treatment of noninsulin-dependent diabetes mellitus with enzyme inducers

Noninsulin-dependent diabetics (NIDDs, type II) have hyperglycemia, normal or high plasma immunoreactive insulin levels (IRI), and glucose intolerance .9'13'19'23'29 Hepatic function, as determined by conventional liver tests, is normal or slightly altered,5 whereas the microsomal enzyme activity, as measured in vivo and in vitro, is reduced.27'28'34 Glucose tolerance in

This study was supported in part by a grant from Carlo Erba, A.B., Stockholm, Sweden.

Received for publication Oct. 20, 1982.

Accepted for publication Dec. 4, 1982.

Reprint requests to: Dr. Eero A. Sotaniemi, Clinical Research Unit, Department of Internal Medicine, University of Oulu, SF-90220 Oulu 22, Finland.

826

Treatment of noninsulin-dependent diabetes mellitus with

enzyme inducers

Although treated adequately with antidiabetic drugs, diet, exercise, and education, patients with

noninsulin-dependent diabetes mellitus (NIDDM) may develop resistance to treatment. In

NIDDM hepatic microsomal enzyme activity is reduced and since postreceptional glucose

metabolism is influenced by these enzymes, we treated the subjects with enzyme-inducing drugs.

These inducers (phenobarbital and medroxyprogesterone acetate) when added as adjuvant therapy to sulfonyl urea regimen, reduced blood glucose and plasma insulin, and increased

microsomal enzyme activity (as indicated by increased antipyrine metabolism). A trial with

placebo did not alter serum glucose levels. Body weight fell and serum aminotransferase levels

were normalized. These changes were reflected by reduction of liver fat content (determined by

light microscopy), by increased surface density of smooth endoplasmic reticulum, and by

repairation of the plasma cell membrane of hepatocytes, as seen in electron micrographs.

Activation of postreceptional events in hepatocytes may thus be a new approach in the treatment

of therapy-resistant type II diabetes.

Eero A. Sotaniemi, M.D., Arno J. Arranto, M.D., Seppo Sutinen, M.D.,

Jan i H. Stengard, M.D., and Sirkka Sutinen, M.A. Oulu, Finland

Clinical Research Unit, Departments of Internal Medicine, and Department of Pathology, University of Oulu

NIDD seems to be influenced, at least in part, by the microsomal enzyme system.

Experimental studies indicate a link between the hepatic microsomal carbohydrate and drug metabolism systems.11,12,14,34,36 A change in one system would be reflected in the other. Stimulation of hepatic enzyme activity is possible with drugs4 and this therapy has resulted in improved hepatocellular function in subjects with reduced activity.24'31 Therapy with the enzyme inducers may thus influence the hepatic handling of glucose in patients with noninsulin-dependent diabetes mellitus (NIDDM).

Our study was undertaken to determine the role of the hepatic enzyme induction on carbohydrate and drug metabolism in diabetics with

Volume 33

Number 6

Table I. Clinical and biochemical data on 10 patients with NIDDM

Reason for admission in all patients was poor disease control.

BMI = body mass index; Gb = glibenclamide; Gz = glipizide; Chi = chlorpropamide; Phen = phenformin = insulin; IHD = ischem c heart disease; HT hypertension; FL = fatty liver.

Table II. BG, plasma insulin, liver function test results, and antipyrine metabolism in 10 patients with NIDDM

Normal laboratory values: BG, 3.5 to 6 mmol//: IRI, 5 to 25 mU//; total bilirubin (Tot bil), 2 to 17 Ull; AP, 60 to 250 U//; SGPT, <40 U//, SGOT, <40 U /l; albumin (ALB), 37 to 54 grnfi; Thromotest (TT), >70%; 0/2, 6.5 to 12.5 hr; clearance, 23.8 to 51.2 ml/min.

*Mean over at least 3 days.

NIDDM who had developed resistance to the previous management with oral antidiabetic drugs, diet, exercise, and education. Pheno- barbital (PB) and medroxyprogesterone acetate (MPA) were selected as inducing agents.4.26'" Blood glucose (BO) and IRI determinations were used to reflect the carbohydrate metabolism, and results of conventional liver function tests and plasma antipyrine clearance rate were used to assess the hepatic function in the diabetics with NIDDM who underwent diagnostic liver biopsy.

