Hepatic sensitivity to insulin: Effects of sulfonylurea drugs

Hepatic Sensitivity to Insulin: Effects of Sulfonylurea Drugs STEFANO

ANTONIO

DEL PRATO,M.D., RICCIO,M.D., and

SAULA

VIGILI

ANTONIO

DE KREUTZENBERG,

TIENGO,

M.D.,

M.D.,

Padova, /ta/y

Insulin regulation of hepatic glucose production (HGP) is altered in non-insulin-dependent diabetes mellitus (NIDDM), resulting in increased glucose output by the liver; this contributes to the elevation in plasma glucose concentration observed both in the basal state and postprandially. Therefore, restoration of normal insulin action in the liver must be a goal of hypoglycemic therapy. Sulfonylureas have been widely used for treatment of NIDDM over the past 30 years. In addition to their stimulatory effect on insulin secretion, these compounds seem to possess extrapancreatic effects. Early in vitro studies shqwed that addition of sulfonylureas to the perfusion medipm of liver preparations could exert a significant suppressive effect on HGP. Subsequent experience suggested that these compounds could act at the level of the insulis receptor as \rejl as at various postreceptor sites. These studies showed that sulfonylureas may inhibit glycogenolysis and gluconeogenesis while stimulating glycogen synthesis. Results obtalned in vivo in NIDDM patients are in agreement with the in vitro studies. Long-term treatment with sulfonylureas is associated with a decline in fasting plasma glucose concentration and a parallel reduction in HGP. Nevertheless, the direct effect of sulfonylurea administration on the liver remains unclear, since the reduction in HGP that occurs during sulfonylurea treatment may be secondary to an overall improvement in insulin secretion. It is also of interest that in insulin-dependent diabetic patients, sulfonylurea administration in combination with insulin injections is not followed by a significant change in HGP. Possible effects of sulfonylureas on glucagon secretion and on the metabolism of free fatty acids (FFAs) may also contribute to improved sensitivity of the liver to the suppressive action of insulin, since these agents appear to reduce plasma glucagon and FFA concentrations. Thus, present data support an extrapancreatic action of sulfonylureas From Cattedra di Malattle del Ricamblo, Urwersity Requests for reprlnts should be addressed

of Padova, Padova, Italy. to Stefano Del Prato, M D., Cat-

tedra dl Malattle del Ricambio, Via Glustinianl, 2, 35100 Padova, Italy.

on the liver. However, it does appear that a certain degree of residual insulin secretion is required for sulfonylurea agents to elicit their hepatic effect.

I

diabetes mellitus n non-insulin-dependent (NIDDM) both the peripheral tissues (mainly muscle) and the liver are resistant to the biologic action of insulin [l]. The abnormality in insulin sensitivity leads to accelerated production of glucose by the liver and impaired glucose disposal by the tissues of the body. Both mechanisms are responsible for the elevation in plasma glucose concentration [l]. In NIDDM the primary factor responsible for the increased plasma glucose level throughout the day is the prevailing fasting concentration [2-51. In NIDDM patients with significant fasting hyperglycemia (~7.8 mmol/L), the basal rate of hepatic glucose production (HGP), measured with a primedcontinuous infusion of 3-[“HIglucose, is significantly elevated, and this is strongly correlated with the increase in fasting plasma glucose concentration

P-51. Basal hepatic glucose production is tightly controlled by the fasting plasma insulin level. In subjects with NIDDM, the basal plasma insulin concentration is elevated [l]. Because both hyperinsulinemia [7,8] and hyperglycemia [8,9J are known to inhibit HGP, an increased rate of liver glucose release in the presence of high plasma levels of insulin and glucose indicates hepatic resistance to the suppressive action of these two major modulators of HGP. The presence of hepatic insulin resistance in NIDDM is readily apparent when the suppressive action of insulin on HGP is evaluated with the glucose clamp technique [lo]. In normal individuals an increment in portal insulin concentration of 35.9 pmol/L is associated with a 50% reduction in HGP; hepatic glucose qutput is suppressed by >90% at a portal insulin concentration of approximately 322.9 pmol/L; and hglf-maxjmal inhibition is achieved at a portal insulin level of 122 pmol/L. In individuals with NIDDM complete suppression of HGP is achieved only at a portal insulin concentration of >717.50 pmol/L; half-maximal inhibition occurs at a portal insulin level of 187 pmol/L.

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TABLE I Effects of Sulfonylurea Agents on In Vitro Hepatic Glucose Production Agent

System

Chloropropamide Chloropropamide Chloropropamide Glybtmde Tolbutamide Tolbutamlde Tolbutamlde

Perfused liver Perfused ltver Hepatocytes Perfused hver Liver slices Liver slices Perfused liver

Species Rat Rat Rat Rat fg!!

