Diabetes and Hyperglycemia in Older Adults

A nice review on aging and genetic factors as contributors to hyperglycemia and diabetes in older individuals. The article was published in Diabetes Care, April 2017. Please find below excerpts, slightly modified for easier and succinct reading.

GT


Introduction

Diabetes is one of the leading chronic medical conditions among older adults, with high risk for vascular comorbidities such as coronary artery disease, physical and cognitive function impairment, and mortality. Despite decades of effort to prevent diabetes, diabetes remains an epidemic condition with particularly high morbidity affecting older adults. In fact, nearly 11 million people in the U.S. aged 65 years or older (more than 26% of adults aged 65 years or older) meet current American Diabetes Association criteria for diabetes (diagnosed and undiagnosed), accounting for more than 37% of the adult population with diabetes. At the same time, adults 65 years or older are developing diabetes at a rate nearly three-times higher than younger adults: 11.5 per 1,000 people compared with 3.6 per 1,000 people among adults aged 20–44 years old. However, increasing research in diabetes and aging has improved our understanding of the pathophysiology of diabetes and its association with aging and led to the development of a number of antihyperglycemic medications. The mechanism of diabetes complications has been previously reviewed. The current paper reviews the pathophysiology of type 2 diabetes among older adults and the implications for hyperglycemia management in this population.

 

Pathophysiology of Type 2 Diabetes

Type 2 diabetes is by far the most prevalent form of diabetes in older adults and is an age-related disorder. The criteria for diagnosing diabetes are the same for all age groups because the risks of diabetes-related complications are associated with hyperglycemia over time across all age groups. Older adults are at high risk for the development of type 2 diabetes due to the combined effects of genetic, lifestyle, and aging influences. These factors contribute to hyperglycemia through effects on both β-cell insulin secretory capacity and on tissue sensitivity to insulin. The occurrence of type 2 diabetes in an older person is complicated by the comorbidities and functional impairments associated with aging.

Hyperglycemia develops in type 2 diabetes when there is an imbalance of glucose production (i.e., hepatic glucose production during fasting) and glucose intake (i.e., food ingestion) as opposed to insulin-stimulated glucose uptake in target tissues, mainly skeletal muscle. Multiple factors in an older person contribute to such an imbalance of glucose regulation. Although resistance to peripheral insulin action contributes to altered glucose homeostasis, current evidence has found that the direct effect of aging on diabetes pathophysiology is through impairment of β-cell function, resulting in a decline in insulin secretion.

 

Genetics

There is a strong genetic predisposition to type 2 diabetes. The genetic susceptibility to type 2 diabetes is polygenic, involving a number of variants, where each allele has a modest effect on the risk of disease in an individual person. Genome-wide association studies, linkage analysis, candidate gene approach, and large-scale association studies have identified ∼70 loci conferring susceptibility to type 2 diabetes. These genetic alleles appear to affect the risk of type 2 diabetes primarily through impaired pancreatic β-cell function, reduced insulin action, or obesity risk.

Genome-wide association studies have consistently found that p16INK4a, a cyclin-dependent kinase inhibitor (CDKI), encoded by the Cdkn2a locus, is associated with type 2 diabetes risks. Expression of p16INK4a was increased in aging mice, and an additional copy of p16INK4awas associated with markedly reduced pancreatic islet cell proliferation. β-Cell proliferation was increased in p16INK4a knockout mice. Therefore, p16INK4a increases with age and appears to mediate an age-associated decline in the replicative capacity of mouse islets; p16INK4a could be a potential link between aging, metabolic derangements, and β-cell failure in type 2 diabetes.

 

Effects of Aging

In the setting of genetic and lifestyle-related risk factors, aging contributes to the development of type 2 diabetes through impaired β-cell function and impaired β-cell adaptation to insulin resistance leading to impaired insulin secretion. Studies in rodents and humans have found that aging may exert a distinct influence on β-cell turnover as well as function.

In older patients who have developed diabetes, autoimmune destruction of β-cells is rarely observed. Limited pathologic investigation suggests that total β-cell mass may be moderately reduced, but severe loss of β-cell mass is uncommon. Pancreatic β-cell mass in adult humans exists in a dynamic state such that the cells can undergo compensatory changes to maintain euglycemia. Aging is thought to be associated with reduced capacity to regenerate β-cells, as suggested by studies involving rodents and humans.

In humans, the baseline β-cell population and appropriate association with other islet cell types is established before 5 years of age. Other studies using C14 or Ki67 have found that human adult β-cell turnover is very low. Similarly among middle-aged and older adults, minimal β-cell regeneration was observed after a mean follow-up period of 1.8 ± 1.2 years after a 50% partial pancreatectomy: β-cell mass and new β-cell formation were not increased, and β-cell turnover was unchanged. The follow-up time of this study may have been too short for human β-cells to replicate, but other studies have also found evidence of slow β-cell proliferation in humans with advancing age.

Pancreatic β-cells appear to primarily compensate for limited replication capacity through hyperplasia and hypertrophy. However, a number of studies have demonstrated a decline in β-cell function and insulin secretion with age in rodents. In humans, the insulin secretion rate in response to glucose was significantly and progressively decreased in older individuals, with the greatest impairment in older individuals with impaired glucose tolerance compared with older individuals with normal glucose tolerance or with younger individuals matched for degree of insulin resistance. In fact, a 50% reduction in β-cell secretory capacity has been observed in older men compared with younger men in response to arginine stimulation.

