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Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, ON, Canada
3To whom correspondence should be addressed. E-mail: Lrobinso{at}uoguelph.ca.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • caffeine • carbohydrate • insulin resistance • hyperinsulinemia • insulin sensitivity index
Type 2 diabetes, which accounts for >90% of all diabetes cases worldwide, currently affects 
6% of the adult population in Western society and is estimated to affect 300 million adults globally in the year 2025 (1,2). It is characterized by insulin resistance and/or abnormal insulin secretion, resulting in a decrease in whole-body glucose disposal. The complications associated with type 2 diabetes, such as retinopathy, nephropathy, and peripheral neuropathy, are a significant cause of morbidity and mortality (2). In addition, individuals with chronic hyperglycemia, insulin resistance, and/or type 2 diabetes are at greater risk for hypertension, dyslipidemia, and cardiovascular disease (3). Although genetic factors may play a role in the etiology of type 2 diabetes (4), there is now convincing evidence that type 2 diabetes is strongly associated with modifiable factors, such as a sedentary lifestyle and obesity. Although the majority of studies investigating lifestyle intervention and type 2 diabetes have focused on reductions in energy and fat intake, weight loss, and physical activity (5,6), many other dietary factors are currently being studied for their potential role in insulin resistance, the hallmark characteristic of type 2 diabetes. One common biologically active food component that has been recently implicated in acute insulin resistance is caffeine.
Caffeine (1,3,7-trimethylxanthine) is a common biologically active food component with potential health implications. The mean intake per capita in Western society is estimated to be 200–400 mg/d (7) with the vast majority consumed from dietary sources such as coffee, tea, cola drinks, and chocolate. In addition, the food industry recently introduced nontraditional dietary sources of caffeine, including energy drinks, gum, water, and alcoholic beverages, all of which may contribute to overall caffeine intake in the population. Recently, Health Canada reported that for the average adult, a daily caffeine intake of 400–450 mg/d is not associated with any adverse effects (8). Interestingly, epidemiologic studies examining coffee consumption in several countries reported that consuming large amounts of coffee drastically reduced the risk of type 2 diabetes (9–13). Although the precise component in coffee responsible for this association is not known, the results are interesting given that several studies have shown that caffeine and the dimethylxanthine, theophylline, negatively affect whole-body glucose disposal and insulin sensitivity in humans (14–18). Given the common consumption of caffeine in today’s society and recent contradictory reports regarding caffeine/coffee use in relation to diabetes risk and insulin sensitivity (9,19), studies investigating the health effects of caffeine are warranted. The purpose of this study was to investigate the effect of caffeine on glucose tolerance and insulin sensitivity responses during an oral glucose tolerance test (OGTT)4 in individuals with type 2 diabetes. We hypothesized that caffeine ingestion before an oral glucose load would negatively affect insulin sensitivity in adult men with type 2 diabetes.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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30 kg/m2 were classified as obese in accordance with the Clinical Guidelines for Identification, Evaluation, and Treatment of Overweight and Obesity in Adults (20).
Experimental design.
Subjects reported to the laboratory on 2 separate occasions, 1 wk apart, after an overnight (10–12 h) fast. A catheter was inserted into an antecubital vein for blood sampling and kept patent with a normal saline drip. A venous blood sample was taken at time –60 min followed by ingestion of either placebo (dextrose) or caffeine (5 mg/kg body weight) capsules with 250 mL of water in a randomized, double-blind design. One hour after capsule ingestion (time = 0 min) a venous blood sample was taken and a 180-min OGTT was initiated by ingestion of 75 g of dextrose (TRUTOL 75, Custom Laboratories). At each trial, the glucose beverage was consumed within 10 min; resting blood samples were taken at 15, 30, 60, 90, 120, 150, and 180 min after consumption of the glucose load. The amount of dextrose administered in the placebo capsules was a small percentage (<1%) of that ingested in the OGTT. This protocol (both the dose and administration of caffeine) was used previously and elicits plasma caffeine concentrations of 30–45 µmol/L (14). Because orally ingested caffeine is rapidly and totally absorbed (i.e., virtually 100% bioavailable), complete absorption occurs within 45–60 min (21), ensuring that peak plasma caffeine concentrations are achieved before ingestion of the OGTT.
