OBJECTIVE-Little is known about the capacity, mechanisms, or timing of growth in ␤-cell mass in humans. We sought to establish if the predominant expansion of ␤-cell mass in humans occurs in early childhood and if, as in rodents, this coincides with relatively abundant ␤-cell replication. We also sought to establish if there is a secondary growth in ␤-cell mass coincident with the accelerated somatic growth in adolescence.RESEARCH DESIGN AND METHODS-To address these questions, pancreas volume was determined from abdominal computer tomographies in 135 children aged 4 weeks to 20 years, and morphometric analyses were performed in human pancreatic tissue obtained at autopsy from 46 children aged 2 weeks to 21 years.RESULTS-We report that 1) ␤-cell mass expands by severalfold from birth to adulthood, 2) islets grow in size rather than in number during this transition, 3) the relative rate of ␤-cell growth is highest in infancy and gradually declines thereafter to adulthood with no secondary accelerated growth phase during adolescence, 4) ␤-cell mass (and presumably growth) is highly variable between individuals, and 5) a high rate of ␤-cell replication is coincident with the major postnatal expansion of ␤-cell mass.CONCLUSIONS-These data imply that regulation of ␤-cell replication during infancy plays a major role in ␤-cell mass in adult humans. Diabetes 57:1584-1594, 2008

4Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MinnesotaOur aims were (1) by computed tomography (CT) to establish a population database for pancreas volume (parenchyma and fat) from birth to age 100 years, (2) in adults, to establish the impact of gender, obesity, and the presence or absence of type-2 diabetes on pancreatic volume (parenchyma and fat), and (3) to confirm the latter histologically from pancreatic tissue obtained at autopsy with a particular emphasis on whether pancreatic fat is increased in type-2 diabetes. We measured pancreas volume in 135 children and 1,886 adults (1,721 nondiabetic and 165 with type-2 diabetes) with no history of pancreas disease who had undergone abdominal CT scan between 2003 and 2006. Pancreas volume was computed from the contour of the pancreas on each CT image. In addition to total pancreas volume, parenchymal volume, fat volume, and fat/parenchyma ratio (F/P ratio) were determined by CT density. We also quantified pancreatic fat in autopsy tissue of 47 adults (24 nondiabetic and 23 with type-2 diabetes). During childhood and adolescence, the volumes of total pancreas, pancreatic parenchyma, and fat increase linearly with age. From age 20-60 years, pancreas volume reaches a plateau (72.4 6 25.8 cm 3 total; 44.5 6 16.5 cm 3 parenchyma) and then declines thereafter. In adults, total (*32%), parenchymal (*13%), and fat (*68%) volumes increase with obesity. Pancreatic fat content also increases with aging but is not further increased in type-2 diabetes. We provide lifelong population data for total pancreatic, parenchymal, and fat volumes in humans. Although pancreatic fat increases with aging and obesity, it is not increased in type-2 diabetes. Clin. Anat. 20:933-942, 2007. V V C 2007 Wiley-Liss, Inc.

OBJECTIVEWe sought to establish β-cell mass, β-cell apoptosis, and β-cell replication in humans in response to obesity and advanced age.RESEARCH DESIGN AND METHODSWe examined human autopsy pancreas from 167 nondiabetic individuals 20–102 years of age. The effect of obesity on β-cell mass was examined in 53 lean and 61 obese subjects, and the effect of aging was examined in 106 lean subjects.RESULTSβ-Cell mass is increased by ∼50% with obesity (from 0.8 to 1.2 g). With advanced aging, the exocrine pancreas undergoes atrophy but β-cell mass is remarkably preserved. There is minimal β-cell replication or apoptosis in lean humans throughout life with no detectable changes with obesity or advanced age.CONCLUSIONSβ-Cell mass in human obesity increases by ∼50% by an increase in β-cell number, the source of which is unknown. β-Cell mass is well preserved in humans with advanced aging.

Metformin is an oral hypoglycemic agent which is most widely used as first-line therapy for type 2 diabetes. Metformin improves hyperglycemia by suppressing hepatic glucose production and increasing glucose uptake in muscle. Metformin also has been shown to reduce cardiovascular events in randomized controlled trials; however, the underlying mechanism remains to be established. Recent preclinical and clinical studies have suggested that metformin not only improves chronic inflammation through the improvement of metabolic parameters such as hyperglycemia, insulin resistance and atherogenic dyslipidemia, but also has a direct anti-inflammatory action. Studies have suggested that metformin suppresses inflammatory response by inhibition of nuclear factor κB (NFκB) via AMP-activated protein kinase (AMPK)-dependent and independent pathways. This review summarizes the basic and clinical evidence of the anti-inflammatory action of metformin and discusses its clinical implication.

Type 2 diabetes (T2DM) is characterized by insulin resistance and β-cell dysfunction. Although, in contrast to type 1 diabetes, insulin resistance is assumed to be a major pathophysiological feature of T2DM, T2DM never develops unless β-cells fail to compensate insulin resistance. Recent studies have revealed that a deficit of β-cell functional mass is an essential component of the pathophysiology of T2DM, implying that β-cell deficit is a common feature of both type 1 and type 2 diabetes. β-cell dysfunction is present at the diagnosis of T2DM and progressively worsens with disease duration. β-cell dysfunction is associated with worsening of glycemic control and treatment failure; thus, it is important to preserve or recover β-cell functional mass in the management of T2DM. Since β-cell regenerative capacity appears somewhat limited in humans, reducing β-cell workload appears to be the most effective way to preserve β-cell functional mass to date, underpinning the importance of lifestyle modification and weight loss for the treatment and prevention of T2DM. This review summarizes the current knowledge on β-cell functional mass in T2DM and discusses the treatment strategy for T2DM.