This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by McLaughlin, T. Articles by Reaven, G. Search for Related Content PubMed PubMed Citation Articles by McLaughlin, T. Articles by Reaven, G.

Differences in Insulin Resistance Do Not Predict Weight Loss in Response to Hypocaloric Diets in Healthy Obese Women¹

Department of Medicine, Stanford University School of Medicine, Stanford, California 94305; and Shaman Pharmaceuticals, Inc., South San Francisco, California 94080-4812

Address all correspondence and requests for reprints to: Gerald M. Reaven, M.D., Shaman Pharmaceuticals, Inc., 213 East Grand Avenue, South San Francisco, California 94080-4812. E-mail: greaven{at}shaman.com

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The current study was initiated to determine whether insulin resistance and/or hyperinsulinemia affected the ability of obese individuals to lose weight in response to hypocaloric diets. Thirty-one obese, nondiabetic women, with values for body mass index ranging from 28.0–35.0 kg/m², volunteered for this program. Resistance to insulin-mediated glucose disposal was assessed by determining their steady state plasma insulin and glucose concentration during the last 30 min of a 180-min infusion of somatostatin, insulin, and glucose. The total integrated insulin response to breakfast and lunch was also determined. After the baseline measurements, volunteers were placed on a hypocaloric diet calculated to lead to a minimum weekly loss of 1% of ideal body weight. Individuals who met the criteria after 30 days of dieting were defined as weight loss successes (n = 20) and continued on the diet for another 30 days. Individuals not meeting the criteria were designated as weight loss failures (n = 12) and were discharged from the study. There was a mean (±SEM) weight loss at 60 days of 9.2 ± 0.4 kg in the 20 individuals defined as weight loss successes, but there was no correlation between weight loss and either steady state plasma glucose or the total integrated insulin response (r < 0.1; P > 0.83). Furthermore, using the same criteria to define insulin sensitivity and insulin resistance as those for therapeutic successes, the therapeutic failures comprised six insulin-sensitive and five insulin-resistant subjects. In summary, insulin-mediated glucose disposal varied widely in nondiabetic, obese women, and there was no relationship between baseline insulin resistance or total integrated insulin response and weight loss. It is concluded that the ability to lose weight on a calorie-restricted diet over a short time period does not vary in obese, healthy women as a function of insulin resistance or hyperinsulinemia.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
IT IS WIDELY recognized that the prevalence of obesity is increasing in the United States and that this represents an important health hazard (1). Evidence has also been published indicating that insulin resistance and compensatory hyperinsulinemia are frequently observed in a population of healthy, nondiabetic volunteers (2, 3), and the prevalence of these defects is increased in obesity (4). However, the relationship, if any, between these two phenomena, is quite controversial. Indeed, the results of six published studies evaluating the relationship between insulin resistance and weight gain yield conflicting results. Thus, results published by Swinburn and colleagues (5) and Schwartz et al. (6) indicated that insulin resistance and hyperinsulinemia predicted decreased weight gain over 3 yr in glucose-tolerant adult Pima Indians. A similar relationship between hyperinsulinemia and decreased weight gain was described in Hispanic and non-Hispanic white, normal glucose-tolerant adults (3, 7, 8). However, in one instance (7), this relationship was limited to the most obese tertile at baseline. In marked contrast, Odeleye and colleagues found that fasting hyperinsulinemia predicted weight gain in Pima Indian children (9), and Sigal et al. (10) showed that the higher the acute insulin response to iv glucose in glucose-tolerant offspring of two parents with type 2 diabetes, the greater the weight gain.

