Somatogenic (i.e. GH) receptors have been studied on liver microsomal membranes from male and female rats. Tracer bovine GH was displaced from its binding sites by GHs of various species, but was displaced only weakly by PRLs. Specific bovine GH binding was 3.5-fold higher to female rat liver membranes than to membranes from males. Streptozotocin-induced diabetes significantly reduced binding, by 80% in females and 50% in males, while insulin therapy to normalize weight gain reversed the decrease in binding. Competitive binding curves were consistent with two independent classes of binding site: low affinity sites with K equal to 0.5 nm-1 in both sexes, and high affinity sites with K equal to 12.1 nm-1 in males and 21.4 nm-1 in females (P less than 0.001). The addition of excess ovine PRL caused a substantial loss of high affinity binding with little loss in the low affinity region, suggesting a weak somatogenic role for ovine PRL. In diabetic animals, low affinity sites were unchanged from normal, while high affinity sites were decreased in number, with no change in affinity, and restored on insulin therapy. Serum immunoreactive rat GH levels were the same in normal and diabetic, male and female animals. These studies suggest that the apparent hepatic resistance to GH seen in diabetes when liver somatomedin release is low despite normal serum GH might be explained by the loss of GH receptors in this condition.

2002;10:401-407. Objective: Obesity is a major risk factor for the development of type 2 diabetes. Tumor necrosis factor (TNF)-␣ is a candidate gene for the development of both obesity and insulin resistance. We investigated whether a common polymorphism in the promoter region (Ϫ308 G/A) of the TNF-␣ gene was associated with increased risk for the development of insulin resistance and cardiovascular disease in an obese Australian population. Research Methods and Procedures: Obese, non-diabetic subjects (146 women and 34 men) were genotyped with polymerase chain reaction-restriction fragment length polymorphism techniques, and anthropometric and biochemical measurements were analyzed. A homeostasis model assessment (HOMA) score was used to gauge the level of insulin resistance. Results: The frequencies of the G allele and the A allele were 0.759 and 0.241, respectively. Subjects homozygous for the A allele had higher fasting insulin levels (226 vs. 131 pM; p Ͻ 0.001), higher HOMA scores (10.2 vs. 5.3; p Ͻ 0.001), higher systolic blood pressure (143 vs. 129 mm Hg; p ϭ 0.02), and lower high-density lipoprotein (HDL) cholesterol (1.13 vs. 1.25 mM; p ϭ 0.04) than did subjects homozygous for the G allele. Whereas an association between insulin resistance and body mass index or waist circumference was seen in all subjects, a highly significant negative correlation of HDL cholesterol to HOMA scores (r ϭ Ϫ0.710; p Ͻ 0.001) occurred in subjects with the A allele only. Discussion: The Ϫ308 G/A TNF-␣ gene variant conveys an increased risk for the development of insulin resistance in obese subjects. The presence of low HDL cholesterol levels further increases the risks associated with insulin resistance in carriers of the A allele.

The Diabetes Knowledge Assessment (DKN) scales were developed to meet a specific need for rapid and reliable knowledge assessment in diabetic patients. Item format and item selection from an initial pool of 89 items were determined by pilot-testing over 300 diabetic subjects. Reliability analysis of the resulting 40 multiple-choice items, with a further sample of 56 subjects, gave a Cronbach's alpha coefficient of 0.92. Parallel forms DKNA, DKNB, and DKNC, each of 15 items selected from the parent set, had alpha coefficients above 0.82 and correlated 0.90 with each other. A full clinical trial, using DKNA, DKNB, and DKNC in randomized order of presentation, was conducted with 219 subjects attending a 2-day diabetes education program. Overall DKN scores improved from 7.6 (51%) to 11.3 (75%). Analysis of variance confirmed that DKNA, DKNB, and DKNC were equivalent forms at pretest. Mean posttest scores on DKNB were lower than the other scales (P less than 0.001), but variances were equivalent for all three. A specific local change in the education program format was found to account for this discrepancy in the DKNB posttest mean. In situations where comprehensive assessment of diabetes knowledge would be time-consuming and unnecessary, these results indicate that rapid and reliable assessment is possible with a scale of only 15 validated items. The development of parallel forms of the scale extends the range of retesting possibilities for diagnosis and research.

