Effect of dietary energy restriction on glucose production and substrate utilization in type 2 diabetes.

Abstract

A total of 8 obese subjects with type 2 diabetes were studied while on a eucaloric diet and after reduced energy intake (25 and then 75% of requirements for 10 days each). Weight loss was 2, 3, and 3 kg after 5, 10, and 20 days, respectively; all of the weight lost was body fat. Fasting blood glucose (FBG) levels fell from 11.9 ± 1.4 at baseline to 8.9 ± 1.6, 7.9 ± 1.4, and 8.8 ± 1.3 mmol/l at days 5, 10, and 20, respectively (P < 0.05, baseline vs. 5, 10, and 20 days). Endogenous glucose production (EGP) was 22 ± 2, 18 ± 2, 17 ± 2, and 22 ± 2 µmol · kg -1 lean body mass (LBM) · min -1 (P < 0.05, days 5 and 10 vs. baseline). Gluconeogenesis measured by mass isotopomer distribution analysis provided 31 ± 4, 41 ± 5, 40 ± 4, and 33 ± 4%, respectively, of the EGP (NS); absolute glycogenolytic contribution to the EGP was 15 ± 2, 11 ± 2, 11 ± 2, and 15 ± 2 µmol · kg -1 LBM · min -1 , respectively (P < 0.001, baseline vs. days 5 and 10 and day 10 vs. day 20). The blood glucose clearance rate increased significantly at day 20 (P < 0.05). Neither lipolysis nor flux of plasma nonesterified fatty acids were altered compared with baseline. In conclusion, severe energy restriction per se independent of major changes in body composition reduces both FBG concentration and EGP in type 2 diabetes, the reduction in EGP results entirely from a reduction of glycogenolytic input into blood glucose, and the duration of reduced glycogenolysis is short-lived after relaxation of energy restriction even without weight gain, but effects on plasma glucose clearance persist and partially maintain the improvement in fasting glycemia. Diabetes 49:1691-1699, 2000 D ietary restriction of total energy intake has been shown to influence fasting blood glucose (FBG) and endogenous glucose production (EGP) before significant changes in body weight or composition occur (1-3). The changes in FBG and EGP are correlated, and most of the effects are seen within 7-10 days of starting caloric restriction (3,4).The glucose-producing pathways affected by energy restriction remain uncertain. Glycogenolysis and gluconeogenesis both contribute to EGP in the postabsorptive state. In nondiabetic humans and rodents, starvation or carbohydraterestricted diets reduce EGP (5,6); in rats, the change in EGP results entirely from reduced glycogenolytic flux to glucose, not reduced gluconeogenesis input. Some previous studies have suggested that predominantly gluconeogenesis is increased in type 2 diabetes, whereas other results suggest that the primary contribution to EGP is from hepatic glycogenolysis (7-9). FBG could also be reduced by energy restriction if the metabolic clearance of glucose were increased. This could be reflected in either increased oxidative or nonoxidative disposal of glucose under fasting conditions.Our laboratory has previously shown that fractional and absolute gluconeogenesis can be measured in rats and in humans by infusing [2-13 C 1 ]glycerol and [U-13 C 6 ]glucose using mass isotopomer distribution analysis (MIDA) to measure the fractional g...

Effects of Moderate Weight Loss and Orlistat on Insulin Resistance, Regional Adiposity, and Fatty Acids in Type 2 Diabetes

“…Prior studies have not directly examined the effects of orlistat on IS measured by a criterion method such as euglycemic insulin infusion. Improved IS is clearly a desirable metabolic effect of weight loss, and prior studies have found this is related to negative energy balance as well as loss of adipose tissue (32)(33)(34). However, because the rates and amounts of weight loss in the orlistat and placebo arms of the intervention were highly comparable, these important factors do not account for the differential effect.…”

De novo lipogenesis in humans: metabolic and regulatory aspects

“…Therefore, HGP is not a constant, like serum sodium concentration or osmolality, but depends upon recent CHO balances. Studies in rats , normal humans Clore et al, 1995) and type II diabetes mellitus (Wing et al, 1994;Kelley et al, 1993;Christiansen et al, 1995) have documented the responsiveness of HGP to recent CHO energy intake. Biochemical mechanisms for this adaptation have been proposed.…”

“…The implication for diseases related to insulin resistance, including type II diabetes, have not been fully explored, although this metabolic adaptation appears to represent the physiologic basis of the therapeutic response to energy restriction (`weight loss') in type II diabetes (Wing et al, 1994;Kelley et al, 1993;Christiansen et al, 1995). (iii) The liver is therefore responsible for whole-body fuel selection in the post-absorptive state.…”

Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study

“…The absolute contribution to plasma glucose from glycogen (glycogenolysis) was calculated as EGP-absolute GNG. Fasting plasma glucose clearance was calculated as the rate of disappearance of glucose (identical to R a glucose under steady-state conditions) divided by the fasting plasma glucose concentration [23]. HOMA-insulin resistance (HOMA-IR) and HOMA-beta cell function (HOMA-B) were calculated as previously described [24].…”