Jeffrey B. Halter

Diabetes in Older Adults

More than 25% of the U.S. population aged ≥65 years has diabetes (1), and the aging of the overall population is a significant driver of the diabetes epidemic. Although the burden of diabetes is often described in terms of its impact on working-age adults, diabetes in older adults is linked to higher mortality, reduced functional status, and increased risk of institutionalization (2). Older adults with diabetes are at substantial risk for both acute and chronic microvascular and cardiovascular complications of the disease. Despite having the highest prevalence of diabetes of any age-group, older persons and/or those with multiple comorbidities have often been excluded from randomized controlled trials of treatments—and treatment targets—for diabetes and its associated conditions. Heterogeneity of health status of older adults (even within an age range) and the dearth of evidence from clinical trials present challenges to determining standard intervention strategies that fit all older adults. To address these issues, the American Diabetes Association (ADA) convened a Consensus Development Conference on Diabetes and Older Adults (defined as those aged ≥65 years) in February 2012. Following a series of scientific presentations by experts in the field, the writing group independently developed this consensus report to address the following questions: 1. What is the epidemiology and pathogenesis of diabetes in older adults? 2. What is the evidence for preventing and treating diabetes and its common comorbidities in older adults? 3. What current guidelines exist for treating diabetes in older adults? 4. What issues need to be considered in individualizing treatment recommendations for older adults? 5. What are consensus recommendations for treating older adults with or at risk for diabetes? 6. How can gaps in the evidence best be filled? According to the most recent surveillance data, the prevalence of diabetes among U.S. adults aged ≥65 years varies from 22 to 33%, depending on the diagnostic criteria …

National Institutes of Health Consensus Development Conference Statement: Geriatric Assessment Methods for Clinical Decision‐making

he population of elderly persons in the developed nations is growing with extraordinary rapidity. Although the majority enjoy good T health, many older people suffer from multiple illnesses and significant disability. Comprehensive assessment methodologies, while not solely applicable to frail elderly persons, are believed to be particularly suited to their situation. These individuals tend to exhibit great medical complexity and vulnerability; have illnesses with atypical and obscure presentations; suffer major cognitive, affective, and functional problems; are especially vulnerable to iatrogenesis; are often socially isolated and economically deprived; and are at high risk for premature or inappropriate institutionalization. To deal with the exceedingly difficult health care issues posed by frail elderly persons, health professionals need to collect, organize, and use a vast array of clinically relevant information. This process, compre-

Workshop on HIV Infection and Aging: What Is Known and Future Research Directions

Highly active antiretroviral treatment has resulted in dramatically increased life expectancy among patients with HIV infection who are now aging while receiving treatment and are at risk of developing chronic diseases associated with advanced age. Similarities between aging and the courses of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome suggest that HIV infection compresses the aging process, perhaps accelerating comorbidities and frailty. In a workshop organized by the Association of Specialty Professors, the Infectious Diseases Society of America, the HIV Medical Association, the National Institute on Aging, and the National Institute on Allergy and Infectious Diseases, researchers in infectious diseases, geriatrics, immunology, and gerontology met to review what is known about HIV infection and aging, to identify research gaps, and to suggest high priority topics for future research. Answers to the questions posed are likely to help prioritize and balance strategies to slow the progression of HIV infection, to address comorbidities and drug toxicity, and to enhance understanding about both HIV infection and aging.

Differential Changes of Autonomic Nervous System Function with Age in Man

To assess the relationship between aging and autonomic nervous system function, cardiovascular and pupillary autonomic nervous system reflexes were measured in subgroups of 103 normal male subjects ranging in age from 19 to 82 years (mean age = 39 years). Both the plasma norepinephrine level, a measure of cardiovascular sympathetic nervous system activity, and the mean arterial blood pressure increased with age (r = 0.68 and 0.67, respectively, both p less than 0.001). In contrast, the plasma epinephrine level, a measure of adrenomedullary sympathetic nervous system activity, was unrelated to age (r = 0.08, p = NS). Respiratory variation of heart rate during beta-adrenergic blockade, an index of cardiac parasympathetic nervous system activity, was reduced in older subjects (r = -0.54, p less than 0.001). Thus, there was evidence of an age-related increase of cardiovascular sympathetic nervous system activity and a reduction of cardiac parasympathetic nervous system activity. These findings are consistent with the hypothesis that there is sympathetic nervous system and parasympathetic nervous system compensation of cardiovascular function in response to an age-related decrease in baroreceptor sensitivity. However, dark-adapted pupil size during parasympathetic nervous system blockade, an index of iris sympathetic nervous system activity, declined with age (r = -0.81, p less than 0.001). The latency time for the pupillary response to a light stimulus, an index of iris parasympathetic nervous system activity, was prolonged in older subjects (r = 0.58, p less than 0.001). Thus, both sympathetic nervous system and parasympathetic nervous system inputs to the iris were diminished in older subjects, findings consistent with the generalized decrease of peripheral somatic nerve function that has been reported with aging in man. It is concluded that autonomic nervous system function also declines with aging, but that other age-related changes such as a decline of baroreceptor sensitivity may lead to compensatory autonomic nervous system response, which could mask underlying functional defects.

