Treatment of type 2 diabetes

Effects of aerobic and resistive training on glycemic control

Data on effects of aerobic and resistance training on glycemic control in established type 2 diabetes are summarized in Tables 4.4.1 and 4.4.2. Many studies lacked an appropriate sedentary control group. This limitation is a concern as intensified patient-doctor interaction may itself improve glycemic control and other metabolic parameters. In many studies, the patients lost weight, which may or may not be a consequence of physical activity and confounds, as does small sample size, interpretation of effects of exercise as compared to weight loss per se on metabolic control. Overall effects of physical training on glycemic control have been modest and in roughly half of the studies non-significant. There are several potential explanations for the failure of exercise to be an effective antihyperglycemic therapy. First, physical training primarily improves insulin sensitivity in skeletal muscle (see below) rather than in the liver, which is the ultimate target of any antihyperglycemic drug [12]. Second, an increase in insulin sensitivity implies that the same amount of glucose can be utilized as before but less insulin is required. In the presence of endogenous insulin secretion, the expected effect of insulin sensitization is thus a decrease in the circulating insulin concentration and an unchanged or slightly lowered blood glucose concentration. However, even this effect has been poorly documented since insulin secretion remained unchanged in 7 out of 9 studies where it was measured (Table 4.4.1). Since muscle insulin sensitivity has improved when it has been quantified directly without reliance on endogenous insulin concentrations [13], it is possible that physical training improves both insulin secretion and sensitivity and that the net effect of these two changes is an unchanged insulin concentration. In this respect resistive training seems more effective since the insulin concentration has consistently been found to decrease

Table 4.4.1 Effects of aerobic exercise training on glycemic control and other parameters in patients with type 2 diabetes.

Year (ref)

Intervention/ Control (na)

Exercise programb times/ week, duration/session

Duration

Blood glucose

Serum insulin

HbA1C

Lipids

BP

BW

Improvement in fitness significant0

Trials with a sedentary control group

1985 [13]

33/13

3/week

3 months

0

0

-

0

0

0

Yes

1991 [98]

30/56

1.7 aerobics sessions/week

37 weeks

0

-

-

-

-

0

No

1992 [99]

38/40

3-4/week, 30-60 min

1-2 months

0e

-

0e

T HDL-C

-

0

No

0 Tg

0 Chol

1995 [100]

16/13

3-4/week, 30-90 min

3 months

-

O

T HDL-C

0

0

Yes

0 Tg

1997 [101]

25/26

3/week,60min

26 weeks

0

O

0

-

0

Yes

1997 [102]

11/12

3/week,30-40min

8 weeks

-

O

0 Tg

-

0

Yes

1997 [103]

10/11

2/week,45min

8 weeks

T

0

-

-

0

Yes

Trials without a sedentary control group

1979 [104]

6

5/week,30min

6 weeks

«

0

-

0 Tg

-

0

Yes

0 Chol

1984 [105]

6

6 weeks

0

0

-

-

-

0

1984 [106]

5

7/week,60min

6 weeks

0

0

0

-

-

0

Yes

1988 [107]

7

3/week,60min

10-15 weeks

«

0

O

0

-

0

Yes

1990 [17]

13

3/week,30min

12-14 weeks

«

0

O

0

0

0

1992 [108]

111

4/week,40-60min

3 months

0

-

0

0 Tg

0

0

-

1993 [109]

10-12

6/week,30min

1-2 months

0

-

0

T HDL-C

-

0

-

1994 [110]

652

Daily exercised

3 weeks

0

-

-

0 Chol

0

0

-

0 LDL-C

0 Tg

1994 [111]

9

3/week,30min

2 years

0

-

0

0

0

0

-

1996 [112]

20

3/week,60min

6 months

0

O

0

-

0

Yes

2000 [113]

13

3/week,40min

3 months

0f

O

0 Chol

0

0

No

0 Tg

T HDL-C

b In most studies,exercise intensity was between 60 and 80% of \/o2maxand was performed using a bicycle or treadmill. c Implies no data;'No' implies \/o2maxor some other measure of fitness was measured but no significant change was observed. d Primarily walking.

e Effect observed in women but not in men. f Reduction in insulin dose.

BP,blood pressure; BW,body weight;Chol,serum total cholesterol;HbA1C,glycosylated hemoglobin A1C;HDL-C, serum high-density lipoprotein cholesterol;LDL-C, serum low-density lipoprotein cholesterol;Tg, serum triglycerides; Vo2 max, maximum aerobic power; -, no data;no change; 0, decrease; T, increase.

