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Prevention of Type 2 Diabetes
Insulin Resistance and ␤-Cell Function
J.-L. Chiasson and Re
´ mi Rabasa-Lhoret
Type 2 diabetes is increasing worldwide in epidemic pro-
(2– 4). Type 2 diabetes will certainly be one of the major portions. Its associated morbidity and mortality is impos-
diseases of the 21st century and should be recognized as a ing a major burden on the health care system. Based on a
better understanding of the pathophysiology of glucose
It is now well established that the development of type intolerance, clinical trials on the prevention of diabetes
2 diabetes results from the interaction between the genetic have been performed. It has now been demonstrated that
makeup of the individuals and their environment (5). The diet and exercise, metformin, acarbose, and troglitazone
development of obesity seems to be an important factor in can prevent or at least delay the development of diabetes
the development of insulin resistance (6,7). If this insulin in subjects with impaired glucose tolerance (IGT). It is
resistance occurs in the presence of a genetically deter- now generally accepted that insulin resistance and ␤-cell
mined propensity to ␤-cell dysfunction, glucose intoler- dysfunction are major factors involved in the development
of diabetes. The relative contribution of insulin resistance
ance can occur (5). Although there is still disagreement versus ␤-cell dysfunction on the pathogenesis of diabetes
over the relative contribution in the alterations in insulin has aroused much debate. These two processes should be
sensitivity versus ␤-cell function in the development of studied in relation to one another: their relationship is
diabetes, it is becoming clear that reductions in both best described as hyperbolic in nature. When this relation-
processes have already occurred by the time hyperglyce- ship is taken into consideration, it becomes evident that
mia develops (8).
subjects at risk of developing type 2 diabetes have ␤-cell
The concept for the prevention of diabetes developed on dysfunction before they develop glucose intolerance. In-
the basis of a better understanding of the pathophysiology sulin resistance may be mostly explained by the presence
of glucose intolerance and stimulated by the ever-increas- of obesity and accelerate the progression to diabetes in
ing burden of the disease. It has now been demonstrated subjects with the propensity to ␤-cell failure. By the time
hyperglycemia occurs, impairment in both insulin sensitiv-
that diabetes can be prevented, or at least delayed, by ity and insulin secretion are present. There are still few
nonpharmacological interventions, such as lifestyle modi- data on insulin sensitivity and insulin secretion from the
fication including diet and exercise (9 –11), and by phar- trials on the prevention of diabetes. The few data that we
do have suggest that most interventions mostly have an
acarbose (12), and troglitazone (13) (Table 1).
effect on insulin resistance. By reducing insulin resis-
The purpose of this article is to discuss the mecha- tance, they protect and preserve the ␤-cell function. No
nism(s) involved in the prevention of type 2 diabetes by intervention has yet shown any direct effect on ␤-cell
those different interventions. Is it through an effect on function. Diabetes 53 (Suppl. 3):S34 –S38, 2004
insulin resistance and/or insulin secretion or through someother mechanisms? In the first part, we will briefly reviewthe pathophysiology of type 2 diabetes. In the second part, we will describe the major intervention trials on the he prevalence of type 2 diabetes is increasing in prevention of type 2 diabetes and discuss the probable epidemic proportions worldwide. It has been mechanism(s) involved in the prevention of diabetes.
estimated that the diabetic population will dou-ble from 150 to 300 million in the next 25 years (1). Furthermore, the long-term complications associated THE PATHOPHYSIOLOGY OF TYPE 2 DIABETES
with diabetes are major causes of morbidity and mortality, For a more detailed discussion on the pathogenesis of type imposing a high financial burden on health care costs 2 diabetes, we refer the readers to the recent review articleby Kahn (14). For the purpose of our discussion, we willbriefly discuss insulin resistance, insulin secretion, and From the Research Centre, Centre Hospitalier de l'Universite´ de Montre´al– their interactions in the development of type 2 diabetes.
Hoˆtel-Dieu, and the Department of Medicine and Nutrition, University ofMontreal, Montreal, Quebec, Canada.
Several longitudinal studies have clearly shown that Address correspondence and reprint requests to Dr. Jean-Louis Chiasson, insulin resistance is a major risk factor for the develop- Research Centre–CHUM–Hoˆtel-Dieu, 3850 St. Urbain St., Rm. 8-202, Montreal ment of type 2 diabetes (15,16). In a prospective study of (Quebec) H2W 1T7, Canada. E-mail: [email protected].
Received for publication 20 March 2004 and accepted in revised form 3 June Pima Indians, Lillioja et al. (15) studied the relative roles of obesity, insulin resistance, and ␤-cell dysfunction in the This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educa- development of type 2 diabetes in subjects with normal tional grant from Servier.
glucose tolerance (n ⫽ 151) or impaired glucose tolerance FSIVGTT, frequently sampled intravenous glucose tolerance test; IGT, impaired glucose tolerance.