SULFONYLUREAACTION ON HEPATICGLUCOSE METABOLISM:IN VITRO STUDIES The ability of sulfonylureas to reduce HGP was first observed more than 30 years ago in rabbit June 24,

1991

The American Journal of Medicine

Reference

Year

-15 to -42 -34 -34 -40 -21

2

1965

26

1977 1985 1987

2’:

1956

ii

1956 1960

-16to -40 Rat

Impaired suppression of HGP by insulin and hyperglycemia may also contribute to postprandial hyperglycemia. A positive correlation between HGP and plasma glucose concentration has been reported in NIDDM patients after an oral glucose load [ll]. These results indicate that enhanced HGP is an important determinant of hyperglycemia in diabetic patients, in both the basal and the postprandial state. Hepatic glucose production represents the sum of two ongoing processes-glycogenolysis and gluconeogenesis-and the accelerated rate of HGP in NIDDM could be due to defects in either of these metabolic pathways. Recently, Consoli et aZ [12] have provided evidence that increased gluconeogenesis accounts for almost all of the increase in basal HGP in NIDDM patients. A rational therapeutic approach to the treatment of hyperglycemia in NIDDM should aim to correct the basic pathogenetic abnormality. Sulfonylurea compounds have played a central role in the therapy of NIDDM for over 30 years. In addition to the well-known ability of sulfonylureas to stimulate insulin release [13-151 and to potentiate glucosemediated insulin secretion [ 16,171, an extrapancreatic action of these compounds has been claimed. This effect has been suggested to involve both glucose uptake by peripheral tissues and suppression of HGP. Several authors [B-20] have drawn attention to the possibility that sulfonylureas may exert a direct action on the liver by modulating the suppressive effect of insulin on HGP. If sulfonylureas do play a role in an improvement in hepatic glucose metabolism, their use would represent a rational approach to reducing fasting and postprandial hyperglycemia of NIDDM. The available in vitro and in vivo information regarding the effects of sulfonylurea on insulinmediated glucose metabolism of the liver will be reviewed below.

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-60

liver slices perfused with a medium containing tolbutamide [21,221. After these initial reports, additional data supporting this finding became available. The inhibition of glucose output in response to sulfonylurea was observed in perfused rat livers and rat hepatocytes cultures [23-2’71 (Table I); the suppression of HGP was as much as 40% in some studies 1271. As a result of these observations, studies have been carried out to identify the specific mechanism by which sulfonylureas reduce HGP. Most of the available data suggest that sulfonylureas act principally by potentiating the effect of insulin. An effect of the sulfonylurea compounds on insulin binding to specific membrane receptors of the hepatocyte was sought by several investigators (Table II). Initial results, obtained with isolated liver membranes [28-301, showed an increase in insulin binding. However, these preliminary observations have not been confirmed when insulin binding was assessed on cultured hepatocytes [31-351 or rat hepatoma cells [361. A post-receptor action was then proposed and the various steps regulating glucose metabolism in the liver were explored. A synopsis of this investigational effort is provided in Table III. The first mechanism to be proposed involved the inhibition of glucose-6-phosphatase by sulfonylureas. Although such an inhibition was confirmed in liver preparations from the rat and the dog [21,22,37], it was readily apparent that the drug concentration required to cause a significant effect on the enzyme was too high to play a physiologic or therapeutic role [371. As discussed earlier, HGP represents the sum of the glucose derived from stored glycogen and that which originates through gluconeogenesis. In 1956 Lang and Sherry 1381 reported that sulfonylureatreated rats exhibited a slower rate of decline in glycogen during fasting. Tyberghein et al [Zl] observed that, in rabbit liver slices, the rate of glycogenolysis was reduced in the presence of tolbutamide. The same effect was shown in perfused livers [391 and isolated hepatocytes [351. The inhibition of glycogen breakdown produced by sulfonylureas seems to be mediated directly by

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TABLE II Effects of Sulfonylurea Agents on Insulin Binding to Hepatocyte Receptors Agent Chlorpropamide Glyburide Glyburide Glyburide Glyburide Gliclazide Gliclazide Glrpmde Glrprzrde Glrprzrde Glrqurdone Glrqurdone Glisolamrde Tolazamrde Tolbutamide

System

Species

Hepatocytes Hepatoma cells Hepatocytes Hepatocytes Hepatocytes Hepatoma cells Hepatocytes Liver membranes Hepatocytes Hepatocytes Liver membranes Liver membranes Hepatoma cells Hepatocytes Hepatoma cells

Year

1983 1982 1983

Rat Rat Rat Rat Rat Rat Rat Rat Rat Rat Rat Rat Rat Rat Rat

1984 1987

1982 1983 1978

1983 1983 1979 1979 1982 1983 1982

ncreased; =Unaffected

TABLE Ill Effects of Sulfonylurea on Liver Glucose Metabolism Agent Tolbutamide Tolbutamide Tolbutamide Glyburide Tolbutamide Tolbutamide Chlorpropamide Glyburide Glyburide Tolbutamide Glyburide Glybunde Gliquidone Glybunde Chlorpropamide Gliclazide Tolbutamide Chlorpropamide Glipizide Tolbutamide Tolbutamide Chlorpropamide Chlorpropamide Glipizide Tolbutamide Tolbutamide

