Dataset Information

Targeting the Pancreatic α-Cell to Prevent Hypoglycemia in Type 1 Diabetes.

ABSTRACT: Life-threatening hypoglycemia is a limiting factor in the management of type 1 diabetes. People with diabetes are prone to develop hypoglycemia because they lose physiological mechanisms that prevent plasma glucose levels from falling. Among these so-called counterregulatory responses, secretion of glucagon from pancreatic α-cells is preeminent. Glucagon, a hormone secreted in response to a lowering in glucose concentration, counteracts a further drop in glycemia by promoting gluconeogenesis and glycogenolysis in target tissues. In diabetes, however, α-cells do not respond appropriately to changes in glycemia and, thus, cannot mount a counterregulatory response. If the α-cell could be targeted therapeutically to restore its ability to prevent hypoglycemia, type 1 diabetes could be managed more efficiently and safely. Unfortunately, the mechanisms that allow the α-cell to respond to hypoglycemia have not been fully elucidated. We know even less about the pathophysiological mechanisms that cause α-cell dysfunction in diabetes. Based on published findings and unpublished observations, and taking into account its electrophysiological properties, we propose here a model of α-cell function that could explain its impairment in diabetes. Within this frame, we emphasize those elements that could be targeted pharmacologically with repurposed U.S. Food and Drug Administration-approved drugs to rescue α-cell function and restore glucose counterregulation in people with diabetes.

SUBMITTER: Panzer JK

PROVIDER: S-EPMC8660986 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Targeting the Pancreatic α-Cell to Prevent Hypoglycemia in Type 1 Diabetes.

Panzer Julia K JK Caicedo Alejandro A

Diabetes 20211201 12

Life-threatening hypoglycemia is a limiting factor in the management of type 1 diabetes. People with diabetes are prone to develop hypoglycemia because they lose physiological mechanisms that prevent plasma glucose levels from falling. Among these so-called counterregulatory responses, secretion of glucagon from pancreatic α-cells is preeminent. Glucagon, a hormone secreted in response to a lowering in glucose concentration, counteracts a further drop in glycemia by promoting gluconeogenesis and ...[more]

PMID: 34872936

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Project description:Background and objectivesAmong people with diabetes mellitus, CKD may promote hypoglycemia through altered clearance of glucose-lowering medications, decreased kidney gluconeogenesis, and blunted counter-regulatory response. We conducted a prospective observational study of hypoglycemia among 105 individuals with type 2 diabetes treated with insulin or a sulfonylurea using continuous glucose monitors.Design, setting, participants & measurementsWe enrolled 81 participants with CKD, defined as eGFR<60 ml/min per 1.73 m2, and 24 control participants with eGFR?60 ml/min per 1.73 m2 frequency-matched on age, duration of diabetes, hemoglobin A1c, and glucose-lowering medications. Each participant wore a continuous glucose monitor for two 6-day periods. We examined rates of sustained level 1 hypoglycemia (<70 mg/dl) and level 2 hypoglycemia (<54 mg/dl) among participants with CKD. We then tested differences compared with control participants as well as a second control population (n=73) using Poisson and linear regression, adjusting for age, sex, and race.ResultsOver 890 total days of continuous glucose monitoring, participants with CKD were observed to have 255 episodes of level 1 hypoglycemia, of which 68 episodes reached level 2 hypoglycemia. Median rate of hypoglycemic episodes was 5.3 (interquartile range, 0.0-11.7) per 30 days and mean time spent in hypoglycemia was 28 (SD 37) minutes per day. Hemoglobin A1c and the glucose management indicator were the main clinical correlates of time in hypoglycemia (adjusted differences 6 [95% confidence interval, 2 to 10] and 13 [95% confidence interval, 7 to 20] fewer minutes per day per 1% higher hemoglobin A1c or glucose management indicator, respectively). Compared with control populations, participants with CKD were not observed to have significant differences in time in hypoglycemia (adjusted differences 4 [95% confidence interval, -12 to 20] and -12 [95% confidence interval, -29 to 5] minutes per day).ConclusionsAmong people with type 2 diabetes and moderate to severe CKD, hypoglycemia was common, particularly with tighter glycemic control, but not significantly different from groups with similar clinical characteristics and preserved eGFR.

Project description:Aims/hypothesisIndividuals with longstanding and recent-onset type 1 diabetes have a smaller pancreas. Since beta cells represent a very small portion of the pancreas, the loss of pancreas volume in diabetes is primarily due to the loss of pancreatic exocrine mass. However, the structural changes in the exocrine pancreas in diabetes are not well understood.MethodsTo characterise the pancreatic endocrine and exocrine compartments in diabetes, we studied pancreases from adult donors with type 1 diabetes compared with similarly aged donors without diabetes. Islet cell mass, islet morphometry, exocrine mass, acinar cell size and number and pancreas fibrosis were assessed by immunohistochemical staining. To better understand possible mechanisms of altered pancreas size, we measured pancreas size in three mouse models of insulin deficiency.ResultsPancreases from donors with type 1 diabetes were approximately 45% smaller than those from donors without diabetes (47.4 ± 2.6 vs 85.7 ± 3.7 g), independent of diabetes duration or age of onset. Diabetic donor pancreases had decreased beta cell mass (0.061 ± 0.025 vs 0.94 ± 0.21 g) and reduced total exocrine mass (42.0 ± 4.9 vs 96.1 ± 6.5 g). Diabetic acinar cells were similar in size but fewer in number compared with those in pancreases from non-diabetic donors (63.7 ± 8.1 × 109 vs 121.6 ± 12.2 × 109 cells/pancreas), likely accounting for the difference in pancreas size. Within the type 1 diabetes exocrine tissue, there was a greater degree of fibrosis. The pancreases in three mouse models of insulin deficiency were similar in size to those in control mice.Conclusions/interpretationPancreases from donors with type 1 diabetes are smaller than normal donor pancreases because exocrine cells are fewer in number rather than smaller in size; these changes occur early in the disease process. Our mouse data suggest that decreased pancreas size in type 1 diabetes is not directly caused by insulin deficiency, but the precise mechanism responsible remains unclear.

Dataset Information

Targeting the Pancreatic α-Cell to Prevent Hypoglycemia in Type 1 Diabetes.

Publications

Targeting the Pancreatic α-Cell to Prevent Hypoglycemia in Type 1 Diabetes.

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