The physiologic effects of insulin on carbohydrate metabolism in health in general and in diabetes are well known. Less understood, but far more intriguing, are the extrapancreatic effects of insulin that go beyond glycemic control to help sense, integrate, and maintain energy balance. Virtually every organ, including the brain, is a target for insulin action. When exogenous insulin is administered directly into the brains of experimental animals, the net effect is anorectic; however, patients with type 2 diabetes who transition to insulin therapy often gain weight—a tendency that opposes good glycemic control and overall therapeutic goals. After the brief review of extrapancreatic insulin-signaling pathways presented here, the physiologic impact of developing insulin resistance in relation to body weight is considered. Attention is then focused on insulin detemir, a long-acting insulin analog that has consistently been associated with less weight gain than conventional formulations such as neutral protamine Hagedorn insulin. Mechanisms offered to explain this effect include the lower incidence of hypoglycemia and less within-patient variability associated with insulin detemir; however, recent observations and considerations of insulin-signaling pathways have shed light on other important properties of insulin detemir that may impart these weight-neutral effects. Namely, albumin binding, faster transport across the blood-brain barrier, and preferential activity in brain and liver are characteristics of insulin detemir that potentially explain the observed weight benefit seen in clinical trials, as well as in the real-world practice setting.