All of the results discussed above were essentially retrospective analyses of data from ongoing epidemiological studies, without any specific intervention to examine the relationship between insulin resistance and/or compensatory hyperinsulinemia and weight gain. As we believed that this latter approach might provide useful new information, we initiated the present study to evaluate the association between insulin resistance and the ability to lose weight in response to a hypocaloric diet in obese nondiabetic females.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The study population consisted of nondiabetic, obese women, who lived in the San Francisco Bay Area. All were volunteers who had responded to advertisements in local papers or had heard of the study by word of mouth. Participation was restricted to women with a body mass index (BMI) between 28.0–35.0 kg/m² and included nine women who were postmenopausal. Exclusions included psychiatric instability, known eating disorder, history of gastrointestinal surgery for weight reduction, active concurrent medical problems, pregnancy, or diabetes, as defined by an oral glucose tolerance test, using the criteria of the National Diabetes Data Group (11). Potential subjects were screened at the Stanford University General Clinical Research Center. BMI was calculated as weight (kilograms) divided by the height (square meters). Weight for all subjects, both before and during the study, was measured on a scale with the subject wearing light clothing. The study was approved by the Stanford University human subjects committee, and all participants gave informed written consent.

Insulin-mediated glucose disposal, as described previously (12, 13), was estimated by determining the steady state plasma insulin (SSPI) and glucose (SSPG) concentrations attained during the last 30 min of an 180-min infusion of somatostatin (250 µg/h), insulin (25 mU/m²·min), and glucose (240 mg/m²·min). Blood was drawn at 10-min intervals from 150–180 min of the infusion to measure plasma glucose (14) and insulin (15) concentrations, and the mean of these four values was used as the SSPI and SSPG concentrations for each individual. As SSPI concentrations are similar for all subjects, the SSPG concentration provides a direct measure of the ability of insulin to mediate disposal of an infused glucose load; the higher the SSPG, the more insulin resistant the individual.

Pancreatic B cell function was estimated by determining the total integrated insulin response after two meals (composition: 43% carbohydrate, 15% protein, and 42% fat). Meals were given at 0800 h and 1200 h, with breakfast comprising 20% and lunch comprising 40% of estimated daily caloric requirement. Insulin concentrations were measured fasting and every hour for a total of 8 h, and the total inte-grated insulin response was quantified by calculating the insulin area under the curve (microunits per mL/8 h) using the trapezoidal method: _{I = 0,. . ., 7} [(insulin t_i + insulin t_i+1)/2)].

All evaluations were conducted at the Stanford General Clinical Research Center. On the first day of hospital admission, initial body weight and height were obtained, and insulin-mediated glucose disposal was quantified. The total integrated insulin response was determined on the second hospital day, after which the period of weight loss began. The Harris-Benedict equation (16) was used to estimate each volunteer’s basal energy expenditure, and an activity factor was added to estimate total caloric requirement (basal energy expenditure x 1.5). Daily caloric intake during the period of weight loss was the total caloric requirement minus 1000 calories, with a lower limit of 1200 Cal/day. Subjects were advised to maintain their usual level of physical activity during the study. The weight loss diet consisted of a commercial liquid nutrition formula plus two high fiber muffins and a sodium supplement daily. Biweekly visits to the General Clinical Research Center were required of all volunteers for evaluation of progress, weight measurement, and food disbursement. The weight loss of all subjects was evaluated at 30 days. Volunteers who had lost, on the average, 1 kg or 1% of their initial body weight/week were defined as weight loss successes and continued on the weight loss diet for another 30 days. The weight attained at 60 days of a hypocaloric diet was used for subsequent data analysis. The individuals who did not meet weight loss criteria at 30 days were considered to be weight loss failures and were discharged from the study.

All data are expressed as the mean ± SEM, and all analyses were performed using Systat 6.0 for Windows (SPSS, Chicago, IL) (17). Unpaired Student’s t test was used for comparison of insulin-resistant and insulin-sensitive subjects with regard to age, initial body weight, weight loss, SSPG, and day-long insulin response. Linear correlation was used to assess the relationship among insulin resistance, total integrated insulin response to meals, and weight loss.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Twenty of the 31 volunteers who were enrolled in the study were followed for the entire 60-day diet period. The average weight loss after 8 weeks of these individuals was 9.2 kg, with a range from 7.0–11.7 kg. Table 1 compares the baseline characteristics of the two groups defined as being either diet successes or diet failures. It is obvious that the two groups were essentially identical with respect to all measured variables. No historical information was obtained during the biweekly visits that accounted for the lack of weight loss in the diet failures.

