Glucagon - the new 'insulin' in the pathophysiology of diabetes.

PURPOSE OF REVIEW: Autoimmune destruction of the ß cells is considered the key abnormality in type 1 diabetes mellitus and insulin replacement the primary therapeutic strategy. However, a lack of insulin is accompanied by disturbances in glucagon release, which is excessive postprandially, but insufficient during hypoglycaemia. In addition, replacing insulin alone appears insufficient for adequate glucose control. This review focuses on the growing body of evidence that glucagon abnormalities contribute significantly to the pathophysiology of diabetes and on recent efforts to target the glucagon axis as adjunctive therapy to insulin replacement. RECENT FINDINGS: This review discusses recent (since 2013) advances in abnormalities of glucagon regulation and their link to the pathophysiology of diabetes; new mechanisms of glucagon action and regulation; manipulation of glucagon in diabetes treatment; and analytical and systems biology tools to study glucagon regulation. SUMMARY: Recent efforts 'resurrected' glucagon as a key hormone in the pathophysiology of diabetes. New studies target its abnormal regulation and action that is key for improving diabetes treatment. The progress is promising, but major questions remain, including unravelling the mechanism of loss of glucagon counterregulation in type 1 diabetes mellitus and how best to manipulate glucagon to achieve more efficient and safer glycaemic control.

Management of Individuals With Diabetes at High Risk for Hypoglycemia: An Endocrine Society Clinical Practice Guideline.

CONTEXT: Hypoglycemia in people with diabetes is common, especially in those taking medications such as insulin and sulfonylureas (SU) that place them at higher risk. Hypoglycemia is associated with distress in those with diabetes and their families, medication nonadherence, and disruption of life and work, and it leads to costly emergency department visits and hospitalizations, morbidity, and mortality. OBJECTIVE: To review and update the diabetes-specific parts of the 2009 Evaluation and Management of Adult Hypoglycemic Disorders: Endocrine Society Clinical Practice Guideline and to address developing issues surrounding hypoglycemia in both adults and children living with diabetes. The overriding objectives are to reduce and prevent hypoglycemia. METHODS: A multidisciplinary panel of clinician experts, together with a patient representative, and methodologists with expertise in evidence synthesis and guideline development, identified and prioritized 10 clinical questions related to hypoglycemia in people living with diabetes. Systematic reviews were conducted to address all the questions. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make recommendations. RESULTS: The panel agreed on 10 questions specific to hypoglycemia risk and prevention in people with diabetes for which 10 recommendations were made. The guideline includes conditional recommendations for use of real-time continuous glucose monitoring (CGM) and algorithm-driven insulin pumps in people with type 1 diabetes (T1D), use of CGM for outpatients with type 2 diabetes at high risk for hypoglycemia, use of long-acting and rapid-acting insulin analogs, and initiation of and continuation of CGM for select inpatient populations at high risk for hypoglycemia. Strong recommendations were made for structured diabetes education programs for those at high risk for hypoglycemia, use of glucagon preparations that do not require reconstitution vs those that do for managing severe outpatient hypoglycemia for adults and children, use of real-time CGM for individuals with T1D receiving multiple daily injections, and the use of inpatient glycemic management programs leveraging electronic health record data to reduce the risk of hypoglycemia. CONCLUSION: The recommendations are based on the consideration of critical outcomes as well as implementation factors such as feasibility and values and preferences of people with diabetes. These recommendations can be used to inform clinical practice and health care system improvement for this important complication for people living with diabetes.

A Systematic Review Supporting the Endocrine Society Guidelines: Management of Diabetes and High Risk of Hypoglycemia.

