Abstract
Pancreatic islet transplantation has become an established approach to β-cell replacement therapy for the treatment of insulin-deficient diabetes. Recent progress in techniques for islet ...isolation, islet culture, and peritransplant management of the islet transplant recipient has resulted in substantial improvements in metabolic and safety outcomes for patients. For patients requiring total or subtotal pancreatectomy for benign disease of the pancreas, isolation of islets from the diseased pancreas with intrahepatic transplantation of autologous islets can prevent or ameliorate postsurgical diabetes, and for patients previously experiencing painful recurrent acute or chronic pancreatitis, quality of life is substantially improved. For patients with type 1 diabetes or insulin-deficient forms of pancreatogenic (type 3c) diabetes, isolation of islets from a deceased donor pancreas with intrahepatic transplantation of allogeneic islets can ameliorate problematic hypoglycemia, stabilize glycemic lability, and maintain on-target glycemic control, consequently with improved quality of life, and often without the requirement for insulin therapy. Because the metabolic benefits are dependent on the numbers of islets transplanted that survive engraftment, recipients of autoislets are limited to receive the number of islets isolated from their own pancreas, whereas recipients of alloislets may receive islets isolated from more than one donor pancreas. The development of alternative sources of islet cells for transplantation, whether from autologous, allogeneic, or xenogeneic tissues, is an active area of investigation that promises to expand access and indications for islet transplantation in the future treatment of diabetes.
Hypoglycemia remains a major barrier to the achievement of target levels of glycemic control for most individuals with insulin‐dependent type 1 diabetes (T1D). Both the loss of β cells and an ...accompanying defect in the α cell response to hypoglycemia predispose patients with T1D to the development of low blood glucose. Increased glucose variability, exposure to hypoglycemia, and impaired awareness of hypoglycemia all contribute to increased risk of experiencing severe hypoglycemia, which is explained by progressive impairment in epinephrine secretion and autonomic symptom generation in response to hypoglycemia leading to defective glucose counterregulation and hypoglycemia unawareness that characterize hypoglycemia‐associated autonomic failure (HAAF). Interruption of HAAF requires interfering with the mechanisms of brain adaptation to low blood glucose that affect central glucose sensing and the autonomic response to hypoglycemia, or avoidance of hypoglycemia that may allow for eventual recovery of counterregulatory and autonomic symptom responses. Strategies for hypoglycemia avoidance that include continuous glucose monitoring may reduce, but do not eliminate, clinically significant hypoglycemia, with ongoing counterregulatory defects and impaired awareness of hypoglycemia. Complete avoidance of hypoglycemia can be achieved following pancreatic islet transplantation and allows for the restoration of counterregulatory and autonomic symptom responses that evidences the potential for reversing HAAF in T1D.
In order to set the stage for future mechanistic investigation of hypoglycemia in type 1 diabetes (T1D), this paper aims to review (1) mechanisms for the development of hypoglycemia in T1D, (2) mechanisms for hypoglycemia‐associated autonomic failure in T1D, (3) hypoglycemia avoidance and counterregulatory responses in T1D, and (4) pancreatic islet transplantation for reversal of hypoglycemia‐associated autonomic failure in T1D.
Atypical antipsychotic (AAP) medications that have revolutionized the treatment of mental illness have become stigmatized by metabolic side effects, including obesity and diabetes. It remains ...controversial whether the defects are treatment induced or disease related. Although the mechanisms underlying these metabolic defects are not understood, it is assumed that the initiating pathophysiology is weight gain, secondary to centrally mediated increases in appetite. To determine if the AAPs have detrimental metabolic effects independent of weight gain or psychiatric disease, we administered olanzapine, aripiprazole, or placebo for 9 days to healthy subjects (n = 10, each group) under controlled in-patient conditions while maintaining activity levels. Prior to and after the interventions, we conducted a meal challenge and a euglycemic-hyperinsulinemic clamp to evaluate insulin sensitivity and glucose disposal. We found that olanzapine, an AAP highly associated with weight gain, causes significant elevations in postprandial insulin, glucagon-like peptide 1 (GLP-1), and glucagon coincident with insulin resistance compared with placebo. Aripiprazole, an AAP considered metabolically sparing, induces insulin resistance but has no effect on postprandial hormones. Importantly, the metabolic changes occur in the absence of weight gain, increases in food intake and hunger, or psychiatric disease, suggesting that AAPs exert direct effects on tissues independent of mechanisms regulating eating behavior.