View larger version (17K): [in this window] [in a new window]   Figure 1. Relationship between insulin resistance (SSPG) and weight loss in absolute terms (left panel) and as a percentage of the initial body weight (right panel).

View larger version (18K): [in this window] [in a new window]   Figure 2. Relationship between total integrated insulin response from 0800–1600 h and weight loss in absolute terms (left panel) and as a percentage of the initial body weight (right panel).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Twenty of the 31 volunteers enrolled in the study qualified as diet successes on the basis of the amount of weight they lost in the first 30 days of the study. All members of this group had lost at least 10% of initial body weight at the end of the 60-day period of observation. It is apparent from the results presented in Figs. 1 and 2 and Table 1 that the ability to successfully lose weight in response to the hypocaloric diet was independent of any baseline differences in either insulin resistance or ambient plasma insulin concentration. It should also be noted that the weight loss was independent of the initial degree of obesity, as assessed by either BMI or the ratio of waist to hip girth. The most insulin-resistant and hyperinsulinemic persons lost weight as effectively as did those who were the most insulin sensitive and had the lowest total integrated insulin responses. Furthermore, if we focus on the 11 individuals defined as weight loss failures, the results presented in Table 2 support the same conclusion. More specifically, baseline values for insulin-mediated glucose disposal and insulin response to meals were similar in individuals designated as either weight loss successes or failures, and the proportions of insulin-resistant and insulin-sensitive individuals in this latter category were quite comparable. Finally, historical information obtained at the biweekly visits did not provide information suggesting that the volunteers who did not lose weight were less active and/or less compliant. To the best of our knowledge, this is the first study in which an experimental intervention was used to evaluate the role, if any, of insulin resistance and/or hyperinsulinemia on regulation of obesity. Consequently, we can only discuss our findings in the context of previous publications evaluating the effect of baseline insulin resistance and/or hyperinsulinemia on subsequent weight gain.

As such, our results are in general agreement with those of Valdez et al. (7), who found in a study of Hispanic and non-Hispanic white women that baseline hyperinsulinemia did not affect subsequent weight gain in two thirds of their population. Our study group also included both Hispanic and non-Hispanic white women, but differed in that all of the volunteers were obese. This observation is of great interest in light of the recent explanation given for the dichotomous finding that hyperinsulinemia predicts less weight gain in adult Pima Indians (5, 6), but more weight gain in Pima children (9). Based upon this apparent paradox, Odeleye and associates (9) suggested that hyperinsulinemia leads to weight gain in nonobese individuals (Pima children), but mitigates weight gain in those already obese (Pima adults).

The possibility that hyperinsulinemia only predicts weight gain in nonobese individuals may help explain why the report of Sigal and associates (10) was the only study on adults concluding that hyperinsulinemia predicted more, not less or similar, weight gain. More specifically, the study by Sigal et al. (10), performed in nondiabetic offspring of two parents with type 2 diabetes, indicated that the height of the acute insulin response to iv glucose was associated with increased weight gain. On the other hand, the ability to generalize from their study is confounded by the fact that weight gain was only enhanced in the subjects who were both hyperinsulinemic and insulin sensitive, an unusual combination, given the very strong direct correlation between insulin resistance and hyperinsulinemia characteristic of nondiabetic populations (2, 3). Furthermore, Hoag et al. (8) did not discern any relationship between initial body weight and subsequent weight gain in their longitudinal study of Hispanic and non-Hispanic whites. Based upon the above considerations, there does not seem to be persuasive evidence that the effect of insulin resistance and/or hyperinsulinemia on weight gain or loss varies as a function of whether the individual is obese or nonobese.