CONTEXT: Interventions targeting hypoglycemia in people with diabetes are important for improving quality of life and reducing morbidity and mortality. OBJECTIVE: To support development of the Endocrine Society Clinical Practice Guideline for management of individuals with diabetes at high risk for hypoglycemia. METHODS: We searched several databases for studies addressing 10 questions provided by a guideline panel from the Endocrine Society. Meta-analysis was conducted when feasible. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess certainty of evidence. RESULTS: We included 149 studies reporting on 43 344 patients. Continuous glucose monitoring (CGM) reduced episodes of severe hypoglycemia in patients with type 1 diabetes (T1D) and reduced the proportion of patients with hypoglycemia (blood glucose [BG] levels <54 mg/dL). There were no data on use of real-time CGM with algorithm-driven insulin pumps vs multiple daily injections with BG testing in people with T1D. CGM in outpatients with type 2 diabetes taking insulin and/or sulfonylureas reduced time spent with BG levels under 70 mg/dL. Initiation of CGM in hospitalized patients at high risk for hypoglycemia reduced episodes of hypoglycemia with BG levels lower than 54 mg/dL and time spent under 54 mg/dL. The proportion of patients with hypoglycemia with BG levels lower than 70 mg/dL and lower than 54 mg/dL detected by CGM was significantly higher than point-of-care BG testing. We found no data evaluating continuation of personal CGM in the hospital. Use of an inpatient computerized glycemic management program utilizing electronic health record data was associated with fewer patients with and episodes of hypoglycemia with BG levels lower than 70 mg/dL and fewer patients with severe hypoglycemia compared with standard care. Long-acting basal insulin analogs were associated with less hypoglycemia. Rapid-acting insulin analogs were associated with reduced severe hypoglycemia, though there were more patients with mild to moderate hypoglycemia. Structured diabetes education programs reduced episodes of severe hypoglycemia and time below 54 mg/dL in outpatients taking insulin. Glucagon formulations not requiring reconstitution were associated with longer times to recovery from hypoglycemia, although the proportion of patients who recovered completely from hypoglycemia was not different between the 2 groups. CONCLUSION: This systematic review summarized the best available evidence about several interventions addressing hypoglycemia in people with diabetes. This evidence base will facilitate development of clinical practice guidelines by the Endocrine Society.

Resolving the conundrum of islet transplantation by linking metabolic dysregulation, inflammation, and immune regulation.

Although type 1 diabetes cannot be prevented or reversed, replacement of insulin production by transplantation of the pancreas or pancreatic islets represents a definitive solution. At present, transplantation can restore euglycemia, but this restoration is short-lived, requires islets from multiple donors, and necessitates lifelong immunosuppression. An emerging paradigm in transplantation and autoimmunity indicates that systemic inflammation contributes to tissue injury while disrupting immune tolerance. We identify multiple barriers to successful islet transplantation, each of which either contributes to the inflammatory state or is augmented by it. To optimize islet transplantation for diabetes reversal, we suggest that targeting these interacting barriers and the accompanying inflammation may represent an improved approach to achieve successful clinical islet transplantation by enhancing islet survival, regeneration or neogenesis potential, and tolerance induction. Overall, we consider the proinflammatory effects of important technical, immunological, and metabolic barriers including: 1) islet isolation and transplantation, including selection of implantation site; 2) recurrent autoimmunity, alloimmune rejection, and unique features of the autoimmune-prone immune system; and 3) the deranged metabolism of the islet transplant recipient. Consideration of these themes reveals that each is interrelated to and exacerbated by the other and that this connection is mediated by a systemic inflammatory state. This inflammatory state may form the central barrier to successful islet transplantation. Overall, there remains substantial promise in islet transplantation with several avenues of ongoing promising research. This review focuses on interactions between the technical, immunological, and metabolic barriers that must be overcome to optimize the success of this important therapeutic approach.

Enhancing the Trustworthiness of the Endocrine Society's Clinical Practice Guidelines.