Table 4.4.2 Effects of resistive exercise training on glycemic control and other parameters in non-diabetic subjects and patients with type 2 diabetes.

Year (ref)

Intervention/ Control (na)

Exercise program

Duration

Blood glucose

Serum insulin

HbA1C

Lipids

BP

(change)b

«

Trials with a sedentary control group

1998 [26]

11/10 Type 2 DM

CWTd 3/week

8 weeks

«

«

«

-

«

«

«

1998 [114]

9/8 Type 2 DM

CWT 5/week

4-6 weeks

«

0e

«

-

Fat % «

«

BW «

Trials without a sedentary control group

1988 [115]

11 NGTc

CWT 3-4/week

16 weeks

«

0

-

î HDL-C

0

Fat % «

«

0 LDL-C

BW «

1989 [116]

15 NGT

CWT

12 weeks

«

0

-

-

-

BW «

«

Fat % 0

FFM î

1994 [117]

11 NGT

CWT

16 weeks

«

0

-

-

-

BW «

«

Fat % 0

FFM î

1997 [118]

18/20 Type 2 DM

Strength training 2/week

5 months

«

0

«

0 Chol

«

«

«

0 Tg

0 LDL-C

1998 [119]

8 Type 2 DM

CWT 2/week

3 months

«

0

«

«

«

-

«

a Number of subjects participating in the intervention vs. control group. b Change in Vo2 max is denoted by arrows:-, no data;no change; T significant increase. cNGT,normal glucose tolerance;Type 2 DM,type 2 diabetes. dCWT,circuit weight training.

e Insulin sensitivity measured by the clamp technique improved 48%. Other abbreviations as in Table 4.4.1

(Table 4.4.2). The mechanism underlying this change is, however, likely to be different from that of aerobic training.

Effects of aerobic and resistive training on insulin sensitivity and markers of cardiovascular risk

Data are limited regarding non-glycemic effects of physical training in type 2 diabetes. In many of the aerobic training studies, potentially beneficial effects in serum lipids (8 out of 14 studies, 57%) and blood pressure (5 out of 7 studies, 71%) were observed (Tables 4.4.1 & 4.4.2). Data are too sparse (no study with a control group) to allow conclusions to be made regarding the effects of resistive training on lipids and lipopro-teins in type 2 diabetic patients. In non-diabetic power athletes, serum triglycerides, HDL and low-density lipoprotein (LDL) cholesterol are comparable to those of sedentary controls [14], and thus lack the changes characterizing aerobically trained athletes.

Hypertriglyceridemia, the hallmark of the dyslipi-demia characterizing type 2 diabetic patients [15], is associated with abnormalities in fibrinolysis and coagulation such as increases in factor VII (FVII) and plasminogen-activator inhibitor 1 (PAI-i) concentrations [16]. In non-diabetic subjects, physical training has been consistently shown to enhance fibrinolysis by decreasing concentrations of PAI-i but data on training effects on such parameters are very limited in type 2 diabetes. Three months of aerobic training, which increased V02 significantly by 12.5%, was associated with no changes in coagulation parameters, including plasminogen or a2-antiplasmin, or in the measures of fibrinolysis but did cause a significant decrease in fibrinogen [17].

Oxidative stress is increased in patients with type 2 diabetes, at least when measured from the total anti-oxidant trapping capacity of plasma, which is inversely related to the HbAlc concentration [18]. The concentration of superoxides and free radicals is also increased and can be reduced by antioxidants such as raloxifene [19], allopurinol [20] and tetrahydro-biopterin [21]. Numerous studies have demonstrated that free radical production (superoxides, hydrogen peroxide, hydroxyl radicals) is increased as oxygen production increases by stimuli such as aerobic exercise [22]. Free radical generation results in lipid peroxida-

