The experimental evidence supporting a direct role for hyperinsulinemia as a cause of insulin resistance remains equivocal. Amylin, an islet beta-cell peptide cosecreted with insulin in response to nutrient stimuli, causes insulin resistance when infused into intact animals or applied to isolated skeletal muscles. We compared measures of amylin and insulin gene expression between control and genetically obese, insulin-resistant Lister Albany/NIH-(LA/N-cp) rats. Pancreatic amylin messenger RNA levels were increased 7.8 +/- 0.7-fold (mean +/- SEM), and plasma amylin-like immunoreactive material was increased 10.9 +/- 1.1-fold (LA/N-lean, 14 +/- 4 pM; LA/N-cp, 153 +/- 16 pM; p less than 0.0001) in obese rats. Pancreatic insulin I mRNA levels were increased 7.4 +/- 0.5-fold, and plasma insulin levels 20.0 +/- 5.0-fold, in these rats (LA/N-lean, 308 +/- 84 pM; LA/N-cp 6,120 +/- 1,540 pM; p less than 0.0001). The EC50 for insulin-stimulated incorporation of glucose into glycogen was about fourfold higher in muscles isolated from obese rats. The present results, coupled with previous observations, support the hypothesis that hyperamylinemia, rather than hyperinsulinemia per se, could have directly caused the insulin resistance in the obese LA/N-cp rats. Hyperamylinemia needs to be considered in future experimental studies probing the relation between hyperinsulinemia and insulin resistance.

We previously reported that the decreased sensitivity of brown adipose tissue (BAT) from obese Zucker rats to the calorigenic effects of norepinephrine is associated with a marked resistance to insulin, and we suggested that this defect may explain, at least in part, the increased energy gain efficiency of fa/fa rats. To test whether insulin resistance and/or diabetes leads to a reduced BAT thermogenesis in other genetic models of obesity, we compared BAT metabolic properties of obese Zucker rats with that of obese-nondiabetic LA/N-cp and obese-diabetic SHR/N-cp rats. It was found that the responsiveness and sensitivity of isolated brown adipocytes to the calorigenic effects of norepinephrine (10-100 mM) were markedly reduced in SHR/N-cp rats as compared to their lean controls (the Vmax was decreased by 3-4 times and the EC50 value was doubled). In the same cells, there was a similar decrease in the respiratory effects of dibutyryl cAMP (DBcAMP), revealing the presence of a major post-receptor defect. Remarkably, total cytochrome oxidase activity (an index of cell mitochondrial content) was also decreased by 3-4 times in SHR/N-cp rats, suggesting that a reduced BAT mitochondrial content is responsible for the defective thermogenesis. Similarly to Zucker rats, adipocytes isolated from SHR/N-cp rats were resistant to the metabolic effects of insulin (glucose transport and antithermogenesis). Cells from obese Zucker rats were also desensitized to the metabolic effects of norepinephrine and insulin but their thermogenic capacity was not reduced. In contrast, all the above parameters were normal in obese-nondiabetic LA/N-cp rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Dolphin. 1989a. Effects of chronic ethanol consumption in atherosclerosis-prone JCR:LA-corpulent rat. Arteriosclerosis 9:122-128. Russell, J. C , R. M. Amy, V. Manickavel, P. J. Dolphin, W. F. Epling, D. Pierce, and D. P. Boer. 1989b. Prevention of myocardial disease in JCR:LA-corpulent rats by running. J. Appl. Physiol. 66:16491655. Russell, J. C , D. G. Koeslag, R. M. Amy, and P. J. Dolphin. 1989c. Independence of myocardial lesions in JCR:LA-corpulent rat on plasma lipid concentration. Clin. Invest. Med. 12:B8. Russell, J. C , D. G. Koeslag, R. M. Amy, and P. J. Dolphin. 1989d. Plasma lipid secretion and clearance in hyperlipidemic JCR:LAcorpulent rats. Arteriosclerosis 9:869-876. Russell, J. C , D. G. Koeslag, P. J. Dolphin, and R. M Amy. 1990. Prevention of myocardial lesions in JCR:LA-corpulent rat by nifedepine. Arteriosclerosis 10:658-664. Shillabeer, G., J. M. Forden, J. C. Russell, and D. C. W. Lau. 1990. Paradoxically slow adipocyte replication and differentiation in corpulent rats. Am. J. Physiol. 258:E368-E376.. Steiner, G. 1986. Hypertriglycemidemia and carbohydrate intolerance: Interrelations and therapeutic implications. Am. J. Cardiol. 57:276306.

To determine the effects of low-dose acarbose (ACB; BAY g 5421; 100 mg/kg diet) on modulation of adiposity, carbohydrate, and lipid metabolism, groups of congenic, pathogen-free male lean and obese LA/N-cp and of obese non-insulin-dependent diabetic (NIDDM) SHR/N-cp rats were fed diets containing 54% carbohydrate, 20% protein, 14% fat, plus other essential nutrients or the same diet with ACB from 12 until 20 weeks of age.

To determine the effects of delayed carbohydrate (CHO) absorption on glycemic status, weight gain (WG), and serum lipid profiles (cholesterol, triglycerides) in adult obese-diabetic rats with chronic obesity, hyperlipidemia, and non-insulin-dependent diabetes (NIDDM), groups of lean and obese, male and female Wistar fatty rats were fed diets containing 54% CHO as sucrose (SU) or cornstarch (CS), 20% protein (10% casein plus 10% lactalbumin), 16% fat (equal parts lard, corn oil, cocount oil, and beef tallow) plus other essential nutrients from 22 until 30 weeks of age, or the SU diet plus acarbose (ACB; 150 mg/kg diet).

We have studied the effects of the inclusion of acarbose in a high carbohydrate diet fed to rats with type I diabetes (streptozotocin-treated) and to rats with genetically induced type II diabetes (SHR/N-cp rats). Although the SHR/N-cp rats had only a slightly elevated fasting blood sugar, the oral glucose tolerance curve in these rats was markedly higher than that in normal rats. Administration of acarbose for 5 weeks (10 mg/100 g diet) greatly improved glucose tolerance in the type II diabetic antimals. In streptozotocin-diabetic rats, in which fasting blood sugar was extremely high, feeding of acarbose had little or no effect on the hyperglycemia.

The main experimental animal model for human diabetes has been the alloxan - or streptozotocin-treated animal. Such preparations resemble human type I or insulin-dependent diabetes. Recently a rat model has been introduced that exhibits characteristics of type n or insulin-independent diabetes. This is the SHR/N-cp rat developed by C.T. Hansen at the National Institutes of Health (1) and studied in detail by Michaelis et al.(2). This animal is obese, hyperinsulinemic and hyperlipidemic. The fasting blood sugar is only slightly elevated, but the glucose tolerance curve is markedly abnormal. The diabetes manifested in this animal is thus caused not by a lack of insulin but rather by resistance to the action of the hormone. Hypertension is absent in young rats but develops slowly with age. A genetically related animal, the LA/N-lean rat, is not diabetic and is used as a control in the studies reported here. In our recent investigations of the effect of diabetes on metabolism we have used these animal models as well as the streptozotocin-diabetic rat. Our experiments have centered around glycogen metabolism, and because of the involvement of uracil nucleotides in the synthesis of glycogen, the metabolism of these intermediates has also been studied.