In an effort to enhance the trustworthiness of its clinical practice guidelines, the Endocrine Society has recently adopted new policies and more rigorous methodologies for its guideline program. In this Clinical Practice Guideline Communication, we describe these recent enhancements-many of which reflect greater adherence to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to guideline development-in addition to the rationale for such changes. Improvements to the Society's guideline development practices include, but are not limited to, enhanced inclusion of nonendocrinologist experts, including patient representatives, on guideline development panels; implementation of a more rigorous conflict/duality of interest policy; a requirement that all formal recommendations must be demonstrably underpinned by systematic evidence review; the explicit use of GRADE Evidence-to-Decision frameworks; greater use and explanation of standardized guideline language; and a more intentional approach to guideline updating. Lastly, we describe some of the experiential differences our guideline readers are most likely to notice.

Update on the safety of thiazolidinediones.

Diabetic patients are at increased risk for developing cardiovascular disease, and they constitute a large proportion of the global cardiovascular disease burden. Although multiple drugs exist for treating the hyperglycemia associated with diabetes, few have been shown to reduce cardiovascular risk. Great hope surrounded the arrival of the thiazolidinediones-drugs that favorably affect insulin sensitivity, inflammation, and some aspects of lipid profiles in diabetic patients. However, the cardiovascular effects of these agents are varied, and studies have suggested that they may be associated with increases in ischemic heart disease and heart failure, as well as with an increased risk for bone fracture. The following article provides a summary of important studies that have been published regarding the safety profiles of these agents. Findings from two recently published trials, RECORD and BARI 2D, are emphasized in this paper.

Minimizing Glucose Excursions (GEM) With Continuous Glucose Monitoring in Type 2 Diabetes: A Randomized Clinical Trial.

This study aimed to compare conventional medication management of type 2 diabetes (T2D) to medication management in conjunction with a lifestyle intervention using continuous glucose monitoring to minimize glucose excursions. Thirty adults (63% female; mean age, 53.3 years) who were diagnosed with T2D for less than 11 years (mean, 5.6 years), had glycated A1c (HbA1c) ≥ 7.0% (51 mmol/mol) (mean 8.8%, [73 mmol/mol]), and were not using insulin, were randomly assigned in a 1:2 ratio to routine care (RC) or 4 group sessions of glycemic excursion minimization plus real-time CGM (GEMCGM). Assessments at baseline and 5 months included a physical exam, metabolic and lipid panels, a review of diabetes medications, and psychological questionnaires. For the week following assessments, participants wore a blinded activity monitor and completed 3 days of 24-hour dietary recall. A subgroup also wore a blinded CGM. GEMCGM participants significantly improved HbA1c (from 8.9% to 7.6% [74-60 mmol/mol] compared with 8.8% to 8.7% [73-72 mmol/mol] for RC (P = .03). Additionally, GEMCGM reduced the need for diabetes medication (P = .01), reduced carbohydrate consumption (P = .009), and improved diabetes knowledge (P = .001), quality of life (P = .01) and diabetes distress (P = .02), and trended to more empowerment (P = .05) without increasing dietary fat, lipids, or hypoglycemia. Confirming our prior research, GEMCGM appears to be a safe, effective lifestyle intervention option for adults with suboptimally controlled T2D who do not take insulin.

Reduced daily risk of glycemic variability: comparison of exenatide with insulin glargine.

BACKGROUND: Conventional methods describing daily glycemic variability (i.e., standard deviation and coefficient of variation) do not express risk. Low and High Blood Glucose Indices (LBGI and HBGI, respectively) and Average Daily Risk Range (ADRR) are parameters derived from self-monitored blood glucose (SMBG) data that quantify risk of glycemic excursions and temporal aspects of variability. In the present study, variability parameters were used to assess effects of exenatide and insulin glargine on risk of acute blood glucose extremes. METHODS: New (LBGI, HBGI, and ADRR) and conventional variability analyses were applied retrospectively to SMBG data from patients with type 2 diabetes suboptimally controlled with metformin and a sulfonylurea plus exenatide or insulin glargine as a next therapeutic step. Exenatide- (n = 282) and insulin glargine-treated (n = 267) patients were well matched. RESULTS: Exenatide treatment reduced ADRR overall (exenatide, mean +/- SEM, 16.33 +/- 0.45; insulin glargine, 18.54 +/- 0.49; P = 0.001). Seventy-seven percent of exenatide-treated patients were at low risk for glucose variability compared with 62% of glargine-treated patients (P = 0.00023). LBGI for exenatide remained minimal for all categories and significantly lower than glargine for all comparisons, and HBGI for exenatide remained low or moderate for all categories and significantly lower than glargine after the morning and evening meals. Reduced variability in exenatide-treated patients was shown by conventional methods but provided no indications of risk. CONCLUSIONS: Average glycemic control was similar for both treatment groups. However, exenatide treatment minimized risk for glycemic variability and extremes to a greater degree than insulin glargine treatment.