Enzyme inducers in noninsulin-dependent diabetes 827

Methods

Our subjects were seven women and three men with N1DDM. The relevant clinical data are given in Tables I and II. Before the trial cardiac function was clinically compensated, if necessary, and kidney function, as evaluated by a creatinine clearance test, was normal. A percutaneous liver biopsy was performed to evalu- ate the hepatic involvement associated with the altered liver function tests. None of the subjects had previously been treated with drugs known to induce the hepatic microsomal enzyme sys-

Diabetes Patient Age Liver Other Enzyme

Years Therapy No. (yr) Sex BM! diagnosis diseases inducer

Patient No.

BG Liver function tests An tipyrine

Fasting* (mmolll)

Mean daily*

(mmolll) IRI

(mUll) Tot. bil (pmolll)

AP Ull

SGPT (Ull)

SGOT (Ull)

Alb (gmll)

IT (%)

t1/2

(hr) Clearance (ml/min)

1 12.3 10.1 12.4 3 113 9 6 44 100 13.4 32.6 2 13.5 14.7 7.4 7 260 55 38 44 100 8.2 46.2 3 9.4 8.9 40.0 8 187 71 34 41 80 18.4 21.0 4 12.4 12.3 7.4 14 200 96 51 40 40 13.4 26.0 5 14.4 15.1 12.9 7 270 48 23 45 100 12.0 27.9 6 12.7 10.1 34.3 8 253 165 91 47 75 13.7 37.0 7 16.1 15.3 10.5 6 171 17 21 44 100 13.2 31.8 8 12.3 13.8 33.7 4 230 180 73 46 100 21.2 28.0 9 11.9 12.2 37.4 6 399 38 20 39 60 15.0 24.0

10 13.0 13.8 38.7 5 150 32 40 45 100 8.9 31.8

1 49 25.3 6 Gb, Gz, Phen FL No PB 2 51 32.0 4 Gb, Chi FL IHD MPA 3 51 37.2 3 Gb, Phen FL IHD PB 4 52 30.5 8 Phen, Gb, Chi FL HT MPA 5 61 26.7 7 Phen, Gb, Gz, Chl, I FL + fibrosis IHD PB 6 63 37.9 3 Gb, Chl FL IHD MPA 7 64 26.4 6 Chi, Phen, Gb, I FL IHD PB 8 68 26.0 9 Chl, Gb, Gz FL + fibrosis IHD PB 9 72 29.1 10 Gb, Gz, Phen FL IHD PB

10 72 28.7 11 Phen, Gb, Chi, I FL + fibrosis IHD PB

828 Sotaniemi et al.

20 0 -

150

10 0

5.0

A

Placebo Inducer

Fig. 1. Fasting (A) and mean dai y (B) BG levels before and after therapy with placebo and enzyme-inducing drugs (PB and MPA) in 10 diabetics with NIDDM. Block rectangle is normal range.

tem.4 One subject used alcohol occasionally, and none were smokers. Ten age- and sex- matched subjects with normal liver histology served as control subjects; these subjects had previously had abnormal results on liver function tests.

The studies were carried out at the Clinical Research Unit (CRU). During the first visit the management of diabetes mellitus was once again discussed by a nurse. The diet was calculated on the basis of weight and height, and the mean energy intake was 5.5 -± 0.9 mEday, which is equivalent to 60 to 80 kJ/kg body weight (conversion from SI to traditional units 4.2 mJ = 1000 kcal). During the hospital stay, carbohydrates constituted 45%, fat 35%, and protein 20% of the total daily diet. The daily distribution of energy was: 15% at 8 A.M., 5% at 10 A.M., 25% at noon, 15% at 1.30 P.M., 25% at 4.30 P.M., and 15% at 8 P.M. The same schedule was followed at later visits.