Impaired pancreatic β-cell adaptation to insulin resistance appears to be an important contributing factor to age-related glucose intolerance and risk for diabetes. Although aging per se has a minimal effect on insulin action directly, many older individuals develop insulin resistance as a result of diminished physical activity, obesity, and loss of lean body mass, particularly those with a disproportional loss of skeletal muscle over adipose tissue. Age had no independent effect on insulin sensitivity when controlled for obesity; age-related reductions in insulin sensitivity are likely the result of an age-related increase in adiposity rather than a consequence of advanced chronological age.

Insulin resistance with aging appears to reflect predominantly lifestyle factors such as poor diet and diminished physical activity. These changes lead to decreased lean body mass and increased adiposity, particularly visceral adiposity, with aging. More than 35% of U.S. adults aged 60 years or older are obese, having a BMI of 30 kg/m2 or greater. An absolute or relative increase of body adiposity, particularly central body adiposity, often associated with advancing age, appears to account in large part for the age-related increase in insulin resistance. Even among adults without diabetes, intraabdominal fat mass correlates with insulin resistance and age after controlling for obesity. However, insulin resistance is more closely associated with abdominal adiposity than with age. In addition to excessive caloric intake, increased body adiposity is partly related to a sedentary lifestyle, which is common among older adults; for example, only 12% of adults aged 75 or older engage in 30 min of physical activity 5 or more days per week, and 65% report no leisure time physical activity. Increasing physical activity in older adults reduces insulin resistance, reduces the risk of developing diabetes, and improves glycemic control in people with diabetes.

Low-grade inflammation and stress-response changes associated with obesity and aging are likely to contribute to the increased risk of type 2 diabetes among older adults. Aging and obesity are both thought to be independently associated with the development of low-grade inflammation, and proinflammatory cytokines, such as C-reactive protein, interleukin 6, and tumor necrosis factor-α, have been found to inhibit insulin signaling and increase insulin resistance and risk of type 2 diabetes.

The role of mitochondrial function in aging and type 2 diabetes remains unclear. Older adults were found to have a decrease in mitochondrial function compared with younger adults (i.e., decreased ATP synthesis); however, older adults with normal glucose tolerance had similar ATP production level compared with older adults with impaired glucose tolerance. On the other hand, exercise reverses age-related declines in mitochondrial oxidative capacity and ATP production, which may be part of the underlying mechanism through which exercise improves insulin sensitivity.

There is a maladaptive response to insulin resistance in the setting of impaired β-cell function leading to further impairment of insulin secretion and progression to impaired glucose tolerance and type 2 diabetes. Hyperglycemia, in turn, contributes directly to insulin resistance and impairs pancreatic β-cell function, effects described as glucose toxicity. Such glucose toxicity sets up a vicious cycle of maladaptive mechanisms leading to further deterioration of β-cell function and more severe insulin resistance.

 

Comorbidities and Their Effect on Insulin Sensitivity and Secretion

Coexisting illness is another factor that can affect insulin sensitivity and insulin secretion in an older person. Hypertension, for example, is common in older people and has been associated with diminished insulin sensitivity. Furthermore, any acute illness can precipitate hyperglycemia because of effects of stress hormones to cause insulin resistance combined with the α-adrenergic effects of catecholamines released during stressful illness to inhibit insulin secretion.

Medications used in treating chronic medical conditions may induce or increase insulin resistance or worsening hyperglycemia among patients with diabetes. Glucocorticoids, for example, promote hepatic gluconeogenesis, thus increasing hyperglycemia, and contribute to insulin resistance by increasing visceral fat and promoting proteolysis, lipolysis, free fatty acid production, and fat accumulation in the liver.

Impaired glucose regulation over time leads to overt diabetes, which in turn leads to microvascular or macrovascular complications. Diabetes-associated complications, along with other comorbidities prevalent among older adults, such as arthritis, cognitive impairment, and depression, may contribute to decreased physical activity and disability. All of these changes can further impair glucose regulation and adversely affect glycemic management.

 

Conclusions

Older adults are at high risk for the development of type 2 diabetes as a result of the combined effects of genetic, lifestyle, and aging influences. Despite the advancement in understanding the pathophysiology of type 2 diabetes, more research is needed to elucidate the underlying molecular mechanisms of how aging is related to type 2 diabetes and to diabetes-related complications. Prevention of type 2 diabetes and treatment of hyperglycemia in older adults should emphasize lifestyle interventions based on the pathophysiology of the development of type 2 diabetes and their numerous benefits on the overall health of older adults. With the aging of β-cell function, the addition of one or more medications to achieve glycemic control targets may be needed. However, the overall management of hyperglycemia needs to be individualized for older adults based on individuals' likelihood of benefiting from tight control versus the risks associated with implementing complex management regimens, especially when insulin or a sulfonylurea drug is included. A comprehensive assessment involving the individual’s comorbidities and geriatric syndromes, including cognitive and functional status, can help tailor the treatment plan