Glucose homeostasis
VII. Gastrointestinal tract
A number of hormones secreted by neuroendocrine cells in the GI tract play a role in glucose homeostasis. The incretins glucagonlike peptide 1 (GLP-1) and glucose- dependent insulinotropic polypeptide (GIP) amplify glucose-stimulated insulin secretion and suppress glucagon secretion.5,6 In individuals with T2DM, there is a reduced GLP-1 effect as well as resistance to the action of GIP, resulting in decreased secretion of insulin.6 Ghrelin, produced predominantly by the stomach, plays a regulatory role in insulin secretion and may be diabetogenic.18 The transporter SGLT-1 is responsible for absorption of glucose in the small intestine.9,23 A receptor for sweet-tasting compounds is also expressed in the GI tract, where it is involved in intestinal absorption, metabolic regulation, and glucose homeostasis.24 Changes in gut microbiota may lead to low-grade inflammation, which in turn leads to development of insulin resistance.25 Therapies targeting the GI tract include -glucosidase inhibitors, which slow intestinal carbohydrate digestion and absorption, and biguanides, which reduce glucose absorption.17 VIII. Adipocytes
Adipocytes also play a pivotal role in glucose homeostasis and hyperglycemia. Obesity, particularly in the abdomen, is thought to contribute to the pathogenesis of T2DM.5 Hypertrophied adipocytes become insulin-resistant, and their capacity to store fat is diminished.6,26 January 2013
Moreover, obesity induces a release of proinflammatory cytokines from hypertrophied adipocytes and inflammatory cells, leading to impaired insulin signaling.25 Adipocytes also secrete free fatty acids—which impair glucose utilization in skeletal muscle, promote glucose production by the liver, and impair -cell function—and adipokines—which can cause insulin resistance in skeletal muscle and the liver.5,25 The biguanides and thiazolidinediones increase peripheral insulin sensitivity in patients with T2DM.17 Unmet needs in the management of diabetes
Early therapeutic intervention is important in T2DM to preserve -cell function, increase insulin sensitivity, and prevent micro- and macrovascular complications.7 A number of organs and tissues that play key roles in the regulation of glucose homeostasis in healthy individuals, as well as in the dysfunctional glucose homeostasis exhibited in individuals with T2DM, are targets for current and emerging therapies. Most of the currently available non-insulin pharmacologic interventions—which can be used alone or in combination to target key organs and tissues—generally rely on residual insulin signaling to be effective.27 Multiple agents are currently available to improve glycemic control in patients for whom diet and exercise alone are insufficient; however, many patients with T2DM still do not achieve their treatment goals.2,3 Emerging data regarding novel pathophysiologic mechanisms responsible for glucose homeostasis may point to new treatment options in T2DM. These could potentially include pharmacologic targeting of key organs and tissues with mechanisms dissociated from insulin and pancreatic function. ■