitivity. A reduction in mitochondrial function¹⁴ may also contribute to age-related glucose intolerance by reducing oxidative metabolism, physical fitness, and oxidative capacity. Low concentrations of adiponectin, leptin, and insulin-like growth factor 1 (IGF-1) and high concentrations of tumor necrosis factor-α (TNF-α) are associated with aging and have been linked to increased insulin resistance and incident diabetes.^14–16

Fall in Insulin Secretion

Insulin secretion diminishes by 0.7%/year with increasing age because of reduced function and increased apoptosis of pancreatic beta cells.¹⁷ Beta cell autoimmunity may lead to the activation of an acute-phase response in older adults with diabetes, with hypersecretion of interleukins, C-reactive protein, and TNF-α, which may reduce insulin secretion.¹⁸ Disturbances in the physiology of the gut-derived incretins, gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), may be another factor involved in beta cell dysfunction.¹⁹ Both peptides enhance insulin secretion after meals and may have a role in maintaining beta cell growth, proliferation, and inhibition of apoptosis. Aging is associated with reduced levels and function of these peptides.²⁰

Diabetes in older adults is associated with increased atherosclerosis, premature aging, and increased disability. Older adults with diabetes frequently have at least one comorbid chronic disease in addition to diabetes, and as many as 40% have at least three conditions.²¹ The comorbidity burden is even higher in nursing home residents with diabetes. For example, those with diabetes have more cardiovascular disease, visual problems, pressure sores, limb amputations, and kidney failure than residents without diabetes.²² In a retrospective case review of 75 U.K. nursing home residents with diabetes, significant levels of disability were shown in areas of continence, feeding, mobility, and communication. The average number of comorbidities per individual was four (range, one to eight).²³ The mortality rate was 34% after 1 year of follow-up, indicating severe comorbidity.²⁴ In another study, residents with diabetes had a greater comorbidity burden (hierarchic condition category, 1.90 vs. 1.58), used more prescribed medications, and experienced more hospitalizations than residents without diabetes (37% vs. 18%).¹¹

Geriatric Syndromes

Geriatric syndromes, such as cognitive and physical dysfunction, depression, falls, and urinary incontinence, are common in older adults with diabetes and may have subtle presentations.²⁵ Diabetes is associated with a twofold increased risk of being unable to perform daily physical tasks, such as walking, doing housework, or climbing stairs, and a 1.6-fold greater risk of difficulties performing basic personal care, such as bathing, using the toilet, dressing, and eating. Diabetes complications, such as neuropathy, arthritis, and vascular disease, are contributors to physical disability in older adults with diabetes.^26,27 The Study of Osteoporotic Fractures report²⁸ has shown that diabetes also increases the risk of falls (odds ratio [OR], 2.78; 95% confidence interval [CI], 1.82 to 4.25). A history of arthritis, musculoskeletal pain, depression, poor vision, and peripheral neuropathy are the main predictors of falling among older adults with diabetes.²⁸ The risk of developing Alzheimer disease or vascular dementia is twofold higher in older adults with diabetes compared to age-matched adults without diabetes.²⁹ In the Health, Aging, and Body Composition Study, older adults (70 to 79 years old) with diabetes had an increased incidence of depression compared with persons without diabetes (23.5% vs. 19.0%; hazard ratio [HR], 1.31; 95% CI, 1.07 to 1.61).³⁰

Frailty

Frailty is a condition characterized by a reduction in physiologic reserve and the ability to resist physical or psychological stressors.³¹ Its definition is largely based on the presence of three or more phenotypes (e.g., weight loss, weakness, decreased physical activity, exhaustion, slow gait speed).³² Frailty is viewed as a wasting disease, with weight loss being one of its criteria. Undernutrition, which is common in older adults, seems to be a risk factor for frailty. In the United States, about 16% of older adults living in the community are undernourished. These figures rise to 59% in long-term care institutions and to 65% in acute-care hospitals.³³

Sarcopenia—muscle mass loss—is a component of frailty, which seems to be accelerated when diabetes is present. In a community study of 3153 participants older than 65 years, appendicular lean mass loss in men with diabetes was twice that of men without diabetes (3.0% vs. 1.5%) and, in women with diabetes, was 1.8 times that of those without diabetes (3.4% vs. 1.9%) over 4 years of follow-up. The mechanisms explaining these results may be related to reduced muscle protein synthesis as a result of lower testosterone and IGF-1 levels and increased muscle protein breakdown caused by a higher rate of inflammation.³⁴ Diabetes also causes sarcopenia through the catabolic effect of insulin deficiency and by increasing intramyocellular lipid accumulation.³⁵ In another study, older adults with type 2 diabetes had accelerated declines in leg lean mass, muscle strength, and longer sit-to-stand time compared to those with normoglycemia.³⁶ Another factor related to malnutrition and frailty may be oral health. For example, optimal nutrition may not be maintained because of poor dentition, dry mouth, reduced taste sensation, palatability, and appetite change with increasing age.³⁷

Lifestyle modifications include changes in diet, weight reduction, smoking cessation (the single most effective means of reducing mortality⁴²), and regular exercise to reduce visceral obesity and improve insulin sensitivity.