System Liver homogenate Liver homogenate Liver homogenate Perfused liver Hepatocytes Liver slice Hepatocytes Perfused liver Hepatocytes Liver homogenate Hepatocytes Hepatocytes Hepatocytes Hepatocytes Hepatocytes Perfused liver Perfused liver Hepatocytes Hepatocytes Perfused liver Perfused liver Perfused liver Hepatocytes Hepatocytes Perfused liver Perfused liver

Species

Mechanism

Rat Rat/dog Rat Rat Rat

G-6Pase* Gd-Pase G6-Pase Glycogenolysrs Glycogenolysrs Glycogenolysrs Phosphorylase Phosphorylase Phosphorylase Phosphorylase Glycogen syntheses Glycogen synthesis Glycogen synthesis Glycogen synthesis Fructose-2,6-P,t Fructose-Z,dP, Fructose-2,6.P, Glycolysis Glycolysis Glycolysis Glycolysis Gluconeogenesis Gluconeogenesis Gluconeogenesis Gluconeogenesrs Gluconeogenesis

K”” Rat Rat 0% Rat Rat Rat Rat Rat Rat Rat Rat Rat Rat Rat Rat Rat Rat Rat Rat

Effect

Reference

1 =

;:

1 =

it

Year

1956 1956 1956 1959 1987

I I =

;7 26 z;

1 ii I I t =

1956 %:

:i 35 44

1987 1956 1984 1987 ‘1;:;

1986 1984

4”: 44

%i

:5

‘1;;:

I

:;

iE

I

ii 41 43

1986 1987 1974 1986

1 t t

I

“crease; &Reduction; =Unaffected. ;lucose-6-phosphatase; tfructose-2,6-bisphosphate.

reduced activation of phosphorylase [22,25,271. However, Davidson and Sladen [35] failed to observe any change in the enzyme’s activity in cultured rat hepatocytes and reported a stimulation of glycogen synthesis. This has been confirmed by Fleig et al [34] and Rinninger et al [40]. A direct effect of the sulfonylurea agent on glycogen synthase was also apparent in Davidson and Sladen’s study [35]. In summary, in vitro studies show that sulfonylurea compounds may inhibit glycogenolysis and stimulate glycogen synthesis. The former may explain why these drugs reduce glucose output from the liver; the latter may explain, at least in part, the improvement in glucose disposal after glucose June 24,

ingestion. It should be noted that most of the studies showing positive results reviewed above support the hypothesis that the sulfonylureas act in the liver by potentiating the effects of insulin. An effect on liver glucose metabolism is usually fully expressed only in the presence of insulin. In addition to the inhibition of glycogenolysis, evidence has accumulated to indicate that sulfonylureas reduce the rate of gluconeogenesis in both the perfused liver 141-431 and isolated hepatocytes [44,45]. In these studies a concomitant increase in the rate of hepatic glycolysis was also observed [41,43-461. Fructose-2,6-bisphosphate is an important regulator of intracellular glucose metabolism that simultaneously increases the glycolytic flux 1991

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and decreases gluconeogenesis. To date, two of the three different sulfonylureas investigated (Table III) have been shown to increase the intracellular concentration of fructose-2,6-bisphosphate. This change in fructose-2,6-bisphosphate may represent the mechanism of action whereby sulfonylureas regulate liver glucose metabolism. On the basis of the information reviewed above, it is apparent that sulfonylurea agents are capable of altering hepatic glucose metabolism in vitro. If expressed in vivo, these actions could result in a decline in HGP and in an increase in hepatic glucose uptake in NIDDM patients treated with sulfonylureas. Such an effect could lead to a reduction in the fasting plasma glucose concentration, a lower mean daily glucose level, and a decrease in glycosylated hemoglobin.

SULFONYLUREAACTION ON HEPATICGLUCOSE PRODUCTION:IN VIVO STUDIES In the post-absorptive state, the major determinant of plasma glucose concentration is the rate of HGP [l]. Studies performed in NIDDM patients have suggested that the sulfonylurea compounds may reduce fasting plasma glucose concentrations primarily by suppressing basal HGP [l&20,47]. Kolterman et al [19] have measured HGP in NIDDM individuals before and after 3 and 18 months of sulfonylurea treatment. Patients were divided into responders and nonresponders. In responders, HGP declined to near normal values, but no changes in HGP were found in nonresponder patients. There was a strong correlation between the fasting blood glucose level and HGP, both before and after treatment with sulfonylurea. A positive correlation (r = 0.81, p < 0.005) was also present between the decrement in the fasting serum glucose after 3 months of therapy and the corresponding decrement in basal HGP. In other words, the main difference between responders and nonresponders was the ability of the sulfonylurea to reduce HGP. Since no changes in liver glucose output occurred in nonresponder patients, even those who had the largest increment in insulin secretion, the authors concluded that the effect of sulfonylurea on hepatic glucose metabolism could represent a direct effect of the drug on the liver. However, the mechanism(s) responsible for this action remain under debate. De Fronzo and colleagues have shown that, in some NIDDM patients, basal hepatic glucose production is reduced after sulfonylurea treatment, with no increase in endogenous insulin secretion [l&47]. From these results they suggested that the drug may exert a direct effect on the liver or may act synergistically with 6A-32s

