Triglyceride-induced diabetes associated with familial lipoprotein lipase deficiency

Raised plasma triglycerides (TGs) and nonesterified fatty acid (NEFA) conce ntrations are thought to play a role in the pathogenesis of insulin-resista nt diabetes. We report on two sisters with extreme hypertriglyceridemia and overt diabetes, in whom surgical normalization of TGs cured the diabetes. In all of the family members (parents, two affected sisters, ages 18 and 15 years, and an Ii-year-old unaffected sister), we measured oral glucose tol erance, insulin sensitivity (by the euglycemic-hyperinsulinemic clamp techn ique), substrate oxidation (indirect calorimetry), endogenous glucose produ ction (by the [6,6-H-2(2)]glucose technique), and postheparin plasma lipopr otein lipase (LPL) activity. In addition, GC-clamped polymerase chain react ion-amplified DNA from the promoter region and the 10 coding LPL gene exons were screened for nucleotide substitution. Two silent mutations mere found in the father's exon 4 (Glu(118) Glu) and in the mother's exon 8 (Thr(361) Thr), while a nonsense mutation (Ser(447) Ter) was detected in the mother' s exon 9. Mutations in exons 4 and 8 were inherited by the two affected gir ls. At 1-2 years after the appearance of hyperchylomicronemia, both sisters developed hyperglycemia with severe insulin resistance. Because medical th erapy (including high-dose insulin) failed to reduce plasma TGs or control glycemia, lipid malabsorption was surgically induced by a modified biliopan creatic diversion. Within 3 weeks of surgery, plasma TGs and NEFA and chole sterol levels were drastically lowered. Concurrently, fasting plasma glucos e levels fell from 17 to 5 mmol/l (with no therapy), while insulin-stimulat ed glucose uptake, oxidation, and storage were all markedly improved. Throu ghout the observation period, plasma TG levels were closely correlated with both plasma glucose and insulin concentrations, as measured during the ora l glucose tolerance test. These cases provide evidence that insulin-resista nt diabetes can be caused by extremely high levels of TGs.