Laboratory analyses.
Blood samples were analyzed for glucose, insulin, C-peptide, proinsulin, FFA, and glycerol. Whole-blood glucose was analyzed immediately by a glucose oxidase method (YSI 2300 Stat Plus Glucose Analyzer). At each time point, 7 mL of blood was collected in a nonheparinized tube and allowed to clot at room temperature. Samples were then centrifuged at room temperature for 10 min at 1200 x g and serum was stored at –20°C until analyzed for insulin, C-peptide, proinsulin (0, 30, 60, 90, 120, and 180 time points only), FFA, and glycerol. All blood metabolites were determined as the mean of duplicate determinations. To minimize the effects of assay variability, samples from each subject were analyzed in the same assay. RIA kits were used to measure serum insulin (Coat-a-Count Insulin, Intermedico Diagnostic Products), C-peptide in samples treated with aprotinin (Human C-peptide RIA kit, Linco Research), and proinsulin (Human Proinsulin RIA kit, Linco Research). The minimal detectable limit for insulin was 8.7 pmol/L and the intra- and interassay CVs were 3 and 7%, respectively. The Intermedico insulin kit has a 40% crossreactivity with proinsulin, whereas the proinsulin kit has specificities of 100% for intact proinsulin, 95% for des-31,32-proinsulin, and <0.1% for human insulin. Thus, the actual measurement is proinsulin-like compounds, but for simplicity, this is referred to as proinsulin. We compared the Intermedico insulin kit with a human insulin–specific RIA kit from Linco with <0.2% crossreactivity with proinsulin and found a strong correlation (R2 = 0.94) between the 2 kits (data not shown). Serum FFA were measured using a NEFA kit from Wako Chemicals, and glycerol was analyzed according to the method of Lowry and Passoneau (22).
Calculations and statistical analysis. Areas under the curve (AUCs) for glucose, insulin, C-peptide and proinsulin were calculated for both the caffeine and placebo trials during the 3-h OGTT (time 0 to 180 min) using the trapezoid method (23). The ratio of proinsulin/insulin was calculated at time 0 min (immediately before OGTT) and at 30 min of the OGTT because this was suggested to accurately reflect ß cell secretion (24). Whole-body insulin sensitivity during the OGTT was estimated using the equation described by Matsuda and DeFronzo (25). This equation gives an insulin sensitivity index (ISI) that is significantly correlated (r = 0.73, P < 0.0001) with the rate of whole-body glucose disposal during a hyperinsulinemic-euglycemic clamp (25). We acknowledge that our calculation of the ISI was based on serum insulin and whole-blood glucose as opposed to plasma concentrations of these metabolites as described in the above equation; however the data were used for comparative purposes only.
Data were analyzed for time and treatment effects using a 2-way ANOVA with repeated measures. Significant differences (P 
0.05) were identified using Tukey’s post-hoc analysis (Sigma Stat 2.03, 1997). Significant (P 0.05) treatment differences in AUC were determined using a paired t test. Results are presented as means ± SEM.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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30 kg/m2). The blood glucose concentration of fasting subjects was 6.7 ± 0.3 mmol/L (Table 1), which meets the WHO (26) diagnostic criteria for type 2 diabetes [whole-blood (venous) fasting glucose concentration 6.1 mmol/L]. Dietary analysis of self-reported food records for the 3 d before each experiment showed that the mean total energy intake of the subjects was 8950 ± 377 kJ/d (2130 ± 91 kcal/d), and the percentages of energy from carbohydrates, fat, and protein were 47 ± 1, 34 ± 1, and 19 ± 1%, respectively. The total energy and nutrient intakes of each subject did not differ significantly before each experiment (data not shown).
