Type 2 diabetes is characterized by impaired insulin secretion. Some but not all studies suggest that a decrease in ␤-cell mass contributes to this. We examined pancreatic tissue from 124 autopsies: 91 obese cases (BMI >27 kg/m 2 ; 41 with type 2 diabetes, 15 with impaired fasting glucose [IFG], and 35 nondiabetic subjects) and 33 lean cases (BMI <25 kg/m 2 ; 16 type 2 diabetic and 17 nondiabetic subjects). We measured relative ␤-cell volume, frequency of ␤-cell apoptosis and replication, and new islet formation from exocrine ducts (neogenesis). Relative ␤-cell volume was increased in obese versus lean nondiabetic cases (P ‫؍‬ 0.05) through the mechanism of increased neogenesis (P < 0.05). Obese humans with IFG and type 2 diabetes had a 40% (P < 0.05) and 63% (P < 0.01) deficit and lean cases of type 2 diabetes had a 41% deficit (P < 0.05) in relative ␤-cell volume compared with nondiabetic obese and lean cases, respectively. The frequency of ␤-cell replication was very low in all cases and no different among groups. Neogenesis, while increased with obesity, was comparable in obese type 2 diabetic, IFG, or nondiabetic subjects and in lean type 2 diabetic or nondiabetic subjects. However, the frequency of ␤-cell apoptosis was increased 10-fold in lean and 3-fold in obese cases of type 2 diabetes compared with their respective nondiabetic control group (P < 0.05). We conclude that ␤-cell mass is decreased in type 2 diabetes and that the mechanism underlying this is increased ␤-cell apoptosis. Since the major defect leading to a decrease in ␤-cell mass in type 2 diabetes is increased apoptosis, while new islet formation and ␤-cell replication are normal, therapeutic approaches designed to arrest apoptosis could be a significant new development in the management of type 2 diabetes, because this approach might actually reverse the disease to a degree rather than just palliate glycemia. Diabetes 52:102-110, 2003

A simulation model of the glucose-insulin system in the postprandial state can be useful in several circumstances, including testing of glucose sensors, insulin infusion algorithms and decision support systems for diabetes. Here, we present a new simulation model in normal humans that describes the physiological events that occur after a meal, by employing the quantitative knowledge that has become available in recent years. Model parameters were set to fit the mean data of a large normal subject database that underwent a triple tracer meal protocol which provided quasi-model-independent estimates of major glucose and insulin fluxes, e.g., meal rate of appearance, endogenous glucose production, utilization of glucose, insulin secretion. By decomposing the system into subsystems, we have developed parametric models of each subsystem by using a forcing function strategy. Model results are shown in describing both a single meal and normal daily life (breakfast, lunch, dinner) in normal. The same strategy is also applied on a smaller database for extending the model to type 2 diabetes.

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

1Insulin resistance increases and muscle oxidative capacity decreases during aging, but lifestyle changesespecially physical activity-may reverse these trends. Here we report the effect of a 16-week aerobic exercise program (n ‫؍‬ 65) or control activity (n ‫؍‬ 37) performed by men and women aged 21-87 years on insulin sensitivity and muscle mitochondria. Insulin sensitivity, measured by intravenous glucose tolerance test, decreased with age (r ‫؍‬ ؊0.32) and was related to abdominal fat content (r ‫؍‬ ؊0.65). Exercise increased peak oxygen uptake (VO 2peak ; 10%), activity of muscle mitochondrial enzymes (citrate synthase and cytochrome c oxidase, 45-76%) and mRNA levels of mitochondrial genes (COX4, ND4, both 66%) and genes involved in mitochondrial biogenesis (PGC-1␣, 55%; NRF-1, 15%; TFAM, 85%). Exercise also increased muscle GLUT4 mRNA and protein (30 -52%) and reduced abdominal fat (5%) and plasma triglycerides (25%). None of these changes were affected by age. In contrast, insulin sensitivity improved in younger people but not in middle-aged or older groups. Thus, the muscle mitochondrial response to 4 months of aerobic exercise training was similar in all age-groups, although the older people did not have an improvement in insulin sensitivity. Diabetes 52: 1888 -1896, 2003 T he number of people with type 2 diabetes and impaired glucose tolerance is rapidly increasing (1,2). Key factors contributing to this increase in diabetes include age, obesity, and sedentary lifestyle (3-8). Exercise is a readily available intervention that can increase insulin action (9 -14) and prevent the onset of diabetes (15-18). An important question is whether the effects of aerobic exercise on insulin action are diminished with advancing age. A recent study reported that a vigorous 7-day exercise program increased insulin sensitivity and muscle glucose transporter (GLUT4) content by a similar amount in younger (22 years) and older (61 years) people (12). However, current health and fitness guidelines for healthy adults recommend exercising at more moderate intensities at least 3 days per week over long periods (19). Thus, the first purpose of the current study was to determine whether a 4-month program of bicycle training that could be readily followed by most elderly individuals would lead to a similar improvement in insulin sensitivity in men and women across a wide age span.Skeletal muscle is the major site of insulin-mediated glucose disposal and is implicated in the pathogenesis of insulin resistance and diabetes (20,21). Several pieces of evidence suggest that insulin action may be related to the oxidative capacity of skeletal muscle. First, aerobic exercise training improves both insulin sensitivity and activity of oxidative enzymes in muscle (22,23). Second, people who are obese and insulin resistant or have type 2 diabetes tend to have lower activity of muscle oxidative enzymes (24,25). Third, insulin infusion preferentially stimulates the synthesis rate of mitochondrial proteins in skeletal muscle (26) and increa...