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endogenous insulin. On the other hand, Best et al [20] have postulated that chlorpropamide reduces basal hepatic glucose output through stimulation of endogenous insulin secretion. An additional factor, which complicates the interpretation of the results obtained after long-term therapy with sulfonylurea, is the reduction in plasma glucose concentration. Recent studies have indicated that glucose per se may be a general cellular toxin and that persistently elevated plasma glucose levels may inhibit both insulin action and secretion. Kosaka et al [4] have shown that improvement of glucose control, regardless of the means by which it is obtained (i.e., diet or sulfonylurea or insulin therapy), invariably leads to a significant and similar improvement in insulin secretion and glucose tolerance. This “glucose toxicity” concept has received experimental support from animal studies. In diabetic rats, the reduction of the ambient plasma glucose concentration by phlorizin (an agent that decreases the plasma glucose level by the inhibition of tubular glucose reabsorption and possesses no insulin action) enhances insulin secretion [48] and insulin action [49,50]. Therefore, the reduction in hepatic glucose production after longterm treatment with sulfonylurea in NIDDM may be secondary to an overall improvement in glucose control. One approach that has been used to examine whether the effect of sulfonylureas on HGP is direct or requires the stimulation of insulin secretion is the study of patients with insulin-dependent diabetes mellitus (IDDM). If sulfonylurea drugs were to suppress hepatic glucose output directly or act synergistically with insulin to exert their hepatic action, one would expect a significant reduction in hepatic glucose release after their administration to IDDM patients. If any increase in insulin secretion were required, no effect on HGP would be observed. This hypothesis was tested by Simonson et al [51], who studied the effect of sulfonylurea therapy in five IDDM and eight NIDDM patients. The effect of the ingestion of 20 mg glyburide on hepatic glucose production was evaluated in all patients while they were receiving a maintenance insulin infusion. In IDDM, no decline in hepatic glucose release followed the ingestion of the drug, a result that does not support a direct effect on HGP or a synergistic action of the drug with insulin to lower HGP. In contrast, when the sulfonylurea was administered to insulin-requiring NIDDM patients, basal hepatic glucose production dropped significantly. This reduction was associated with a significant increment in plasma C-peptide concentration, suggesting that stimulation of endogenous insulin

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secretion was the primary factor responsible for the suppression of hepatic glucose production. In recent studies we have further investigated a possible direct effect of sulfonylurea drugs on the liver in a group of NIDDM patients previously treated with diet alone [52]. The patients were studied twice. On both occasions they received a continuous glucose infusion (2 mglkgimin) together with a primed-continuous 3-[“HIglucose infusion, in order to evaluate glucose turnover and the rate of hepatic glucose production. Placebo was given on one occasion, and on the other, 240 mg gliclazide was administered before starting the glucose infusion. Gliclazide administration resulted in a smaller increase in plasma glucose concentration after the glucose infusion (+3.4 versus 2.1 mmol/L), and this improvement in glucose tolerance was also associated with a greater suppression of HGP (Figure 1). The decrement in plasma glucose concentration correlated directly with the decrement in liver glucose output (r = 0.63, p ~0.05). No significant difference was found in plasma insulin or C-peptide concentrations or suppression of plasma glucagon and free fatty acid (FFA) levels, with or without drug administration. These findings suggest that the greater inhibition of HGP was due to an effect of the sulfonylurea on insulin-mediated HGP suppression. To determine whether gliclazide can act independently of an increase in plasma insulin concentration, placebo or 240 mg gliclazide were administered to five NIDDM patients receiving a 240minute somatostatin infusion with an insulin/glucagon infusion designed to maintain basal plasma concentration of the hormones. Under these experimental conditions no difference was apparent in plasma glucose concentration and HGP after the administration of placebo or gliclazide [52]. The results of these studies indicate that gliclazide may exert a specific action on the liver, but that in order to elicit its effect on HGP, a rise in plasma insulin concentration must occur. These results are in agreement with in vitro studies and suggest a possible direct action of the sulfonylurea compounds on liver glucose metabolism; this effect probably results from a potentiation of the biologic effects of circulating insulin. It should be noted that a pharmacologic dose of gliclazide was used in our studies. The physiologic effect of our observations compared with the normal in vivo situation, where the sulfonylurea drugs stimulate endogenous insulin secretion, remains to be quantified. However, the available information supports the view that extrapancreatic effects can be obtained in diabetic patients who still retain a certain degree of insulin secretion, whereas a trivial effect can be expected

ON GLICLAZIDE I DEL PRATO ET AL

600 r

-2 ‘g5001

l*

I

Gliclazide

Placebo

0

z.E : 10

b

5 -20 t s t

*

I

-30 L

Figure 1. Plasma glucose Incremental area above baseline and hepatic glucose production (HGP) decremental area below baseline during glucose infusion (2 mgi kg/mln) with administration of placebo or gliclazide (240 mg orally) in non-lnsulindependent diabetic patients. * p < 0.05.