The relationships between diabetes and pancreatic ductal adenocarcinoma (PDAC) are complex. Longstanding type 2 diabetes (T2DM) is a risk factor for pancreatic cancer, but increasing epidemiological ...data point to PDAC as also a cause of diabetes due to unknown mechanisms. New-onset diabetes is of particular interest to the oncology community as the differentiation of new-onset diabetes caused by PDAC as distinct from T2DM may allow for earlier diagnosis of PDAC. To address these relationships and raise awareness of the relationships between PDAC and diabetes, a symposium entitled Diabetes, Pancreatogenic Diabetes, and Pancreatic Cancer was held at the American Diabetes Association's 76th Scientific Sessions in June 2016. This article summarizes the data presented at that symposium, describing the current understanding of the interrelationships between diabetes, diabetes management, and pancreatic cancer, and identifies areas where additional research is needed.
Patients with type 1 diabetes who do aerobic exercise often experience a drop in blood glucose concentration that can result in hypoglycemia. Current approaches to prevent exercise-induced ...hypoglycemia include reduction in insulin dose or ingestion of carbohydrates, but these strategies may still result in hypoglycemia or hyperglycemia. We sought to determine whether mini-dose glucagon (MDG) given subcutaneously before exercise could prevent subsequent glucose lowering and to compare the glycemic response to current approaches for mitigating exercise-associated hypoglycemia.
We conducted a four-session, randomized crossover trial involving 15 adults with type 1 diabetes treated with continuous subcutaneous insulin infusion who exercised fasting in the morning at ∼55% VO
for 45 min under conditions of no intervention (control), 50% basal insulin reduction, 40-g oral glucose tablets, or 150-μg subcutaneous glucagon (MDG).
During exercise and early recovery from exercise, plasma glucose increased slightly with MDG compared with a decrease with control and insulin reduction and a greater increase with glucose tablets (
< 0.001). Insulin levels were not different among sessions, whereas glucagon increased with MDG administration (
< 0.001). Hypoglycemia (plasma glucose <70 mg/dL) was experienced by six subjects during control, five subjects during insulin reduction, and none with glucose tablets or MDG; five subjects experienced hyperglycemia (plasma glucose ≥250 mg/dL) with glucose tablets and one with MDG.
MDG may be more effective than insulin reduction for preventing exercise-induced hypoglycemia and may result in less postintervention hyperglycemia than ingestion of carbohydrate.
Impaired awareness of hypoglycemia (IAH) and severe hypoglycemic events (SHEs) cause substantial morbidity and mortality in patients with type 1 diabetes (T1D). Current therapies are effective in ...preventing SHEs in 50-80% of patients with IAH and SHEs, leaving a substantial number of patients at risk. We evaluated the effectiveness and safety of a standardized human pancreatic islet product in subjects in whom IAH and SHEs persisted despite medical treatment.
This multicenter, single-arm, phase 3 study of the investigational product purified human pancreatic islets (PHPI) was conducted at eight centers in North America. Forty-eight adults with T1D for >5 years, absent stimulated C-peptide, and documented IAH and SHEs despite expert care were enrolled. Each received immunosuppression and one or more transplants of PHPI, manufactured on-site under good manufacturing practice conditions using a common batch record and standardized lot release criteria and test methods. The primary end point was the achievement of HbA1c <7.0% (53 mmol/mol) at day 365 and freedom from SHEs from day 28 to day 365 after the first transplant.
The primary end point was successfully met by 87.5% of subjects at 1 year and by 71% at 2 years. The median HbA1c level was 5.6% (38 mmol/mol) at both 1 and 2 years. Hypoglycemia awareness was restored, with highly significant improvements in Clarke and HYPO scores (P > 0.0001). No study-related deaths or disabilities occurred. Five of the enrollees (10.4%) experienced bleeds requiring transfusions (corresponding to 5 of 75 procedures), and two enrollees (4.1%) had infections attributed to immunosuppression. Glomerular filtration rate decreased significantly on immunosuppression, and donor-specific antibodies developed in two patients.