To determine the dose-response characteristics for the effects of insulin on glucose production, glucose utilization, and overall glucose metabolism in normal man, 15 healthy subjects were infused with insulin for 8 h at sequential rates ranging from 0.2 to 5.0 mU.kg-1.min-1; each rate was used for 2 h. Glucose production and utilization were measured isotopically ([3-3H]glucose). Tissue insulin receptor occupancy was estimated from erythrocyte insulin binding. Glucose production was completely suppressed at plasma insulin concentrations of approximately 60 microunits/ml. Maximal glucose utilization (10-11 mg.kg-1.min-1) occurred at insulin concentrations of 200-700 microunits/ml. The concentration of insulin causing half-maximal glucose utilization (55 + 7 microunits/ml) was significantly greater than that required for half-maximal suppression of glucose production (29 +/- 2 microunits/ml, P less than 0.01). Maximal effects of insulin on glucose production and utilization occurred at plasma insulin concentrations causing 11 and 49% insulin receptor occupancy, respectively. The above dose-response relationships indicate that in man 1) glucose production is more sensitive to changes in plasma insulin concentration than is glucose utilization; 2) both hepatic and peripheral tissues may contain "spare" insulin receptors; and 3) relatively minor changes in plasma insulin concentration or insulin receptor function can cause appreciable alterations in glucose metabolism.

Aims/hypothesis: Type 1 diabetes is widely held to result from an irreversible loss of insulin-secreting beta cells. However, insulin secretion is detectable in some people with long-standing type 1 diabetes, indicating either a small population of surviving beta cells or continued renewal of beta cells subject to ongoing autoimmune destruction. The aim of the present study was to evaluate these possibilities. Materials and methods: Pancreatic sections from 42 individuals with type 1 diabetes and 14 non-diabetic individuals were evaluated for the presence of beta cells, beta cell apoptosis and replication, T lymphocytes and macrophages. The presence and extent of periductal fibrosis was also quantified. Results: Beta cells were identified in 88% of individuals with type 1 diabetes. The number of beta cells was unrelated to duration of disease (range 4-67 years) or age at death (range 14-77 years), but was higher (p<0.05) in individuals with lower mean blood glucose. Beta cell apoptosis was twice as frequent in type 1 diabetes as in control subjects (p<0.001), but beta cell replication was rare in both groups. The increased beta cell apoptosis in type 1 diabetes was accompanied by both increased macrophages and T lymphocytes and a marked increase in periductal fibrosis (p<0.001), implying chronic inflammation over many years, consistent with an ongoing supply of beta cells. Conclusions/interpretation: Most people with long-standing type 1 diabetes have beta cells that continue to be destroyed. The mechanisms underlying increased beta cell death may involve both ongoing autoimmunity and glucose toxicity. The presence of beta cells despite ongoing apoptosis implies, by definition, that concomitant new beta cell formation must be occurring, even after long-standing type 1 diabetes. We conclude that type 1 diabetes may be reversed by targeted inhibition of beta cell destruction.

In order to determine whether differences in body fat distribution result in specific abnormalities of free fatty acid (FFA) metabolism, palmitate turnover, a measure of systemic adipose tissue lipolysis, was measured in 10 women with upper body obesity, 9 women with lower body obesity, and 8 nonobese women under overnight postabsorptive (basal), epinephrine stimulated and insulin suppressed conditions. Results: Upper body obese women had greater (P < 0.005) basal palmitate turnover than lower body obese or nonobese women (2.8±0.2 vs. 2.1±0.2 vs. 1.8±0.2 Mmolt kg lean body mass (LBM)-1 * min-, respectively), but a reduced (P < 0.05) net lipolytic response to epinephrine (59±7 vs. 79±5 vs. 81±7 Mmol palmitate/kg LBM, respectively). Both types of obesity were associated with impaired suppression of FFA turnover in response to euglycemic hyperinsulinemia compared to nonobese women (P < 0.005). These specific differences in FFA metabolism may reflect adipocyte heterogeneity, which may in turn affect the metabolic abberations associated with different types of obesity. These findings emphasize the need to characterize obese subjects before studies.

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.