E D I T O R I A L
Impaired Glucose Tolerance The irrepressible -cell? mpaired glucose tolerance (IGT) as a clinical entity has gained increased attention in recent years (1). Three main factors can account for this. First, the recognition of increased risk for cardiovascular disease that is associated with IGT (1,2) has resulted in a plea to recognize IGT as a disease state in its own right (1). Secondly, the role of IGT as a risk factor for diabetes has been accepted by the scientific community, despite caveats about the use of the oral glucose tolerance test (OGTT) in its diagnosis. For example, it functions as the primary screening tool and the basis for intervention in the multicenter National Institutes of Health–sponsored Diabetes Prevention Project (3). The increased risk in IGT amounts to a 3–9% likelihood per year of developing type 2 diabetes (4). Thirdly, new options for treatment of IGT have emerged. This emergence is a by-product of the dramatic increase in the availability of oral agents for treatment of type 2 diabetes, which also provides new opportunities for preventive strategies. To justify the risks of pharmacological treatment in a prediabetic state, identification of people at high risk for diabetes is required. Hence, the choice of IGT (3,4). Focus on IGT has also been associated with attempts to understand underlying mechanisms; greater understanding may help improve prediction of diabetes and enhance development of targeted therapies. In this issue, Larsson and Ahrén (5) report on defects in islet physiology that may contribute further to our understanding of the pathogenesis of IGT. In a population-based study of postmenopausal Swedish women, these investigators studied IGT, applying World Health Organization criteria to an OGTT. Of 108 women evaluated, 34% had IGT (5). This group had slightly elevated systolic blood pressure and serum triglyceride levels, although BMI measurements, waist-to-hip ratios, and body fat content were similar to those of the normal glucose tolerance group (NGT). Insulin sensitivity was measured using a glucose clamp, and insulin and glucagon secretion were evaluated using glucose and arginine infusions. Women with IGT were shown to have both insulin
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DIABETES CARE, VOLUME 23, NUMBER 5, MAY 2000
resistance and reduced insulin secretion; the latter was particularly evident when expressed in terms of each subject’s insulin sensitivity as a disposition index. The utility of this approach (6) was well demonstrated, because insulin secretion, though similar in both groups, was found to be significantly reduced when evaluated in relation to the degree of insulin resistance present. The investigators also found hyperglucagonemia, manifesting as an increase in arginine-stimulated secretion and a reduced suppressibility of glucagon during hyperglycemia. A novel aspect of this study is the finding that there was an inverse relationship between insulin sensitivity and glucagon secretion in these subjects. Previous studies support the concept that glucagon may be involved in the pathogenesis of IGT. This concept derives from studies of glucagon suppressibility during oral glucose loading. The normal physiological suppression of glucagon secretion in response to elevated plasma glucose is lost in diabetes (7,8) and is also impaired in IGT (9). A concomitant decrease in early insulin secretion in response to oral glucose is also observed. This combined defect alters the insulin-to-glucagon ratio and, as a result, leads to failure of the normal suppression of endogenous glucose production that occurs after oral glucose ingestion (10). This, in turn, contributes to elevated plasma glucose concentrations that are characteristic of IGT. Insulin resistance (5) also plays a role in IGT by impairing glucose disposal and providing resistance to hepatic insulin action. However, secretory abnormalities can cause IGT in the absence of insulin resistance. Shah et al. (11) studied normal subjects with a combined hormonal defect, i.e., insulin secretion and glucagon suppressibility were both reduced experimentally during glucose loading. This experiment resulted in a marked reduction in glucose tolerance with a failure to suppress endogenous glucose production. When normal suppressibility of glucagon was allowed to occur, endogenous glucose production and glucose tolerance were normalized. These
authors suggest that improving postprandial suppressibility of plasma glucagon may be a therapeutic target in IGT. What are the mechanisms responsible for the abnormalities in glucagon secretion that occur in IGT? Both exaggerated responses to secretagogues and failure of suppressibility of glucagon are tied to abnormal -cell function (7,8). Types 1 and 2 diabetes and IGT each have different degrees of insulin-secretory dysfunction, and all are associated with abnormal regulation of glucagon secretion. This is explained by the inhibitory effect of insulin on glucagon release (12) and by evidence for local control of -cell function by insulin within the islet (13). Reducing the inhibitory influence of insulin can account for a difference in both the tonic control and the stimulation of glucagon secretion observed in IGT (5,7–9). Thus, abnormalities in glucagon that are characteristic of IGT can be explained by dysfunction in islet