Very low-density lipoprotein metabolism in an unusual case of lipoatrophic diabetes

Very B. Franklin, H. Ginsberg,

W. U. Haque, H. C. Yeh, M. N. B. Horlick, J. R. Paterniti,

Jr, J. Gibson,

A. N. Le, and F. Ginsberg-Fellner Complete acquired lipoatrophic diabetes (LD) is characterized by nonketotic insulin-resistant diabetes, elevated very low-density lipoprotein IVLDLI triglyceride (TG) levels, and absent subcutaneous fat. We studied a young child in whom LD atypically developed after the onset of type 1 diabetes mellitus. On uncontrolled home diet the patient had triglyceride levels over 1,000 mg/dL on multiple occasions. In order to demonstrate the effects of caloric and dietary-fat restriction on VLDL metabolism, ‘H-glycerol and autologous “‘1-VLDL were used to quantitate the turnover of VLDL-TG and VLDLapolipoprotein B (ape B) during two periods of caloric restriction. Consumption of a 9DO-kcal 46-g fat diet resulted in a plasma triglyceride level of 1363 mg/dL (ten-fold elevation). This hypertriglyceridemia was associated with markedly increased production rates of both VLDL-TG (73.7 mg/kg/h) and VLDL-apo B (126.9 mg/kg/d). Consumption of a 900-kcal 26-g fat diet resulted in a plasma TG level of 663 mg/dL. This reduction in plasma TG was associated with a 40% decrease in VLDL-TG production rate (PR) (45.1 mg/kg/h). There was no change in the production rate (PR) of VLDL-apo B. The hypertriglyceridemia in this patient was due to marked over production of VLDL. Furthermore, the studies demonstrate: (1) the independent benefits of caloric and dietary-fat restriction in the treatment of LD. and (2) that fat restriction lowered plasma triglyceride by its effect on the VLDL-TG production rate.

L

IPOATROPHIC DIABETES (LD) is a rare heterogeneous disorder in which there is insulinresistant nonketotic diabetes mellitus, hypertriglyceridemia, absence of subcutaneous adipose tissue, and typical somatic features.“* Most commonly LD is an acquired disease, although congenital forms occur. Both types may show either partial or complete absence of subcutaneous fat tissue. The etiology of LD is unknown, and several treatment modalities including caloric” and fat restriction’; substitution of medium-chain triglycerides for dietary long-chain fatty acids7; drug therapy with pimozide,6,8.9 fenfluramine,“,” or diazoxide”; and plasmapheresis’3 have been used with varying effectiveness. Experimental evidence of a disturbance in the hypothalamic-pituitary13-16axis suggests a role for the central nervous system in the etiology of the disease. Autonomic dysfunction has been demonstrated as we11.17While varying abnormalities of the insulin receptor have been demonstrated,4’18 these probably do not explain the insulin resistance in LD because there is no correlation between the receptor defect and the clinical abnormality. In its complete form, LD is associated with From the Departments of Pediatrics, Radiology, and Medicine, of the Mount Sinai School of Medicine, New York City, NY; and the Department of Pediatrics, St. Joseph Mercy Hospital. Pontiac, Michigan. Presented in part at the 1982 ADA National Meeting at San Francisco. This work was supported in part by the following: PH5HL28077; RR-71 Division of Research Resources, General Clinical Research Center. Address reprint requests to Dr Bonita Franklin, Department of Pediatrics, The Mount Sinai School of Medicine, One Gustave L. Levy Place. New York, NY 10029. 0 1984 by Grune & Stratton Inc. 002&0495/84/3309-0004~03.00/0

814

increased morbidity and mortality primarily due to myocardial infarction and hepatic failure, with death in the third to fourth decades.” Studies have shown that starvation diets, in time, decrease hepatomegaly and hypertriglyceridemia, possibly by decreasing plasma insulin levels, reducing the degree of insulin resistance, and mobilizing hepatic fat.4.16Chait et al” found that diazoxide treatment of a hyperinsulinemic individual resulted in reduced plasma insulin levels and a fall in the very low-density lipoprotein (VLDL) production rate. This suggested a central role for insulin in the hypertriglyceridemia of LD. We have used dietary therapy in an insulin-deficient diabetic 21/2-year-old child with a variant form of complete acquired LD, and have demonstrated a marked reduction in VLDL triglyceride (VLDL-TG) levels in association with both total caloric restriction and dietaryfat restriction. Kinetic studies were carried out to quantitate VLDL-TG and VLDL-apolipoprotein B (VLDL-apo B) production rates during these two periods of nutrient restriction. CASE