In rats, prolonged feeding of high glycemic index (GI) starch results in basal hyperinsulinemia and an elevated insulin response to an intravenous glucose tolerance test (IVGTT). The aim of this study was to assess hepatic and peripheral insulin resistance (IR) using euglycemic hyperinsulinemic clamps. Insulin sensitivity, epididymal fat deposition and fasting leptin concentrations were compared in rats fed isocalorically a low or high GI diet for 7 wk (45% carbohydrate, 35% fat and 20% protein as energy) or a high fat diet (20% carbohydrate, 59% fat and 21% protein as energy) for 4 wk so that final body weights were similar. At the end of the study, high GI rats had higher basal leptin concentration and epididymal fat mass than the low GI group, despite comparable body weights. High GI and high fat feeding both resulted in the higher insulin response during IVGTT, but impaired glucose tolerance was seen only in rats fed high fat. The GI of the diet did not affect basal and clamp glucose uptake or hepatic glucose output, but high fat feeding induced both peripheral and hepatic IR. The findings suggest that hypersecretion of insulin without IR may be one mechanism for increased fat deposition in rats fed high GI diets. J. Nutr. 131: 99 -104, 2001.

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Leptin is reported to have effects in peripheral tissues that are independent of its central effects on food intake and body weight. In this study, the acute effects of a single dose of recombinant mouse leptin on lipid and glucose metabolism in lean and gold thioglucose-injected obese mice were examined. Changes were measured 2 h after leptin injection. In lean mice, liver and white adipose tissue (WAT) lipogenesis was inhibited. The activity of the pyruvate dehydrogenase complex (PDHCa), the rate-determining step for glucose oxidation, was reduced in heart, liver, quadriceps muscle, and both brown and white adipose tissues. Muscle and liver glycogen and liver triglyceride (TG) content was unchanged, but muscle TG was decreased. In obese mice, liver and WAT lipogenesis was inhibited and PDHCa reduced in heart and quadriceps muscle. Muscle and liver glycogen was decreased but not TG. Serum insulin was reduced in obese but not lean mice. These results are consistent with a role for leptin in the maintenance of steady-state energy stores by decreasing lipid synthesis and increasing fat mobilization, with decreased glucose oxidation occurring as a result of increased fatty acid oxidation.

MALONEY, CHRIS A., ALISON K. GOSBY, JENNY L. PHUYAL, GARETH S. DENYER, JANET M. BRYSON, AND IAN D. CATERSON. Site-specific changes in the expression of fat-partitioning genes in weanling rats exposed to a low-protein diet in utero. Obes Res. 2003;11:461-468. Objective: Intrauterine growth restriction is associated with increased prevalence of the metabolic syndrome in adult life, including increased adiposity. The aim of this study was to investigate if maternal protein energy malnutrition is associated with changes in expression of genes involved in fat partitioning in weanling rats. Research Methods and Procedures: Time-mated mothers were placed on one of two isocaloric diets, low protein [(LP), 8% protein] or control (20% protein). All mothers remained on the diet throughout pregnancy and lactation. A third group received control for 2 weeks and was switched to LP for the last week of pregnancy and lactation [late low protein (LLP) group]. Offspring were analyzed at weaning for serum glucose, nonesterified fatty acids, triglyceride, and insulin. Expression of the genes acetyl-coenzyme A carboxylase, fatty acid synthase, and carnitine palmitoyl transferase 1 were measured in liver, quadriceps muscle, and subcutaneous white adipose tissue using semiquantitative reverse transcription-polymerase chain reaction. Results: LLP and LP offspring were shorter, weighed less, had reduced serum insulin and nonesterified fatty acids, and had increased serum glucose, serum triglycerides, and hepatic triglycerides. Hepatic gene expression of acetyl-coenzyme A carboxylase and fatty acid synthase was increased 2-fold in LLP and LP offspring (p Ͻ 0.001). These changes were not seen in muscle or subcutaneous white adipose tissue. CPT-1 gene expression was unaltered in all tissues examined. Discussion: Maternal protein energy malnutrition programs gene expression of lipogenic enzymes in the liver of weanling offspring in a manner favoring fat synthesis that may predispose these offspring to fat accumulation and insulin resistance later in life.

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