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INTRODUCTION

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Diabetes mellitus is a spectrum of common metabolic disorders, arising from a variety of pathogenic mechanisms, all resulting in hyperglycemia. The number of individuals with diabetes is rising rapidly throughout the world. Both genetic and environmental factors contribute to its pathogenesis, which involves insufficient insulin secretion, reduced responsiveness to endogenous or exogenous insulin, increased glucose production, and/or abnormalities in fat and protein metabolism. The resulting hyperglycemia may lead to both acute symptoms and metabolic abnormalities. However, the major sources of the morbidity of diabetes are the chronic complications that arise from prolonged hyperglycemia, including retinopathy, neuropathy, nephropathy, and cardiovascular disease. Fortunately, these chronic complications can be mitigated in many patients by sustained control of the blood glucose. There are now a wide variety of treatment options for hyperglycemia that target different processes involved in glucose regulation or dysregulation.

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Following a brief review of glucose homeostasis and the pathogenesis of diabetes, this chapter discusses the general approaches and specific agents used in the therapy of diabetes. The last section describes agents used for hypoglycemia.

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PHYSIOLOGY OF GLUCOSE HOMEOSTASIS

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Regulation of Blood Glucose. In healthy humans, blood glucose is tightly maintained despite wide fluctuations in glucose consumption, utilization, and production. The maintenance of glucose homeostasis, generally termed glucose tolerance, is a highly developed systemic process involving the integration of several major organs through multilayered communication (Figure 43–1). Although endocrine control of blood glucose, primarily through the actions of insulin, is of central importance, myriad levels of inter-organ communication, via other hormones, nerves, local factors and substrates, also play a vital role. The pancreatic β cell is central in this homeostatic process, adjusting the amount of insulin secreted very precisely to promote glucose uptake after meals and to regulate glucose output from the liver during fasting.

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Figure 43–1.

Insulin, glucagon, and glucose homeostasis. A. Fasting State–In healthy humans plasma glucose is maintained in a range from 4.4-5 mM, and fatty acids near 400 μM. In the absence of nutrient absorption from the GI tract, glucose is supplied primarily from the liver and fatty acids from adipose tissue. With fasting, plasma insulin levels are low, and plasma glucagon is elevated, contributing to increased hepatic glycogenolysis and gluconeogenesis; low insulin also releases adipocytes from inhibition, permitting increased lipogenesis. Most tissues oxidize primarily fatty acids during fasting, sparing glucose for use by the CNS. B. Prandial State–During feeding, nutrient absorption causes an increases in plasma glucose, resulting in release of incretins from the gut and neural stimuli that promote insulin secretion. Under the control of insulin, the liver, sekletal muscle and adipose tissue actively take up glucose. Hepatic glucose production and lipolysis are inhibited, and total body glucose oxidation increases. The brain senses plasma glucose concentrations and provides regulatory inputs contributing to fuel homeostasis. The boldness of the arrows reflects relative intensity of action; a dashed line indicates little or no activity.

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