The aromatase-knockout (ArKO) mouse provides a useful model to examine the role that estrogens play in development and homeostasis in mammals. Lacking a functional Cyp19 gene, which encodes aromatase, the ArKO mouse cannot synthesize endogenous estrogens. We examined the adipose depots of male and female ArKO mice, observing that these animals progressively accumulate significantly more intraabdominal adipose tissue than their wild-type (WT) littermates, reflected in increased adipocyte volume at gonadal and infrarenal sites. This increased adiposity was not due to hyperphagia or reduced resting energy expenditure, but was associated with reduced spontaneous physical activity levels, reduced glucose oxidation, and a decrease in lean body mass. Elevated circulating levels of leptin and cholesterol were present in 1-year-old ArKO mice compared with WT controls, as were elevated insulin levels, although blood glucose levels were unchanged. Associated with these changes, a striking accumulation of lipid droplets was observed in the livers of ArKO animals. Our findings demonstrate an important role for estrogen in the maintenance of lipid homeostasis in both males and females.estrogen deficiency ͉ obesity ͉ insulin ͉ cholesterol ͉ leptin A romatase is encoded by the Cyp19 gene and catalyzes the final step in the biosynthesis of C 18 estrogens from C 19 steroids. The sexually dimorphic distribution of adipose tissue in humans has implicated sex steroids in the regulation of adiposity and distribution of fat depots. Thus, whereas premenopausal women tend to have a lower body or gynoid distribution of fat, men and postmenopausal women tend to have an upper body or android distribution of fat. This phenotype is associated with a greater risk of insulinresistant diabetes, cardiovascular disease, and breast cancer (1). Estrogen insufficiency is thought to be largely responsible for the increase in adiposity during menopause because postmenopausal women who receive estrogen replacement therapy do not display the characteristic abdominal weight gain pattern usually associated with menopause (2). The role that estrogens play in lipid metabolism in the body is also highlighted by the fact that individuals of both sexes with natural mutations of the gene encoding aromatase, the enzyme responsible for estrogen biosynthesis, develop truncal obesity, insulin resistance, hypercholesterolemia, and hypertriglyceridemia (3-6).We have recently developed a mouse model of estrogen insufficiency by targeted disruption of the aromatase gene: the aromatase-knockout (ArKO) mouse (7). In the course of these studies, we observed that the animals displayed a progressive increase in adiposity as compared with wild-type (WT) littermates. The aim of the present investigation was to characterize the obese phenotype of these animals in the expectation that this would throw light on the role of estrogens in lipid homeostasis. Materials and MethodsMice. ArKO mice were generated by disrupting the Cyp19 gene as described (7). Heterozygous males and fema...

Insulin action was assessed by using the hyperinsulinemic (approximately 800 pmol/L) euglycemic clamp in rats fed equal amounts of glucose or fructose (35% of calories) for 4 wk. The glucose infusion rate required to maintain euglycemia was decreased in fructose-fed animals (14.6 +/- 1.4 vs 21.8 +/- 1.1 for glucose-fed rats, p less than 0.001) with this whole-body effect contributed to equally by an impairment in hepatic insulin action and a reduction in peripheral glucose disposal in a range of tissues. There was no difference in basal glucose turnover, energy expenditure, or postprandial blood glucose and insulin responses to the diets. In the fructose-fed rats there was an increase in fasting triglyceride levels by 2 wk. Euglycemic clamp glucose disposal correlated positively and clamp hepatic glucose output correlated negatively with fasting triglyceride levels. In summary, fructose but not glucose feeding led to impaired insulin action in both the liver and peripheral tissues, effects that may depend on antecedent circulating triglyceride levels.

OBJECTIVE -To determine the long-term effect of low glycemic index dietary advice on metabolic control and quality of life in children with type 1 diabetes.RESEARCH DESIGN AND METHODS -Children with type 1 diabetes (n ϭ 104) were recruited to a prospective, stratified, randomized, parallel study to examine the effects of a measured carbohydrate exchange (CHOx) diet versus a more flexible low-glycemic index (GI) dietary regimen on HbA 1c levels, incidence of hypo-and hyperglycemia, insulin dose, dietary intake, and measures of quality of life over 12 months.RESULTS -At 12 months, children in the low-GI group had significantly better HbA 1c levels than those in the CHOx group (8.05 Ϯ 0.95 vs. 8.61 Ϯ 1.37%, P ϭ 0.05). Rates of excessive hyperglycemia (Ͼ15 episodes per month) were significantly lower in the low-GI group (35 vs. 66%, P ϭ 0.006). There were no differences in insulin dose, hypoglycemic episodes, or dietary composition. The low-GI dietary regimen was associated with better quality of life for both children and parents.CONCLUSIONS -Flexible dietary instruction based on the food pyramid with an emphasis of low-GI foods improves HbA 1c levels without increasing the risk of hypoglycemia and enhances the quality of life in children with diabetes. Diabetes Care 24:1137-1143, 2001T ype 1 diabetes is one of the most challenging medical disorders because of the demands it imposes on day-to-day life. Good glycemic control, as judged by HbA 1c levels, is clearly related to reduced risk of microvascular complications (1). Although diet plays a major role in the overall management of type 1 diabetes, it is often classed as the most difficult aspect of treatment (2,3). Furthermore, there are surprisingly few longterm studies to support current dietary recommendations. Weighed carbohydrate "exchanges," introduced in the 1950s, have been used to ensure an even distribution of complex carbohydrates throughout the day. Carbohydrate counting and higher carbohydrate intake are now recommended, although in practice, emphasis is still placed on limiting carbohydrates to a specified level and avoiding refined sugars (4,5).Different carbohydrate foods affect blood glucose levels to varying degrees, as measured by their glycemic index (GI) (6,7). Foods such as legumes and dairy products have a low GI, whereas ordinary breads, potatoes, and rice have a high GI (8). Carbohydrate counting and "exchange" diets imply that equal carbohydrate portions have the same effect on glycemia. Not only is the theoretical basis of the exchange system questionable, it is difficult to understand and implement without knowing the carbohydrate content of food (9). Several studies have shown that exchange diets do not improve glycemic control (9,10) and that many children with diabetes and their parents cannot understand or follow them (11-13). It has also been suggested that quantifying carbohydrate intake may be associated with some physiological and psychological problems, including disordered eating behavior (14). This information and the emergi...

