Vanessa J. Briscoe

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:

Effects of Acute Hypoglycemia on Inflammatory and Pro-atherothrombotic Biomarkers in Individuals With Type 1 Diabetes and Healthy Individuals

OBJECTIVE Recent large randomized trials have linked adverse cardiovascular and cerebrovascular events with hypoglycemia. However, the integrated physiological and vascular biological mechanisms occurring during hypoglycemia have not been extensively examined. Therefore, the aim of this study was to determine whether 2 h of moderate clamped hypoglycemia could decrease fibrinolytic balance and activate pro-atherothrombotic mechanisms in individuals with type 1 diabetes and healthy individuals. RESEARCH DESIGN AND METHODS Thirty-five healthy volunteers (19 male and 16 female subjects age 32 ± 2 years, BMI 26 ± 2 kg/m2, A1C 5.1 ± 0.1%) and twenty-four with type 1 diabetes (12 male and 12 female subjects age 33 ± 3 years, BMI 24 ± 2 kg/m2, A1C 7.7 ± 0.2%) were studied during either a 2-h hyperinsulinemic (9 pmol · kg−1 · min−1) euglycemic or hypoglycemic (2.9 ± 0.1 mmol/l) clamp or both protocols. Plasma glucose levels were normalized overnight in type 1 diabetic subjects prior to each study. RESULTS Insulin levels were similar (602 ± 44 pmol/l) in all four protocols. Glycemia was equivalent in both euglycemic protocols (5.2 ± 0.1 mmol/l), and the level of hypoglycemia was also equivalent in both type 1 diabetic subjects and healthy control subjects (2.9 ± 0.1 mmol/l). Using repeated ANOVA, it was determined that plasminogen activator inhibitor (PAI-1), vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), E-selectin, P-selectin, interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and adiponectin responses were all significantly increased (P < 0.05) during the 2 h of hyperinsulinemic hypoglycemia as compared with euglycemia in healthy control subjects. All measures except PAI-1 were also found to be increased during hypoglycemia compared with euglycemia in type 1 diabetes. CONCLUSIONS In summary, moderate hypoglycemia acutely increases circulating levels of PAI-1, VEGF, vascular adhesion molecules (VCAM, ICAM, E-selectin), IL-6, and markers of platelet activation (P-selectin) in individuals with type 1 diabetes and healthy individuals. We conclude that acute hypoglycemia can result in complex vascular effects including activation of prothrombotic, proinflammatory, and pro-atherogenic mechanisms in individuals with type 1 diabetes and healthy individuals.

Effects of Intensive Therapy and Antecedent Hypoglycemia on Counterregulatory Responses to Hypoglycemia in Type 2 Diabetes

OBJECTIVE—The physiology of counterregulatory responses during hypoglycemia in intensively treated type 2 diabetic subjects is largely unknown. Therefore, the specific aims of the study tested the hypothesis that 1) 6 months of intensive therapy to lower A1C <7.0% would blunt autonomic nervous system (ANS) responses to hypoglycemia, and 2) antecedent hypoglycemia will result in counterregulatory failure during subsequent hypoglycemia in patients with suboptimal and good glycemic control. RESEARCH DESIGN AND METHODS—Fifteen type 2 diabetic patients (8 men/7 women) underwent 6-month combination therapy of metformin, glipizide XL, and acarbose to lower A1C to 6.7% and 2-day repeated hypoglycemic clamp studies before and after intensive therapy. A control group of eight nondiabetic subjects participated in a single 2-day repeated hypoglycemic clamp study. RESULTS—Six-month therapy reduced A1C from 10.2 ± 0.5 to 6.7 ± 0.3%. Rates of hypoglycemia increased to 3.2 episodes per patient/month by study end. Hypoglycemia (3.3 ± 0.1 mmol/l) and insulinemia (1,722 ± 198 pmol/l) were similar during all clamp studies. Intensive therapy reduced (P < 0.05) ANS and metabolic counterregulatory responses during hypoglycemia. Antecedent hypoglycemia produced widespread blunting (P < 0.05) of neuroendocrine, ANS, and metabolic counterregulatory responses during subsequent hypoglycemia before and after intensive therapy in type 2 diabetic patients and in nondiabetic control subjects. CONCLUSIONS—Intensive oral combination therapy and antecedent hypoglycemia both blunt physiological defenses against subsequent hypoglycemia in type 2 diabetes. Prior hypoglycemia of only 3.3 ± 0.1 mmol/l can result in counterregulatory failure in type 2 diabetic patients with suboptimal control and can further impair physiological defenses against hypoglycemia in intensively treated type 2 diabetes.