As discussed above, the report by Sigal et al. (10) is the only study in adults that found hyperinsulinemia to predict increased weight gain. Although this disparity could not be accounted for by differences in initial body weight, there are two differences in experimental protocol that could be responsible. The most obvious difference is that Sigal et al. (10) only studied offspring of two parents with type 2 diabetes, and the applicability of findings in this highly specialized population to the world at large can certainly be questioned. Secondly, questions can be raised as to the validity of the method used by Sigal and associates (10) to quantify insulin action based on mathematical modeling of the plasma glucose and insulin responses to an acute iv glucose challenge (18). This approach has been shown to correlate very poorly with the glucose-insulin clamp technique (19, 20). Indeed, the inadequacy of this initial approach was recognized by Bergman, with the introduction of the tolbutamide-assisted (21) and the insulin-assisted (22) modifications. In contrast, estimates of insulin resistance with the technique used in the present study and that of Swinburn and associates (5) have been shown to have a correlation coefficient of more than 0.9 (23).

Although our results are unequivocal in showing that the ability to lose weight in association with a hypocaloric diet is independent of a baseline degree of insulin resistance and hyperinsulinemia, any conclusions must be tempered by discussing the limitations of our study. In the first place, the period of experimental observation was only 2 months in duration, and it is certainly possible that our inability to find an effect of either insulin resistance or hyperinsulinemia on weight loss in association with a hypocaloric diet would have been different if the study had been carried out longer.

Another important difference between the current interventional study and previous longitudinal observations is that our experimental subjects were given a defined hypocaloric diet. As such, it could be argued that the power of an organized weight loss program, buttressed by frequent reenforcement by the healthcare professionals involved in the study, would minimize the more subtle impact of insulin resistance and hyperinsulinemia on long term regulation of weight in a free living population.

Consequently, it may be most appropriate to view the results presented as a pilot study, highlighting the need to perform a more extensive interventional evaluation of the effect of insulin resistance and hyperinsulinemia on weight loss in a larger number of obese individuals observed over a longer time period. In conclusion, we have shown that neither insulin resistance nor hyperinsulinemia affects the ability of obese individuals to lose weight in response to a calorically restricted diet. These results emphasize the fact that there is not unanimity concerning the effect, if any, of variations in insulin metabolism on energy balance. At the least, these results should 1) be encouraging in that the predicted outcome of a hypocaloric diet could be achieved in two thirds of a volunteer population regardless of the baseline degree of insulin resistance and/or hyperinsulinemia, and 2) highlight the need to perform the additional studies needed to provide definitive answers to this important healthcare issue.

	Footnotes

 
¹ This work was supported by NIH Research Grants RR-00070 and HL-08506.

Received September 9, 1998.

Revised October 21, 1998.