The blood samples for liver function tests

Placebo Inducer

Clin. Pharmacol. Ther. June 1983

were drawn after an overnight fast. Three to 4 hr later the liver biopsy (ThruCut needle)32 was performed. Antipyrine, 20 mg/kg, dissolved in 100 ml of fruit juice, was given to each patient after an overnight fast. Plasma specimens were obtained by venipuncture before and 1, 3, 6, 9, 12, 24, and 30 hr after dosing. Samples for blood glucose determination were taken four times dailyafter an overnight fast, at noon, in midafternoon, and in the evening. Plasma IRI was assayed from the blood samples drawn after the overnight fast.

Serum concentrations of albumin and total bilirubin and the activities of SGOT, SGPT, and alkaline phosphatase (AP) were determined by standard AutoAnalyzer techniques (Techni- con). The thrombotest was by an automatic analyzer (Thrombolab). The blood glucose content was determined by the hexokinase method (Glucoquant) and plasma insulin by radioim- munoassay with the Riagnost insulin kit (Boeh- ringwerke AG).

Control Control SULP+HONYLUREA SULPHONYLUREA

Volume 33 Number 6

u 100 0 uJ

-cE

>- 50.0 a_

200

150

10 0

6 0

Phenformin 1Glipizide Glib enclamide

The plasma antipyrine content was determined by a gas-liquid chromatography method, with phenacetin as the internal standard.23' 30

Liver histology. A percutaneous liver biopsy was performed a day before the antipyrine test. The material for the histologic studies was obtained by an accepted method.' Liver changes were quantified by morphometry with the use of the principles of Weibel et al.38 a method we had used before.'

Therapy with enzyme-inducing drugs. The subjects had been treated with sulfonylureas and biguanides and three had also been treated with insulin. During the first hospital stay the drugs were changed for all patients to glipizide or to chlorpropamide. Eight weeks later the subjects were readmitted to the CRU and in each case a placebo tablet was added to the drug regimen and subjects were told "this new tablet may or may not potentiate the effect of your antidia-


InsiulnIChlorpropamide Placebo.. Phenobarbital

1/82 5/182

Fig. 2. Graph illustrating the increase in BG during phenformin and glibenclamide treatment, the poor response to glipizide, insulin, and chlorpropamide alone, and the marked BG decrease and antipyrine metabolism increase after addition of PB in a patient with NIDDM (case 5).

betic drug." The inducers, 100 mg PB at bed- time and 10 to 20 mg/day MPA, were intro- duced in the same way as the placebo, 8 wk later, if the blood glucose level did not change. Subjects remained on any drugs that they were taking for either heart disease or hypertension (Table I).

The plasma t1/2 was read from the linear part of the concentration/time curve on a semilog graph. The trapezoidal rule was used for calcu- lation of the AUC, and the area to infinite time was added by integration [(Ct/k), where Ct is the last concentration value and k is the elimi- nation rate constant, calculated from the equation 0.693/t1/2)]. The apparent clearance rate (CL) was calculated from the equation CL = D/AUC, where D is the oral dose of the drug. Student's t test and regression analysis were used for the statistical treatment of the data.

// I I

10/74 1/81 8/81 9/81 11/81

Results

Our patients with NIDDM were elderly people (Table I) who had developed resistance to the management of their diabetes during a period of from 3 to 11 yr. Four were obese (body mass index over 30) and the others had a normal weight. Fasting and mean daily BG levels were elevated (Fig. 1, Table II) and results of tests for urine glucose were negative or slightly positive; none of the patients had any tendency to ketosis. Serum fasting insulin level was evaluated in five and normal in five patients.

Liver function tests showed elevation of SGPT levels in six, SGOT levels in four, and AP levels in four patients. The serum albumin total bilirubin and Thrombotest results were normal in all. Liver biopsy showed fatty liver in all subjects and three had, in addition, fibrosis. The rate of antipyrine metabolism was lower than in age- and sex-matched controls (Table III).

Addition of the placebo tablet to the management of diabetes did not alter the mean (-± SD) BG levels (fasting BG before placebo, 12.8 ± 1.7 mmol// and after placebo, 13.4 ± 2.5 mmolu; mean daily BG before placebo,

For abbreviations, see footnote to Table IL

P values for differences between means: *<0.05; 1i<0.01; 1<0.00l (controls/patients before inducing drugs). P values for differences between means: §<0.05; 1.<0.01; (patients before/after inducing drugs.).