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0.001) after ingestion of dextrose in both the placebo and caffeine trials. Despite the prolonged elevated serum insulin concentration after caffeine ingestion, blood glucose concentration was also increased (P < 0.01) compared with the placebo trial. In particular, blood glucose was significantly higher for the last 90 min of the OGTT (from 90 to 180 min after dextrose ingestion). In the placebo trial, blood glucose returned to baseline (0 min) concentration by 180 min post-OGTT, whereas in the caffeine trial, glucose concentration remained significantly higher than baseline at 180 min. Overall, blood glucose AUC during the OGTT was significantly increased (16%) after ingestion of caffeine compared with placebo (Table 2).
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FFA and glycerol. Serum FFA concentration increased (P < 0.001) from –60 to 0 min in the caffeine, but not placebo trial (Fig. 4). However, after dextrose ingestion, serum FFA started to decrease; at 30 min, it was no longer different from the fasting (–60 min) concentration in the caffeine trial. In both the placebo and caffeine trials, serum FFA concentrations were lower during the last 2 h of the OGTT (from 60 to 180 min) compared with the start of the OGTT. Unlike FFA, the increase in serum glycerol immediately after caffeine ingestion (from –60 to 0 min) was not significant (P = 0.09). In addition, in both the placebo and caffeine trials, serum glycerol concentrations did not change during the OGTT, with the exception of a lower (P < 0.04) serum glycerol concentration at 120 min (compared with 0 min) in the caffeine trial. In the caffeine trial, serum FFA concentration remained higher than placebo for the initial 120 min of the OGTT (P < 0.01), whereas serum glycerol was significantly higher after caffeine than after placebo ingestion for the entire 3 h OGTT with the exception of the 60-min time point.
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Although this study was not designed to assess the mechanism(s) by which caffeine leads to acute insulin resistance, there are several factors that could be involved. It is not known whether the caffeine-induced elevation in serum insulin was due to an increase in insulin secretion, a decrease in insulin clearance, or a combination of these actions. In the current study, there were no changes in serum insulin or C-peptide concentrations until after initiation of the OGTT, suggesting that it is unlikely that caffeine directly stimulated insulin secretion and/or inhibited insulin clearance. Furthermore, studies with hyperinsulinemic clamps confirmed that methylxanthines impair glucose disposal (15–17). However, because it was reported that pharmacologic caffeine doses could directly stimulate ß cell secretion of insulin (30), we measured serum C-peptide and proinsulin to further investigate this issue. Because C-peptide and insulin are secreted in equimolar amounts, serum concentrations usually change in parallel. In the current study, the serum C-peptide AUC increased to the same extent (25%) as insulin, but unlike insulin, the increase was not significant (P = 0.1). This may not be entirely unexpected because a recent study with obese, nondiabetic men found that C-peptide did not significantly increase as a result of caffeine ingestion, whereas insulin did (28). It is possible that subjects in the current study experienced elevated serum insulin concentrations as a result of both increased insulin secretion and decreased insulin clearance. The effect of caffeine on proinsulin in type 2 diabetes has not been previously reported and although caffeine increased proinsulin AUC during the OGTT, it did not alter the proinsulin/insulin ratio, suggesting that caffeine was not interfering with proinsulin processing or enhancing secretion of immature vesicles. Because the proinsulin/insulin ratio did not change, this supports our previous suggestions that caffeine may directly or indirectly induce acute peripheral insulin resistance (14,15), which in turn would stimulate greater insulin secretion. Overall, the mechanism for the acute insulin-resistant state after caffeine ingestion in persons with type 2 diabetes remains to be established.