Optimizing Postprandial Glucose Management in Adults With Insulin-Requiring Diabetes: Report and Recommendations.

Faster-acting insulins, new noninsulin drug classes, more flexible insulin-delivery systems, and improved continuous glucose monitoring devices offer unprecedented opportunities to improve postprandial glucose (PPG) management and overall care for adults with insulin-treated diabetes. These developments led the Endocrine Society to convene a working panel of diabetes experts in December 2018 to assess the current state of PPG management, identify innovative ways to improve self-management and quality of life, and align best practices to current and emerging treatment and monitoring options. Drawing on current research and collective clinical experience, we considered the following issues for the ∼200 million adults worldwide with type 1 and insulin-requiring type 2 diabetes: (i) the role of PPG management in reducing the risk of diabetes complications; (ii) barriers preventing effective PPG management; (iii) strategies to reduce PPG excursions and improve patient quality of life; and (iv) education and clinical tools to support endocrinologists in improving PPG management. We concluded that managing PPG to minimize or prevent diabetes-related complications will require elucidating fundamental questions about optimal ways to quantify and clinically assess the metabolic dysregulation and consequences of the abnormal postprandial state in diabetes and recommend research strategies to address these questions. We also identified practical strategies and tools that are already available to reduce barriers to effective PPG management, optimize use of new and emerging clinical tools, and improve patient self-management and quality of life.

Behavioral Strategies to Lower Postprandial Glucose in Those with Type 2 Diabetes May Also Lower Risk of Coronary Heart Disease.

INTRODUCTION: Efforts to lower glycosylated hemoglobin (A1c) in patients with type 2 diabetes (T2D) are intended to reduce the risk of diabetic complications, but A1c is not the only factor contributing to this risk. Consequently, we re-analyzed published data from a broad-spectrum lifestyle intervention that lowered A1c to assess its effectiveness in lowering the overall risk of two complications of T2D, namely, coronary heart disease (CHD) and stroke. METHODS: Data from 37 adults who participated in a randomized clinical trial of a lifestyle intervention intended to reduce postprandial glucose (PPG) were re-analyzed for their pre- and post-treatment risk of CHD and stroke using the T2D-specific UK Prospective Diabetes Study (UKPDS) v2.0 risk algorithm. RESULTS: Compared to participants who received routine care, those using the lifestyle intervention had a significantly greater reduction in 10-year risk for CHD, but not for stroke. CONCLUSION: These secondary analyses suggest that broad-spectrum lifestyle interventions that focus on lowering PPG may lower the risk of future CHD, which could guide future research. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02432391.

Postoperative Hypoglycemia Is Associated With Worse Outcomes After Cardiac Operations.