Insulin secretion in diabetes mellitus

A brief review of the normal physiology of insulin secretion is given. The dual role of glucose to directly stimulate insulin release and to potentiate insulin secretion to other islet regulators is emphasized. The B cell of the pancreatic islet is discussed as a metabolic integrator for nutrients, modulated by neural and hormonal input. A feedback model for the normal regulation of glucose concentrations is also described. This model is based on a closed loop between the islet, the liver and peripheral tissues for the production and utilization of glucose. Diabetes mellitus with overt hyperglycemia is characterized by impaired pancreatic B-cell function; however, in noninsulin-dependent diabetic subjects, many aspects of insulin secretion are maintained by a compensatory increase in plasma glucose concentration. The model shows why this increase in plasma glucose occurs and the importance of this hyperglycemia to the restoration of insulin responses to nonglucose secretagogues, second-phase insulin secretion to glucose and basal insulin. The model can account for the usual stability of plasma glucose in noninsulin-dependent diabetes mellitus and the very high glucose levels and lack of glucose stability in insulin-dependent diabetes mellitus. Sulfonylurea drugs increase insulin secretion, but this increase is dependent on the glucose level. Thus, the augmented B-cell function can be masked by a decrease in plasma glucose concentrations. During long-term therapy, the insulin level and responses are unchanged despite lower concentrations of glucose. Therefore, it is hypothesized that sulfonylureas still act by enhancement of B-cell function.

Aldose Reductase Inhibition Improves Nerve Conduction Velocity in Diabetic Patients

To assess the potential role of polyol-pathway activity in diabetic neuropathy, we measured the effects of sorbinil--a potent inhibitor of the key polyol-pathway enzyme aldose reductase--on nerve conduction velocity in 39 stable diabetics in a randomized, double-blind, cross-over trial. During nine weeks of treatment with sorbinil (250 mg per day), nerve conduction velocity was greater than during a nine-week placebo period for all three nerves tested: the peroneal motor nerve (mean increase [+/- S.E.M.], 0.70 +/- 0.24 m per second, P less than 0.008), the median motor nerve (mean increase, 0.66 +/- 0.27, P less than 0.005), and the median sensory nerve (mean increase, 1.16 +/- 0.50, P less than 0.035). Conduction velocity for all three nerves declined significantly within three weeks after cessation of the drug. These effects of sorbinil were not related to glycemic control, which was constant during the study. Although the effect of sorbinil in improving nerve conduction velocity in diabetics was small, the findings suggest that polyol-pathway activity contributes to slowed nerve conduction in diabetics. The clinical applicability of these observations remains to be determined, but they encourage further exploration of this approach to the treatment or prevention of diabetic neuropathy.

Diabetes in Older Adults: A Consensus Report

More than 25% of the U.S. population aged 65 years has diabetes mellitus (hereafter referred to as diabetes), 1 and the aging of the overall population is a significant driver of the diabetes epidemic. Although the burden of diabetes is often described in terms of its impact on working-age adults, diabetes in older adults is linked to higher mortality, reduced functional status, and increased risk of institutionalization. 2 Older adults with diabetes are at substantial risk for both acute and chronic microvascular and cardiovascular complications of the disease. Despite having the highest prevalence of diabetes of any age-group, older persons and/or those with multiple comorbidities have often been excluded from randomized controlled trials of treatments—and treatment targets— for diabetes and its associated conditions. Heterogeneity of health status of older adults (even within an age range) and the dearth of evidence from clinical trials present challenges to determining standard intervention strategies that fit all older adults. To address these issues, the American Diabetes Association (ADA) convened a Consensus Development Conference on Diabetes and Older Adults (defined as those aged 65 years) in February 2012. Following a series of scientific presentations by experts in the field, the writing group independently developed this consensus report to address the following questions:

