Both type 1 and type 2 diabetes have been associated with reduced performance on multiple domains of cognitive function and with structural abnormalities in the brain. With an aging population and a ...growing epidemic of diabetes, central nervous system–related complications of diabetes are expected to rise and could have challenging future public health implications. In this review, we will discuss the brain structural and functional changes that have been associated with type 1 and type 2 diabetes. Diabetes duration and glycemic control may play important roles in the development of cognitive impairment in diabetes, but the exact underlying pathophysiological mechanisms causing these changes in cognition and structure are not well understood. Future research is needed to better understand the natural history and the underlying mechanisms, as well as to identify risk factors that predict who is at greatest risk of developing cognitive impairment. This information will lead to the development of new strategies to minimize the impact of diabetes on cognitive function.
Abstract
Glucose homeostasis requires an organism to rapidly respond to changes in plasma glucose concentrations. Iatrogenic hypoglycemia as a result of treatment with insulin or sulfonylureas is the ...most common cause of hypoglycemia in humans and is generally only seen in patients with diabetes who take these medications. The first response to a fall in glucose is the detection of impending hypoglycemia by hypoglycemia-detecting sensors, including glucose-sensing neurons in the hypothalamus and other regions. This detection is then linked to a series of neural and hormonal responses that serve to prevent the fall in blood glucose and restore euglycemia. In this review, we discuss the current state of knowledge about central glucose sensing and how detection of a fall in glucose leads to the stimulation of counterregulatory hormone and behavior responses. We also review how diabetes and recurrent hypoglycemia impact glucose sensing and counterregulation, leading to development of impaired awareness of hypoglycemia in diabetes.
To review the evidence about the impact of hypoglycemia on patients with diabetes that has become available since the past reviews of this subject by the American Diabetes Association and The ...Endocrine Society and to provide guidance about how this new information should be incorporated into clinical practice.
Five members of the American Diabetes Association and five members of The Endocrine Society with expertise in different aspects of hypoglycemia were invited by the Chair, who is a member of both, to participate in a planning conference call and a 2-day meeting that was also attended by staff from both organizations. Subsequent communications took place via e-mail and phone calls. The writing group consisted of those invitees who participated in the writing of the manuscript. The workgroup meeting was supported by educational grants to the American Diabetes Association from Lilly USA, LLC and Novo Nordisk and sponsorship to the American Diabetes Association from Sanofi. The sponsors had no input into the development of or content of the report.
The writing group considered data from recent clinical trials and other studies to update the prior workgroup report. Unpublished data were not used. Expert opinion was used to develop some conclusions.
Consensus was achieved by group discussion during conference calls and face-to-face meetings, as well as by iterative revisions of the written document. The document was reviewed and approved by the American Diabetes Association's Professional Practice Committee in October 2012 and approved by the Executive Committee of the Board of Directors in November 2012 and was reviewed and approved by The Endocrine Society's Clinical Affairs Core Committee in October 2012 and by Council in November 2012.
The workgroup reconfirmed the previous definitions of hypoglycemia in diabetes, reviewed the implications of hypoglycemia on both short- and long-term outcomes, considered the implications of hypoglycemia on treatment outcomes, presented strategies to prevent hypoglycemia, and identified knowledge gaps that should be addressed by future research. In addition, tools for patients to report hypoglycemia at each visit and for clinicians to document counseling are provided.
Diabetes alters cerebral metabolism, structure, and function. Both hyperglycemia and therapy-associated hypoglycemia are believed to have an impact on the brain, and this impact may depend on the age ...of the individual, their stage of neurological development, and whether they have Type 1 or Type 2 diabetes. Hypoglycemia in children with Type 1 has consistently been associated with a reduction in neurocognitive function, but such a finding has not been seen in adults with Type 1 diabetes. Both hypoglycemia and hyperglycemia have been linked with dementia in adults with Type 2 diabetes. In both Type 1 and Type 2 diabetes, recurrent episodes of treatment-associated hypoglycemia impair how well the brain can sense and respond to subsequent episodes of hypoglycemia. In this brief review, we will review how diabetes affects the brain with a focus on investigations done in our own laboratory. We have focused on using high magnetic field imaging and spectroscopy to identify subtle changes in brain structure and metabolism that may contribute to the long-term cerebral complications of diabetes. We have found evidence of microstructural changes in white matter regions, reduced gray matter density, and reduced activation of the thalamus in response to recurrent hypoglycemia in patients with Type 1 diabetes.
Glucagon is secreted by the pancreatic alpha cell and has long been known to oppose insulin action. A lyophilized form of the hormone has been available to treat episodes of insulin-induced ...hypoglycemia in insulin-treated people with diabetes for decades, but the difficulty of use was a barrier to widespread utilization. Newer formulations of glucagon are stable at room temperature in single-use devices that many caregivers find are easier to use than the original glucagon emergency kit. In this review , we will review what is known about the role of glucagon in normal physiology and diabetes and then discuss how the research in this area has been translated into treatment for metabolic conditions.