Small-intestinal absorption of fructose was investigated in healthy human subjects by sequential breath-hydrogen measurements. Fifty-eight percent of 103 subjects produced greater than 20 microL H2/L after consuming 50 g pure fructose in water. About half of those who absorbed fructose incompletely (incomplete absorbers) had abdominal symptoms. Malabsorption of medium doses of pure fructose may therefore be common in man. When 25 g pure fructose was consumed, only 19% of 21 poor absorbers (of 50 g fructose) still produced excess breath H2. When glucose was taken with fructose, the frequency and amount of excessive breath H2 was substantially reduced. This facilitating phenomenon is not generally known but is important because in natural foods fructose occurs in association or in combination (as sucrose) with glucose. Plasma fructose responses were not lower in poor absorbers presumably because these responses depend more on how much fructose passes through the liver than on how much is absorbed.

The purpose of the study was to compare the in vitro starch digestibility and postprandial blood glucose response of conventionally-cooked versus factory-processed foods. Carbohydrate portions of three unprocessed foods (boiled rice, sweet corn, and potato) and six processed foods (instant rice, Rice Bubbles, corn chips, Cornflakes, instant potato, and potato crisps) were incubated for 3 h with human saliva and porcine pancreatin. The proportion of starch digested was significantly higher (p less than 0.05) for the processed forms of rice, corn, and potato compared with the respective conventionally cooked foods. In six healthy volunteers who ingested 50 g carbohydrate portions of the above foods the processed foods produced a higher glycemic index (p less than 0.05) in all but one instance. The exception was potato crisps which gave a similar glycemic response to boiled potato.

OBJECTIVE: Altered fat distribution is a consequence of menopause, but the mechanisms responsible are unknown. Estrogen insufficiency in humans can be modeled using ovariectomized rats. We have shown that increased adiposity in these rats is due to reduced physical activity and transient hyperphagia, and can be reversed with 17b-estradiol treatment. The aims of this study were to examine whether this altered energy balance is associated with circulating leptin insufficiency, central leptin insensitivity, decreased hypothalamic leptin receptor (Ob-Rb) expression, and=or increased hypothalamic neuropeptide Y (NPY). METHODS: Plasma leptin levels, adipose tissue ob gene expression, energy balance responses to i.c.v. leptin, hypothalamic ObRb expression and NPY concentration in five separate hypothalamic regions were measured in adult female rats after either ovariectomy or sham operations. RESULTS: Obesity was not associated with hypoleptinemia or decreased ob gene expression in ovariectomized rats; however, it was associated with insensitivity to central leptin administration. Food intake was less suppressed and spontaneous physical activity was less stimulated by leptin. This was not due to decreased hypothalamic Ob-Rb expression. NPY concentration in the paraventricular nucleus of the hypothalamus was elevated in the ovariectomized rats, consistent with leptin insensitivity; however this effect was transient and disappeared as body fat and leptin levels increased further and hyperphagia normalized. CONCLUSION: Impaired central leptin sensitivity and overproduction of NPY may contribute to excess fat accumulation caused by estrogen deficiency.

To examine whether reduced rates of oxidative (G0x) and nonoxidative (N.x) glucose metabolism in non-insulin-dependent diabetes mellitus (NIDDM) are due to reduced glucose uptake, intrinsic defects in intracellular glucose metabolism or increased fat oxidation (Fox), indirect calorimetry was performed at similar glucose uptake rates in eight nonobese NIDDM and eight comparable nondiabetic subjects. Three glucose clamp studies were performed: one in the nondiabetic and two in the NIDDM subjects. In the nondiabetic subjects, glucose uptake was increased to 7.62±0.62 mg/kg of fat-free mass (FFM) per min by increasing serum insulin to 309 pmol/liter at a glucose concentration of 5.1 mmol/liter. By raising the concentration of either serum glucose or insulin fourfold in the NIDDM subjects, glucose uptake was matched to nondiabetic subjects (8.62±0.49 and 8.59±0.51 mg/kg FFM per min, respectively, P = NS). Skeletal muscle glycogen synthase activity and plasma lactate levels were measured to characterize N0X.When glucose uptake was matched to nondiabetics by hyperglycemia or hyperinsulinemia, G0x was reduced by 26-28% in NIDDM (P < 0.025) whereas Fox was similar. N0x was greater in NIDDM (P < 0.01) and was accompanied by increases in circulating lactate levels. Glycogen synthase activity was reduced by 41% (P < 0.025) when glucose uptake was matched by hyperglycemia. Glycogen synthase activity was normalized in NIDDM, however, when glucose uptake was matched by hyperinsulinemia.Therefore, a defect in G0x exists in nonobese NIDDM subjects which cannot be overcome by increasing glucose uptake or insulin. Since both glucose uptake and Fox were similar in the two subject groups these factors were not responsible for reduced G0x. Increased N0x in NIDDM is primarily into lactate. Reduced glycogen synthase activity in NIDDM is independent of glucose uptake but can be overcome by increasing the insulin concentration. (J. Clin. Invest. 1990. 85:522-529.) glucose oxidation * glycogen synthase -non-insulin-dependent diabetes mellitus

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