RESUMO
We evaluated the potential for a monoclonal antibody antagonist of the glucagon receptor (Ab-4) to maintain glucose homeostasis in type 1 diabetic rodents. We noted durable and sustained improvements in glycemia which persist long after treatment withdrawal. Ab-4 promoted ß-cell survival and enhanced the recovery of insulin+ islet mass with concomitant increases in circulating insulin and C peptide. In PANIC-ATTAC mice, an inducible model of ß-cell apoptosis which allows for robust assessment of ß-cell regeneration following caspase-8-induced diabetes, Ab-4 drove a 6.7-fold increase in ß-cell mass. Lineage tracing suggests that this restoration of functional insulin-producing cells was at least partially driven by α-cell-to-ß-cell conversion. Following hyperglycemic onset in nonobese diabetic (NOD) mice, Ab-4 treatment promoted improvements in C-peptide levels and insulin+ islet mass was dramatically increased. Lastly, diabetic mice receiving human islet xenografts showed stable improvements in glycemic control and increased human insulin secretion.
Assuntos
Anticorpos Monoclonais/farmacologia , Diabetes Mellitus Experimental/terapia , Células Secretoras de Glucagon/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Receptores de Glucagon/antagonistas & inibidores , Animais , Glicemia/metabolismo , Peptídeo C/metabolismo , Linhagem da Célula/efeitos dos fármacos , Transdiferenciação Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/terapia , Expressão Gênica , Glucagon/antagonistas & inibidores , Glucagon/metabolismo , Células Secretoras de Glucagon/metabolismo , Células Secretoras de Glucagon/patologia , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/fisiologia , Transplante das Ilhotas Pancreáticas , Camundongos , Camundongos Endogâmicos NOD , Tamanho do Órgão/efeitos dos fármacos , Receptores de Glucagon/genética , Receptores de Glucagon/metabolismo , Resultado do TratamentoRESUMO
AIMS: Insulin is lipogenic and may invoke inflammation. We wished to determine if well controlled human and mice with type 1 diabetes had iatrogenic hyperinsulinemia as an explanation for the increased rate of coronary artery disease (CAD) in type 1 diabetes. METHODS: Type 1 diabetic subjects with HbA1C less than 7.0% had plasma insulin measured before and one hour after a Boost® challenge and a dose of subcutaneously administered insulin. These levels were compared with non-diabetic humans. Plasma insulin levels in well controlled NOD mice with type 1 diabetes were measured 3 h and 17 h after their usual dose of insulin. Hepatic cholesterol-relevant CAD and inflammation markers were measured in the NOD mice. RESULT: Marked iatrogenic hyperinsulinemia was observed in patients at levels of approximately two times higher than in non-diabetic controls. Similar findings were present in the NOD mice. Hepatic CAD risk markers were increased by insulin, but did not exceed normal expression levels in non-diabetic mice with lower insulin. In contrast, insulin-mediated stimulation of pro-inflammatory mediators TNF-α and IL-1ß remained significantly higher in hyperinsulinemic NOD than non-diabetic mice. CONCLUSION: Optimal insulin therapy in mice and humans with type 1 diabetes causes iatrogenic hyperinsulinemia and subsequently promotes pro-inflammatory macrophage response independent of hepatic cholesterol-relevant CAD markers. The tight glycemic control in type 1 diabetes may thus increase the risk for atherogenesis via inflammation.