Summary
The plasma free fatty acid and triglyceride transport kinetics in 16 non-obese and 7 obese maturity onset diabetics with hypertriglyceridaemia have been compared with results obtained in 27 control subjects. Changes in glucose and insulin responses were evaluated in relation to the lipid parameters. All the diabetics showed elevated plasma FFA levels and turnover rates. In the non-obese diabetics the plasma triglyceride turnover rate was within the normal range and their hypertriglyceridaemia was due to impaired triglceride clearance. In the obese diabetics the plasma triglyceride turnover rate was increased and they also had some impairment of triglyceride clearance, so that in them a double mechanism was observed to account for their hypertriglyceridaemia. The insulin levels in the diabetics were similar to, or greater than, those found in the controls. Our results suggested that the enhanced lipolysis and impaired triglyceride clearance observed in the diabetic patients were a manifestation of insulin unresponsiveness in adipose tissue and that the changes in insulin and glucose relationship could be secondary to elevated FFA and triglyceride levels. Further confirmation was obtained by the finding of an exaggerated insulin response to a glucose challenge in normal subjects infused with Intralipid. Treatment with phenethylbiguanide (Phenformin) significantly lowered the plasma FFA and triglyceride concentration in both diabetic groups. This was associated with normalisation of both plasma FFA turnover and triglyceride clearance. It also reduced the triglyceride turnover rate to the normal range in the obese diabetics. These changes were associated with a fall of plasma glucose and insulin levels to within the normal range. These results suggested an effect of Phenformin in reducing the rate of lipolysis leading to improved glucose tolerance.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Albano, J.D., Ekins, R.P., Maritz, G., Turner, B.C.: A sensitive precise radio-immuno assay of serum insulin relying on charcoal separation of bound and free hormone moieties. Acta endocr. (Kbh.)70, 487–509 (1972)
Albrink, M.J., Lavietes, P.H., Man, E.B.: Vascular disease and serum lipids in diabetes mellitus; observations over thirtv years. Ann. intern. Med.58, 305–323 (1963)
Avogaro, P., Capri, C., Gazzolato, G., Pais, M.: Lipid disorders in diabetes mellitus. Acta diabet. lat.9, 540–561 (1972)
Bagdade, J.D., Porte, D., Jr., Bierman, E.L.: Acute insulin withdrawal and the regulation of plasma triglyceride removal in diabetic subjects. Diabetes17, 127–132 (1968)
Basso, L.V., Havel, R.J.: Hepatic metabolism of free fatty acids in normal and diabetic dogs. J. clin. Invest.49, 537–547 (1970)
Brown, J.D., Stone, D.B., Steele, A.A.: Mechanism of action of antilipolytic agents: comparison of the effects of insulin, tolbutamide and phenformin on lipolysis induced by dibutyryl cyclic AMP plus theophylline. Metabolism18, 926–929 (1969)
Boberg, J., Carlson, L.A.: Determination of heparin induced lipoprotein lipase activity in human plasma. Clin. chim. Acta10, 420–427 (1964)
Boberg, J., Carlson, L.A., Hallberg, D.: Application of new intravenous fat tolerance test in the study of hypertriglyceridaemia in man. J. Atheroscler. Res.9, 159–169 (1969)
Carlson, L.A.: Serum lipids in men with myocardial infarction. Acta med. scand.167, 399–413 (1960)
Carlson, L.A., Böttiger, L.E.: Ischaemic heart disease in relation to fasting values of plasma triglycerides and cholesterol. Lancet1972 I, 865–868
