Pathophysiology of Type 2 Diabetes and Modes of Action of Therapeutic Interventions

Abstract

At least 90% of the 12 to 15 million persons with diabetes mellitus in the United States, half of whose condition remains undiagnosed, have type 2 diabetes. Type 2 diabetes is preceded by a long period of impaired glucose tolerance, a reversible metabolic state associated with increased prevalence of macrovascular complications. Thus, at the time of diagnosis, long-term complications have developed in almost one fourth of patients. Susceptibility to type 2 diabetes requires genetic (most likely polygenic) and acquired factors, and its pathogenesis involves an interplay of progressive insulin resistance and beta-cell failure. The ideal treatment of type 2 diabetes should reverse insulin resistance and beta-cell dysfunction in most treated patients and prevent, delay, or reverse long-term complications. Current strategies are aimed at amelioration of insulin resistance (diet, exercise, weight loss, and metformin and troglitazone therapy), augmentation of insulin supply (sulfonylurea and insulin therapy), or limitation of postprandial hyperglycemia (acarbose therapy). Future therapies probably will target (1) insulin resistance, using a multifaceted approach; (2) hepatic glucose production, using gluconeogenesis inhibitors; (3) excess nonesterified fatty acid production, using lipolysis inhibitors; and (4) fat oxidation, using carnitine palmitoyltransferase I and II inhibitors. Attempts also could be made to stimulate energy expenditure and increase nonoxidative glucose disposal by means of beta 3-adrenoceptor agonists. One promising strategy is an attack on multiple pathophysiological processes by combining antidiabetic agents with disparate mechanisms of action. Thus, we now have unprecedented resources for drug therapy for diabetes, with great opportunity for innovative combinations. It is hoped that these expanded choices will provide the tools necessary for a more efficient management of type 2 diabetes and prevention of its long-term complications.

Comorbidities of Diabetes and Hypertension: Mechanisms and Approach to Target Organ Protection

“…3,5,6 In addition, hyperglycemia promotes the formation of toxic advanced glycated end products and induces glomerular hyperfiltration, aberrant growth factor expression, and free radical damage from reactive oxygen species. [7][8][9][10][11][12][13] The pathogenesis of macrovascular disease is mutifactorial, with significant contributions from dyslipidemia, hypertension, hyperglycemia, insulin resistance, dysfibrinolysis, obesity, and lifestyle factors such as sedentary habits and smoking. 14 The basic atherosclerosis processes leading to coronary, cerebrovascular, or peripheral vascular disease are similar in all patients, but those with hypertension and diabetes appear to have accelerated development of advanced lesions.…”

Current Therapies and Emerging Targets for the Treatment of Diabetes

“…The use of current combination therapies has been reviewed [272]. Of equal importance to glycemic control is the regulation of the peripheral metabolic side effects of hyperglycemia.…”

Atypical Antipsychotic Drug Use and Diabetes

“…Individuals with abdominal obesity, hypertension, dyslipidemia, or glucose intolerance and those with a family history of type II diabetes mellitus are at higher risk of having insulin resistance. Defects leading to insulin resistance may occur at prereceptor (circulating antagonists or abnormal circulating form of insulin), receptor (decreased receptor number or affinity), or postreceptor (abnormal signal transduction and phosphorylation or decreased glucose transport protein molecules) levels [79]. Henderson et al [9]postulated that AAP drugs might induce glucose metabolism abnormality at the postreceptor level.…”