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The prevalence of diabetes mellitus (DM) increased by 49% between 1990 and 2000, reaching nearly epidemic proportions. In 2010, DM (type 1 or 2) was estimated to affect nearly 30% (10.9 million) of people 65 years and older and 215,000 of those younger than 20 years. Macrovascular and microvascular complications can occur; DM is a major cause of heart disease and stroke, and is the seventh leading cause of death in the United States. Based on 2007 data, the economic impact of DM is considerable, with total costs, direct medical costs, and indirect costs estimated at $174 billion, $116 billion, and $58 billion, respectively. Normal glucose regulation is maintained by an intricate interaction between pancreatic β-cells (insulin/amylin), pancreatic α-cells (glucagon), and associated organs (eg, intestines, liver, skeletal muscle, adipose tissue). Newly elucidated mechanisms include the involvement of the kidneys in glucose regulation, as well as central glucose regulation by the brain. The central defects in type 2 diabetes mellitus (T2DM) are decreased insulin secretion, glucoregulatory hormone deficiency/resistance, and insulin resistance, resulting in abnormal glucose homeostasis. This article provides an extensive review of mechanisms involved in physiologic blood glucose regulation and imbalances in glucose homeostasis.

While not traditionally discussed, the kidneys' contributions to maintaining glucose homeostasis are significant and include such functions as release of glucose into the circulation via gluconeogenesis, uptake of glucose from the circulation to satisfy their energy needs, and reabsorption of glucose at the level of the proximal tubule. Renal release of glucose into the circulation is the result of glycogenolysis and gluconeogenesis, respectively involving the breaking down and formation of glucose-6-phosphate from precursors (eg, lactate, glycerol, amino acids). With regard to renal reabsorption of glucose, the kidneys normally retrieve as much glucose as possible, rendering the urine virtually glucose free. The glomeruli filter from plasma approximately 180 grams of D-glucose per day, all of which is reabsorbed through glucose transporter proteins that are present in cell membranes within the proximal tubules. If the capacity of these transporters is exceeded, glucose appears in the urine. The process of renal glucose reabsorption is mediated by active (sodium-coupled glucose cotransporters) and passive (glucose transporters) transporters. In hyperglycemia, the kidneys may play an exacerbating role by reabsorbing excess glucose, ultimately contributing to chronic hyperglycemia, which in turn contributes to chronic glycemic burden and the risk of microvascular consequences. This article provides an extensive review of the kidneys' role in normal human physiology, the mechanisms by which they contribute to glucose regulation, and the potential impact of glucose imbalance on the kidneys.

Although there are numerous effective pharmacotherapeutic agents available to treat type 2 diabetes, 5% to 10% of the population with diabetes experience secondary failure. To help combat this issue, it is imperative that clinicians understand the limitations of some current therapies. Secondary failure can be due to decreasing beta cell function, poor adherence to treatment, weight gain, reduction of exercise, changes in diet, or illness. Glycemic control and cardiovascular risk reduction are of paramount concern; however, the nonglycemic effects of several new therapies to treat diabetes may be advantageous and positively affect the long-term cost of therapy. The discoveries of amylin and glucagonlike peptide-1 have furthered our understanding of the abnormalities involved in diabetes, enabling the development of additional therapeutic options. Incretin-based therapy, including incretin mimetics such as exenatide and the yet-to-be-approved dipeptidyl peptidase-4 inhibitors, and new basal and inhaled insulin may change the way we currently treat type 2 diabetes.