Corder, C.N., Kalkhoff, R.K.: Hepatic lipid metabolism in alloxan diabetic rats. J. Lab. clin. Med.73, 551–563 (1969)
Cramp, D.G.: New automated method for measuring glucose by glucose oxidase. J. clin. Path.20, 910–912 (1967)
Cramp, D.G., Robertson, G.R.: The fluorimetric assay of triglyceride by a semi-automated method. Analyt. Biochem.25, 246–251 (1968)
Csorba, T.R., Matsuda, I., Kalant, N.: Effects of insulin and diabetes on flux rates of plasma glucose and free fatty acids. Metabolism15, 262–270 (1966)
Davidson, P.C., Albrink, M. J.: Abnormal plasma insulin response with high plasma triglycerides independent of clinical diabetes or obesity (Abs.) J. clin. Invest.45, 1000 (1966)
Dole, V.P.: A relation between non-esterified fatty acids in plasma and the metabolism of glucose. J. clin. Invest.35, 150–154 (1956)
Elkeles, R.S., Lowy, C., Wyllie, A.D.H., Young, J.L., Fraser, T.R.: Serum insulin, glucose and lipid levels among mild diabetics in relation to incidence of vascular complications. Lancet1971 I, 880–883
Elkeles, R.S.: The direct effect of oral hypoglycaemic agents on glucose metabolism by adipose tissue. Horm. Metab. Res.4, 178–182 (1972)
Farquhar, J.W., Frank, A., Gross, R.C., Reaven, G. M.: Glucose, insulin and triglyceride responses to high and low carbohydrate diets in man. J. clin. Invest.45, 1648–1656 (1966)
Ford, S., Jr., Bozian, R.C., Knowles, H.C., Jr.: Interactions of obesity and glucose and insulin levels in hypertriglyceridaemia. Amer. J. clin. Nutr.21, 904–910 (1968)
Friedberg, S. J., Klein, R.F., Trout, D.L., Bogdonoff, M.D., Estes, E.H.: The incorporation of plasma free fatty acids into plasma triglycerides in man. J. clin. Invest.40, 1846–1855 (1961)
Gomez, F., Jéquier, E., Chabot, V., Büber, V., Felber, J.-P.: Carbohydrate and lipid oxidation in normal human subjects: its influence on glucose tolerance and insulin response to glucose. Metabolism21, 381–391 (1972)
Greenough, W.B., III., Crespin, S.R., Steinberg, D.: Hypoglycaemia and hyperinsulinaemia in response to raised free fatty acid levels. Lancet1967 II, 1334–1336
Gries, F.A., Oberdisse, K.: Fettstoffwechselstörungen und Diabetes Mellitus. Dtsch. med. Wschr.95, 727–734 (1970)
Havel, R.J., Carlson, L.A.: Serum lipoproteins, cholesterol and triglycerides in coronary heart disease. Metabolism11, 195–197 (1962)
Havel, R.J., Kane, J.P., Baiasse, E.O., Segal, N., Basso, L.V.: Splanchnic metabolism of free fatty acids and production of triglycerides of very low density lipoproteins in normotriglyceridaemic and hypertriglyceridaemic humans. J. clin. Invest.49, 2017–2035 (1970)
Hayes, T.M.: Plasma lipoproteins in adult diabetes. Clin. Endocr.1, 247–251 (1972)
Keen, H., Jarrett, R.J.: The effect of carbohydrate tolerance on plasma lipids and atherosclerosis in man. In proceedings of the Second International Symposium on atherosclerosis, pp. 435 (Ed. Jones, R.J.). Berlin-Heidelber-New York: Springer-Verlag 1970
Khachadurian, A.K., Uthman, S.M.: Plasma lipids in diabetes mellitus. J. méd. liban.24, 105–115 (1971)
Kissebah, A.H., Fraser, T.R.: The in vitro14C-cyclic AMP production by normal human adipose tissue in response to some hormones and in uncontrolled and controlled diabetic adipose tissue. Horm. Metab. Res.4, 72–77 (1972)
Kissebah, A.H., Harrigan, P., Wynn, V.: Mechanism of hypertriglyceridaemia associated with contraceptive steroids. Horm. Metab. Res.5, 184–190 (1973)
Kissebah, A.H., Adams, P.W., Wynn, V.: Measurement of plasma free fatty acid and triglyceride kinetics in man. In preparation (1973)