12.7 ± 2.3 mmol// and after placebo, 12.1 ± 2.6 mmol//; NS). Therapy with the enzyme inducers PB and MPA, reduced BG significantly (Fig. 1, Table III). Fig. 2 shows that the BG responses to biguanide, sulfonylureas, and insulin were not significant in a patient with NIDDM (case 5, Table I). PB, however, induced a marked BG decrease and an increase in antipyrine metabolism.

IRI levels fell in seven subjects, was unchanged in two, and increased in one (from 7.4 to 12.7 mU//). The decrease in the seven subjects was significant (Table III). Body weight decreased in six subjects, increased in one, and was unchanged in three. The mean decrease in all 10 subjects was from 75.3 -± 13.3 (SD) to 73.7 ± 12.4 kg (P < 0.05).

Serum aminotransferase levels decreased (Table III), whereas the change in the other liver test results was insignificant. Antipyrine metabolism rose in all subjects (Table III).

To demonstrate the effect of enzyme- inducing compounds on liver histology light (LM) and electronmicroscopic (EM) findings before and after inducing therapy with PB in a

patient with NIDDM (case 5) are given (Figs. 3

and 4). On examination of LM findings, the

BG Antipyrine

Fasting (mmol ll)

Mean daily

(mmoll1)

Plasma IRI

(mUll) t1/2

(hr) CL

(ml/mm)

Control subjects Mean 4.9 5.0 9.0 8.9 42.9 SD 0.6 0.5 1.8 2.2 13.3

Diabetics with NIDDM Before inducing drugs

Mean 12.81: 12.7$ 24.3* 13.7* 30.6 SD 1.7 2.3 13.4 3.9 7.1

After inducing drugs Mean 9.111 9.011 17.1§ 10.71 50.21 SD 1.7 1.8 9.7 9.6 21.9

830 Sotaniemi et al. Con. Pharmacol. Ther. June 1983

Table III. Biochemical data and drug metabolism study results in 10 diabetics with N1DDM and changes in these values after treatment with hepatic enzyme-inducing drugs as compared with age- and sex-matched controls

Volume 33

Number 6

Liver function test results

most conspicuous change was reduction in fat content; in morphometry it fell from 32 to 15

vol% EM examination revealed a decrease in collagen fibers in the pericellular space (morphometric change from 22.7% to 15.7% in volume density of collagen), increase in the surface density of the smooth endoplasmic reticulum (from 0.46 to 1.71 ilk- I ) and regenerative changes in the plasma cell membrane of the hepatocytes

The enzyme-inducing drugs did not alter the therapy of concomitant diseases; drug therapies for heart disease and hypertension were not af- fected.

Discussion

The liver plays a central role in carbohydrate metabolism .5,9,10,12,29 Insulin and glucagon binding to specific receptors on the plasma membrane of the hepatocytes initiates the events that mediate the hormone action inside the cells and causes the biological response.6'16'19 During this process, glucose is converted into metabolic energy or stored as glycogen in the liver and as

fat in the adipose tissue.29 The carbohydrate balance is disturbed in NIDDM patients, who often have hyperglycemia without insulin defi-

ciency (as those in this study). Normalization of the BG levels, the primary therapeutic goal in

these patients, is achieved by oral antidiabetic


drugs, diet, exercise, and education. In some patients with NIDDM, however, resistance may develop'6; this was the problem our patients had at the starting point of this study.

Patients with NIDDM have reduced microsomal enzyme activity ,27'28'34 and since the glucose metabolism is influenced by these enzymes, we treated the subjects with inducing drugs. The response was good; BG levels dropped 30% from the pretherapy level and the plasma IRI indicated a tendency towards normal values, both changes being associated with ac- tivated microsomal enzyme system (indicated by stimulated antipyrine metabolism). Our data thus seem to confirm the hypothesis3'7'9 that postreceptional events may play an important role in the diabetic state of NIDDM. Since BG levels are related to the number of insulin receptors,16 there must be a close functional syn- chronization between insulin-receptor activity and intracellular enzymatic glucose handling. It

is therefore possible that the regulation of the receptor activity and postreceptional events may be influenced by the enzymatic activity in the hepatocytes .