Aging is associated with increased insulin resistance through the loss of skeletal muscle mass.¹² Muscle mass is dependent on a balance between muscle protein synthesis and breakdown; protein intake with exercise training synergistically increases skeletal muscle mass in older adults. In one trial, protein supplementation for frail older adults who were engaged in resistance training resulted in muscle hypertrophy and increases in muscle strength, muscle mass, and performance.⁴³ A diet that is high in fiber and potassium and low in saturated fats and refined carbohydrates and salt may help achieve an ideal body weight and improve the lipid profile, significantly lowering blood pressure and reducing the overall cardiovascular risk.⁴⁴ In the Diabetes Prevention Program, lifestyle interventions, including modest weight reduction, healthy low-fat diet, and regular exercise reduced the development of diabetes; this beneficial effect persisted for up to 10 years after the end of the study, especially in older adults (≥60 years).⁴⁵ Additional benefits of exercise for older adults may include increased muscle strength and improved walking balance. The Look AHEAD (Action for Health in Diabetes) study in middle-aged and older adults with type 2 diabetes has shown that weight loss and improved fitness lower the risk of loss of mobility.⁴⁶

Hyperglycemia

Although the evidence for reducing microvascular disease by tight glycemic control has been established, there is ongoing debate about whether reducing blood glucose to near-normal levels results in a lower incidence of cardiovascular events (Table 90-1).^47–50 In frail older adults, the benefit of blood glucose control diminishes in the presence of other comorbidities. In a decision analysis to assess the effects of baseline health status on prioritization of therapy, blood pressure control conferred a larger benefit than glucose control for older adults (75 to 79 years), and the expected benefits of both therapies steadily declined as the level of comorbidity and functional impairment increased.⁵¹ Therefore, in older adults who are frail, with multiple comorbidities and functional impairment, tight control may be more harmful by inducing hypoglycemia. It is important to address individual goals of therapy, guided by patient preferences, life expectancy, comorbidities, and influences of therapy on quality of life. The advantages and disadvantages of hypoglycemic medications in older adults with diabetes are detailed in Table 90-2.

A target systolic blood pressure of about 140 mm Hg is reasonable in older adults with diabetes because maintenance of a systolic pressure between 130 and 140 mm Hg is associated with a reduction of adverse cardiovascular outcomes in older adults with hypertension and diabetes. Tighter control, however, is not warranted, because this may be associated with increased adverse events. In the International Verapamil SR-Trandolapril (INVEST) Study, controlling systolic blood pressure to less than 130 mm Hg was not associated with better cardiovascular outcomes than usual control of 130 to 140 mm Hg in individuals 55 years of age and older, and it was associated with a nonsignificant increased risk of mortality (11.0% vs. 10.2%; adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 0.99 to 1.45; P = .06).⁵² Tight blood pressure control (target < 120 mm Hg systolic) was also not beneficial and was associated with adverse outcomes in older adults (40 to 79 years) with diabetes.⁵³ The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) also had similar conclusions for older adults, mean age 66 ± 7 years, of whom 57% were older than 65 years.⁵⁴ Two meta-analyses of older adults with diabetes did not show reduced myocardial infarction or mortality rates with a systolic blood blood pressure less than 140 mm Hg.^55,56 In much older adults (>80 years), the targets may be even more relaxed. The Hypertension in the Very Elderly Trial (HYVET), which included older adults older than 80 years, with sustained systolic blood pressure higher than 180 mm Hg, 7% of whom had diabetes, showed a significant 33.7% reduction in cardiovascular events (HR, 0.66; 95% CI, 0.53 to 0.82; P < .001), with a target blood pressure control of 150/80 mm Hg. However, the individuals included in the HYVET study were healthier than those in the general population, with a low baseline rate of known cardiovascular disease (CVD; 11.5%), myocardial infarction (3.1%), and heart failure (2.9%). Therefore, the results may not apply to all older adults, especially those with multiple comorbidities or living in nursing homes.⁵⁷ In another community study of people older than 85 years, there was a U-shaped relationship, with a systolic blood pressure of 164.2 mm Hg (95% CI, 154.1 to 183.8 mm Hg) being associated with the lowest mortality suggesting that the optimal systolic blood pressure for this age group could be more than 140 mm Hg.⁵⁸ Thiazide diuretics, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers are reasonable first-choice agents although higher doses of diuretics may worsen blood glucose levels and the lipid profile. Most people will require more than one antihypertensive agent.