BACKGROUND: Hypoglycemia is a known risk of intensive postoperative glucose control in patients undergoing cardiac operations. However, neither the consequences of hypoglycemia relative to hyperglycemia, nor the possible interaction effects, have been well described. We examined the effects of postoperative hypoglycemia, hyperglycemia, and their interaction on short-term morbidity and mortality. METHODS: Single-institution Society of Thoracic Surgeons (STS) database patient records from 2010 to 2014 were merged with clinical data, including blood glucose values measured in the intensive care unit (ICU). Exclusion criteria included fewer than three glucose measurements and absence of an STS predicted risk of morbidity or mortality score. Primary outcomes were operative mortality and composite major morbidity (permanent stroke, renal failure, prolonged ventilation, pneumonia, or myocardial infarction). Secondary outcomes included ICU and postoperative length of stay. Hypoglycemia was defined as below 70 mg/dL, and hyperglycemia as above 180 mg/dL. Simple and multivariable regression models were used to evaluate the outcomes. RESULTS: A total of 2,285 patient records met the selection criteria for analysis. The mean postoperative glucose level was 140.8 ± 18.8 mg/dL. Overall, 21.4% of patients experienced a hypoglycemic episode (n = 488), and 1.05% (n = 24) had a severe hypoglycemic episode (<40 mg/dL). The unadjusted odds ratio (UOR) for operative mortality for patients with any hypoglycemic episode compared with those without was 5.47 (95% confidence interval [CI] 3.14 to 9.54), and the UOR for major morbidity was 4.66 (95% CI 3.55 to 6.11). After adjustment for predicted risk of morbidity or mortality and other significant covariates, the adjusted odds (AOR) of operative mortality were significant for patients with any hypoglycemia (AOR 4.88, 95% CI 2.67 to 8.92) and patients with both events (AOR 8.29, 95% CI 1.83 to 37.5) but not hyperglycemia alone (AOR 1.62, 95% CI 0.56 to 4.69). The AOR of major morbidity for patients with both hypoglycemic and hyperglycemic events was 14.3 (95% CI 6.50 to 31.4). CONCLUSIONS: Postoperative hypoglycemia is associated with both mortality and major morbidity after cardiac operations. The combination of both hyperglycemia and hypoglycemia represents a substantial increase in risk. Although it remains unclear whether hypoglycemia is a cause, an early warning sign, or a result of adverse events, this study suggests that hypoglycemia may be an important event in the postoperative period after cardiac operations.

A novel analytical method for assessing glucose variability: using CGMS in type 1 diabetes mellitus.

BACKGROUND: Marked blood glucose (BG) fluctuations may increase the risk of some complications associated with diabetes. Acute BG excursions are common in patients with diabetes, but are not usually quantified, nor can they be captured by glycosylated hemoglobin level. This study evaluated the sensitivity of novel analytical methods for assessing BG variability using CGMS (Medtronic Minimed, Northridge, CA) data from patients treated with pramlintide, a drug that acutely reduces postprandial hyperglycemia when added to insulin therapy. METHODS: Retrospective analyses were done on 24-h CGMS profiles obtained from 22 evaluable subjects with type 1 diabetes using insulin pumps and receiving preprandial three times daily injections of placebo (n = 6) or 30 microg of pramlintide (n = 16) for 4 weeks. CGMS data were recorded at baseline, after 4 weeks of treatment, and after 2 weeks off-treatment. Three parameters were calculated for each time period: variability (BG rate of change), an index for severe hypoglycemia [low BG index (LBGI)], and an index for marked hyperglycemia [high BG index (HBGI)]. RESULTS: The mean postprandial BG rate of change was significantly lower after 4 weeks of pramlintide treatment compared with placebo treatment (0.87 vs. 1.21 mg/dL/min, P < 0.01) without changes in average glycemia, illustrating the sensitivity of this parameter to medication effects. The HBGI and LBGI indicated a decreased risk of hyperglycemia without a significant increase in risk of hypoglycemia after 4 weeks of pramlintide. CONCLUSIONS: These results suggest the potential utility of several novel methods for assessing variability and glycemic extremes to gauge the effects of pharmacological interventions not captured by glycosylated hemoglobin.

Glycemic load, exercise, and monitoring blood glucose (GEM): A paradigm shift in the treatment of type 2 diabetes mellitus.