REPORT

TG was the 7 lb 14 oz product of a normal full-term pregnancy and vaginal delivery. At 4 months of age she had a varicella infection. At 14 months she was hospitalized with the diagnosis of diabetes mellitus and pneumonia. An arterial PH was 7.16,4+ large ketonuria was present, and blood glucose was 445 mg/dL. She was discharged on twice daily U-100 insulin, 2 units Regular/S units NPH before breakfast, and 2 units Regular/4 units NPH before dinner. Abdominal distention due to massive hepatosplenomegaly was noted, and she lost IO lb over the next few weeks. Triglycerides on a home diet were 348 mg/dL. At 16 months of age there was persistent generalized lymphadenopathy, hepatosplenomegaly (both liver and spleen were 6 cm below the costal rim), an emaciated appearance, and loss of subcutaneous adipose tissue except on her face. Lipoatrophic diabetes mellitus of the acquired type was diagnosed. Ultrasound examination showed marked hepatomegaly,

Metabolism, Vol 33, No 9 (September). 1984

815

LIPOPROTEIN METABOLISM IN LIPODYSTROPHY

increased internal echoes consistent with parenchymal changes, and possible pancreatitis. A liver biopsy examined with both light and electron microscopy showed fatty change, but no evidence of cirrhosis, hepatitis, or abnormal storage material. She was uncontrolled on subcutaneous insulin in the usual doses, and intravenous (IV) insulin up to 70 U per day was used. A trial of the proteolytic enzyme inhibitor trasylol (aprotinin, Mobay Chemicals, New York, NY) plus a total insulin dose of 28 U (2 U/kg body wieght/d) divided throughout the day was given subcutaneously with no substantial improvement. Four months after onset of lipoatrophy and 7 months after onset of diabetes mellitus, she was admitted to Mount Sinai Hospital in New York City. She had a voracious appetite and for a brief period consumed over 2400 kcal in hospital per day without weight gain. Subsequently, she was given a diet consisting of 1500 kcal/d (120 kcal/kg), was regulated on an insulin dose so that urinary glucose losses were minimal, and still failed to gain weight. A trial of withholding insulin and giving an unlimited diet for 20 hours resulted in a fasting blood glucose of 655 mg/dL and fasting triglycerides of 1710 mg/dL. Thereafter, insulin was given subcutaneously either by three daily injections or by subcutaneous infusion via an Alza pump (Alza Corp, Palo Alto, Calif) and diet was 1500 kcal/d. HgbA,C decreased from 6.4% to 4.5% (in our laboratory the normal range is 2.2% to 4.0% for children). At the time of discharge her insulin requirement was 66 U/d, a four-fold increase from her initial dose at diagnosis. After discharge, glucose control worsened and glycosylated hemoglobin rose again. C-peptide, measured by radioimmunoassay (RIA) (CalbiochemBehring, San Diego, Calif), was 1.9 ng/mL when blood glucose was 350 mg/dL, indicating low endogenous-insulin production. An IV insulin tolerance test at 37 months with 0.3 U/kg decreased blood glucose by only 30% in one hour (491 to 345 mg/dL). No antiinsulin receptor antibodies were present and studies of fibroblast glucose transport and insulin receptors were normal (courtesy of Dr Jeffrey Flier). Insulin antibody titers (Bioscience Laboratory, Van Nuys, Calif) were 1:32 for both beef and pork insulin. No fat tissue could be aspirated from the buttocks or thigh at 20 months of age. At 23 months of age the patient developed xanthomas that improved periodically after prolonged periods of tight bloodglucose control, but never disappeared totally. Multiple comparisons of the patient’s liver and spleen size were made by ultrasonography between 21 and 39 months of age. The relative enlargement of liver and spleen varied in this interval, with increased spleen size more predictably following periods of severe hypertriglyceridemia and elevated HgbA,C. At 39 months of age when TG was over 10,000

