Medha N. Munshi

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 …

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:

Loss of estrogen upregulates osteoblastogenesis in the murine bone marrow. Evidence for autonomy from factors released during bone resorption.

Loss of sex steroids causes an increase in both the resorption and formation of bone, with the former exceeding the latter. Based on evidence that the increased bone resorption after estrogen loss is due to an increase in osteoclastogenesis, we hypothesized that estrogen loss also stimulates osteoblastogenesis. We report that the number of mesenchymal osteoblast progenitors in the murine bone marrow was increased two- to threefold between 2 and 8 wk after ovariectomy and returned to control levels by 16 wk. Circulating osteocalcin, as well as osteoclastogenesis and the rate of bone loss, followed a very similar temporal pattern. Inhibition of bone resorption by administration of the bisphosphonate alendronate led to a decrease of the absolute number of osteoblast progenitors; however, it did not influence the stimulating effect of ovariectomy on osteoblastogenesis or osteoclastogenesis. These observations indicate that the increased bone formation that follows loss of estrogen can be explained, at least in part, by an increase in osteoblastogenesis. Moreover, they strongly suggest that unlike normal bone remodeling, whereby osteoblast development is stimulated by factors released from the bone matrix during osteoclastic resorption, estrogen deficiency unleashes signals that can stimulate the differentiation of osteoblast progenitors in a fashion that is autonomous from the need created by bone resorption, and therefore, inappropriate.

Hyperhomocysteinemia following a methionine load in patients with non-insulin-dependent diabetes mellitus and macrovascular disease

In the setting of an outpatient diabetic clinic, we determined whether macrovascular disease in patients with diabetes mellitus is associated with hyperhomocysteinemia (elevated plasma homocysteine [H(e)] concentrations) following a methionine load. Methionine-load tests were performed in 18 healthy controls, 11 diabetics without vascular disease (five insulin-dependent [IDDM] and six non-insulin-dependent [NIDDM]); and 17 diabetics with vascular disease (five IDDM and 12 NIDDM). All subjects were male, and there was no significant difference in mean age among the three groups. We measured plasma H(e) concentrations before and 2, 4, 6, 8, and 24 hours after an oral methionine load. Hyperhomocysteinemia (peak plasma H(e) concentration > control mean +/- 2 SD) occurred with significantly greater frequency (seven of 18, 39%) in patients with NIDDM as compared with age-matched controls (7%), being more common in those with macrovascular disease (five of 12, 41%). The area under the curve (AUC) over 24 hours, reflecting the total period of exposure to H(e), was also elevated with greater frequency in patients with NIDDM and macrovascular disease (33%) as compared with controls (0%). We conclude that hyperhomocysteinemia is associated with macrovascular disease in a significant proportion of patients with NIDDM. Further investigation of this association may determine whether hyperhomocysteinemia contributes to the increased frequency and accelerated clinical course of vascular disease in patients with diabetes mellitus.

Frequent hypoglycemia among elderly patients with poor glycemic control.

BACKGROUND Episodes of hypoglycemia are particularly dangerous in the older population. To reduce the risk of hypoglycemia, relaxation of the standard hemoglobin A(1c) (HbA(1c)) goals has been proposed for frail elderly patients. However, the risk of hypoglycemia in this population with higher HbA(1c) levels is unknown. METHODS Patients 69 years or older with HbA(1C) values of 8% or greater were evaluated with blinded continuous glucose monitoring for 3 days. RESULTS Forty adults (mean [SD] age, 75 [5] years; HbA(1C) value, 9.3% [1.3%]; diabetes duration, 22 [14] years; 28 patients [70%] with type 2 diabetes mellitus; and 37 [93%] using insulin) were evaluated. Twenty-six patients (65%) experienced 1 or more episodes of hypoglycemia (glucose level <70 mg/dL). Among these, 12 (46%) experienced a glucose level below 50 mg/dL and 19 (73%), a level below 60 mg/dL. The average number of episodes was 4; average duration, 46 minutes. Eighteen patients (69%) had at least 1 nocturnal episode (10 pm to 6 am). Of the total of 102 hypoglycemic episodes, 95 (93%) were unrecognized by finger-stick glucose measurements performed 4 times a day or by symptoms. CONCLUSIONS Hypoglycemic episodes are common in older adults with poor glycemic control. Raising HbA(1C) goals may not be adequate to prevent hypoglycemia in this population.

Enhancement of Vasoreactivity and Cognition by Intranasal Insulin in Type 2 Diabetes

OBJECTIVE To determine acute effects of intranasal insulin on regional cerebral perfusion and cognition in older adults with type 2 diabetes mellitus (DM). RESEARCH DESIGN AND METHODS This was a proof-of-concept, randomized, double-blind, placebo-controlled intervention evaluating the effects of a single 40-IU dose of insulin or saline on vasoreactivity and cognition in 15 DM and 14 control subjects. Measurements included regional perfusion, vasodilatation to hypercapnia with 3-Tesla MRI, and neuropsychological evaluation. RESULTS Intranasal insulin administration was well tolerated and did not affect systemic glucose levels. No serious adverse events were reported. Across all subjects, intranasal insulin improved visuospatial memory (P ≤ 0.05). In the DM group, an increase of perfusion after insulin administration was greater in the insular cortex compared with the control group (P = 0.0003). Cognitive performance after insulin administration was related to regional vasoreactivity. Improvements of visuospatial memory after insulin administration in the DM group (R2adjusted = 0.44, P = 0.0098) and in the verbal fluency test in the control group (R2adjusted = 0.64, P = 0.0087) were correlated with vasodilatation in the middle cerebral artery territory. CONCLUSIONS Intranasal insulin administration appears safe, does not affect systemic glucose control, and may provide acute improvements of cognitive function in patients with type 2 DM, potentially through vasoreactivity mechanisms. Intranasal insulin-induced changes in cognitive function may be related to vasodilatation in the anterior brain regions, such as insular cortex that regulates attention-related task performance. Larger studies are warranted to identify long-term effects and predictors of positive cognitive response to intranasal insulin therapy.