AIMS: This preliminary RCT investigated whether an integrated lifestyle modification program that focuses on reducing postprandial blood glucose through replacing high with low glycemic load foods and increasing routine physical activities guided by systematic self-monitoring of blood glucose (GEM) could improve metabolic control of adults with type 2 diabetes mellitus, without compromising other physiological parameters. METHODS: Forty-seven adults (mean age 55.3 years) who were diagnosed with type 2 diabetes mellitus for less than 5 years (mean 2.1 years), had HbA1c ≥ 7% (mean 8.4%) and were not taking blood glucose lowering medications, were randomized to routine care or five 1-h instructional sessions of GEM. Assessments at baseline and 6 months included a physical exam, metabolic and lipid panels, and psychological questionnaires. RESULTS: The GEM intervention led to significant improvements in HbA1c (decreasing from 8.4 to 7.4% [69-57 mmol/mol] compared with 8.3 to 8.3% [68-68 mmol/mol] for routine care; Interaction p<.01) and psychological functioning without compromising other physiological parameters. CONCLUSIONS: Consistent with a patient-centered approach, GEM appears to be an effective lifestyle modification option for adults recently diagnosed with type 2 diabetes mellitus.

Altered glycemia and brain-update and potential relevance to the aging brain.

Hyperglycemia characterizes diabetes mellitus and is linked to its chronic and acute complications. Cognitive dysfunction in diabetes occurs especially in longstanding disease and with poor glycemic control. Recent data in humans suggests that hyperglycemia causes acute cognitive dysfunction. The underlying mechanisms are unknown but deserve further research as diabetes is becoming epidemic and will likely contribute increasingly to premature cognitive decline. The primary side effect of diabetes treatment is hypoglycemia, particularly resulting from insulin treatment. CNS adaptations to acute and chronic hypoglycemia underlie the inability of some people to promptly recognize and defend against the risk of serious hypoglycemia. Data from human and animal models may help explain how altered glycemia affects brain function both acutely and chronically. Improved mechanistic understanding of altered glycemia's effects could prevent the adverse impact of diabetes upon the CNS and give new insights into effects that may exist in normal aging.

GLUT8 glucose transporter is localized to excitatory and inhibitory neurons in the rat hippocampus.

Fluorescence immunohistochemistry was performed to characterize the distribution and phenotype of GLUT8-positive neurons in rat brain and to compare the cellular distribution of GLUT8 with GLUT3 in the hippocampus. Based upon the absence of co-localization with the non-neuronal markers GFAP (astroglial) and OX42 (microglial), it appears that GLUT8 is expressed exclusively in neurons. At the cellular level, GLUT8 immunofluorescence was localized to neuronal cell bodies and the most proximal dendrites of inhibitory and excitatory neurons while GLUT3 immunofluorescence was localized to the neuropil in the hippocampus. These results demonstrate that GLUT8 is a neuron-specific glucose transporter expressed in the neuronal cell bodies of excitatory and inhibitory neurons in the rat hippocampus.

Cerebral glucose metabolism in diabetes mellitus.

The brain uses glucose as its primary fuel. Cerebral metabolism of glucose requires transport through the blood-brain barrier, glycolytic conversion to pyruvate, metabolism via the tricarboxylic acid cycle and ultimately oxidation to carbon dioxide and water for full provision of adenosine triphosphate (ATP) and its high-energy equivalents. When deprived of glucose, the brain becomes dysfunctional or can be even permanently damaged. Glucose is stored as glycogen within astrocytes with potential importance for tolerance of hypoglycemia. Glycogen may also be important for the metabolic response to somatosensory stimulation and coupling of blood flow and cellular metabolism. Uncontrolled diabetes has a variety of adverse effects upon brain metabolism and function. Many aspects of function that affect the brain may be indirectly linked to cerebral glucose metabolism. Neurotransmitter metabolism, cerebral blood flow, blood-brain barrier and microvascular function may all be affected to varying degrees by either hypoglycemia or uncontrolled diabetes mellitus.