Table 1. Effect of

Total

mg/dL an abdominal computed tomography (CT) scan showed that the density was markedly decreased in the kidney, spleen, muscles, and pancreas, and slightly decreased in the liver. The decrease in density was consistant with fat infiltration. The subcutaneous fat was scanty and not clearly seen. Test Methods Prior to all studies, informed consent was obtained from the patient’s parents. Approval of the protocol was given by the Research Committee of the Mount Sinai School of Medicine. Detailed investigations of dietary regulation of plasma lipids were carried out on five separate hospital admissions. The patient was given diets of known total caloric value with specified amounts of fat, carbohydrate, and protein. The solid meals were prepared in the Clinical Research Center using a computerized listing of over 100 foods of known composition. Food was divided into six meals, and all meals were consumed in the hospital. The diet consumed at home (designated as “U” in Table 1) was estimated by our research nutritionist to contain between 2400 and 3000 kcal/d. During four of the five hospitalizations (#I, 3,4, 5) the patient was placed on 15% fat diets, containing either 65 kcal/kg (total intake 900 to 1000 kcal/d, or 100 kcal/kg (total intake 1500 kcal/d) to assess the effect of caloric restriction. During hospitalization #2, the patient was first given a 15% fat, 100 kcal/kg diet and then switched to a 40% fat, 65 kcal/kg diet. In this case her total fat intake was 25 g at first and then increased to 40 g, despite a reduction in total calories. During all admissions the patient received varying amounts of insulin three times per day to maintain blood glucose at or below 180 mg/dL. As a result of observations made during the admissions described above the patient was readmitted to the Mount Sinai Hospital Clinical Research Center at 25 months and at 33 months of age for two lipoprotein-turnover studies. Prior to each turnover experiment she received a study diet for five days. During each of these periods her triglycerides rapidly stabilized such that her mean plasma-TG level for the three days prior to each study was within 10% of the steady-state level during the study (see Table 2). Study 1 diet was 900 kcal, 40 g fat, (40% carbohydrate, 40% fat, and 20% protein) in six equicaloric meals. Study 2 diet was 900 kcal, 25 g fat (55% carbohydrate, 25% fat, and 20% protein). Radiolabeled autologous VLDL was prepared for each study using 50 mL of blood. Isolated VLDL was iodinated with 13’1(New England Nuclear) for each study by previously described methods.” 100 uCi of 2-‘H-glycerol (New England Nuclear, Boston, Mass) and 25 uCi of ‘3’I-VLDL were given by rapid IV injection at the beginning of each turnover

Caloric intake and Fat on Plasma Lipid Levels Lipid Levels

Diet Insulin Dose Admission 1

(U/kg/d) 2.1

Total Calories HgbA C%

6.0

5.2 2

3

4.0

5.0

Total

TG

Cholesterol

(Kcal/kg/d)

% Fat

Fat (g)

(mg/dL)

(mg/dLI

U*

U

U

1,710

166

1,500

15

25.5

630

122

15

25.5

805

148

40

1,500

4.0

900t

40

4.9

U

U

U

900

15

15

219

U

U 15

U 16.7

4,940 545

8.8

4.9 4

2.9

5

2.9

2.9 2.9

lU = Unlimited

Total

at home diet.

tDietary change made after 2 weeks.

8.8

7.3

1,000 U

U

U

1,000

15

16.7

1,435

195

2,035

284

11.434 2,453

169

360 185 756 366

816

FRANKLIN ET AL

Table 2.

Lipoprotein

Turnover

Studies IDDM

Studv 1 205.0

Total cholesterol concentration fmg/dL) Total TG concentration (mg/dL)

1383 & 81

Total LDL concentration fmg/dL)

301

VLDL-TG concentration (mg/dL)

1120 * 124

VLDL-TG FCR (per hour) VLDL-TG PR (mg/kg/h) VLDL-apo 8 concentration (mg/dL)

217.9

* 5.1

662.7

t 31

98.4

+ 7.5T

0.134

73.7

45.1

r 5

51.8

219 + 22**

57

148 f 24**

26& 0.33

13 f 0.07

6.0 r 0.54

* 8

A

160 ? 18 107 f 14

562 f 25

0.110 47.5

N0rfllal

Studv 2

+ 16.5

5.8 + 1.4

VLDL-apo 8 FCR (per hour)

0.186

0.145

0.37

r 0.09

VLD-apo 8 PR fmg/kg/d)

126.9

107.9

23.6

+ 9.0

3.8 f 1.04*’ 0.31

+ .03$

10.9 f 2.2$ -

B

169 + 9” 74 * 5’. 2.6 r 0.56’. 0.24

r .03$

3.8 5 0.6$ -

-

Study 1 diet consisted of 900 kcal, 40 g fat and study 2 diet consisted of 900 kcal, 25 g fat. FCR is the fractional catabolic rate. PR is the production rate. All concentrations are given k SD based on ten samples. Normal childhood values are given for total cholesterol, total TG, total LDL, and VLDL-TG. l

*Values for lipids in IDDM are taken from Vlachokosta.25

fTurnover data for IDDM were taken from Pietri.” ” A” indicates conventional treatment, and “8” strict control. All other values are for normal adults. ‘Study 1 LDL single sample. TStudy 2 LDL mean of three samples.