Malaisse, W.J., Malaisse-Lagae, F.: Stimulation of insulin secretion by non-carbohydrate metabolites. J. Lab. clin. Med.72, 438–448 (1968)
Nestel, P.J., Whyte, H.M.: Plasma free fatty acid and triglyceride turnover in obesity. Metabolism17, 1122–1128 (1968)
Nikkilä, E.A., Pykälistö, O.: Induction of adipose tissue lipoprotein lipase by nicotinic acid. Biochem. Biophys. Acta152, 421–423 (1968)
Nikkilä, E.A., Taskinen, M.R.: Hypertriglyceridaemia and insulin secretion, a complex casual relationship. In: Atherosclerosis, Procs. Second Intern. Symp., p. 220 (Ed. Jones, R.J.). Berlin-Heidelberg-New York: Springer-Verlag 1970
Nikkilä, E.A., Kekki, M.: Polymorphism of plasma triglyceride kinetics in normal human adult subjects. Acta. med. scand.190, 49–59 (1971)
Mkkilä, E.A., Kekki, M.: Plasma triglyceride transport kinetics in diabetes mellitus. Metabolism22, 1–22 (1973)
Östman, J.: Studies in vitro on fatty acid metabolism of human subcutaneous adipose tissue in diabetes mellitus. Acta. med. scand.177, 639–655 (1965)
Randle, P. J., Garland, P.B., Hales, C.N., Newsholme, E.A.: The glucose fatty acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet1963 I, 785–789
Reaven, G.M., Hill, D.B., Gross, R.C., Earquhar, J. W.: Kinetics of triglyceride turnover of very low density lipoproteins of human plasma. J. clin. Invest.44, 1826–1833 (1965)
Sailer, S., Sandhofer, F., Braunsteiner, H.: Beziehungen zwischen Blutzuckerspiegel, Umsatzrate der freien Fettsäuren und Fettsäureeinbau in Plasmatriglyceride bei Diabetikern. Klin. Wschr.45, 86–91 (1967)
Sailer, S., Bolzano, K., Sandhofer, F., Spath, P., Braunsteiner, H.: Triglyceridspiegel und Insulinkon-zentration im Plasma nach oraler Glukosegabe bei Patienten mit primärer kohlenhydratinduzierter Hypertriglyceridämie. Schweiz. med. Wschr.98, 1512–1518 (1968)
Salaman, M.R., Robinson, D.S.: Clearing-factor lipase in adipose tissue. A medium in which the enzyme activity of tissues from starved rats increasesin vitro. Biochem. J.99, 640–647 (1966)
Schalch, D.S., Kipnis, D.M.: Abnormalities in carbohydrate tolerance associated with elevated plasma non-esterified fatty acids. J. clin. Invest.44, 2010–2020 (1965)
Seyffert, W.R., Jr., Madison, L.L.: Physiologic effects of metabolic fuels on carbohydrate metabolism. I. Acute effect of elevation of plasma free fatty acids on hepatic glucose output, peripheral glucose utilization, serum insulin and plasma glucagon levels. Diabetes16, 765–776 (1967)
Shafrir, E., Biale, Y.: Effect of experimental hypertriglyceridaemia on tissue and serum lipoprotein lipaseactivity. Europ. J. clin. Invest.1, 19–24 (1970)
Steele, R.: In: “Tracer probes in steady state systems”, p. 23. Springfield, Illinois: Charles C. Thomas 1971
Stout, R.W., Vallance-Owen, J.: Insulin and Atheroma. Lancet1969 I, 1078–1080
Winegrad, A.I.: In: Handbook of Physiology, p. 319 (Ed. Renold, A.E., Cahill, G.F.). Baltimore: Williams and Wilkins 1965
Wing, D.R., Robinson, D. S.: Clearing factor lipase in adipose tissue. A possible role of adenosine-3-5-(cyclic)-monophosphate in the regulation of its activity. Biochem. J.109, 841–849 (1968)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kissebah, A.H., Adams, P.W. & Wynn, V. Inter-relationship between insulin secretion and plasma free fatty acid and triglyceride transport kinetics in maturity onset diabetes and the effect of phenethylbiguanide (Phenformin). Diabetologia 10, 119–130 (1974). https://doi.org/10.1007/BF01219667
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF01219667