Aims/hypothesis Type 2 diabetes is regarded as inevitably progressive, with irreversible beta cell failure. The hypothesis was tested that both beta cell failure and insulin resistance can be reversed by dietary restriction of energy intake. Methods Eleven people with type 2 diabetes (49.5± 2.5 years, BMI 33.6±1.2 kg/m 2 , nine male and two female) were studied before and after 1, 4 and 8 weeks of a 2.5 MJ (600 kcal)/day diet. Basal hepatic glucose output, hepatic and peripheral insulin sensitivity and beta cell function were measured. Pancreas and liver triacylglycerol content was measured using three-point Dixon magnetic resonance imaging. An age-, sex- and weight-matched group of eight non-diabetic participants was studied. Results After 1 week of restricted energy intake, fasting plasma glucose normalised in the diabetic group (from 9.2± 0.4 to 5.9±0.4 mmol/l; p=0.003). Insulin suppression of hepatic glucose output improved from 43±4% to 74±5% (p= 0.003 vs baseline; controls 68±5%). Hepatic triacylglycerol content fell from 12.8±2.4% in the diabetic group to 2.9± 0.2% by week 8 (p=0.003). The first-phase insulin response increased during the study period (0.19±0.02 to 0.46± 0.07 nmol min �1 m �2 ; p<0.001) and approached control

/pdf/reversal-of-type-2-diabetes-normalisation-of-beta-cell-1xoh4salsw.pdf

Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol

OBJECTIVE— Little is known about the capacity, mechanisms, or timing of growth in β-cell mass in humans. We sought to establish if the predominant expansion of β-cell mass in humans occurs in early childhood and if, as in rodents, this coincides with relatively abundant β-cell replication. We also sought to establish if there is a secondary growth in β-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 ) β-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 β-cell growth is highest in infancy and gradually declines thereafter to adulthood with no secondary accelerated growth phase during adolescence, 4 ) β-cell mass (and presumably growth) is highly variable between individuals, and 5 ) a high rate of β-cell replication is coincident with the major postnatal expansion of β-cell mass. CONCLUSIONS— These data imply that regulation of β-cell replication during infancy plays a major role in β-cell mass in adult humans.

https://diabetes.diabetesjournals.org/content/diabetes/57/6/1584.full.pdf

β-Cell Replication Is the Primary Mechanism Subserving the Postnatal Expansion of β-Cell Mass in Humans

OBJECTIVE. The purpose of this study was to assess which of a number of methods of measuring attenuation on CT scans is best for prediction of hepatic fat content.MATERIALS AND METHODS. This retrospective study was approved by our institutional review board. Consecutively registered patients who underwent liver resection for metastatic disease formed the study group. Attenuation measurements were obtained from 12 regions of interest in the liver and three in the spleen on both unenhanced and portal phase contrast-enhanced preoperative hepatic CT images. Hepatic attenuation measurements were analyzed both with and without normalization with the spleen. Normalization included both differences and ratios between hepatic and splenic attenuation values. Pathologic fat content was graded semiquantitatively as a percentage of the nonneoplastic liver parenchyma of the resected specimen. Average attenuation values of the liver were compared with pathologic fat content, as were the differences and ratios between he...

https://www.ajronline.org/doi/pdfplus/10.2214/AJR.06.0992

Comparison of CT Methods for Determining the Fat Content of the Liver

OBJECTIVE —Insulin resistance, associated with increased lipolysis, results in a high exposure of nonadipose tissue to lipids. Experimental data indicate that fatty infiltration of pancreatic islets may also contribute to β-cell dysfunction, but whether this occurs in humans in vivo is unknown. RESEARCH DESIGN AND METHODS —Using proton magnetic resonance spectroscopy and oral glucose tolerance tests, we studied the association of pancreatic lipid accumulation in vivo and various aspects of β-cell function in 12 insulin-naive type 2 diabetic and 24 age- and BMI-matched nondiabetic men. RESULTS —Patients versus control subjects had higher A1C, fasting plasma glucose, and insulin and triglyceride levels and lower HDL cholesterol, but similar waist circumference. Median (interquartile range) pancreatic fat content in patients and control subjects was 20.4% (13.4–43.6) and 9.7% (7.0–20.2), respectively ( P = 0.032). Pancreatic fat correlated negatively with β-cell function parameters, including the insulinogenic index adjusted for insulin resistance, early glucose-stimulated insulin secretion, β-cell glucose sensitivity, and rate sensitivity (all P P P = 0.006). CONCLUSIONS —These findings indicate that pancreatic lipid content may contribute to β-cell dysfunction and possibly to the subsequent development of type 2 diabetes in susceptible humans.

https://care.diabetesjournals.org/content/diacare/30/11/2916.full.pdf

Pancreatic Fat Content and β-Cell Function in Men With and Without Type 2 Diabetes

OBJECTIVE We 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 METHODS We 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. RESULTS β-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. CONCLUSIONS β-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.

/pdf/b-cell-mass-and-turnover-in-humans-effects-of-obesity-and-m0o3r46e73.pdf

β-Cell Mass and Turnover in Humans: Effects of obesity and aging

Our 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 +/- 25.8 cm(3) total; 44.5 +/- 16.5 cm(3) parenchyma) and then declines thereafter. In adults, total ( approximately 32%), parenchymal ( approximately 13%), and fat ( approximately 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.

/pdf/pancreas-volumes-in-humans-from-birth-to-age-one-hundred-1e2hs5jool.pdf

M. Allen-Auerbach

Papers

Pancreas volumes in humans from birth to age one hundred taking into account sex, obesity, and presence of type-2 diabetes