Transplanted PHPI provided glycemic control, restoration of hypoglycemia awareness, and protection from SHEs in subjects with intractable IAH and SHEs. Safety events occurred related to the infusion procedure and immunosuppression, including bleeding and decreased renal function. Islet transplantation should be considered for patients with T1D and IAH in whom other, less invasive current treatments have been ineffective in preventing SHEs.
To provide a snapshot of the profile of adults and youth with type 1 diabetes (T1D) in the United States and assessment of longitudinal changes in T1D management and clinical outcomes in the T1D ...Exchange registry.
Data on diabetes management and outcomes from 22,697 registry participants (age 1-93 years) were collected between 2016 and 2018 and compared with data collected in 2010-2012 for 25,529 registry participants.
Mean HbA1c in 2016-2018 increased from 65 mmol/mol at the age of 5 years to 78 mmol/mol between ages 15 and 18, with a decrease to 64 mmol/mol by age 28 and 58-63 mmol/mol beyond age 30. The American Diabetes Association (ADA) HbA1c goal of <58 mmol/mol for youth was achieved by only 17% and the goal of <53 mmol/mol for adults by only 21%. Mean HbA1c levels changed little between 2010-2012 and 2016-2018, except in adolescents who had a higher mean HbA1c in 2016-2018. Insulin pump use increased from 57% in 2010-2012 to 63% in 2016-2018. Continuous glucose monitoring (CGM) increased from 7% in 2010-2012 to 30% in 2016-2018, rising >10-fold in children <12 years old. HbA1c levels were lower in CGM users than nonusers. Severe hypoglycemia was most frequent in participants ≥50 years old and diabetic ketoacidosis was most common in adolescents and young adults. Racial differences were evident in use of pumps and CGM and HbA1c levels.
Data from the T1D Exchange registry demonstrate that only a minority of adults and youth with T1D in the United States achieve ADA goals for HbA1c.
Problematic hypoglycemia, defined as two or more episodes per year of severe hypoglycemia or as one episode associated with impaired awareness of hypoglycemia, extreme glycemic lability, or major ...fear and maladaptive behavior, is a challenge, especially for patients with long-standing type 1 diabetes. Individualized therapy for such patients should include a composite target: optimal glucose control without problematic hypoglycemia. Therefore, we propose a tiered, four-stage algorithm based on evidence of efficacy given the limitations of educational, technological, and transplant interventions. All patients with problematic hypoglycemia should undergo structured or hypoglycemia-specific education programs (stage 1). Glycemic and hypoglycemia treatment targets should be individualized and reassessed every 3-6 months. If targets are not met, one diabetes technology-continuous subcutaneous insulin infusion or continuous glucose monitoring-should be added (stage 2). For patients with continued problematic hypoglycemia despite education (stage 1) and one diabetes technology (stage 2), sensor-augmented insulin pumps preferably with an automated low-glucose suspend feature and/or very frequent contact with a specialized hypoglycemia service can reduce hypoglycemia (stage 3). For patients whose problematic hypoglycemia persists, islet or pancreas transplant should be considered (stage 4). This algorithm provides an evidence-informed approach to resolving problematic hypoglycemia; it should be used as a guide, with individual patient circumstances directing suitability and acceptability to ensure the prudent use of technology and scarce transplant resources. Standardized reporting of hypoglycemia outcomes and inclusion of patients with problematic hypoglycemia in studies of new interventions may help to guide future therapeutic strategies.
The main goal of treatment for type 1 diabetes is to control glycaemia with insulin therapy to reduce disease complications. For some patients, technological approaches to insulin delivery are ...inadequate, and allogeneic islet transplantation is a safe alternative for those patients who have had severe hypoglycaemia complicated by impaired hypoglycaemia awareness or glycaemic lability, or who already receive immunosuppressive drugs for a kidney transplant. Since 2000, intrahepatic islet transplantation has proven efficacious in alleviating the burden of labile diabetes and preventing complications related to diabetes, whether or not a previous kidney transplant is present. Age, body-mass index, renal status, and cardiopulmonary status affect the choice between pancreas or islet transplantation. Access to transplantation is limited by the number of deceased donors and the necessity of immunosuppression. Future approaches might include alternative sources of islets (eg, xenogeneic tissue or human stem cells), extrahepatic sites of implantation (eg, omental, subcutaneous, or intramuscular), and induction of immune tolerance or encapsulation of islets.
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