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The Use of Tolbutamide-Induced Hypoglycemia to Examine the Intraislet Role of Insulin in Mediating Glucagon Release in Normal Humans¹

University Department of Medicine (S.R.P., E.G.), Clinical Sciences Centre and Diabetes Centre (S.R.H.), Northern General Hospital, Sheffield, United Kingdom, S5 7AU; and Department of Pharmacology and Therapeutics (A.R.H., G.T.T.), Royal Hallamshire Hospital, Sheffield, United Kingdom, S10 2JF

Address all correspondence and requests for reprints to: Dr. Steven R. Peacey, Department of Endocrinology, Christie Hospital, Wilmslow Road, Manchester M20 4BX, United Kingdom.

	Abstract

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Disruption of intraislet mechanisms could account for the impaired glucagon response to hypoglycemia in type 1 diabetes. However, in contrast to animals, there is conflicting evidence that such mechanisms operate in humans. We have used iv tolbutamide (T) (1.7 g bolus + 130 mg/h infusion) to create high portal insulin concentrations and compared this with equivalent hypoglycemia using an iv insulin infusion (I) (30 mU/m²·min). Ten normal subjects underwent two hypoglycemic clamps; mean glucose; I (53 ± 1 mg/dL); and T (53 ± 1 mg/dL) (2.9 ± 0.04 mmol/L vs. 2.9 ± 0.05 mmol/L), held for 30 min. During hypoglycemia, mean peripheral insulin levels were greater with I (59 ± 4 mU/L) than T (18 ± 3 mU/L), P < 0.001. Calculated peak portal insulin concentrations were greater during T (282 ± 28 mU/L) than I (78 ± 4 mU/L), P < 0.00005. The demonstration of a reduced glucagon response during T-induced hypoglycemia (111 ± 8 ng/L vs. 135 ± 12 ng/L, P < 0.05) with higher portal insulin concentrations suggests that intraislet mechanisms may contribute to the release of glucagon during hypoglycemia in man.

	Introduction

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A NUMBER of studies in man have established the prime importance of the rise in glucagon among the physiological responses to hypoglycemia (1, 2, 3). The mechanism whereby glucagon is released from pancreatic -cells during hypoglycemia is poorly understood. It has been proposed that insulin may have a paracrine role, by tonically inhibiting glucagon release from adjacent -cells (4). The reduction in endogenous insulin secretion, as blood glucose falls, reduces the intraislet insulin concentration, with resulting disinhibition of the -cell and glucagon release.

In patients with type 1 diabetes, the glucagon response to hypoglycemia declines with increasing duration of disease (5, 6), increasing the risk of severe hypoglycemic episodes during therapy. However, the glucagon response to other secretagogues, such as arginine, remains intact (5, 7), suggesting an afferent defect with failure of the -cell to recognize hypoglycemia. This could be related to a disruption of intraislet relationships as the ß-cell population is progressively destroyed.

There is persuasive evidence from animal models supporting the above hypothesis (8), but the experimental data in human subjects are conflicting (9, 10, 11, 12). The experimental approach in human studies has been to compare the effects of high and low dose peripheral insulin infusions (I). The model produces variable suppression of endogenous insulin secretion depending upon the I rate, with changing portal insulin concentrations generally similar to peripheral insulin concentrations.

We have developed an alternative experimental model of hypoglycemia, with glucagon responses measured during hypoglycemia, induced by either insulin or a sulfonylurea [tolbutamide (T)]. We set out to test the paracrine hypothesis by comparing glucagon responses with hypoglycemia when the -cell was exposed to either high or low intraislet insulin concentrations.

	Subjects and Methods

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Ten normal subjects with no family history of diabetes (3 female, 7 male, mean age 28 ± 1.3 (SEM) yr, mean body mass index 24.5 ± 0.9 kg/m²) were studied on two occasions in random order, at least 4 weeks apart. Subjects were studied in the fasted state at 0800 h. A 21-gauge cannula was inserted into the nondominant antecubital fossa and a 19 gauge cannula inserted retrogradely into the hand on the same side. The hand was placed in a heated box at 60 C (13) and the cannula kept patent between sampling using 0.9% sodium chloride (Baxter Healthcare, Thetford, Norfolk, UK).