Accepted October 27, 1998.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Rosenbaum M, Leibel RL, Hirsch J. 1997 Obesity. N Engl J Med. 337:396–406.[Free Full Text]
2. Hollenbeck C, Reaven GM. 1987 Variations in insulin-stimulated glucose uptake in healthy individuals with normal glucose tolerance. J Clin Endocrinol Metab. 64:1169–1173.[Abstract/Free Full Text]
3. Reaven GM, Brand RJ, Chen Y-DI, Mathur AK, Goldfine I. 1993 Insulin resistance and insulin secretion are determinants of oral glucose tolerance in normal individuals. Diabetes. 42:1324–1332.[Abstract]
4. Ferrannini E, Natali A, Bell P, Cavallo-Perin P, Lalic N, Mingrone G. 1997 Insulin resistance, and hypersecretion in obesity. J Clin Invest. 100:1166–1173.[Medline]
5. Swinburn BA, Nyomba BL, Saad MF, et al. 1991 Insulin resistance associated with lower rates of weight gain in Pima Indians. J Clin Invest. 88:168–173.
6. Schwartz MW, Boyko EJ, Kahn SE, et al. 1995 Reduced insulin secretion: an independent predictor of body weight gain. J Clin Endocrinol Metab. 80:1571–1576.[Abstract/Free Full Text]
7. Valdez R., et al. 1994 Predictors of weight change in a bi-ethnic population. The San Antonio Heart Study. Int J Obesity. 18:85–91.
8. Hoag S, Marshall JA, Jones RH, Hamman RF. 1995 High fasting insulin levels associated with lower rates of weight gain in persons with normal glucose tolerance: The San Luis Valley Diabetes Study. Int J Obesity. 19:175–180.[Medline]
9. Odeleye OE, de Courten M, Pettit DJ, Ravussin E. 1997 Fasting hyperinsulinemia is a predictor of increased body weight gain and obesity in Pima Indian children. Diabetes. 46:1341–1345.[Abstract]
10. Sigal RJ, El-Hashimy M, Martin BC, et al. 1997 Acute postchallenge hyperinsulinemia predicts weight gain. Diabetes. 46:1025–1029.[Abstract]
11. National Diabetes Data Group. 1979 Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes. 28:1039–1057.[Medline]
12. Shen S-W, Reaven GM, Farquhar J. 1980 Comparison of impedance to insulin-mediated glucose uptake in normal subjects and in subjects with latent diabetes. J Clin Invest. 49:2151–2160.[CrossRef]
13. Harano Y, Ohgaku S, Hidaka H, et al. 1977 Glucose, insulin and somatostatin infusion for the determination of insulin sensitivity. J Clin Endocrinol Metab 45:1124–1127.
14. Kadish AK, Litle RL, Sternberg JC. 1963 A new and rapid method for determination of glucose by measurement of rate of oxygen consumption. Clin Chem 14:116–131.
15. Hales CN, Randle PJ. 1963 Immunoassay of insulin with insulin-antibody precipitate. Biochem J 88:137–146.
16. Harris JA, Benedict FG. A biometric study of basal metabolism in man. Washington DC: Carnegie Institute of Washington; Publication 279:1919.
17. SPSS. 1996 Systat 6.0 for Windows. Chicago: SPSS.
18. Bergman RN, Finegood DT, Ader M. 1986 Assessment of insulin sensitivity in vivo. Endocr Rev. 6:45–86.[Abstract/Free Full Text]
19. Donner CC, Fraze E, Chen Y-DI, Hollenbeck CB, Foley JE, Reaven GM. 1985 Presentation of a new method for specific measurement of in vivo insulin-stimulated glucose disposal in humans: comparison of this approach with the insulin clamp and minimal model techniques. J Clin Endocrinol Metab. 60:723–726.[Abstract/Free Full Text]
20. Foley JE, Chen Y-DI, Lardinois CK, Hollenbeck CB, Liu GC, Reaven GM. 1985 Estimates of in vivo insulin action in humans: comparison of the insulin clamp and the minimal model techniques. Horm Metab Res. 17:406–409.[Medline]
21. Bergman RN, Prager R, Volund A, Olefsky JM. 1987 Equivalence of the insulin sensitivity index in man derived by the minimal model method and the euglycemic glucose clamp. J Clin Invest. 79:790–800.
22. Welch S, Gebhart SS, Bergman RN, Phillips LS. 1990 Minimal model analysis of intravenous glucose tolerance test-derived insulin sensitivity in diabetic subjects. J Clin Endocrinol Metab 71:1508–1518.
23. Greenfield MS, Doberne L, Kraemer FB, Tobey TA, Reaven GM. 1981 Assessment of insulin resistance with the insulin suppression test and the euglycemic clamp. Diabetes. 30:387–392.[Abstract]

This article has been cited by other articles:

				Z. T. Bloomgarden Gut Hormones, Obesity, Polycystic Ovarian Syndrome, Malignancy, and Lipodystrophy Syndromes Diabetes Care, July 1, 2007; 30(7): 1934 - 1939. [Full Text] [PDF]

				T. McLaughlin, F. Abbasi, C. Lamendola, and G. Reaven Heterogeneity in the Prevalence of Risk Factors for Cardiovascular Disease and Type 2 Diabetes Mellitus in Obese Individuals: Effect of Differences in Insulin Sensitivity Arch Intern Med, April 9, 2007; 167(7): 642 - 648. [Abstract] [Full Text] [PDF]

				R. S. Legro A 27-Year-Old Woman With a Diagnosis of Polycystic Ovary Syndrome JAMA, February 7, 2007; 297(5): 509 - 519. [Abstract] [Full Text] [PDF]