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in non-C-peptide-secreting IDDM patients.

individuals,

such as

INDIRECTEFFECTSOF SULFONYLUREADRUGS ON HEPATICGLUCOSEMETABOLISM HGP is regulated by a number of factors, including hormones, the availability of substrates, and neural stimulation. As discussed earlier, insulin and hyperglycemia suppress HGP. In contrast, glucagon has a potent stimulatory effect as do other counterregulatory hormones. The ratio of the portal concentrations of insulin to glucagon exerts a powerful modulation on HGP. Plasma glucagon concentrations are inappropriately increased in NIDDM subjects throughout the entire day [53]. Recently, Baron et al [54] have shown that elevated plasma glucagon levels are largely responsible for the elevated rates of HGP and hepatic resistance to insulin. An inhibition of glucagon secretion by sulfonylurea drugs may, therefore, result in a reduction in glucagon stimulation of HGP. In vitro evaluation of pancreatic hormone secretion has provided conflicting results. Glucagon secretion after sulfonylurea stimulation has been reported to be increased [54,551, decreased [56-581, or unaffected [59,60]. Using the perfused rat pancreas, Grodsky et al [62] found that low doses of tolbutamide caused an increase in phasic glucagon secretion, whereas an inhibition was induced by higher concentrations of the drug. However, the minimum dose required to elicit the suppressive effect was far beyond the therapeutic range. In normal individuals, short-term administration of sulfonylureas did not affect the basal plasma glucagon concentration [62,63], nor did it alter argininestimulated glucagon secretion [63]. Controversial results have been obtained in IDDM patients 164,651. Long-term sulfonylurea therapy in NIDDM has been reported to reduce glucagon levels significantly [66,67], but this has not been a consistent finding [68]. In preliminary investigations we have observed no effect of pharmacologic doses of gliclazide on the suppression of plasma glucagon concentration after intravenous glucose infusion

BY. In conclusion, the available data do not support the concept that sulfonylureas reduce HGP by inhibiting a-cell function. NIDDM is characterized by multiple metabolic disturbances that involve both glucose and lipid metabolism. Regulation of FFA metabolism is impaired [lo] and plasma FFA concentrations are increased throughout the day [69]. Moreover, the increase in plasma FFA is associated with an enhanced rate of FFA oxidation [lo]. It has been shown that an increase in FFA oxidation in the liver provides an abundant energy supply to drive 6A-346

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gluconeogenesis [70]. In NIDDM patients, the increase in basal HGP is almost entirely due to activation of gluconeogenesis [12]. Therefore, a decrease in the rate of lipolysis by sulfonylureas could explain, at least in part, the reduction in the elevated rates of HGP in NIDDM. Consistent with this hypothesis, an antilipolytic effect of tolbutamide has been demonstrated on adipocytes [71,72]. The antilipolytic action occurs through inhibition of the hormone-sensitive lipase [73]. In vivo, sulfonylurea treatment is also associated with a reduction in plasma FFA concentrations [66,74]. Despite the evidence summarized above, one must be cautious in attributing the reduction in HGP during long-term sulfonylurea therapy in NIDDM to a direct effect. on glucagon secretion and/or FFA metabolism. Insulin is a potent inhibitor of a-cell secretory function and is a powerful antilipolytic agent and it is more likely that the change in the plasma levels of glucagon and FFA following sulfonylurea administration are related to increased insulin secretion and improved metabolic control.

CONCLUSION This review of the literature allows us to speculate about the effect of the sulfonylureas on hepatic glucose metabolism in NIDDM during long-term therapy. The primary and quantitatively most important effect of sulfonylureas is the stimulation of insulin secretion. The resultant increase in portal insulin concentration leads to a suppression of hepatic glucose production. This stimulatory effect on insulin secretion is potentiated by a direct action of the drug on glucose metabolism by the liver. The reduction in the basal rate of HGP leads to a reduction in the fasting plasma glucose concentration. Because the prevailing fasting plasma glucose concentration is the primary determinant of the mean glucose level, overall glycemic control is improved, and this in turn increases tissue sensitivity to insulin. There is also some evidence to suggest that the sulfonylureas exert a direct effect on peripheral tissues to enhance insulin action [75,76]. The reduction in plasma glucose concentration and the improvement in insulin sensitivity account for the frequent observation that plasma insulin concentrations tend to return to pretreatment levels after long-term therapy with sulfonylureas, despite maintenance of good metabolic control. In the sequence of events described above, the liver plays a key role in the improvement of plasma glucose levels and overall metabolic control observed after sulfonylurea therapy. Such an interpretation is consistent with the fact that the liver is the first target organ of secreted insulin and that

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sulfonylureas simultaneously insulin release and potentiate liver.