secretion. However, resistance to secreted products of the islets may also play a role. This was illustrated by Kulkarni et al. (14), who demonstrated the functional importance of insulin receptors in the islets of Langerhans in a model of insulin resistance of the -cell. Using a tissue-specific -cell insulin-receptor knockout mouse, they found impaired insulin secretion due (presumably) to reduction of a stimulatory influence of insulin on the -cell (15). If resistance to insulin action occurs in the -cell, it may also apply to the -cell and thereby contribute to a reduction in the ability of insulin to inhibit glucagon secretion. What evidence do we have for -cell insulin resistance? The findings of Larsson and Ahrén (5) provide support for this possibility, because their glucagon secretion data are best explained at this time by islet insulin resistance. Their data demonstrating a negative or hyperbolic correlation between insulin resistance and glucagon secretion suggest that subjects who are least sensitive to insulin have the highest glucagon levels. This is what one might predict if systemic insulin resistance was also expressed in the -cell and if -cell 569
Editorial
insensitivity to insulin is of physiological importance. The finding that insulin-resistant obese subjects with normal tolerance have nonsuppressible glucagon, despite having enough insulin to maintain NGT, further supports this concept (16). Nonsuppressible glucagon may therefore be an early islet defect that precedes insulin deficiency. However, the putative role of insulin resistance at the -cell remains speculative until these clinical findings (5,16) are confirmed. A mouse model with a tissue-specific -cell insulin-receptor knockout may also provide us with further understanding of the functional relationships between islet cells and the mechanisms for the glucagonsecretory dysfunction in IGT. With increased focus on IGT, whether as disease or precursor, we will inevitably learn more that will enable us to provide improved therapeutic options. Abnormalities in islet function in IGT, including the role of glucagon, represent potentially important targets for future therapeutic action, along with more commonly considered targets such as insulin resistance and dyslipidemia. ELI IPP, MD From the Clinical Study Center, Harbor–University of California at Los Angeles Medical Center, Torrance, California. Address correspondence to Eli Ipp, MD, HarborUCLA Medical Center, Clinical Study Center, Box 16, 1000 W. Carson St., Torrance, CA 90502. E-mail:
[email protected].
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References 1. Perry RC, Baron AD: Impaired glucose tolerance: why is it not a disease? Diabetes Care 22:883–885, 1999 2. Haffner SM: The importance of hyperglycemia in the non-fasting state to the development of cardiovascular disease. Endocr Rev 19:583–592, 1998 3. The Diabetes Prevention Program: Design and methods for a clinical trial in the prevention of type 2 diabetes. Diabetes Care 22: 623–634, 1999 4. Edelstein SL, Knowler WC, Bain RP, Andres R, Barrett-Connor EL, Dowse GK, Haffner SM, Pettitt DJ, Sorkin JD, Muller DC, Collins VR, Hamman RF: Predictors of progression from impaired glucose tolerance to NIDDM: an analysis of six prospective studies. Diabetes 46:701–710, 1997 5. Larsson H, Ahrén B: Islet dysfunction in insulin resistance involves impaired insulin secretion and increased glucagon secretion in postmenopausal women with impaired glucose tolerance. Diabetes Care 23:650– 657, 2000 6. Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward WK, Beard JC, Palmer JP, Porte D Jr: Quantification of the relationship between insulin sensitivity and -cell function in human subjects: evidence for a hyperbolic function. Diabetes 42:1663– 1672, 1993 7. Unger RH, Orci L: Glucagon and the A cell: physiology and pathophysiology. Pt. 1. N Engl J Med 304:1518–1524, 1981 8. Unger RH, Orci L: Glucagon and the A cell: physiology and pathophysiology. Pt. 2. N Engl J Med 304:1575–1580, 1981
9. Gerich JE: Metabolic abnormalities in impaired glucose tolerance. Metabolism 46 (Suppl. 1):40–43, 1997 10. Mitrakou A, Kelley D, Mokan M, Veneman T, Pangburn T, Reilly J, Gerich J: Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med 326:22–29, 1992 11. Shah P, Basu A, Basu R, Rizza R: Impact of lack of suppression of glucagon on glucose tolerance in humans. Am J Physiol 277: E283–E290, 1999 12. Samols E, Tyler J, Marks V: Glucagoninsulin interrelationships. In Glucagon; Molecular Physiology, Clinical and Therapeutic Implications. Lefebvre PJ, Unger RH, Eds. New York, Pergamon Press, 1972, p. 151– 174 13. Maruyama H, Hisatomi A, Orci L, Grodsky GM, Unger RH: Insulin within islets is a physiologic glucagon release inhibitor. J Clin Invest 74:2296–2299, 1984 14. Kulkarni RN, Bruning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR: Tissue-specific knockout of the insulin receptor in pancreatic β cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 96:329–339, 1999 15. Aspinwall CA, Lakey JR, Kennedy RT: Insulin-stimulated insulin secretion in single pancreatic β cells. J Biol Chem 274: 6360–6365, 1999 16. Borghi VC, Wajchenberg BL, Cesar FP: Plasma glucagon suppressibility after oral glucose in obese subjects with normal and impaired glucose tolerance. Metabolism 33: 1068–1074, 1984
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