Pharmacologic management of hyperglycemia in diabetes mellitus: implications for physical therapy.

Diabetes mellitus is a costly, chronic disease that affects millions of Americans each year. The classic triad of diabetes management includes diet, exercise, and pharmacological intervention. A variety of complications may result due to this chronic disease, and manipulation of the triad of treatment factors may be necessary in order to effectively treat the individual patient. Physical therapists are consulted in both the primary care of patients with diabetes and in the case of complications; therefore, an understanding of the various forms of the disease, the complications, and the treatment approaches is necessary for comprehensive patient management. The purposes of this article are to give an overview of the disease and its common complications and to discuss the various treatment approaches with emphasis on the pharmacological interventions and physical therapy concerns.

Insulin and Na-dependent alanine transport in skeletal muscle of obese Zucker (fa/fa) rats.

Obese Zucker (fa/fa) rat skeletal muscle is characterized by a reduced rate of muscle protein deposition possibly due to alterations in amino acid transport. The purpose of the present study was to investigate alanine transport in plasma membrane vesicles from skeletal muscle of lean and obese Zucker rats, facilitating the study of alanine transport independent of cellular metabolism. Initial rates of alanine transport were measured in the presence and absence of Na using a rapid filtration technique, and the properties of membranes from control and maximally insulin-treated lean and obese Zucker rats were studied. For lean rats, the maximal stimulation (Vmax) for Na-dependent alanine transport was 207 pmol.mg-1.s-1, and the half-maximal affinity constant (K1/2) was 2.3 mM. Insulin treatment increased the Vmax to 387 pmol.mg-1.s-1 with no changes in K1/2. For the obese rats, the Vmax for Na-dependent alanine transport was 248 pmol.mg-1.s-1, and the K1/2 was 2.8 mM. These values were not changed by insulin treatment. Thus Na-dependent alanine transport in obese rat skeletal muscle is resistant to stimulation by insulin; this alteration may contribute to the abnormal muscle protein metabolism observed in these animals.

Exercise, unlike insulin, promotes glucose transporter translocation in obese Zucker rat muscle.

Insulin or exercise stimulates skeletal muscle glucose transport, most likely by increasing both the number and activity of glucose transporters in the plasma membrane. Skeletal muscle glucose transport of genetically obese Zucker rats (fa/fa) displays a severe insulin resistance that results, at least in part, from a failure of net transporter translocation to the cell membrane (King, P., E. D. Horton, M. Hirshman, and E. S. Horton. J. Clin, Invest. 90: 1568-1575, 1992). The purpose of the present study was to determine if the obese rat muscle was also resistant to the action of acute exercise to increase glucose transport and, if so, to determine if the defect involved transporter translocation as seen in the resistance to insulin. The muscle glucose transport system was investigated in plasma membranes isolated from postprandial, sedentary or acutely exercised, lean and obese Zucker rats. Measurements of D- and L-glucose uptake by membrane vesicles under equilibrium exchange conditions indicated that an acute bout of exercise resulted in a threefold increase in the maximum velocity (Vmax) for lean animals (5.7 vs. 17.6 nmol.mg protein-1.min-1) and a 4.5-fold increase in the Vmax for obese rats (4.1 vs. 18.6 nmol.mg protein-1.min-1). For both lean and obese animals, this increase in transport was associated with an increase in transporter number measured by cytochalasin B binding (1.6- and 2.2-fold, respectively) and with an increase in the average carrier turnover number (1.9- and 2.0-fold, respectively). The results indicate that, unlike a maximal insulin stimulus, acute exercise of the obese Zucker rat promotes both transporter translocation and transporter activation in skeletal muscle.

Duration of improved muscle glucose uptake after acute exercise in obese Zucker rats.

Skeletal muscle is insulin resistant in the obese Zucker rat. Endurance training reduces muscle insulin resistance, but the effects of a single acute exercise session on muscle insulin resistance in the obese Zucker rat are unknown. Therefore, insulin responsiveness of muscle glucose uptake was measured in 15-week-old obese rats either 1, 48, or 72 hours after two hours of intermittent exercise (30:30 min; work:rest). Hindlimbs of sedentary lean (LS) and obese (OS) rats and exercised obese (OE) rats were perfused after a 10-hour fast under both basal (0 mU x ml(-1)) and maximal (20 mU x ml(-1)) insulin concentrations to measure net glucose uptake. Insulin responsiveness of net glucose uptake was significantly reduced in OS compared to LS (8.5 +/- 1.6 vs 15.3 +/- 2.0 micromol x g(-1) x h(-1), respectively). Compared to OS, insulin responsiveness of net glucose uptake was significantly increased by 56% and 80% at 1 hour and 48 hours after acute exercise. However, 72 hours after acute exercise, the increased insulin responsiveness of net glucose uptake was no longer evident. These results indicate that improved responsiveness of muscle glucose uptake persists for at least 48 hours after two hours of acute intermittent exercise in 15-week-old obese Zucker rats.

Training-induced vascular and metabolic adaptations in normo(11 week)- and hyper(18 week)-glycemic obese Zucker rats.

The purpose of this study was to investigate the peripheral vascular and metabolic adaptations induced by aerobic training in normoglycemic (11-week-old) and hyperglycemic (18-week-old) insulin-resistant male obese Zucker rats (OZR). OZR were treadmill trained 6-11 (T6-11), 11-18 (T11-18), or 6-18 (T6-18) weeks of age at 15 m/min. 17 percent grade, 1 hour/day, 5 days/week. Forty-eight hours after the last training session and after a 12 hour fast, a tail vein blood sample was obtained for analysis of glucose and insulin concentrations, cholesterol, and glycosylated hemoglobin fraction. Glucose uptake and hindlimb vascular resistance were measured during extracorporeal perfusion of the hindlimb (1.0mU insulin/ml). Trained animals were compared to sedentary age-matched obese (S-OZR) and lean (LZR) animals. S-OZR were hyperinsulinemic and obese at 6 weeks of age, mildly hypercholesterolemic and hyperglycemic at 11 weeks, and profoundly hyperglycemic at 18 weeks. Training did not affect body weight or serum cholesterol. Fasting insulin and glucose concentrations were not different between sedentary and trained OZR, except T6-18 which had higher insulin and lower glucose concentrations. The insulin/glucose ratio was lower in OZR animals and was not altered by 6-7 week training (T6-11, T11-18), but was normalized by 12 week training (T6-18). No significant differences in glycosylated hemoglobin fractions were observed between groups. Normalization of glucose uptake was observed in trained 11-week-old OZR, and a statistically non-significant (P = 0.10) 40 percent improvement was observed in trained 18-week-old OZR. Hindlimb vascular resistance was elevated in the S-OZR, relative to LZR, at 11 and 18 weeks of age, and was reduced with training. One hour/day exercise training normalized hindlimb vascular resistance and glucose uptake in 11-week-old OZR, but only moderately improves these vascular and metabolic variables in 18-week-old hyperglycemic animals. Prolonged (12 weeks) training reduced the severity of fasting hyperglycemia in older animals, but at the expense of an increased fasting insulin concentration.