Characteristic of our NIDDM patients was also fatty liver with or without fibrosis and elevation of the serum aminotransferase levels. The mechanism by which the inducing drugs improve the glucose tolerance is not clear, but several factors, such as activation of the hepatic microsomal enzyme system, improved availability of the glucose (and insulin) in the circu- lation, and reparative changes in the hepatocellular membranes, may be involved. Improved antipyrine metabolism indicates enhanced microsomal enzyme activity.32'33'37 Consequently, activation of glucose-6-phosphatase and glycogen synthetase, the microsomal enzymes participating in postreceptional glucose metabolism in the hepatocytes, may occur. Patients with NIDDM have reduced gluco se-6-phosphatase activity,* whereas in juvenile diabetes (type I),21

and in diabetic animals, the activity is increased.' This enzyme activation may result in normalized glucose output and glycogen storage in the ce11s29 that, in part, may explain the BG

*Unpublished observation.

Tot bil (p.mo111)

AP (U11)

SGPT (U11)

SGOT (U11)

ALB (gm/1)

TT (%)

7.3 190.6 25.1 22.4 44.3 85.3 2.4 30.0 4.2 7.6 2.4 13.7

6.9 233.0 71.1* 41.1 43.5 85.5 2.8 79.0 59.2 25.9 2.6 21.4

5.9 212.1 38.411 25.3* 43.6 87.7 2.3 86.9 45.8 15.6 4.3 21.3

Fig. 3. Micrograph of liver needle biopsy material taken before PB from a patient with NIDDM (case 5). Note moderate fatty infiltration (arrows) and slight increase of collagen fibers (asterisks). (Magnification x 125.)

decrease in our patients. Therapy with inducers has also been associated with a decrease in pen- cellular collagen fibers2 and an increase in liver blood flow.22 These changes, together with the reduction in liver fat content noted here, are known to reduce intrahepatic pressure and blood shunting,'5 and may have contributed to greater availability of glucose (and insulin) to the hepatocytes.

In patients with NIDDM insulin receptors on the cells are reduced in number, a phenomenon that correlates inversely with plasma IRI levels.1" The normal or high fasting plasma IR1

noted here suggests that our patients had decreased receptors before therapy with inducing drugs. The decline in IRI levels during hepatic induction thus indicates enhancement in recep- tion on the hepatocytes. This assumption is supported by the reparative changes in the plasma membrane of the cells (Fig. 4) and also

by the finding that serum aminotransferase levels fell during the trial, a sign of normalized membrane permeability.18 It is also possible that there might be changes in the secretion or degradation of insulin in patients with NIDDM in whom enzyme activity is enhanced. Our data demonstrate that therapy with inducers may lower the high plasma IRI levels in patients with NIDDM, and this seems to be connected with improved control of type II diabetes.

There was a significant decrease in the weight of our patients during the therapy with enzyme inducers and this may have a beneficial effect on diabetes contro1.8'18'17 Decrease in body weight is not, however, known to be related to improved microsomal enzyme activity in patients with NIDDM.28 Thus, activation of the microsomal enzymes participating in postreceptional glucose metabolism cannot be ex- plained solely by weight loss, since normaliza-

832 Sotaniemi et al. Clin. Pharmacol. Ther. June 1983

Volume 33 Number 6


Fig. 4. Electron micrograph of liver biopsy material taken after the therapy with PB in a patient with NIDDM (case 5). Note almost normal intracellular space (arrows) between hepatocytes and hy- pertrophic smooth endoplasmic reticulum (SER) at upper right. f = fat globule; m = mitochondria; and g = Golgi apparatus. (Magnification x 10,000.)

tion of enzymatic function does not occur as a

result. It can be said that enzyme inducers may be

useful in adjuvant therapy for diabetics with NIDDM who have reduced microsomal enzyme activity without insulin deficiency. This kind treatment is not curative, but it leads to better diabetes control. More than 200 drugs with inducing properties are available.4 We selected PB and MPA because in our earlier studies24.31

they induced improvement in hepatic metabolism without side effects. Activation of the liver enzyme system suggests a new approach to the handling of NIDDM.

