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      Genetic Predisposition for Type 2 Diabetes, but Not for Overweight/Obesity, Is Associated with a Restricted Adipogenesis

      1 , 1 , 2 , 2 , *

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          Development of Type 2 diabetes, like obesity, is promoted by a genetic predisposition. Although several genetic variants have been identified they only account for a small proportion of risk. We have asked if genetic risk is associated with abnormalities in storing excess lipids in the abdominal subcutaneous adipose tissue.

          Methodology/Principal Findings

          We recruited 164 lean and 500 overweight/obese individuals with or without a genetic predisposition for Type 2 diabetes or obesity. Adipose cell size was measured in biopsies from the abdominal adipose tissue as well as insulin sensitivity (HOMA index), HDL-cholesterol and Apo AI and Apo B. 166 additional non-obese individuals with a genetic predisposition for Type 2 diabetes underwent a euglycemic hyperinsulinemic clamp to measure insulin sensitivity. Genetic predisposition for Type 2 diabetes, but not for overweight/obesity, was associated with inappropriate expansion of the adipose cells, reduced insulin sensitivity and a more proatherogenic lipid profile in non-obese individuals. However, obesity per se induced a similar expansion of adipose cells and dysmetabolic state irrespective of genetic predisposition.


          Genetic predisposition for Type 2 diabetes, but not obesity, is associated with an impaired ability to recruit new adipose cells to store excess lipids in the subcutaneous adipose tissue, thereby promoting ectopic lipid deposition. This becomes particularly evident in non-obese individuals since obesity per se promotes a dysmetabolic state irrespective of genetic predisposition. These results identify a novel susceptibility factor making individuals with a genetic predisposition for Type 2 diabetes particularly sensitive to the environment and caloric excess.

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          Most cited references 10

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          Impact of obesity on metabolism in men and women. Importance of regional adipose tissue distribution.

          The distribution of adipose tissue thickness, fat cell weight (FCW), and number (FCN) were studied in four regions in randomly selected middle-aged men and women and in 930 obese individuals. Both the obese and the randomly selected men were found to have the largest adipose tissue thickness in the abdominal region. Women, however, showed a relative preponderance for the gluteal and femoral regions. FCW increased with expanding body fat up to a maximal size of approximately 0.7-0.8 micrograms/cell in each region. After this increase in FCW, a more rapid increase in FCN was found. For the same degree of relative overweight, men had higher triglyceride, fasting glucose, and insulin levels; higher sums of glucose and insulin levels during an oral glucose tolerance test; and higher blood pressure. Furthermore, elevated fasting glucose levels (greater than 7.4 mM) occurred twice as often in the males. These differences between males and females persisted even after body fat matching. A male risk profile was seen in women characterized by abdominal obesity (high waist/hip circumference ratio) as compared to women with the typical peripheral obesity. Stepwise multiple regression analyses in both women and men showed the obesity complications to be associated in a first step to waist/hip circumference or body fat and in a second to abdominal fat cell size. It may thus be concluded that: (a) In both obese and nonobese subjects, regional differences exist between the sexes with regard to adipose tissue distribution. (b) Moderate expansion of body fat is mainly due to FCW enlargement, which is subsequently followed by increased FCN. (c) Men and women with a male abdominal type of obesity are more susceptible to the effect of excess body fat on lipid and carbohydrate metabolism.
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            Adipocyte Turnover: Relevance to Human Adipose Tissue Morphology

            OBJECTIVE Adipose tissue may contain few large adipocytes (hypertrophy) or many small adipocytes (hyperplasia). We investigated factors of putative importance for adipose tissue morphology. RESEARCH DESIGN AND METHODS Subcutaneous adipocyte size and total fat mass were compared in 764 subjects with BMI 18–60 kg/m2. A morphology value was defined as the difference between the measured adipocyte volume and the expected volume given by a curved-line fit for a given body fat mass and was related to insulin values. In 35 subjects, in vivo adipocyte turnover was measured by exploiting incorporation of atmospheric 14C into DNA. RESULTS Occurrence of hyperplasia (negative morphology value) or hypertrophy (positive morphology value) was independent of sex and body weight but correlated with fasting plasma insulin levels and insulin sensitivity, independent of adipocyte volume (β-coefficient = 0.3, P < 0.0001). Total adipocyte number and morphology were negatively related (r = −0.66); i.e., the total adipocyte number was greatest in pronounced hyperplasia and smallest in pronounced hypertrophy. The absolute number of new adipocytes generated each year was 70% lower (P < 0.001) in hypertrophy than in hyperplasia, and individual values for adipocyte generation and morphology were strongly related (r = 0.7, P < 0.001). The relative death rate (∼10% per year) or mean age of adipocytes (∼10 years) was not correlated with morphology. CONCLUSIONS Adipose tissue morphology correlates with insulin measures and is linked to the total adipocyte number independently of sex and body fat level. Low generation rates of adipocytes associate with adipose tissue hypertrophy, whereas high generation rates associate with adipose hyperplasia.
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              Insulin sensitivity, insulin release and glucagon-like peptide-1 levels in persons with impaired fasting glucose and/or impaired glucose tolerance in the EUGENE2 study.

              We examined the phenotype of individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) with regard to insulin release and insulin resistance. Non-diabetic offspring (n=874; mean age 40+/-10.4 years; BMI 26.6+/-4.9 kg/m(2)) of type 2 diabetic patients from five different European Centres (Denmark, Finland, Germany, Italy and Sweden) were examined with regard to insulin sensitivity (euglycaemic clamps), insulin release (IVGTT) and glucose tolerance (OGTT). The levels of glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) were measured during the OGTT in 278 individuals. Normal glucose tolerance was found in 634 participants, while 110 had isolated IFG, 86 had isolated IGT and 44 had both IFG and IGT, i.e. about 28% had a form of reduced glucose tolerance. Participants with isolated IFG had lower glucose-corrected first-phase (0-10 min) and higher second-phase insulin release (10-60 min) during the IVGTT, while insulin sensitivity was reduced in all groups with abnormal glucose tolerance. Similarly, GLP-1 but not GIP levels were reduced in individuals with abnormal glucose tolerance. The primary mechanism leading to hyperglycaemia in participants with isolated IFG is likely to be impaired basal and first-phase insulin secretion, whereas in isolated IGT the primary mechanism leading to postglucose load hyperglycaemia is insulin resistance. Reduced GLP-1 levels were seen in all groups with abnormal glucose tolerance and were unrelated to the insulin release pattern during an IVGTT.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                12 April 2011
                : 6
                : 4
                [1 ]Department of Medicine, Karolinska Institute at Karolinska Hospital, Huddinge, Stockholm, Sweden
                [2 ]The Lundberg Laboratory for Diabetes Research, Center of Excellence for Metabolic and Cardiovascular Research, Department of Molecular and Clinical Medicine, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
                University of Tor Vergata, Italy
                Author notes

                Conceived and designed the experiments: PA US. Performed the experiments: EA AH. Analyzed the data: PA EA AH US. Contributed reagents/materials/analysis tools: PA EA AH US. Wrote the paper: PA US.

                Arner et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 5
                Research Article
                Diabetic Endocrinology
                Diabetes Mellitus Type 2



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