In light of recent reports that long-term, moderate-to-heavy coffee drinking results in protection from type 2 diabetes (9–13), it is critical to note that the current study used pure caffeine instead of a caffeine-containing beverage, such as coffee, as well as to consider the influence of acute vs. chronic ingestion of biologically active food components. First, coffee and other caffeine-containing products are comprised of numerous biologically active compounds, including phenolic compounds (e.g., chlorogenic acids, caffeic acid), polysaccharides, minerals (e.g., magnesium), and lipids, with caffeine accounting for only 2% of coffee’s chemical profile (31). Thus, it is entirely possible that some component of the remaining 98% of coffee’s constituents acts as an antagonist to the action of caffeine. Results from acute studies in lean humans suggest that although ingestion of either pure caffeine or caffeine as a component of coffee before an OGTT impairs glucose tolerance, the responses are not equivalent, with pure caffeine resulting in greater glucose intolerance (32). A recent study by Shearer et al. (33) using a synthetic quinide, representative of those found in roasted coffee, showed increased whole-body glucose disposal in rats, suggesting a possible mechanism by which coffee exerts its putative antidiabetic effects. Other compounds in coffee with known antioxidant activity (34,35) may also play a role in protection against insulin resistance and type 2 diabetes (36). Although the antioxidant activity of coffee could potentially be related to its caffeine content (34), at physiologic caffeine concentrations, it is most likely associated with other compounds in coffee (e.g., caffeic acid) (35). The ingestion of caffeine as a component of coffee has not been studied in persons with type 2 diabetes, but warrants further investigation.
Another potential explanation for the divergent roles of caffeine/coffee in type 2 diabetes may be that habitual coffee drinkers, as studied in recent epidemiologic reports (9–13), may become adapted to the negative effects of caffeine on glucose tolerance. Although it is not known whether this occurs, it is noteworthy that, if habituation does take place, the current study as well as other studies (18,28) showed that it must be reversed within the 48 h that subjects withdraw from caffeine before the test day. Studies are currently ongoing in our laboratory to investigate caffeine habituation and glucose homeostasis. Overall, the relation between caffeine ingestion and glucose homeostasis is complex, making it difficult to compare results from acute metabolic studies with those from population-based studies examining chronic use of coffee and other caffeinated beverages. A recent report describing the J-shaped relationship between coffee consumption and risk of developing acute coronary syndrome (37) provides further support that establishing the potential health implications of dietary caffeine is a difficult task.
Although we observed significant caffeine-induced impairments in glucose management, the current results should be interpreted with caution because the biological and clinical relevance of such changes has not yet been established. Nonetheless, our findings may be of importance given the following: 1) caffeine is a biologically active food component found in an increasing number of novel products on the market (e.g., "energy drinks" and alcoholic beverages) and has been shown in several studies to acutely impair insulin sensitivity; 2) an alarming and rapidly escalating number of individuals are affected by insulin resistance and/or type 2 diabetes; and 3) insulin resistance and/or abnormal glucose metabolism are associated with numerous metabolic abnormalities. Limitations of the current work include the small number of study participants and their relatively poor glycemic status. It is not known whether caffeine would have a negative effect on insulin sensitivity in better-controlled type 2 diabetics and/or other types of abnormal glucose metabolism, such as impaired glucose tolerance. Also, due to potential confounding effects on glucose tolerance, subjects were instructed to withdraw from alcohol, exercise, caffeine, and oral hypoglycemic medication for 48 h before each experiment. Because this situation may not be representative of all persons with type 2 diabetes, results should again be interpreted with caution until further studies with more realistic study designs are conducted. Current ongoing studies in our laboratory are investigating the effect of caffeine (in the form of coffee) and carbohydrate ingestion on blood glucose management using a protocol that is more representative of every day life. Although it may be premature to establish dietary recommendations for caffeine use in the prevention and management of type 2 diabetes, this common biologically active food component should be recognized for its potential effect on insulin resistance.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by a grant from the Natural Sciences and Engineering Research Council (NSERC) of Canada Collaborative Health Research Grant (T.G.). D.S.B. and L.E.R. were supported by an NSERC postgraduate scholarship and postdoctoral fellowship, respectively.
4 Abbreviations used: AUC, area under the curve; ISI, insulin sensitivity index; OGTT, oral glucose tolerance test.
Manuscript received 19 April 2004. Initial review completed 20 May 2004. Revision accepted 4 July 2004.
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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