Pathophysiology of insulin secretion in non-insulin-dependent diabetes mellitus

The pathogenesis of the abnormal metabolic state in patients with non-insulin-dependent diabetes (NIDDM) is controversial. Even the term NIDDM stirs controversy because of the easily drawn inference that individuals with this form of diabetes do not need insulin treatment. Yet many patients with NIDDM are treated with insulin; some even develop hyperosmolar coma if not given insulin. Ketoacidosis, however, is very infrequent in this syndrome, implying that these patients are not dependent on insulin treatment to prevent mass mobilization of fatty acids and ketone bodies. The phrase noninsulin-dependent is therefore appropriate when used in this restricted fashion but inappropriate when used to imply adequacy of insulin secretion. The evaluation of the adequacy of islet function in this syndrome has been complex, since there is no standard of insulin output that can be defined for normal islets without specifying the physiologic setting under which the assessment has been made. For example, individuals with normal glucose levels but variable degrees of obesity have widely varying insulin secretion rates. Thus, the choice of controls is critical when comparing islet function in NIDDM to normal. In addition, the efficiency of the B-cell response to a challenge (e.g., oral glucose tolerance test) can markedly influence the magnitude of the stimulatory glucose level during the period of testing. For example, a subject with some impairment of insulin output will tend to become more hyperglycemic during the test. The hyperglycemia may then stimulate more insulin secretion so that the overall insulin output may appear equal to or even greater than that of a normal individual. In such a closed-loop system, strict control of input variables is necessary to evaluate whether or not insulin secretion is normal. As will be discussed, control of glucose level and other variables is seldom accomplished in dynamic glucose tolerance tests. As will be presented in this review, the development of appropriately controlled studies of islet function has provided convincing evidence that islet B-cell function is abnormal in patients with NIDDM. Since these studies are based on an understanding of normal islet function, normal islet B-cell physiology is discussed before pathophysiology. Finally, the implications of this analysis for the treatment of NIDDM with diet, hypoglycemic sulfonylureas, and insulin will be discussed.

Quantitative Evaluation of Cardiac Parasympathetic Activity in Normal and Diabetic Man

Heart rate and RR variation (the standard deviation of the mean RR interval for a 5-min period) were evaluated as measurements of cardiac parasympathetic nervous system activity in fasting supine diabetic (N = 22) and comparable age normal (N = 22) subjects. The rate of breathing did not effect heart rate, but was inversely related to the RR variation (r = 0.89, P < 0.01). Heart rate was increased (P < 0.0001) and RR variation decreased (P < 0.05) during β-adrenergic stimulation with isoproterenol and during parasympathetic blockade with atropine (both P < 0.0001). Hence, the cardiac effects of β-adrenergic stimulation may mimic the effects of diminished parasympathetic function. To evaluate parasympathetic control of RR variation, independently of possible effects of increased sympathetic activities, studies were performed during β-adrenergic blockade with propranolol. RR variation during propranolol was less both in 14 diabetic subjects without clinical symptoms of autonomic neuropathy (P < 0.005) and in 8 diabetics with clinical symptoms of autonomic neuropathy (P < 0.001) when compared with 22 age-comparable normal subjects. The measurement of RR variation was very reproducible with a day-to-day coefficient of variation of 9.7 ± 2.8﹪ (x̄ ± SEM) in diabetic subjects with stable hyperglycemia. It is concluded that supine RR variation during a deep respiratory rate and during β-adrenergic blockade is a sensitive, quantitative, and reproducible method to evaluate parasympathetic nervous activity in normal and diabetic subjects. Furthermore, cardiac parasympathetic activity may be diminished in diabetic subjects before clinical symptoms of autonomic neuropathy are evident.

Autonomic Neural Dysfunction in Recently Diagnosed Diabetic Subjects

Because onset of autonomic neural dysfunction in the diabetic syndrome has not been well established, sensitive and quantitative measures of autonomic nervous system (ANS) function were made in 19 non-insulin-dependent (NIDD) and 14 insulin-dependent (IDD) recent-onset diabetic subjects. The known duration of diabetes mellitus in the NIDD subjects was ≤ 12 mo. The duration in the IDD subjects was ≤ 24 mo. RR-variation during beta adrenergic blockade (an index of an ANS reflex involving the cardiac parasympathetic nervous system [PNS] pathway) was smaller than that of control subjects in both NIDD (P < 0.001) and IDD subjects (P < 0.01). This PNS abnormality was not likely to be due to volume depletion since acute volume depletion induced by furosemide in six normal subjects (1608 ± 105 ml, mean ± SEM) did not change RR-variation. Dark-adapted pupil size after topical PNS blockade (an index of iris sympathetic nervous system [SNS] activity) was also smaller in both groups of diabetic subjects (NIDD, P < 0.01; IDD, P < 0.05). Pupillary latency time (an index of an ANS reflex involving iris PNS pathway) was prolonged in the NIDD subjects (P < 0.005) but was not significantly altered in the IDD subjects. Thus, it would appear that the ANS is impaired soon after the diagnosis of diabetes mellitus. We hypothesize that early impairment of the ANS is common in IDD and NIDD subjects. This finding is consistent with the hypothesis that abnormal carbohydrate metabolism is an important factor in the etiology of diabetic autonomic neuropathy.