Synthesis Rate of Muscle Proteins, Muscle Functions, and Amino Acid Kinetics in Type 2 Diabetes

Abstract

Improvement of glycemic status by insulin is associated with profound changes in amino acid metabolism in type 1 diabetes. In contrast, a dissociation of insulin effect on glucose and amino acid metabolism has been reported in type 2 diabetes. Type 2 diabetic patients are reported to have reduced muscle oxidative enzymes and VO 2max . We investigated the effect of 11 days of intensive insulin treatment (T 2 D؉) on whole-body amino acid kinetics, muscle protein synthesis rates, and muscle functions in eight type 2 diabetic subjects after withdrawing all treatments for 2 weeks (T 2 D؊) and compared the results with those of weight-matched lean control subjects using stable isotopes of the amino acids. Whole-body leucine, phenylalanine and tyrosine fluxes, leucine oxidation, and plasma amino acid levels were similar in all groups, although plasma glucose levels were significantly higher in T 2 D؊. Insulin treatment reduced leucine nitrogen flux and transamination rates in subjects with type 2 diabetes. Synthesis rates of muscle mitochondrial, sarcoplasmic, and mixed muscle proteins were not affected by glycemic status or insulin treatment in subjects with type 2 diabetes. Muscle strength was also unaffected by diabetes or glycemic status. In contrast, the diabetic patients showed increased tendency for muscle fatigability. Insulin treatment also failed to stimulate muscle cytochrome C oxidase activity in the diabetic patients, although it modestly elevated citrate synthase. In conclusion, improvement of glycemic status by insulin treatment did not alter whole-body amino acid turnover in type 2 diabetic subjects, but leucine nitrogen flux, transamination rates, and plasma ketoisocaproate level were decreased. Insulin treatments in subjects with type 2 diabetes had no effect on muscle mitochondrial protein synthesis and cytochrome C oxidase, a key enzyme for ATP production.

Role of insulin in the regulation of human skeletal muscle protein synthesis and breakdown: a systematic review and meta-analysis

“…However, in response to long-term intensive s.c. insulin treatment, Halvatsiotis et al found no difference in mitochondrial, sarcoplasmic or mixed MPS compared with healthy controls who did not receive insulin [50]. Whether increased AA intake in insulin-treated patients with diabetes will lead to increased muscle mass is not known.…”

Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts

“…However, it is unclear whether the muscle specimens obtained from amputated limbs in that study (34) were from patients under suboptimal glucose control and͞or with peripheral vascular disease. Recent studies performed in people with type 2 DM demonstrated that 2 wk of insulin treatment did not stimulate COX activity and mitochondrial protein synthesis (12).…”

“…At 0400 hours of each inpatient period, a priming dose of L-[1,2-13 C]leucine (1.8 mg͞kg of FFM) was administered through a peripheral forearm vein. This was followed by a continuous infusion of L- [1,[2][3][4][5][6][7][8][9][10][11][12][13] C]leucine (1.8 mg͞kg of FFM per h). Insulin [1.5 milliunits (mU)͞kg of FFM per min] or normal saline infusion was randomized and began at 0700 hours.…”

“…A recent report by Boirie et al (11) on miniature swine has also demonstrated that insulin infusion preferentially stimulates the fractional synthesis rate (FSR) of skeletal muscle mitochondrial proteins. In contrast, 2 wk of insulin treatment did not stimulate muscle mitochondrial protein synthesis and cytochrome c oxidase (COX) activity in people with type 2 diabetes mellitus (DM) (12). Skeletal muscle insulin resistance in people with type 2 DM is associated with a reduced proportion of fatigue resistant slowoxidative (type I) muscle fibers compared with fatigable fastglycolytic muscle fibers (type II) (7,8).…”

Hyperammonemia in uncontrolled Type2 Diabetes Mellitus

“…Diabetes is associated with the occurrence of well described microvascular complications that affect different organs, leading most commonly to retinopathy, nephropathy and peripheral neuropathy, the development of which is dependent on the duration of the disease and glycaemia control [17]. the term -diabetic encephalopathy‖ was introduced in 1950 to describe the complication of diabetes resulting on brain dysfunction and leading to cognitive impairment.…”