Type 1 diabetes: exercise and hypoglycemia

The Diabetes Control and Complications Trial demonstrated that tight control of diabetes management greatly reduces the risk of microvascular complications of diabetes. Unfortunately, tight control of blood glucose can also result in hypoglycemia, especially in patients with type 1 diabetes mellitus (T1DM). It is now widely recognized that antecedent hypoglycemia can blunt neuroendocrine, autonomic nervous system (ANS), and metabolic counterregulatory responses to subsequent hypoglycemia. Thus, blunted counterregulatory defenses against falling plasma glucose levels are a major risk factor for hypoglycemia in people with diabetes. This risk is also complicated by a difference in responses between males and females. Because of the qualitative similarity of neuroendocrine, ANS, and metabolic responses to hypoglycemia and exercise, we developed studies to determine whether neuroendocrine and ANS counterregulatory dysfunction play a role in the pathogenesis of exercise-related hypoglycemia in T1DM. Results from these studies have shown that neuroendocrine (catecholamine and glucagon), ANS (muscle sympathetic nerve activity), and metabolic (lipolysis and glucose kinetics) responses are blunted during exercise after antecedent hypoglycemia, and that there is a sexual dimorphism in responses. Similarly, antecedent episodes of exercise can blunt counterregulatory responses during subsequent hypoglycemia, thereby creating reciprocal feed-forward vicious cycles that increase the risk of hypoglycemia during either stress.

Effects of a Selective Serotonin Reuptake Inhibitor, Fluoxetine, on Counterregulatory Responses to Hypoglycemia in Healthy Individuals

OBJECTIVE—Hypoglycemia commonly occurs in intensively-treated diabetic patients. Repeated hypoglycemia blunts counterregulatory responses, thereby increasing the risk for further hypoglycemic events. Currently, physiologic approaches to augment counterregulatory responses to hypoglycemia have not been established. Therefore, the specific aim of this study was to test the hypothesis that 6 weeks’ administration of the selective serotonin reuptake inhibitor (SSRI) fluoxetine would amplify autonomic nervous system (ANS) and neuroendocrine counterregulatory mechanisms during hypoglycemia. RESEARCH DESIGN AND METHODS—A total of 20 healthy (10 male and 10 female) subjects participated in an initial single-step hyperinsulinemic (9 pmol · kg−1 · min−1)-hypoglycemic (means ± SE 2.9 ± 0.1 mmol/l) clamp study and were then randomized to receive 6 weeks’ administration of fluoxetine (n = 14) or identical placebo (n = 6) in a double-blind fashion. After 6 weeks, subjects returned for a second hypoglycemic clamp. Glucose kinetics were determined by three-tritiated glucose, and muscle sympathetic nerve activity (MSNA) was measured by microneurography. RESULTS—Despite identical hypoglycemia (2.9 ± 0.1 mmol/l) and insulinemia during all clamp studies, key ANS (epinephrine, norepinephrine, and MSNA but not symptoms), neuroendocrine (cortisol), and metabolic (endogenous glucose production, glycogenolysis, and lipolysis) responses were increased (P < 0.01) following fluoxetine. CONCLUSIONS—This study demonstrated that 6 weeks’ administration of the SSRI fluoxetine can amplify a wide spectrum of ANS and metabolic counterregulatory responses during hypoglycemia in healthy individuals. These data further suggest that serotonergic transmission may be an important mechanism in modulating sympathetic nervous system drive during hypoglycemia in healthy individuals.

Effects of the Selective Serotonin Reuptake Inhibitor Fluoxetine on Counterregulatory Responses to Hypoglycemia in Individuals With Type 1 Diabetes

OBJECTIVE—Previous work has demonstrated that chronic administration of the serotonin reuptake inhibitor (SSRI) fluoxetine augments counterregulatory responses to hypoglycemia in healthy humans. However, virtually no information exists regarding the effects of fluoxetine on integrated physiological counterregulatory responses during hypoglycemia in type 1 diabetes. Therefore, the specific aim of this study was to test the hypothesis that 6-week use of the SSRI fluoxetine would amplify autonomic nervous system (ANS) counterregulatory responses to hypoglycemia in individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS—Eighteen type 1 diabetic patients (14 men/4 women aged 19–48 years with BMI 25 ± 3 kg/m2 and A1C 7.0 ± 0.4%) participated in randomized, double-blind 2-h hyperinsulinemic (9 pmol · kg−1 · min−1)-hypoglycemic clamp studies before and after 6 weeks of fluoxetine administration (n = 8) or identical placebo (n = 10). Glucose kinetics was determined by 3-tritiated glucose. Muscle sympathetic nerve activity (MSNA) was determined by microneurography. RESULTS—Hypoglycemia (2.8 ± 0.1 mmol/l) and insulinemia (646 ± 52 pmol/l) were similar during all clamp studies. ANS, neuroendocrine, and metabolic counterregulatory responses remained unchanged in the placebo group. However, fluoxetine administration significantly (P < 0.05) increased key ANS (epinephrine, norepinephrine, and MSNA), metabolic (endogenous glucose production and lipolysis), and cardiovascular (systolic blood pressure) counterregulatory responses during hypoglycemia. CONCLUSIONS—This study has demonstrated that 6-week administration of the SSRI fluoxetine can amplify ANS and metabolic counterregulatory mechanisms during moderate hypoglycemia in patients with type 1 diabetes. These data also suggest that the use of fluoxetine may be useful in increasing epinephrine responses during hypoglycemia in clinical practice.