References 1. Arranto AJ, Sotaniemi EA: Morphologic altera-

tions in patients with alpha-methyldopain- duced liver damage after short- and long-term

exposure. Scand J Gastroenterol 16:853-863, 1981. Arranto AJ, Rautio A: Sotaniemi EA: Pericellu- lar collagen in alcoholics with liver cirrhosis. Res Commun Chem Pathol Pharmacol 35:121- 135, 1982. Caro JF, Amatruda JM: Insulin receptors in hepatocytes: postreceptor events mediate down regulation. Science 210:1029-1031, 1980. Conney AH: Pharmacological implications of microsomal enzyme induction. Pharmacol Rev 19:317-366, 1967. Creutzfeldt W, Frerichs H, Sickinger K: Liver diseases and diabetes mellitus, in Popper H, Schaffner F, editors: Progress in liver diseases. New York, 1970, Grune and Stratton, pp. 371- 407. Czech MP: Insulin action. Am J Med 70:142- 150, 1981. Davidson MB, Kaplan SA: Increased insulin binding by hepatic plasma membranes from diabetic rats. J Clin Invest 59:22-30, 1977. DeFronzo R, Ferrannini E, Hendler R, Wahren

J, Felig P: Influence of hyperinsulinemia, hyperglycemia and the route of glucose adminis- tration on splanchmic glucose exchange. Proc Natl Acad Sci 75:5173-5177, 1978. DeFronzo RA, Ferrannini E: The pathogenesis of non-insulin-dependent diabetes. An update. Medicine 61:125-140, 1982. Felig P, Wahren J, Hendler R: Influence of oral glucose ingestion on splanchnic glucose and gluconeogenic substrate metabolism in man. Di- abetes 24:468-475, 1975. Fouts JR, Rogers LA: Morphological changes in the liver accompanying stimulation of microsomal drug metabolizing enzyme activity by phenobarbital, chloradane, benzpyrene or methyl- cholantrene in rats. Pharmacol Exp Ther 147- 148: 112-119, 1965. Hammond E-SF, Striffler JS, Cardell RR: Mor- phological and biochemical observations on hepatic glycogen metabolism in mice on a con- trolled feeding schedule II. Streptozotocin-diabetic mice. Dig Dis Sci 27:692-700, 1982. Himsworth HP, Kerr RB: Insulin sensitive and insulin-insensitive types of diabetes mellitus. Clin Sci 4:119-152, 1939. Holloway CT, Carfield SA: Effect of diabetes and insulin replacement on the lipid properties of hepatic smooth endoplasmic reticulum. Lipids 16:525-532, 1981. Israel Y, Orrego H: Hepatocyte demand and substrate supply as factors in the susceptibility to alcoholic liver injury: pathogenesis and preven- tion. Clin Gastroenterol 10:355-373, 1981. Kahn CR: Insulin receptors and syndromes of insulin resistance. Diabetes Care 5(suppl. 1):

98-101, 1982. LeBlanc J, Nadeau A, Boulay M, Rousseau- Migneron S: Effects of physical training and adiposity on glucose metabolism and '25I-insulin binding. J Appl Physiol 46:235-239, 1979. Miyake S: The mechanism of release of hepatic enzymes in various liver disease. 2. Altered activity ratios of GOT GPT in serum and liver of patients with liver disease. Acta Med Okayama 33:343-358, 1979. Olefsky JM: The insulin receptor: its role in insulin resistance in obesity and diabetes. Diabetes 25:1154-1162, 1976. Orrenius S, Ericson JLE: On the relationship of liver glucose-6-phosphatase to the proliferation of endoplasmic reticulum in phenobarbital induction. J Cell Biol 31:243-256, 1966. Patrick SJ, Tulloch JA: Glucose-6-phosphatase activity in human diabetes. Lancet 1:811-812, 1957. Pirttiaho HI, Sotaniemi EA, Pelkonen RO, Pit- kanen U: Hepatic blood flow and drug metabolism in patients on enzyme inducing anticon- vulsants. Eur J Clin Pharmacol 22:441-445, 1982.