Hypoglycaemia, which occurs when blood levels of glucose fall below what is considered a normal range, is a well-known complication of insulin therapy in individuals with type 1 diabetes mellitus. ...Despite advances in diabetes mellitus management, hypoglycaemia has continued to affect the majority of these individuals, leading to suboptimal care and decreased quality of life. Multiple epidemiological studies have demonstrated the risks associated with hypoglycaemic events. With this understanding, various advances have been made in therapeutics for diabetes mellitus management. Diabetes mellitus education continues to form the foundation for management and prevention of hypoglycaemia. The advent of newer diabetes mellitus technologies and newer insulins herald improvements in management strategies and hypoglycaemia prevention. Improved understanding of these newer approaches is needed to ensure delivery of safe and effective care to individuals with type 1 diabetes mellitus, leading to reductions in both the short-term and long-term morbidity and mortality associated with hypoglycaemic events.
The deleterious effects of diabetes mellitus on the retinal, renal, cardiovascular, and peripheral nervous systems are widely acknowledged. Less attention has been given to the effect of diabetes on ...cognitive function. Both type 1 and type 2 diabetes mellitus have been associated with reduced performance on numerous domains of cognitive function. The exact pathophysiology of cognitive dysfunction in diabetes is not completely understood, but it is likely that hyperglycemia, vascular disease, hypoglycemia, and insulin resistance play significant roles. Modalities to study the effect of diabetes on the brain have evolved over the years, including neurocognitive testing, evoked response potentials, and magnetic resonance imaging. Although much insightful research has examined cognitive dysfunction in patients with diabetes, more needs to be understood about the mechanisms and natural history of this complication in order to develop strategies for prevention and treatment.
Objective: The aim is to provide guidelines for the evaluation and management of adults with hypoglycemic disorders, including those with diabetes mellitus.
Evidence: Using the recommendations of the ...Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, the quality of evidence is graded very low (⊕○○○), low (⊕⊕○○), moderate (⊕⊕⊕○), or high (⊕⊕⊕⊕).
Conclusions: We recommend evaluation and management of hypoglycemia only in patients in whom Whipple’s triad—symptoms, signs, or both consistent with hypoglycemia, a low plasma glucose concentration, and resolution of those symptoms or signs after the plasma glucose concentration is raised—is documented. In patients with hypoglycemia without diabetes mellitus, we recommend the following strategy. First, pursue clinical clues to potential hypoglycemic etiologies—drugs, critical illnesses, hormone deficiencies, nonislet cell tumors. In the absence of these causes, the differential diagnosis narrows to accidental, surreptitious, or even malicious hypoglycemia or endogenous hyperinsulinism. In patients suspected of having endogenous hyperinsulinism, measure plasma glucose, insulin, C-peptide, proinsulin, β-hydroxybutyrate, and circulating oral hypoglycemic agents during an episode of hypoglycemia and measure insulin antibodies. Insulin or insulin secretagogue treatment of diabetes mellitus is the most common cause of hypoglycemia. We recommend the practice of hypoglycemia risk factor reduction—addressing the issue of hypoglycemia, applying the principles of intensive glycemic therapy, and considering both the conventional risk factors and those indicative of compromised defenses against falling plasma glucose concentrations—in persons with diabetes.
The Endocrine Society Guideline for the evaluation and management of adults with hypoglycemic disorders including those with diabetes mellitus.
Objective:
To review the evidence about the impact of hypoglycemia on patients with diabetes that has become available since the past reviews of this subject by the American Diabetes Association and ...The Endocrine Society and to provide guidance about how this new information should be incorporated into clinical practice.
Participants:
Five members of the American Diabetes Association and five members of The Endocrine Society with expertise in different aspects of hypoglycemia were invited by the Chair, who is a member of both, to participate in a planning conference call and a 2-day meeting that was also attended by staff from both organizations. Subsequent communications took place via e-mail and phone calls. The writing group consisted of those invitees who participated in the writing of the manuscript. The workgroup meeting was supported by educational grants to the American Diabetes Association from Lilly USA, LLC and Novo Nordisk and sponsorship to the American Diabetes Association from Sanofi. The sponsors had no input into the development of or content of the report.
Evidence:
The writing group considered data from recent clinical trials and other studies to update the prior workgroup report. Unpublished data were not used. Expert opinion was used to develop some conclusions.
Consensus Process:
Consensus was achieved by group discussion during conference calls and face-to-face meetings, as well as by iterative revisions of the written document. The document was reviewed and approved by the American Diabetes Association's Professional Practice Committee in October 2012 and approved by the Executive Committee of the Board of Directors in November 2012 and was reviewed and approved by The Endocrine Society's Clinical Affairs Core Committee in October 2012 and by Council in November 2012.
Conclusions:
The workgroup reconfirmed the previous definitions of hypoglycemia in diabetes, reviewed the implications of hypoglycemia on both short- and long-term outcomes, considered the implications of hypoglycemia on treatment outcomes, presented strategies to prevent hypoglycemia, and identified knowledge gaps that should be addressed by future research. In addition, tools for patients to report hypoglycemia at each visit and for clinicians to document counseling are provided.
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