On one occasion (insulin arm), we infused soluble insulin (Human Actrapid, Novo Nordisk Pharmaceuticals Ltd, Crawley, West Sussex, UK; 25 U added to 48 mL of 0.9% sodium chloride and 2 mL autologus blood) at 30 mU/m²·min, into the antecubital vein (IVAC 770, IVAC Corporation, San Diego, CA). On the other (T arm), 1.7 g of T (Hoechst UK Ltd, Hounslow, Middlesex, UK) were given iv over 3 min into the antecubital vein, followed by a continuous infusion of T at 130 mg/h after time = 10 min. A total of 2 g iv T was used in each subject in an attempt to achieve sufficient insulin secretion to maintain blood glucose at 50 mg/dL (2.8 mmol/L) for 30 min. The T regimen was devised to achieve near-steady state T concentrations using data from a previous study of T pharmacokinetics (14).

Twenty percent glucose (Baxter Healthcare) was given into the antecubital vein by infusion pump (IVAC 591, IVAC Corporation) and the rate adjusted according to arterialized-venous blood glucose measurements made every 3–5 min using a glucose oxidase method (YSI 2300, Yellow Springs Instruments, Yellow Springs, OH). Five subjects received T in their first study, and five received insulin, but all were unaware of the experimental conditions.

From time -30 to zero min, basal samples were taken for analysis of insulin, C-peptide, glucagon, and epinephrine. The blood glucose was lowered immediately from the start, to reach and maintain a target nadir of 50 mg/dL (2.8 mmol/L). The rate of fall of blood glucose concentration was matched for the two studies within each individual. Blood was taken for insulin and C-peptide at 5, 10, and 20 min and for insulin, C-peptide, glucagon, and epinephrine at the start of the hypoglycemic plateau and 15 and 30 min later (H0, H15, and H30). Blood samples were separated and stored at -70 C for later assay of epinephrine (15), glucagon (16), C-peptide (17), and total insulin (18).

Portal insulin concentrations were calculated by fitting a least-squares spline to the C-peptide data and insulin secretion rates calculated using a two compartment model, as previously described (19). Model parameters, as described by Polonsky (20), were used and portal venous insulin concentrations estimated, as described by DeFronzo (21), and adjusted for nonsteady-state conditions (22).

Results are expressed as mean ± SEM and P < 0.05 considered significant. We generally combined data in an overall measure of area under the curve (AUC) and compared these by paired t test. Repeated-measures ANOVA with Tukey’s analysis was used for serial comparisons of the insulin and C-peptide data. Ethical approval was granted by the Northern General Hospital Research Ethics Committee.

	Results

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Glucose

Arterialized-venous whole blood glucose concentrations were matched during induction of hypoglycemia. The mean time interval between zero min and the start of the hypoglycemic plateau was similar in the insulin arm to the T arm [35.0 ± 2.0 (range 30–50) min vs. 34.2 ± 1.8 (range 25–45) min]. During the hypoglycemic plateau (H0–H30) blood glucose concentrations were similar with insulin and T (53 ± 1 mg/dL vs. 53 ± 1 mg/dL; 2.9 ± 0.04 mmol/L vs. 2.9 ± 0.05 mmol/L) (Fig. 1). The Dextrose infusion rates were no different between studies (AUC, 25 ± 5 ml vs. 20 ± 3 mL; P = 0.27) (Fig. 1).

View larger version (22K): [in this window] [in a new window]   Figure 1. Blood glucose concentration and glucose infusion rates (mean ± SEM). Glucose values were matched during insulin- (--) and T-induced (--) hypoglycemia (53 ± 1 mg/dL vs. 53 ± 1 mg/dL, P = NS (not significant), during the 30-min hypoglycemic plateau) (2.9 ± 0.04 mmol/L vs. 2.9 ± 0.05 mmol/L, P = NS). AUC dextrose 20% infusion rates were similar (25 ± 5 mL vs. 20 ± 3 mL, P = NS).

