Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future

Abstract

Normal regulation of glucose metabolism is determined by a feedback loop involving the islet β-cell and insulin-sensitive tissues in which tissue sensitivity to insulin determines the magnitude of the β-cell response. When insulin resistance is present, the β-cell maintains normal glucose tolerance by increasing insulin output. It is only when the β-cell is incapable of releasing sufficient insulin in the presence of insulin resistance that glucose levels rise. While β-cell dysfunction has a clear genetic component, environmental changes play a vital role. Modern approaches have also informed regarding the importance of hexoses, amino acids and fatty acids in determining insulin resistance and β-cell dysfunction as well as the potential role of alterations in the microbiome. A number of new treatment approaches have been developed, but more effective therapies that slow the progressive loss of β-cell function are needed. Recent clinical trials have provided important information regarding approaches to prevent and treat type 2 diabetes as well as some of the adverse effects of these interventions. However, additional long-term studies of medications and bariatric surgery are required in order to identify novel approaches to prevention and treatment, thereby reducing the deleterious impact of type 2 diabetes.

Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion

“…These factors favour low grade tissue inflammation and insulin resistance [10][11][12][13][14]. The ultimate cause of hyperglycaemia, however, is insufficient insulin secretion as a consequence of impaired glucoseinduced insulin secretion (GIIS), dedifferentiated beta cells or beta cell apoptosis [15][16][17][18][19][20].…”

Effects of Glucocorticoid Treatment on β- and α-Cell Mass in Japanese Adults With and Without Diabetes

“…b-Cell dysfunction is a hallmark of both T1DM and T2DM (27). It has been reported that BCM is decreased by .90% and by 30% to 65% in patients with T1DM (1) and T2DM (2,11,(28)(29)(30)(31), respectively, suggesting that deficits of both b-cell function and BCM, collectively called "b-cell functional mass," are a core pathogenetic feature of diabetes.…”

“…These findings suggest that, unlike T1DM and T2DM, the development of GC-induced diabetes is mainly associated with insulin resistance and/or b-cell dysfunction, but not necessarily a deficit of BCM. This may explain why patients with GC-induced diabetes often achieve complete remission after withdrawal of GC administration (21), whereas patients with T2DM rarely achieve its remission (27).…”

Drugs for the Treatment of Type II Diabetes: A Visit to the Past and a Look to the Future

“…1,2 Nestes indivíduos, diversos mecanismos estão conhecidamente associados ao estabelecimento da resistência à insulina, incluindo a predisposição genética, a glicotoxicidade, a lipotoxicidade, o estresse oxidativo e o estabelecimento de um quadro inflamatório generalizado, caracterizando o diabetes tipo II como um distúrbio endócrino, metabólico e inflamatório crônico e sistêmico, de natureza complexa e multifatorial. 5,6 A hiperglicemia associada ao diabetes representa um grave fator de risco para complicações microvasculares e macrovasculares, incluindo a retinopatia, a neuropatia e a nefropatia, e está também relacionada ao rápido avanço de diversas doenças cardiovasculares. 7…”

“…17 O fármaco 1 era, à época, o menos popular, devido à menor potência hipoglicemiante. Porém, na década de 1970, a fenformina (5) e a buformina (6) foram retiradas do mercado pela indução de acidose lática fatal e grave dano renal. Por apresentar um perfil de segurança bastante superior, a metformina (1) é a única biguanida atualmente empregada como fármaco antidiabético.…”