Adhesion Molecules, Altered Vasoreactivity, and Brain Atrophy in Type 2 Diabetes

OBJECTIVE To investigate the effects of inflammation on perfusion regulation and brain volumes in type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 147 subjects (71 diabetic and 76 nondiabetic, aged 65.2 ± 8 years) were studied using 3T anatomical and continuous arterial spin labeling magnetic resonance imaging. Analysis focused on the relationship between serum soluble vascular and intercellular adhesion molecules (sVCAM and sICAM, respectively, both markers of endothelial integrity), regional vasoreactivity, and tissue volumes. RESULTS Diabetic subjects had greater vasoconstriction reactivity, more atrophy, depression, and slower walking. Adhesion molecules were specifically related to gray matter atrophy (P = 0.04) and altered vasoreactivity (P = 0.03) in the diabetic and control groups. Regionally, sVCAM and sICAM were linked to exaggerated vasoconstriction, blunted vasodilatation, and increased cortical atrophy in the frontal, temporal, and parietal lobes (P = 0.04–0.003). sICAM correlated with worse functionality. CONCLUSIONS Diabetes is associated with cortical atrophy, vasoconstriction, and worse performance. Adhesion molecules, as markers of vascular health, have been indicated to contribute to altered vasoregulation and atrophy.

Management of Diabetes in Long-term Care and Skilled Nursing Facilities: A Position Statement of the American Diabetes Association

Diabetes is more common in older adults, has a high prevalence in long-term care (LTC) facilities, and is associated with significant disease burden and higher cost. The heterogeneity of this population with regard to comorbidities and overall health status is critical to establishing personalized goals and treatments for diabetes. The risk of hypoglycemia is the most important factor in determining glycemic goals due to the catastrophic consequences in this population. Simplified treatment regimens are preferred, and the sole use of sliding scale insulin (SSI) should be avoided. This position statement provides a classification system for older adults in LTC settings, describes how diabetes goals and management should be tailored based on comorbidities, delineates key issues to consider when using glucose-lowering agents in this population, and provides recommendations on how to replace SSI in LTC facilities. As these patients transition from one setting to another, or from one provider to another, their risk for adverse events increases. Strategies are presented to reduce these risks and ensure safe transitions. This article addresses diabetes management at end of life and in those receiving palliative and hospice care. The integration of diabetes management into LTC facilities is important and requires an interprofessional team approach. To facilitate this approach, acceptance by administrative personnel is needed, as are protocols and possibly system changes. It is important for clinicians to understand the characteristics, challenges, and barriers related to the older population living in LTC facilities as well as the proper functioning of the facilities themselves. Once these challenges are identified, individualized approaches can be designed to improve diabetes management while lowering the risk of hypoglycemia and ultimately improving quality of life.

Risk Factors Associated With Severe Hypoglycemia in Older Adults With Type 1 Diabetes

OBJECTIVE Severe hypoglycemia is common in older adults with long-standing type 1 diabetes, but little is known about factors associated with its occurrence. RESEARCH DESIGN AND METHODS A case-control study was conducted at 18 diabetes centers in the T1D Exchange Clinic Network. Participants were ≥60 years old with type 1 diabetes for ≥20 years. Case subjects (n = 101) had at least one severe hypoglycemic event in the prior 12 months. Control subjects (n = 100), frequency-matched to case subjects by age, had no severe hypoglycemia in the prior 3 years. Data were analyzed for cognitive and functional abilities, social support, depression, hypoglycemia unawareness, various aspects of diabetes management, C-peptide level, glycated hemoglobin level, and blinded continuous glucose monitoring (CGM) metrics. RESULTS Glycated hemoglobin (mean 7.8% vs. 7.7%) and CGM-measured mean glucose (175 vs. 175 mg/dL) were similar between case and control subjects. More case than control subjects had hypoglycemia unawareness: only 11% of case subjects compared with 43% of control subjects reported always having symptoms associated with low blood glucose levels (P < 0.001). Case subjects had greater glucose variability than control subjects (P = 0.008) and experienced CGM glucose levels <60 mg/dL for ≥20 min on 46% of days compared with 33% of days in control subjects (P = 0.10). On certain cognitive tests, case subjects scored worse than control subjects. CONCLUSIONS In older adults with long-standing type 1 diabetes, greater hypoglycemia unawareness and glucose variability are associated with an increased risk of severe hypoglycemia. A study to assess interventions to prevent severe hypoglycemia in high-risk individuals is needed.

Dynamical glucometry: Use of multiscale entropy analysis in diabetes

Diabetes mellitus (DM) is one of the worlds most prevalent medical conditions. Contemporary management focuses on lowering mean blood glucose values toward a normal range, but largely ignores the dynamics of glucose fluctuations. We probed analyte time series obtained from continuous glucose monitor (CGM) sensors. We show that the fluctuations in CGM values sampled every 5 min are not uncorrelated noise. Next, using multiscale entropy analysis, we quantified the complexity of the temporal structure of the CGM time series from a group of elderly subjects with type 2 DM and age-matched controls. We further probed the structure of these CGM time series using detrended fluctuation analysis. Our findings indicate that the dynamics of glucose fluctuations from control subjects are more complex than those of subjects with type 2 DM over time scales ranging from about 5 min to 5 h. These findings support consideration of a new framework, dynamical glucometry, to guide mechanistic research and to help assess and compare therapeutic interventions, which should enhance complexity of glucose fluctuations and not just lower mean and variance of blood glucose levels.