increase pancreatic insulin action on the

REFERENCES 1. De Fronzo RA. The trrumvirate: p cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 1988: 37: 667-87. 2. Perley MJ, Krpnis DM. Plasma rnsulin responses to oral and intravenous glucose: studres rn normal and drabetrc subjects. J Clin Invest 1967; 46: 1954-62. 3. Luft R, Waingot R, Efendrc S. On the pathogenesis of maturity-onset drabetes. Diabetes Care 1981; 4: 58-63. 4. Kosaka K, Kuzuya T, Akanuma Y, Agura R. Increase in tnsul~n response after treatment of maturity-onset diabetes is independent of the mode of treatment. Drabetologra 1980; 18: 23-8. 5. Del Prato S, Vigili de Kreutzenberg S, Riccio A. Partial recovery of insulin secretion and action after combined insulin-sulfonylurea treatment In Type 2 (non-rnsulindependent) diabetic patients wrth secondary failure to oral agents. Drabetologta 199!; 33: 688-95. 6. De Fronzo RA, Ferrannrnr E, Simonson DC. Fasting hyperglycemia rn non-insulindependent diabetes mellrtus: contribution of excessive hepatic glucose production and Impaired tissue glucose uptake. Metabolism 1989; 38: 387-95. 7. Cherrington AD, Stevenson RW, Steiner KE, et al. Insulin, glucagon, and glucose as regulator of hepatic glucose uptake and production in vivo. Drabetes Metab Rev 1987; 3: 307-32. 8. De Fronzo RA, Ferranninr E. Regulation of hepatic glucose metabolism In humans. Drabetes Metab Rev 1987; 3: 415-59. 9. Sacca L, Hendler R. Sherwin RS. Hyperglycemia inhibits glucose production rn man Independent of changes in glucoregulatory hormones. J Clin Endocrrnol Metab 1978; 47: 1160-7. 10. Groop LC. Bonadonna RC, Del Prato S, eta/. Glucose and free-fatty acid metabolism In non-Insulin-dependent diabetes mellitus. Evrdence for multiple sites of insuIrn resrstance. J Clin Invest 1989; 84: 205-13. 11. Ferrannini E, Srmonson DC, Katz LD. et a/. The disposal of an oral glucose load rn patients with non-insukn-dependent diabetes. Metabolism 1988; 37: 79-85. 12. Consolr A, Nuqharr N, Capani F, Gerich J. Predominant role of gluconeogenesrs rn Increased hepabc glucose production rn NIDDM. Diabetes 1989; 38: 550-7. 13. Loubatieres A. The hypoglycemic sulfonamrdes: hrstory and development of the problem from 1942 to 1945. Ann NY Acad SCI 1957; 71: 4-11. 14. Grodsky GM. In Hasselblatt A, Bruchausen FV, eds: Handbook of experimental pharmacology, vol 32. Berlin: Springer-Verlag, 1975: l-16. 15. Greenfield MS, Doberne L, Rosenthal M, et al. Effect of sulfonylurea treatment on in VIVOrnsukn secretion and action in patients with non-insulrn-dependent diabetes mellitus. Drabetes 1982; 31: 307-12. 16. Pfeifer MA, Halter JB, Graf R, Porte D Jr. Potenbatron of insulin secretron to non-glucose stimulr rn normal man by tolbutamide. Diabetes 1980; 29: 335-40. 17. Yalow RS. Block H. Villazon M, Berson SA. Comparison of plasma insulin levels followerg administratron of tolbutamide and glucose. Diabetes 1960; 9: 356-62. 18. De Fronzo RA, Srmonson DC. Oral sulfonylurea agents suppress hepatic glucose production In non-Insulin-dependent drabetrc indrvrduals. Drabetes Care 1984; 7 (Suppl 1): 72-80. 19. Kolterman OG, Gray RS, Shaprro G, Scarlett JP, Griffin J, Olefsky JM. The acute and chronrc effects of sulfonylurea therapy rn type II diabetic subJects. Diabetes 1984; 33: 346-54. 20. Best JD, Judzewitsch RG, Pferfer MA, Beard JC, Halter JB, Porte D Jr. The effect of chronic sulfonylurea therapy on hepabc glucose production rn non-insulin-dependent drabetes. Drabetes 1982; 31: 333-8. 21. Tyberghein JM, Halsey YD, Williams RH. Action of butyltolylsulfonylurea on lrver glycogenolysrs. Proc Sot Exp Biol Med 1956; 92: 322-4. 22. Berthet J, Sutherland EW, Makman MH. Observabon on the action of certain sulfonylurea derrvatives. Metaboksm 1956; 5: 768-73. 23. Pogatsa G, Kaldor A. Effect of chlorpropamide on urea synthesis and glycogenolysis rn the liver. Diabetes 1965; 14: 209-11. 24. Kaldor A, Pogatsa G. Direct rnhrbition of hepatic glycogenolysis by tolbutamide. Lancet 1960; 2: 439. 25. Blumenthal SA. Potentiatron of the hepatrc actron of insulin by chlorpropamide. Diabetes 19n; 26: 485-9. 26. Blumenthal SA, Moses AM. lnhibrtion of hormonal activation of hepabc phosphorilase by chlorpropamide: evidence for rntracellular site of drug action. Endocrrnology 1985; 116: 660-4. 27. McGurnness OP, Green DR, Cherrington AD. Glyburrde sensttczes perfused rat liver to insulin-induced suppression of glucose output. Diabetes 1987; 36; 472-6.