During the the insulin arm, the peripheral insulin concentration remained constant (mean 59 ± 4 mU/L) and was significantly greater than the peripheral insulin concentration measured during the T arm, which fell throughout (31 ± 6 mU/L, P < 0.001 at H0; 15 ± 2 mU/L, P < 0.001 at H15; 9 ± 1 mU/L, P < 0.001 at H30). The peripheral insulin AUC measured from time zero min was significantly greater in the insulin arm (3732 ± 377 mU/L·min vs. 2101 ± 191 mU/L·min, P < 0.02) (Fig. 2).

View larger version (19K): [in this window] [in a new window]   Figure 2. Peripheral insulin, portal insulin, and C-peptide concentrations (mean ± SEM) during insulin- (--) and T-induced (--) hypoglycemia. Significant differences, as shown (*, P < 0.05; **, P < 0.01; #, P < 0.001).

During induction of hypoglycemia, the calculated portal insulin concentration was greater in the T arm (5 min: 274 ± 22 mU/L, P < 0.001; 10 min: 221 ± 15 mU/L, P < 0.001; 20 min: 128 ± 13 mU/L, P < 0.01) than during the insulin arm (mean 69 ± 3 mU/L), and the peak portal insulin concentration achieved was greater during the T arm (282 ± 28 mU/L vs. 78 ± 4 mU/L, P < 0.00005). During the hypoglycemic plateau, the portal insulin concentration was higher during the insulin study at H30 (63 ± 4 mU/L vs. 13 ± 3 mU/L, P < 0.05). The portal insulin AUC from time = zero min was greater in the T arm than in the insulin arm (7581 ± 595 mU/L·min vs. 4248 ± 442 mU/L·min, P < 0.001) (Fig. 2).

Glucagon

Glucagon increased significantly from baseline during both the T (P < 0.00005) and insulin (P < 0.00005) arms but reached a lower peak value in the T arm, as compared with the insulin arm (111 ± 8 ng/L vs. 135 ± 12 ng/L, P < 0.05). The glucagon AUC above baseline from zero min, was significantly lower during the T arm than during the insulin arm (2336 ± 239 ng/L·min vs. 3141 ± 321 ng/L·min, P < 0.01) (Fig. 3).

View larger version (19K): [in this window] [in a new window]   Figure 3. Significantly greater peak (P < 0.05) and AUC above baseline (P < 0.01) glucagon response occurred during insulin- (--), as compared with T-induced (--) hypoglycemia. No difference was found in epinephrine responses.

Epinephrine increased significantly from baseline in both the T (P < 0.00001) and insulin (P < 0.0005) arms. Peak epinephrine response was similar in both studies (1.8 ± 0.1 nmol/L vs. 1.9 ± 0.3 nmol/L, P = 0.6). The epinephrine AUC above baseline from zero min was similar in both arms (29.5 ± 3 nmol/L·min vs. 29.0 ± 5.6 nmol/L·min, P = 0.93) (Fig. 3).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our data show that both the peak and overall glucagon response to hypoglycemia induced by T were reduced when compared with those elicited at similar glucose levels with insulin. Estimated portal insulin concentrations were greater during the T infusion than those produced by insulin. By contrast, peripheral insulin concentrations were greater during I. These data suggest that local insulin release from adjacent ß-cells inhibits -cell secretion and support the hypothesis that the glucagon response to hypoglycemia is, at least in part, modulated through an intraislet - and ß-cell interaction (4).

There is strong experimental support for intraislet mechanisms from animal models (8, 23), but human experimental data are less consistent. Two studies have reported reduced glucagon responses to hypoglycemia in normal subjects when peripheral insulin concentrations were supraphysiological (9, 10), reflecting an inhibitory effect of insulin on the -cell, although neither study examined an intraislet effect directly. However, using a similar experimental design, Davis et al. (12) found no impairment in glucagon secretion after induction of hypoglycemia with equally high concentrations of peripheral insulin. Bolli et al. (11) tested the counterregulatory response to hypoglycemia in normal subjects after an antecedent infusion of either high- or low-dose insulin-producing variable C-peptide suppression. They found no difference in the glucagon response and concluded that this was strong evidence against the existence of an intraislet role for insulin in humans in mediating the glucagon response to hypoglycemia.

