DIABETES CARE, VOLUME 23, NUMBER 1, JANUARY 2000 1 T he roles of insulin deficiency and t reatment in protein homeostasis are well documented in type 1 diabetes (1–8) but insulin’s role in type 2 diabetes remains uncertain. The American Dia- betes Association recently concluded that t here were insufficient data on which to make firm dietary protein rec o mmend a- tions (9), and one expert renewed the call for more res ea rch (10). We have repo rt ed that protein metabolism is accelerated in moderately hyperglycemic obese diabetic subjects when compared with an obese co nt rol group during a weight-maintain- ing diet with ample protein intake (11). These alterations were corrected with eu- glycemia from exogenous insulin (12, 13). However, euglycemia with a very- lo w - energy diet (VLED) did not com- pletely reestablish nitrogen equilibrium in diabetic, in contrast to nondiabetic, sub- jects. This suggested that type 2 diabetic subjects have altered adaptive mecha- nisms for protein sparing, independent of the protein quality (11,12). When gly- cemia was normalized with insulin at the onset of the VLED, nitrogen balance was im p roved but equilibrium was still not achieved (13). The question rem a ined whether protein metabolism and nitro gen balance could be corrected using the con- ventional approach to treatment that com- bines moderate energy restriction with oral hypoglycemic agents (OHA). We in- vestigated the effects of OHA on pro t ein metabolism during both isoenergetic feed- ing (ISO) and 4 weeks of energy res t r ic- tion or low-energy diet (LED). With ISO, we aimed for the best possible glycemic co nt rol, whereas with LED, the goal was euglycemia . RESEARCH DESIGN AND M E TH O D S Subjects A total of 13 obese subjects with type 2 dia- betes (7 women, 6 men) and 10 obese non- diabetic control subjects (9 women, 1 man) were admitted to the Clinical Inves- tigation Unit of the Royal Victoria Hospital (Table 1). OHAs were stopped 1 week be- fo re admission. Consent was obtained ac- co rding to the Institutional Human Ethics Committee. Clinical and laboratory evalua- tions showed no evidence of hepatic, car- d io va sc ula r, hematologic, renal or pul- mo na ry dysfunction, or gout. The subjects perf o rmed two half-hour walks each day. The ISO diet was a weight-maintaining liq- F rom the McGill Nutrition and Food Science Center (R.G., K.S., J.A.M., E.B.M.), Royal Victoria Hospital; and the School of Dietetics and Human Nutrition (P .J.H.J.), McGill University, Montréal, Québec, Canada. Address correspondence and reprint requests to Dr. Réjeanne Gougeon, McGill Nutrition and Food Science Cent re, Royal Victoria Hospital, 687 Pine Ave. W., Montréal, Québec, Canada H3A 1A1. E-mail: rgo ugeo n@ rvhmed.la n.mcgill.ca . Received for publication 15 March 1999 and accepted in revised form 22 September 1999. Abbreviatio ns : 3MH, N -methylhistidine; B, protein breakdown; BMI 2 5 , body weight corresponding to a BMI of 25; FFM, fat-free mass; FSG, fasting serum glucose; ISO, isoenergetic diet; LED, low-energy diet; OHA, oral hypoglycemic agent; Q, nitrogen flux; S, protein synthesis; S-B, net protein synthesis; VLED, very- lo w - energy diet. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. E ffects of Oral Hypoglycemic Agents and Diet on Protein Metabolism in Type 2 D i a b e t e s O R I G I N A L A R T I C L E O BJE C TI V E — We tested whether oral hypoglycemic agents (OHA), gliclazide with or without metformin, during an isoenergetic (ISO) and then a low-energy diet (LED) improve the altered kinetics of whole-body protein metabolism in type 2 diabetes. RESEARCH DESIGN AND M ETHODS — A total of 13 type 2 diabetic patients (aged 51 ± 2 years, weight 110 ± 5 kg, BMI 41 ± 1 kg/m 2 , fasting glucose [FSG] 11.5 ± 0.9 mmol/l) (means ± SEM) and 10 obese control subjects (48 ± 3 years, 98 ± 6 kg, 37 ± 2 kg/m 2 , FSG 5.5 ± 0.3 mmol/l) consumed an ISO, 1.5 g kg –1 day –1 protein for a body weight correspon din g to a BMI of 25 (BMI 25 ), a formula diet (7 days for obese control subjects, 15 days for diabetic patients), and then a 28-day LED with 50% of the energy of ISO but the same protein intake (101 ± 2 g/day). OHAs were given during ISO (days 8–15) and LED. On days 6–8 (and 12–14 for diabetic subjects) of ISO and 26–28 of LED, the 60-h oral 15 N-glycine method was used to obtain nitrogen flux (Q), synthesis (S), and breakdown (B). Muscle protein catabolism was estimated from N -methylhistidine (3MH) excretion . RE SU LTS — During ISO with hyperglycemia, Q, and B adjusted for fat-free mass, sex, and age were higher and nitrogen balance and net endogenous protein synthesis (S-B) lower than in control subjects ( P 0.05). OHA decreased FSG (9 ± 1 mmol/l) and 3MH and increased plasma insulin–to–glucose ratio, nitrogen retention, and S-B to levels in control subjects. The change in S-B correlated with that in FSG ( r = 0.845, P = 0.001) and in fasting plasma C-peptide ( r = 0.852, P = 0.0005). With LED and OHA, weight decreased 6.3 kg, glycemia reached near-n ormal levels, and nitrogen equilibrium was maintained; Q decreased by 7%, S and B by 11% ( P 0.05) to values found in control subjects. C O N C L U SI O N S — OHA during ISO corrected protein turnover in relation to glycemia and plasma C-peptide. The LED maintained protein homeostasis in obese control subjects and, in diabetes patients with OHA, normalized protein metabolism. These findings have im- plications for diet and OHA prescription. Diabetes Care 2 3 :1–8, 2000 RÉJEANNE GOUGEON, PHD K ARIN STYHLER, MSC J OSÉ A. MORAIS, MD PETER J.H. J ONES, PHD ERROL B. MARLISS, MD Clinical Care/Education/Nutrition Downloaded from http://diabetesjournals.org/care/article-pdf/23/1/1/449577/10857959.pdf by guest on 24 June 2022