Diabetes and Cardiovascular Disease in Older Adults: Current Status and Future Directions

Jeffrey B. Halter; Nicolas Musi; Frances McFarland Horne; Jill P. Crandall; Andrew Goldberg; Lawrence Harkless; William R. Hazzard; Elbert S. Huang; M. Sue Kirkman; Jorge Plutzky; Kenneth E. Schmader; Susan Zieman; Kevin P. High

Disclosures

Diabetes. 2014;63(8):2578-2589. 

In This Article

Common Age-Associated Metabolic Changes and Their Impact on Diabetes

Insulin sensitivity appears to decline with age.[12] Skeletal muscle is an important site of age-related insulin resistance. Factors contributing to age-associated insulin resistance include visceral adiposity and associated adipokines and inflammation, oxidative stress, mitochondrial dysfunction, and possibly an intrinsic decline in insulin sensitivity in muscle fibers. One pathway linking aging, muscle, and risks for diabetes and CVD is shown in Fig. 2.

Figure 2.

A proposed pathway linking aging, muscle, and risks for diabetes and CVD. Source: Nair KS. Aging muscle. Am J Clin Nutr 2005;81:953–963. T2DM, type 2 diabetes mellitus.

Age-associated declines in protein synthesis and quality result in accumulations of damaged proteins and impaired muscle strength and quality at a time when accumulating oxidative damage, DNA damage and degradation, and declines in mitochondrial copy number and mitochondrial protein synthesis render muscle mitochondria less able to produce ATP.[13] Notably, exercise increases insulin sensitivity and reverses age-related declines in mitochondrial oxidative capacity and ATP production, and resistance training increases the content of a novel PGC-1α splicing isoform associated with hypertrophy and enhanced muscle strength.[14]

Another mechanism links aging, pancreatic β-cell impairments, and diabetes risks. Even among people with normal glucose tolerance, insulin secretion is impaired with age, possibly because of a decrease in pancreatic islet mass and β-cell proliferative capacity (reviewed in 15). β-Cell impairments are progressively worse in prediabetes and overt diabetes. Alterations in the expression of cell-cycle proteins that control cellular senescence, such as p16INK4A, might play a role in age-related declines in β-cell function.[15] Under conditions of uncomplicated obesity and associated declines in insulin sensitivity, β-cells can adapt by producing more insulin.[15] However, metabolic stressors and increasing defects in glucose regulation can overwhelm adaptive mechanisms. Thus, diabetes is accompanied by a loss of functional β-cells and a resulting decline in insulin secretion.[16]

Older individuals with type 2 diabetes tend to be overweight and deconditioned with central adiposity and insulin resistance, which promote dyslipidemia and atherogenesis[12] (Fig. 2). The metabolic abnormalities associated with diabetic dyslipidemia include insulin resistance, hypertriglyceridemia, an abnormal distribution of apoB-enriched low-density and remnant lipoprotein particles, and low HDL cholesterol. Excess fat deposition in the liver in type 2 diabetes triggers the overproduction of triglyceride- and apoB-enriched lipoproteins. Hepatic fat accumulation also induces overproduction of inflammatory proteins that alter levels of hepatic lipase, cholesterol ester transfer proteins, and lipoprotein lipase. These alterations lead to the remodeling of large, buoyant LDL into small, dense, apoB-laden remnant lipoproteins and the alteration of HDL composition into particles enriched in triglyceride and deficient in cholesterol ester and apoA-I. This dysfunctional HDL exhibits reduced cholesterol efflux, anti-inflammatory, antioxidative, and antiapoptotic capacity that activate macrophages and endothelial and smooth muscle cells while the abnormal LDL remnants are deposited into the vessel wall, accelerating foam cell formation and atherogenesis.[17] Ultimately, insulin resistance and lipotoxicity enhance inflammation, amyloid formation, macrophage proliferation, and smooth and endothelial cell activation and thereby accelerate atherogenesis and plaque formation further. These abnormalities in HDL and LDL function may contribute to the heightened inflammation, amyloid deposition, and increased reactive oxygen species that also contribute to β-cell failure.[18] The effects of age on all these risk factors, as well as on the primary and secondary mechanisms underlying dyslipidemia and accelerated atherosclerosis in individuals with type 2 diabetes, is a fertile area for future investigation.

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