High Fat Diet Regulation of β-Cell Proliferation and β-Cell Mass

Abstract

Type 2 Diabetes (T2D) is characterized by relative insulin insufficiency, caused when peripheral tissues such as liver, muscle, and adipocytes have a decreased response to insulin. One factor that elevates the risk for insulin resistance and T2D is obesity. In obese patients without T2D and initially in people who develop T2D, pancreatic-cells are able to compensate for insulin resistance by increasing-cell mass, effected by increased proliferation and hypertrophy, as well as increased insulin secretion per-cell. In patients that go on to develop T2D, however, this initial period of compensation is followed by-cell failure due to decreased proliferation and increased apoptosis. The forkhead box transcription factor FoxM1 is required for-cell replication in mice after four weeks of age, during pregnancy, and after partial pancreatectomy. We investigated whether it is also required for-cell proliferation due to diet-induced obesity. Type 2 diabetes (T2D) results from a relative deficit of insulin, generally due to a blunted response to insulin signaling in peripheral tissues. The risk for developing T2D is exacerbated by weight gain and the metabolic changes that accompany a high-energy diet, which include elevated blood glucose with a resulting increase in insulin levels as well as increased circulating free fatty acids (FFA). In adult humans, every 5% weight gain is associated with an approximate 20% increase in the risk of insulin resistance [1]. In the U.S., men and women gain an average of approximately 0.5-1 pound per year between the ages of 25-55 years, and thereafter lose weight [2], although this statistic masks a substantial weight gain in a large proportion of the population. Over a ten year period, 38% of men and 37% of women between the ages of 25 and 44 gain between five and 15 pounds; 10% of men and 15% of women gain between 15 and 25 pounds, and 3.5% of men and 6.5% of women gain more than 25 pounds [2]. A disturbing trend that likely contributes to high obesity rates is that those people who are overweight at baseline are more likely to gain weight within ten years than their lean counterparts [2, 3].