The T-glucose clamp has been used to compare portal and peripheral insulin delivery in humans (24). We previously have used a similar approach to develop an alternative model of hypoglycemia when comparing symptomatic, cognitive, and peripheral physiological responses to hypoglycemia produced by either insulin or T in normal subjects (25). In the present study, we lowered blood glucose from the start of the experiment, which resulted in sufficient T-stimulated insulin secretion to maintain moderate hypoglycemia for 30 min. The considerable inhibitory effect of glucopenia on insulin secretion (26) was reflected in the marked fall in calculated portal insulin concentration after 30 min of T-induced hypoglycemia. Nevertheless, the overall estimated portal insulin concentrations were sufficiently different for us to be confident that the -cells were exposed to greater insulin concentrations during T-induced hypoglycemia.

Our study design prevented us from matching peripheral insulin concentrations in both arms. Because pharmacological insulin concentrations can inhibit glucagon release (9, 10), this raises the possibility that the different glucagon responses are caused by unequal peripheral insulin concentrations. However, the peripheral insulin levels during the T infusion were either equivalent or below those observed during the insulin arm, reflecting the fall in endogenous insulin secretion during hypoglycemia. As we observed not a reduced, but an increased glucagon response during insulin-induced hypoglycemia, we believe that our data are the result of different insulin concentrations within the islets.

The calculated peak portal insulin concentration was some 4-fold greater during the T arm, compared with the insulin arm. However, insulin concentrations probably were far higher within the islet during the early phase of the T infusion because the vascular anatomy within the islet results in the -cells receiving blood directly from adjacent ß-cells (27, 28). It is perhaps surprising that we did not observe a greater difference in glucagon response, indeed, that any rise in glucagon occurred during the T arm. One possible explanation is that the inhibitory effect of a falling blood glucose had overcome sulfonylurea-stimulated insulin release soon after the onset of hypoglycemia but that the fall in intraislet insulin concentrations had not led to a fall in estimated portal insulin concentrations by the end of the experiment. Alternatively, it suggests that other mechanisms contribute to glucagon release during hypoglycemia (29, 30).

A reduced glucagon response to hypoglycemia also could occur if T had a direct inhibitory effect on the -cell, independent of blood glucose. We did not include a T control arm in the present study. However, in a previous study (25), we showed that a T infusion had no effect on plasma glucagon concentration while blood glucose was maintained at 5 mmol/L for 2 h. Indeed, T has a mild stimulatory effect on glucagon secretion in ß-cell-deficient type 1 diabetic subjects (31).

Previous studies have suggested that supraphysiological peripheral insulin concentrations can modify other components of the physiological response to hypoglycemia although the data are conflicting (10, 12). Peripheral insulin levels generally were higher throughout the I arm, yet the epinephrine responses were very similar. These data confirm previous work, indicating that peripheral insulin levels in the high physiological range do not alter the sympathoadrenal response to hypoglycemia (9, 25, 32).

In summary, we have demonstrated that the glucagon response to mild hypoglycemia is diminished if endogenous insulin secretion is maintained pharmacologically as blood glucose falls. This model of hypoglycemia suggests that intraislet insulin secretion contributes to the release of glucagon from pancreatic -cells during hypoglycemia and provides support for a paracrine effect of insulin in man.

	Acknowledgments

 
We would like to thank Caroline Bedford and Sandra Marlow for nursing assistance in this study; Linda Ashworth, Caroline Caudwell, and David Forster for technical assistance; and Ian Braithwaite (Hoechst, UK Ltd).

	Footnotes

 
¹ This work was supported by a project grant from the British Diabetic Association (to E.G.). Financial support also was provided in part by grants from the Research Committee, Northern General Hospital Trust and the Special Trustees, Royal Hallamshire Hospital, Sheffield.

Received October 7, 1996.

Revised January 8, 1997.

Accepted January 31, 1997.

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