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28. Greenstein BD. Improved rnsulrn receptor assay: effects of an antidiabebc sulfonylurea on liver membrane insulin receptors from obese hyperglycemic mice. Br J Pharmacol 1979; 66: 317-22. 29. Bachmann W, Bdttger I, Haslbeck M, Mehnert H. Extrapancreatic actron of sulphonylureas: effect of gliquidone on insulin and glucagon binding to rat liver plasma membranes. Eur J Clrn Invest 1979; 9: 411-5. 30. Fernglos MN, Lebovrtz HE. Sulphonylureas Increase the number of rnsulrn receptors. Nature 1978; 276: 184-5. 31. Do&-Krtabgr J, Alengnn F, Freychet P. Sulphonylureas in vitro do not alter Insulin binding or insulin effect on ammo acid transport in rat hepatocytes. Diabetologia 1983; 24: 441-4. 32. Nowak SM, McCaleb ML, Lockwood DH. Extrapancreatic action of sulfonylurea: hypoglycemrc effects are not dependent on altered insulin binding or inhibition of transglutamrnase. Metabolism 1983; 32: 398-402. 33. Salhanick Al, Konowitz P, Amatruda JM. Potentiabon of insulin action by a sulfonylurea in prrmary cultures of hepatocytes from normal and diabetic rats. Drabetes 1983; 32: 206-12. 34. Flerg W, Noether-Fleig G, Fussgaenger R, Ditschuneit H. Modulation by a sulfonylurea of Insulin-dependent glycogenesis, but not of Insulin binding, in cultured hepatocytes. Evrdence for a post-receptor mechanism of action. Diabetes 1984; 33: 285-90. 35. Davidson MB, Sladen G. Effect of glyburide on glycogen metabolrsm rn cultured rat hepatocytes. Metabolrsm 1987; 36: 925-30. 36. Vignen R, Pezzrno V, Wong KY, Goldfine ID. Comparison of the in vitro effect of biguanides and sulfonylureas on insultn brnding to its receptors in target cells. J Clin Endocrrnoi Metab 1982; 54: 95-100. 37. Ashmore J, Cahill GF, Hastings AB. Inhibition of glucose-6-phosphatase by hypoglycemic sulfonuylureas. Metabolism 1956; 5: 771-7. 38. Lang S, Sherry S. Some effects of Orrnase in the rat. Metabolism 1956; 5: 733-8. 39. Mrller LL, Sokal JE, Sarcrone El. Effects of glucagon and tolbutamide on glycogen in Isolated perfused rat liver. Am J Physiol 1959; 197: 286-8. 40. Rinninger F, Kirsch D, Harrng HU, Kemmler W. Extrapancreatic actron of the sulphonylurea girquidone: post-receptor effect on rnsulrn-stimulated glycogen synthesis rn rat hepatocytes rn primary culture. Diabetologia 1984; 26: 462-5. 41. Schonborn J, Poser W, Panten U, Hasselblatt A. Effect of hypoglycemic sulfonylurea on hepatic fructose metabolism in the rat. Horm Metab Res 1974; 6: 284-9. 42. Blumenthal SA, Whitmer KR. Hepatrc effect of chlorpropamide. lnhrbrtion of glucagon-stimulated gluconeogenesrs in perfused livers of fasted rats. Diabetes 1979; 28: 646-50. 43. Pate1 TB. Effects of tolbutamrde on gluconeogenesis and glycolysis in isolated perfused rat liver. Am J Physrol 1986; 250: E82-6. 44. Monge L, Mojena M, Ortega JL, Samper B, Cabello MA, Feliu JE. Chlorpropamide raises fructose-26brphosphate concentration and inhibits gluconeogenesis in isolated rat hepatocytes. Diabetes 1986; 35: 89-96. 45. Cabello MA, Monge L, Samper B, Feliu JE. Effect of glipizide on hepatic fructose26brphosphate concentration and glucose metabolrsm. Metabolism 1987; 36: 738. 46. Matsutanr A, Kaku K, Kaneko T. Tolbutamrde stimulates fructose-2,dbiphosphate formation in perfused rat liver. Diabetes 1984; 33: 495-8. 47. Simonson DC, Ferranntni E, Bevrlacqua S, et al. Mechanism of improvement rn glucose metaboksm after chronrc glyburide therapy. Drabetes 1984; 33: 838-45. 48. Rossett L, Shulman GI, Zawalrch W, De Fronzo RA. Effect of chronic hyperglycemia on in VIVO insulin secrebon in partially pancreatectomized rats. J Clin Invest 1987; 80: 1037-44. 49. Rossett L, Smrth D, Shulman GI, Papachristou D, De Fronzo RA. Correctron of hyperglycemra with phlorrzrn normalizes bssue sensitivrty to insukn in diabetic rats. J Clan Invest 1987; 79: 1510-5. 50. Lrsato G, Cusrn I, Terrattaz J, Del Prato S, Janrenaud B. Correctron of hyperglycemra but not hypoinsulinemra restores rnsulrn actron m streptozotocin (STZ) dtabetrc rats. Diabetes 1989 (Suppl 2): 89A. 51. Simonson DC, Del Prato S, Castellrno P, Groop L, De Fronzo RA. Effect of glyburrde on glycemrc control, rnsulrn requirement, and glucose metabolrsm in Insulin-treated diabetic pabents. Diabetes 1987; 36: 136-46. 52. Lisato G, RICCIO A, Vigil1 de Kreutzenberg S, Trengo A, Del Prato S. Hepatic acbon of gliclazrde treatment in type 2 (non-insulin-dependent) drabetes mellitus. Drabetologta 1987; 30: 550A. 53. Reaven GM, Chen YD, Golay A, Swrslocki M, Jaspan JB. Documentation of hyperglucagonemia throughout the day in nonobese and obese patients with non-rnsulindependent drabetes mellitus. J Clan Endocrrnol Metab 1987; 64: 106-10. 54. Baron A, Schaffer L. Shragg P, Kolterman OG. Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II drabetics. Drabetes 1987; 36: 274-83.