Dose Response Effects of Insulin Glargine in Type 2 Diabetes

OBJECTIVE To determine the pharmacokinetic and pharmacodynamic dose-response effects of insulin glargine administered subcutaneously in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS Twenty obese type 2 diabetic individuals (10 male and 10 female, aged 50 ± 3 years, with BMI 36 ± 2 kg/m2 and A1C 8.3 ± 0.6%) were studied in this single-center, placebo-controlled, randomized, double-blind study. Five subcutaneous doses of insulin glargine (0, 0.5, 1.0, 1.5, and 2.0 units/kg) were investigated on separate occasions using the 24-h euglycemic clamp technique. RESULTS Glargine duration of action to reduce glucose, nonessential fatty acid (NEFA), and β-hydroxybutyrate levels was close to or >24 h for all four doses. Increases in glucose flux revealed no discernible peak and were modest with maximal glucose infusion rates of 9.4, 6.6, 5.5, and 2.8 μmol/kg/min for the 2.0, 1.5, 1.0, and 0.5 units/kg doses, respectively. Glargine exhibited a relatively hepatospecific action with greater suppression (P < 0.05) of endogenous glucose production (EGP) compared with little or no increases in glucose disposal. CONCLUSION A single subcutaneous injection of glargine at a dose of ≥0.5 units/kg can acutely reduce glucose, NEFA, and ketone body levels for 24 h in obese insulin-resistant type 2 diabetic individuals. Glargine lowers blood glucose by mainly inhibiting EGP with limited effects on stimulating glucose disposal. Large doses of glargine have minimal effects on glucose flux and retain a relatively hepatospecific action in type 2 diabetes.

The role of glimepiride in the treatment of type 2 diabetes mellitus

Importance of the field: Type 2 diabetes mellitus (T2DM) is increasingly prevalent throughout the world; controlling glycemia is an important part of preventing serious complications of diabetes. Sulfonylureas have been used in the treatment of type 2 diabetes for many years. Areas covered in this review: This article reviews the pharmacological and clinical aspects of glimepiride, a second-generation sulfonylurea. Literature search was conducted in PubMed, and articles selected for relevance to pharmacology or clinical efficacy data from 1994 to 2009, with older references sought as indicated. What the reader will gain: Pharmacology of glimepiride, data regarding clinical efficacy, key comparisons to other agents and emerging concepts related to glimepiride are discussed. Take home message: Therapy with glimepiride improves the relative insulin secretory deficit found in T2DM, has antihyperglycemic efficacy equal to other secretagogues with reduced potential for hypoglycemia and may have additional actions contributing to glycemic control in T2DM.

Effects of Differing Antecedent Increases of Plasma Cortisol on Counterregulatory Responses During Subsequent Exercise in Type 1 Diabetes

OBJECTIVE Antecedent hypoglycemia can blunt neuroendocrine and autonomic nervous system responses to next-day exercise in type 1 diabetes. The aim of this study was to determine whether antecedent increase of plasma cortisol is a mechanism responsible for this finding. RESEARCH DESIGN AND METHODS For this study, 22 type 1 diabetic subjects (11 men and 11 women, age 27 ± 2 years, BMI 24 ± 1 kg/m2, A1C 7.9 ± 0.2%) underwent four separate randomized 2-day protocols, with overnight normalization of blood glucose. Day 1 consisted of morning and afternoon 2-h hyperinsulinemic- (9 pmol · kg−1 · min−1) euglycemic clamps (5.1 mmol/l), hypoglycemic clamps (2.9 mmol/l), or euglycemic clamps with a physiologic low-dose intravenous infusion of cortisol to reproduce levels found during hypoglycemia or a high-dose infusion, which resulted in further twofold greater elevations of plasma cortisol. Day 2 consisted of 90-min euglycemic cycling exercise at 50% Vo2max. RESULTS During exercise, glucose levels were equivalently clamped at 5.1 ± 0.1 mmol/l and insulin was allowed to fall to similar levels. Glucagon, growth hormone, epinephrine, norepinephrine, and pancreatic polypeptide responses during day 2 exercise were significantly blunted following antecedent hypoglycemia, low- and high-dose cortisol, compared with antecedent euglycemia. Endogenous glucose production and lipolysis were also significantly reduced following day 1 low- and high-dose cortisol. CONCLUSIONS Antecedent physiologic increases in cortisol (equivalent to levels occurring during hypoglycemia) resulted in blunted neuroendocrine, autonomic nervous system, and metabolic counterregulatory responses during subsequent exercise in subjects with type 1 diabetes. These data suggest that prior elevations of cortisol may play a role in the development of exercise-related counterregulatory failure in those with type 1 diabetes.