Prescott LF, Adjepon-Yamoah KK, Roberts E: Rapid gas-liquid chromatographic estimation of antipyrine in plasma. J Pharm Pharmacol 25: 205-207, 1973. Rautio A, Sotaniemi EA, Pelkonen RO, Luoma PV: Treatment of alcoholic cirrhosis with enzyme inducers. CLIN PHARMACOL THER 28: 629-637, 1980. Reaven GM, Bernstein R, Davis B, Olefsky JM: Nonketotic diabetes mellitus: Insulin deficiency or insulin resistance. Am J Med 60:80-88, 1976. Saarni H, Ahokas JT, Karki NT, Pelkonen 0, Sotaniemi EA: Dose-dependent effects of medroxyprogesterone acetate on the hepatic drug- metabolizing enzyme system in rats. Biochem Pharmacol 2:1155-1159, 1980. Salmela PI, Sotaniemi EA, Pelkonen RO: Evaluation of drug metabolizing capacity in patients with diabetes mellitus. Diabetes 29:788- 94, 1980. Salmela PI, Sotaniemi EA, Viikari J, Solakivi- Jaakola T, Jarvensivu P: Fenfluramine therapy in non-insulin-dependent diabetic patients: effects on body weight, glucose homeostatis, serum lipoproteins and antipyrine metabolism. Diabe- tes Care 4:535-540, 1981. Sherwin R, Felig P: Pathophysiology of diabetes mellitus. Med Clin North Am 62:695-711, 1978. Sotaniemi EA, Ahlqvist J, Pelkonen RO, Pirt- tiaho H, Luoma PV: Histological changes in the liver and indices of drug metabolism in alcoholics. Eur J Clin Pharmacol 11:295-303, 1977. Sotaniemi EA, Hynynen T, Ahlqvist J, Ahokas JT, Puoskari U, Pelkonen I: Effects of medroxyprogesterone on the liver function and drug metabolism of patients with primary biliary cirrhosis and chronic active hepatitis. J Med 9:117-128, 1978a. Sotaniemi EA, Pelkonen RO, Ahokas JT, Pirttiaho HI, Ahlqvist J: Relationship between in vivo and in vitro drug metabolism in man. Eur J Drug Metab Pharmacokinet 3:39-45, 1978b. Sotaniemi EA, Pelkonen RO, Puukka M: Mea- surement of hepatic drug metabolizing enzyme activity in man. Comparison of three different assays. Eur J Clin Pharmacol 17:267-274, 1980. Sotaniemi EL, Arranto AJ, Tukia M-L: Age, sex and drug metabolism in diabetics. CLIN PHAR- MACOL THER 33:261 (abst), 1983. Stengard JH, Saarni HU, Sotaniemi EA: Effects of medroxyprogesterone acetate (MPA) on hepatic glucose metabolism and microsomal enzyme activity on rats with normal and altered liver. Pharmacology. (In press.) Stengard JH, Arrant° AJ, Sotaniemi EA: He- patic glucose-6-phosphatase activity in subjects with non-insulin dependent diabetes mellitus. (Submitted for publication.)

834 Sotaniemi et al. Clin. Pharmacol. Ther. June 1983

Volume 33 Number 6

Thurman RG, Reinke LA, Belinsky S, Evans RK, Kauffman FC: Co-regulation of the mixed- function oxidation of p-nitro-anisole and glucu- ronidation of p-nitrophenol in the perfused rat liver by carbohydrate reserves. Arch Biochem Biophys 209:137-142, 1981. Vesell ES: The antipyrine test in clinical phar-


macology: Conceptions and misconceptions. CLIN PHARMACOL THER 26:275-286, 1979. Weibel ER, Stäubli W, Gnagi HR, Hess FA: Correlated morphometric and biochemical studies on the liver cell. Morphometric model, ste- reologic methods, and normal morphometric data for rat liver. J Cell Biol 42:68-91, 1969.

Erratum

In the USAN Council's list of new names for the April 1983 issue of the JOURNAL (p 549), "USAN Council List No. 233" should have read "USAN Council List No. 235.

treatment of noninsulin-dependent diabetes mellitus with enzyme inducers

Documents