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SYMPOSIUMON GLICLAZIDEI DEL PRATOET AL 55. Loubatieres AL, Loubatieres-Mariani MM, Alric R, Ribes G. Tolbutamide and glucagon secretion. Diabetologia 1974 10: 271-6. 56. Samols E, Harrrson J. lntraislet negative insulin-glucagon feedback. Metabolism 1976; 25 (Suppl 1): 1443-7. 57. Laube H, Fussganger R, Goberna R, eta/. Effects of tolbutamide on insulin and glucagon secretion of the isolated perfused rat pancreas. Horm Metab Res 1971; 3: 238-42. 58. Ohneda A, Sato M, Matsuda K, et al. Suppression of pancreatic glucagon secre tion by tolbutamide in dogs. Horm Metab Res 1974; 6: 478-82. 59. Samols E, TylerJM, Mialhe P. Suppression of pancreatic glucagon release by the hypoglycaemic sulfonylureas. Lancet 1969; 2: 174-6. 60. Aguilar-Parada E, Eisentraut AM, Unger RH. Effect of HE 419 (glibenclamrde) induced hypoglycemia on pancreatic glucagon secretion. Horm Metab Res 1969; 1 (SUPPI 1): 48-50. 61. Kajinuma H, Kuzuya T, Ide T. Effect of hypoglycemic sulfonamides on glucagon and insulin secretion in ducks and dogs. Diabetes 1974; 23: 412-7. 62. Grodsky GM, Epstein GH, Fanska R, Karam JH. Pancreatic action of the sulfonylureas. Fed Proc 19n; 36: 2714-9. 63. Marco J, Valverde I. Unaltered glucagon secretion after seven days of sulfonylurea administration in normal subjects. Diabetologia 1973; 9 (Suppl): 317-9. 64. Pek S, Fajans SS, Floyd JC, Knopf RF, Conn JW. Failure of sulfonylurea to suppress plasma glucagon in man. Diabetes 1972; 21: 216-23. 65. Bohannon N. Karam J, Lorenzi M, Gerich J, Forsham P. Plasma glucogen levels after tolbutamide or phenphormin in insulin-dependent diabetics. Clin Res 1976; 24: 154A. 66. Fallucca F, lavicoli M. Menzinger G, Mirabella C, Andreani D. Glucagon and growth hormone secretion in insulin-treated diabetics. Effects of added sulfonylureas. Metabolism 1978; 27: 5-11.

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67. Loreti L, Sugase T, Foa PP. Diurnal variation of serum msulin, total glucagon, cortisol, glucos&nd free fatty acids in normal and diabetic subjects before and after treatment with chlorpropamide. Horm Res 1974; 5: 278-92. 68. Tsalikian E, Dunphy TW, Bohannon NV, et al. The effect of chronic oral antidiabetic therapy on insulin and glucagon responses to a meal. Diabetes 19n; 26: 314-21. 68. Unger RH, Aguilar-Parada E, Muller WA, Ersentraut AM. Studies of pancreatic alpha cell function in normal and diabetic subiects. J Clin Invest 1970; 49: 837-48. 70. Golay A, Swislpcki AL, Chen YD, Reaven GM. Relationship between plasma free-fatty acid concentration, endogenous glucose production, and fasting hyperglycemia in normal and non-insulin-dependent diabetic individuals. Metabolism 1987; 36: 692-6. 71. Blumenthal SA. Stimulation of gluconeogenesis by palmitic acid in rat hepatocytes: evidence that this effect can be dissociated from provision of reducing equivalents. Metabolism 1983; 32: 971-6. 72. Allen DO, Largis E, Ashmore J. Antilipolytic action of tolbutamide in isolated fat cells of the rat. Diabetes 1974; 23: 51-4. 73. Shepherd RE, Fain JN. Inhibition of rat fat cell triglyceride lipase by sulfonylureas. Fed Proc 1977; 36: 2732-4. 74. Taskinen MR, Bogardus C, Kennedy A, Howard BW. Multiple disturbances of free-fatty acid metabolism in non-insulin-dependent diabetes. J Clin Invest 1985; 76: 637-44. 75. Beck-Nielsen H, Hother-Nielsen 0, Pedersen 0. Mechanism of action of sulphonylureas with special reference to the extrapancreatic effect: an overview. Diabetic Med 1988; 5: 613-20. 76. Kolterman OG. The impact of sulfonylureas on hepatic glucose metabolism in type II diabetics. Diabetes Metab Rev 1987; 3: 399-414.

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