				P. K. Newby, C. Weismayer, A. Akesson, K. L. Tucker, and A. Wolk Longitudinal Changes in Food Patterns Predict Changes in Weight and Body Mass Index and the Effects Are Greatest in Obese Women J. Nutr., October 1, 2006; 136(10): 2580 - 2587. [Abstract] [Full Text] [PDF]

				Z. T. Bloomgarden Third Annual World Congress on the Insulin Resistance Syndrome: Mediators, antecedents, and measurement Diabetes Care, July 1, 2006; 29(7): 1700 - 1706. [Full Text] [PDF]

				A. G. Pittas, S. K. Das, C. L. Hajduk, J. Golden, E. Saltzman, P. C. Stark, A. S. Greenberg, and S. B. Roberts A Low-Glycemic Load Diet Facilitates Greater Weight Loss in Overweight Adults With High Insulin Secretion but Not in Overweight Adults With Low Insulin Secretion in the CALERIE Trial Diabetes Care, December 1, 2005; 28(12): 2939 - 2941. [Full Text] [PDF]

				M. Noakes, J. B Keogh, P. R Foster, and P. M Clifton Effect of an energy-restricted, high-protein, low-fat diet relative to a conventional high-carbohydrate, low-fat diet on weight loss, body composition, nutritional status, and markers of cardiovascular health in obese women Am. J. Clinical Nutrition, June 1, 2005; 81(6): 1298 - 1306. [Abstract] [Full Text] [PDF]

				C. Lara-Castro and W. T. Garvey Diet, Insulin Resistance, and Obesity: Zoning in on Data for Atkins Dieters Living in South Beach J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4197 - 4205. [Abstract] [Full Text] [PDF]

				G. Reaven, F. Abbasi, and T. McLaughlin Obesity, Insulin Resistance, and Cardiovascular Disease Recent Prog. Horm. Res., January 1, 2004; 59(1): 207 - 223. [Abstract] [Full Text]

				T. McLaughlin, F. Abbasi, K. Cheal, J. Chu, C. Lamendola, and G. Reaven Use of Metabolic Markers To Identify Overweight Individuals Who Are Insulin Resistant Ann Intern Med, November 18, 2003; 139(10): 802 - 809. [Abstract] [Full Text] [PDF]

				C. Beebe Body Weight Issues in Preventing and Treating Type 2 Diabetes Diabetes Spectr, October 1, 2003; 16(4): 261 - 266. [Full Text] [PDF]

				E. J. Mayer-Davis, G. J. Kirkner, A. J. Karter, and D. J. Zaccaro Metabolic Predictors of 5-Year Change in Weight and Waist Circumference in a Triethnic Population: The Insulin Resistance Atherosclerosis Study Am. J. Epidemiol., April 1, 2003; 157(7): 592 - 601. [Abstract] [Full Text] [PDF]

				G. M. Reaven Importance of Identifying the Overweight Patient Who Will Benefit the Most by Losing Weight Ann Intern Med, March 4, 2003; 138(5): 420 - 423. [Abstract] [Full Text] [PDF]

				Z. T. Bloomgarden American Association of Clinical Endocrinologists (AACE) Consensus Conference on the Insulin Resistance Syndrome: 25-26 August 2002, Washington, DC Diabetes Care, March 1, 2003; 26(3): 933 - 939. [Full Text] [PDF]

				T. McLaughlin, F. Abbasi, C. Lamendola, L. Liang, G. Reaven, P. Schaaf, and P. Reaven Differentiation Between Obesity and Insulin Resistance in the Association With C-Reactive Protein Circulation, December 3, 2002; 106(23): 2908 - 2912. [Abstract] [Full Text] [PDF]

				F. Abbasi, B. W. Brown Jr, C. Lamendola, T. McLaughlin, and G. M. Reaven Relationship between obesity, insulin resistance, and coronary heart disease risk J. Am. Coll. Cardiol., September 4, 2002; 40(5): 937 - 943. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by McLaughlin, T. Articles by Reaven, G. Search for Related Content PubMed PubMed Citation Articles by McLaughlin, T. Articles by Reaven, G.