HDL cholesterol was determined after precipitation of other lipoproteins from plasma by Mg++ and dextran sulfate.r3 Apo B concentrations in VLDL were measured using a specific RIA. The activities of hepatic triglyceride lipase (HTGL) and lipoprotein lipase (LPL) in postheparin plasma were determined by the method of Baginsky and BrownF4

study. Plasma samples were drawn for determination of VLDL-apo B and triglyceride-specific radioactivities at the following ten time points: 0, ‘/2, 1, 3, 6, 10, 16, 24, 36, and 48 hours. This schedule permitted full characterization of the complex kinetic data (see Fig 1). The patient received three drops of potassium iodide, three times a day, starting one day before injection of radiolabeled VLDL and continuing for 3 weeks. To eliminate influx of dietary chylomicrons during the 48-hour sampling period, a 900 kcal, 80% carbohydrate, liquid fat-free diet was used beginning 12 hours prior to injection of label. This diet maintains steady-state plasma lipoprotein levels and has been described in detail elsewhere.2’~22All values for VLDL-TG, VLDL-apo B, total cholesterol, and total TG were based on the mean f SD of the ten samples obtained during the turnover study. The specific radioactivity data were used to generate the fractional catabolic and production rates of VLDL-apo B and TG by multicompartmental analysis.20 Production rates (PR) were calculated as the product of the fractional catabolic rate and the pool size, or PR = FCR . plasma volume . concentration of either TG or apo B. An assumed plasma volume for this child of 60 mL/kg body weight was used for calculations. Total plasma and lipoprotein cholesterol and TG levels were determined by enzymatic methods using an Abbott ABA 100 automated spectrophotometer (Abbott Laboratories, Chicago).

RESULTS

The effect of varying total caloric intake and dietary-fat content may be seen in Table 1. During the four admissions when a diet consisting of 15% fat was given, (#l, 3, 4, 5) dietary restriction for 1 to 3 weeks resulted in a prompt decline in both total cholesterol and TG, compared to the values obtained on the day of admission after unlimited diet at home. There was no significant change in HDL cholesterol. The percent decrease was about twice as great in TG (63% to 89%) as in total cholesterol (27% to 52%). In all cases, the dramatic reduction in hypertriglyceridemia occurred within 1 week of admission. During admission #2 the patient was tested after

100 2

u+ = 0

IO

20

30

HOURS

40

50

0

L

I

IO

20

I

I

30

40

HOURS

I 50

Fig 1. Lipoprotein turnover kinetics: (A) ‘HVLDL TG (dpm/mL) and (B) ‘*%VLDL-APO B specific radioactivity kpm/fig). Study 1 (open circles) and study 2 (closed circles).

LIPOPROTEIN METABOLISM

IN LIPODYSTROPHY

equilibration on both a 1500-kcal, 15% fat diet (2 weeks), and on a 900-kcal, 40% fat diet (1 week). The hypertriglyceridemia evident on the 1500-kcal diet (805 mg/dL) worsened on the 900-kcal diet (1435 mg/dL), which was higher in absolute fat content. Thus, increasing the absolute amount of dietary fat resulted in a higher plasma-TG level in this patient despite lower caloric intake. In summary, both total caloric restriction and fat restriction lowered triglycerides independently in this patient. These effects were apparent on multiple admissions, on varying insulin doses, and after periods of both excellent and poor diabetic control (Table 1). LPL was in the low-normal range (for adults) both at 20 and at 37 months of age (8.3 and 5.2 pmol free fatty acid/h/ml, respectively). HTGL was also in the normal range but was three-fold higher when the triglycerides were markedly elevated compared to the activity when plasma TG was only moderately elevated (57.9 and 19.6 pmol free fatty acid/h/ml, for VLDLTG of 4940 v 630 mg/dL respectively at 37 months and 20 months). The results of the two turnover studies are seen in Table 2 and Fig 1. We also show published lipid levels25 and lipoprotein-turnover data26 for patients with type 1 diabetes either poorly or strictly controlled. These data are only available for adult diabetics. Admission TG levels were higher before study 1 compared to study 2. TG levels rapidly fell on both study diets and quickly reached a new steady-state. During each turnover period the patient’s lipids remained stabilized at these new steady-state levels, as seen by the less than 10% variation in the mean of ten samples. Total cholesterol concentration was near normal and similar in both studies, whereas plasma LDL was lower in study 1. During study 1, the production rate of VLDL-TG was mere than ten-fold greater than that of normal adults studied in our laboratory*’ and seven-fold greater than adult diabetics in poor control reported elsewhere.26 In study 2, concomittant with a marked decrease in VLDL-TG level, the VLDL-TG PR was reduced by 40%. The fractional catabolic rate of VLDL-TG was reduced during both studies compared to normals*’ and adult diabetics.26 The VLDL-apo B PR was also markedly elevated during study 1, but only decreased by 10% during study 2. The FCR for VLDL-apo B was reduced during both studies compared to normal adults.” DISCUSSION