⫽ 49). All subjects had body composition assess- 2004 by the American Diabetes Association.
ment, oral and intravenous glucose tolerance tests, and a DIABETES, VOL. 53, SUPPLEMENT 3, DECEMBER 2004

J.-L. CHIASSON AND R. RABASA-LHORET
TABLE 1Intervention studies on the prevention of type 2 diabetes Studies (ref. no.) Lifestyle modifications Da Qing (1997) (9) Diet and/or exercise Diet and exercise Diet and exercise Drug interventions TRIPOD (2002) (13) STOP-NIDDM (2002) (12) hyperinsulinemic-euglycemic clamp study. The insulin re- while only those with IGT also had a significant reduction sistance was the strongest single predictor for diabetes, in insulin sensitivity compared with appropriate control with a 27% cumulative incidence of diabetes over 6 years (Fig. 2). This study provides evidence that impairment of (Fig. 1). The acute plasma insulin response alone was not ␤-cells can occur before insulin resistance is detectable.
a significant predictor for diabetes. However, the combi- However, both seem to be present by the time hypergly- nation of insulin resistance and insulin response provided cemia appears. Other reports have confirmed those obser- the strongest predictor with a 6-year cumulative incidence vations in offspring of two parents with type 2 diabetes of diabetes of 39%. They concluded that insulin resistance (17) or first-degree relatives of someone with type 2 was a major risk factor for the development of diabetes, diabetes (21,22). Taken together, these observations pro- with insulin secretion being an additional but weaker risk vide strong evidence that ␤-cell dysfunction is already factor (15). Warram et al. (17) followed for 25 years 155 present in normal glucose-tolerant individuals genetically offspring of couples who both had type 2 diabetes. Sub- predisposed to develop type 2 diabetes. It also suggests jects who developed diabetes had insulin resistance ⬎10 that insulin resistance can be attributed mostly to obesity years before they developed the disease. However, they and/or reduced physical fitness. This is suggested by a found no evidence of an insulin secretion defect several number of studies indicating that weight loss will reverse years before the development of diabetes. In a few sub- the insulin resistance (23–25) without normalizing the jects, they noticed a gradual decline in insulin secretory insulin secretory defect.
capacity before the onset of diabetes. These observations In interpretation of these observations, it is most often argue in favor of insulin resistance as the primary defect in lost to the observers that insulin sensitivity is itself a the development of diabetes. The major argument support- determinant of the magnitude of the insulin response.
ing insulin resistance as a primary genetic factor leading to Thus, insulin-resistant subjects have a greater insulin diabetes is the observations that its appearance precedes response to glucose, whereas insulin-sensitive subjects detection of impaired ␤-cell function (17,18). However, have a smaller insulin response (26). The relationship Gerich (19) claims that the influence of obesity needs to be between insulin sensitivity and insulin secretion has been taken into consideration and that people at risk for diabe- described as a hyperbolic relationship. The nature of this tes are not insulin resistant relative to appropriate control, relationship implies that the product of insulin sensitivity i.e., obese control! Moreover, although many obese sub- and insulin response is a constant at a given degree of jects are insulin resistant, most of them do not progress to glucose tolerance (26) (Fig. 3). Therefore, when insulin sensitivity varies, a proportional and reciprocal alteration Vaag et al. (20) studied monozyzotic twins, one of whom already had diabetes and one of whom had either normalglucose tolerance or IGT. Those with normal glucosetolerance or IGT had decreased first-phase insulin release, FIG. 2. Insulin secretion and insulin sensitivity in monozygotic twins
FIG. 1. Six-year cumulative incidence of diabetes according to insulin
with normal glucose tolerance, impaired glucose tolerance, or diabetes.
sensitivity and insulin secretion. Adapted from Lillioja et al. (15).
Adapted from Vaag et al. (20).
DIABETES, VOL. 53, SUPPLEMENT 3, DECEMBER 2004

PREVENTION OF TYPE 2 DIABETES
ported by a recent study from Ferrannini et al. (33), whodemonstrated a defect in glucose sensitivity and insulinrelease in IGT subjects that predominated over insulinresistance.
In summary, insulin resistance seems to be explained mostly by the presence of obesity. In fact, weight reduc-tion is associated with a normalization of insulin sensitiv-ity. On the other hand, ␤-cell dysfunction is present yearsbefore glucose intolerance appears, and no interventionhas yet been able to correct this abnormality. This wouldsupport the concept that ␤-cell failure is the primarydefect leading to the development of diabetes. Insulinresistance, acquired though obesity, and decreased physi-cal activity will further accelerate the progression to FIG. 3. Schematic representation of hyperbolic relationship between
diabetes. This would explain the epidemic explosion of insulin sensitivity and insulin secretion in subjects with different
diabetes in a world getting fatter and more sedentary.
glucose tolerance. NGT, normal glucose tolerance. Adapted from Kahn
et al. (26).