LD was first described in 1928*’ but the etiology of this heterogeneous disorder is still unknown. The congenital total form is more severe but less common than the partial lipodystrophy. The glucose intolerance may

817

start in childhood, but diabetes mellitus often has its onset after puberty, and has been treated with or without insulin.*’ Most patients with LD have elevated insulin levels and insulin resistance.6’7’9”2*‘3S29’30 Our patient was unusual in that she initially presented with an episode of diabetic ketoacidosis. However, her loss of subcutaneous adipose tissue, and the development of severe insulin resistance, hypertriglyceridemia, hypermetabolism, hepatosplenomegaly, muscle hypertrophy, and phlebomegaly placed her within the clinical constellation of LD.’ The initial ketoacidosis indicated low endogenous insulin production that was later documented by a low C-peptide value. Hyperlipidemia develops in a variable pattern, predominantly with elevated VLDL triglycerides. The pathophysiologic basis of the hyperlipidemia in LD is unclear. Levels of lipoprotein lipase, a key enzyme in the regulation of fat deposition, have been reported low7~‘6or high4 in LD. In our patient, LPL was low normal. HTGL was also normal but was considerably higher while the patient was more hypertriglyceridemic on a lower insulin dosage. Other investigators have found increased HTGL in non-LD subjects with hypertriglyceridemia. In addition, Kodama reported that a high-fat diet increased HTGL without changing LPL in a LD patient not on insulin.4 Elevated plasma VLDL levels and increased rates of VLDL-TG production have been demonstrated in nonLD hyperinsulinemic, insulin-resistant individuals.3’.32 In a mildly glucose-intolerant hyperinsulinemic LD patient studied by Chait12 administration of diazoxide led to a fall in insulin levels, accompanied by reduction in VLDL production and in serum triglyceride concentration. Our patient is different in that she had no endogenous insulin production, thus endogenous hyperinsulinemia could not have been the cause of the increased VLDL-PR. Although marked overproduction of VLDL appeared to be the major cause of hypertriglyceridemia in our insulin-deficient patient, the PR seemed to be most sensitive to fat consumption, not to the insulin dose or degree of hyperglycemia. Recent studies with somatostatin have also indicated that hyperinsulinism is not a necessary concommitant of increased VLDL-TG PR.33 Apo B, the major structural protein of VLDL that is necessary for secretion of these particles from the liver and intestine,34 IS . produced at increased rates in hypertriglyceridemia.2’.35,36Our patient had a five-fold elevated VLDL-apo B PR, a finding compatible with the elevated VLDL-TG PR. However, whereas 1 week of fat restriction was associated with lower plasma-TG levels and decreased VLDL-TG PR, this intervention had no demonstrable impact on VLDL-apo B PR. Thus, VLDL-TG production appears to be more sus-

818

FRANKLIN

ceptible to short-term dietary manipulations than is VLDL-apo B production. In conclusion, this report concerns a young girl with complete acquired lipatrophic diabetes that was preceded by ketotic diabetes mellitus. CT demonstrated ectopic high-density fat deposition. The disappearance of subcutaneous adipose tissue and its abnormal appearance elsewhere occurred despite low endogenous insulin secretion. Total caloric restriction and dietary-fat restriction both resulted in reduced plasmaTG levels, apparently by independent mechanisms. Kinetic studies showed that overproduction of VLDLTG and VLDL-apo B were the major abnormalities contributing to the hypertriglyceridemia present in this patient. A low-fat diet reduced VLDL-TG PR by 40% with little effect on VLDL-apo B PR. Thus, short-term fat restriction lowered plasma-TG levels by its effect on the VLDL-TG PR, perhaps by reducing

ET AL

the availability of free fatty acids from lipid storage compartments. The recent observation that eucaloric substitution of medium-chain TG for dietary longchain fatty acids improved hyperlipidemia’ supports such a mechanism because medium-chain TG are not components of chylomicra and cannot serve as substrates for ectopic lipid deposition. By restriction of dietary long-chain triglycerides, total fat, and calories the hyperlipidemia associated with increased VLDLPR may be circumvented in this baffling syndrome. ACKNOWLEDGMENl We gratefully acknowledge the expert technical assistance of MS Tung Han, BS in performing the lipoprotein and cholesterol determinations, and the dietary planning by Mrs Diane Lieberman, MS and MS Marsha Kalin. We thank the nursing staff of the General Clinical Research Center for the excellent care given to this patient.

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