THE PREVENTION OF DIABETES: AN EFFECT ON
in insulin output has to occur for glucose tolerance toremain constant. As such, the product of insulin sensitivity INSULIN SENSITIVITY AND/OR INSULIN SECRETION?
and insulin response provides a better measurement of The major intervention trials on the prevention of diabetes ␤-cell function rather than the insulin or C-peptide re- are relatively recent, and analysis of the data is ongoingsponse examined in isolation. When this relationship be- (Table 1). For that reason, we still do not have published tween insulin sensitivity and insulin secretion is taken into data on insulin sensitivity and insulin secretion for those consideration, it becomes evident that subjects who are at high risk of developing type 2 diabetes have demonstrated A number of observational studies suggested that ␤-cell dysfunction at a time when they still have normal weight loss and physical activity could reduce the risk ofglucose tolerance. The first-degree relatives of patients developing diabetes (34 –36). Three prospective interven- with diabetes (27–29) and subjects with IGT (30,31) can all tion studies have now confirmed the efficacy of lifestyle be shown to have ␤-cell dysfunction that is reduced modification, including diet and exercise (9 –11), in reduc- relative to the degree of insulin sensitivity. These cross- ing the risk of type 2 diabetes in a high-risk population sectional data are also supported by a longitudinal study in with IGT. The Da Qing Study (37) was the first to show in Pima Indians who had normal glucose tolerance at base- 577 subjects with IGT that diet and/or exercise could line (32). Those who developed diabetes had a 78% decline lower the risk of diabetes by 39% over 6 years. Using in insulin secretion and a 14% decrease in insulin sensitiv- homeostasis model assessment (HOMA), the authors have ity (Fig. 4). On the other hand, those who did not develop looked at the effect of insulin resistance and ␤-cell dys- diabetes also had an 11% decrease in insulin sensitivity, function on the incidence of diabetes in a subgroup of but the change was associated with a 30% increase in patients (n ⫽ 284) in the four treatment groups (38). Both insulin secretion. In this latter group, the relationship insulin resistance and impaired insulin secretion at base- between insulin sensitivity and insulin release was main- line were significantly associated with the development of tained. Close examination of these responses therefore diabetes at follow up (P ⬍ 0.05, P ⬍ 0.01). When the show the presence of impaired ␤-cell function in subjects subgroup was split in two, according to insulin resistance at risk of developing diabetes, even when these subjects and insulin secretion, those who were less insulin resistant still have normal glucose tolerance. This is further sup- responded better to lifestyle modification. Those who hadgreater insulin secretion, however, did not respond signif-icantly better to the intervention. The missing analysis iswhether intervention per se had any effect on insulinresistance and insulin secretion. Other studies wouldsupport an effect of diet and exercise on insulin resistance(23–25). An effect of lifestyle modification on insulinsecretion, however, is unlikely (24).
In the Finnish Diabetes Prevention Study (DPS) (10), lifestyle modification in subjects (n ⫽ 522) with IGTresulted in a 58% reduction in the risk of diabetes. Thefrequent sampling intravenous glucose tolerance test(FSIVGTT) was done at baseline and repeated at 4 years.
At 4 years, the insulin sensitivity tended to be higher in theintervention group (P ⫽ 0.067) (39). There was a strongcorrelation between weight change and change in insulinsensitivity. In fact, those who lost weight in the controlgroup were also protected against diabetes. Although no FIG. 4. Changes in ␤-cell function and in insulin sensitivity at low
improvement was observed in insulin secretion in the insulin concentration with the development of glucose intolerance.
Adapted from Weyer et al. (32).
intervention group, it declined significantly in the control DIABETES, VOL. 53, SUPPLEMENT 3, DECEMBER 2004 J.-L. CHIASSON AND R. RABASA-LHORET
TABLE 2Average annual incidence rates of diabetes in tertiles of the troglitazone group defined by changes in insulin sensitivity or by changesin IVGTT insulin between baseline and 3 months on trial Change in SI Annual diabetes incidence (%) Change in IVGTT insulin area ⫺1,238 to ⫺3,053 ⫺3,160 to ⫺193,64 Annual diabetes incidence (%) Data are from 108 women randomized to troglitazone who had IVGTTs at baseline and 3 months on trial. P values among subgroups bylog-rank test. *P ⬍ 0.01, †P ⬍ 0.05, and ‡P ⬍ 0.001 vs. diabetes incidence in placebo group (log-rank test). Adapted from Buchanan et al. (42).
group. They concluded that weight change resulted in a in insulin resistance offers a protective effect on the ␤-cell significant improvement in insulin sensitivity, which was and, therefore, has a preservative effect on the ␤-cell associated with a reduction in the incidence of diabetes.
function. Furthermore, all interventions on the prevention Insulin secretion, on the other hand, remained constant in of diabetes so far could not show any effect on ␤-cell those who were able to lose weight (39).
function. At best, it can preserve the insulin secretion At present, no data on insulin sensitivity and insulin capacity by decreasing the stress on the ␤-cells. This secretion in relation to lifestyle modification have been would support the concept that the major genetic defect in published for the Diabetes Prevention Program (40,41); it the development of diabetes is related to ␤-cell dysfunction.
is very likely that observations similar to those of the DPSwill be seen. In addition, no data for the metformin treatment group have yet been published.
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