tion, which is considered harmful. For example, intense, long-duration aerobic exercise has been shown, at least transiently, in two studies to increase LDL susceptibility to oxidation in non-diabetic subjects [23,24]. These data raise the possibility that type 2 diabetic patients may be even more susceptible to exercise-induced oxidative damage. On the other hand, aerobic training is also able to increase the activity of free radical scavenging enzyme systems in red blood cells and skeletal muscle [25]. Thus, training might either deplete or restore antioxidant defense mechanisms in type 2 diabetic patients but there are currently very limited data addressing this issue. F2-isoprostanes consist of a series of chemically stable prostaglandin F2 (PGF2)-like compounds generated from the peroxidation of unsaturated fatty acids in membrane phospholipids independently of the cy-clooxygenase enzyme. The urinary excretion rate of F2-isoprostanes is increased in patients with type 2 diabetes and is thought to reflect increased in vivo lipid peroxidation [19,26]. In the study of Mori et al. [26], urinary excretion of F2-isoprostanes was not altered by 8 weeks of aerobic training consisting of 30-min bicycle ergometer exercise 3 times a week. More data on this topic would, however, be of interest as the above-mentioned antioxidants (allopurinol, raloxifene, tetrahydrobiopterin) not only reduce oxidative stress but also ameliorate endothelial dysfunction in patients with type 2 diabetes [19-21], a change which might serve to protect against future development of atherosclerotic vascular disease [27,28]. In this respect it is of interest that high-intensity aerobic training in normal subjects depletes antioxidants and has been associated with a decrease in endothelial function [29], although less intensive aerobic training regimens have improved endothelial function in healthy subjects [30], in patients with essential hypertension with [31] or without [32] dyslipidemia, in hypercholesterolemia [33], in chronic heart failure [34] and in patients with coronary artery disease [35]. There are no data on effects of aerobic or resistive training on endothelial function in patients with type 2 diabetes.

Mechanisms underlying improvements in insulin action by aerobic and resistive training

Insulin has multiple actions in vivo in normal subjects, all of which could be considered potentially anti-

atherogenic. These include the abilities of insulin to acutely: (i) decrease circulating glucose levels via inhibition of glucose production and stimulation of glucose uptake in skeletal muscle; (ii) decrease serum triglyceride concentrations via inhibition of hepatic VLDL production [36]; (iii) diminish large artery stiffness [37]; (iv) inhibit platelet aggregation [38]; and (v) regulate the autonomic nervous system [39]. All these actions are defective in insulin-resistant conditions [37,39-41] and are likely to contribute to hypertriglyceridemia [42], increased artery stiffness [43], abnormalities in platelet function [40] and inflexibility of the autonomic nervous system [39]. Data on effects of physical training in type 2 diabetic patients are, however, largely confined to insulin stimulation of skeletal muscle glucose uptake.

Insulin-stimulated glucose uptake across skeletal muscle can be calculated by multiplying glucose extraction and delivery [44]. During exercise, glucose uptake increases in the face of a marked increase in blood flow (glucose delivery) and a fall in glucose extraction [45,46]. This implies that blood flow is an important determinant of glucose uptake during exercise. In response to aerobic training, blood flow increases and this occurs similarly in normal subjects and patients with type 2 diabetes [45] (Fig. 4.4.2). The ability of high insulin concentrations to stimulate blood flow after training is better than before training in both normal subjects [47] and patients with type 2 diabetes [45]. Despite a normal blood flow response, the ability of skeletal muscle to extract glucose from the circulation in response to insulin remains lower than in non-►

Fig. 4.4.2 Effect of a 10-week one-legged training program on glucose clearance (a), leg blood flow (b) and glucose extraction (c) in eight non-diabetic (squares) and seven type 2 diabetic patients (circles). The measurements were made before and during three sequential intravenous insulin infusions. Euglycemia was maintained using a variable rate glucose infusion. The type 2 diabetic patients had normal leg blood flows both basally and during the three insulin infusions compared to the non-diabetic subjects. Leg blood flow increased significantly and similarly in the trained leg in both groups. Glucose extraction was lower both before (open circles) and after (closed circles) training in the type 2 diabetic patients compared to normal subjects. A significant improvement was observed in the type 2 diabetic patients in response to physical training at all insulin infusion rates employed. Reproduced with permission from [45].

300 250 200 150 100 50

700 650 600 550 500 450 400 350 300 250 200 0

1000

10000

1000

10000

1000

10000

1000

1000

10000 Insulin (pM)

CONTROL, before and after training, respectively NIDDM, before and after training, respectively

diabetic subjects in patients with type 2 diabetes [45]. A normal response of flow to insulin but a defect in insulin stimulation of glucose extraction has also been found in most [48-50], although not all [51] studies in patients with type 2 diabetes in the untrained state. These data are similar to those recently documented using positron emission tomography-based techniques in insulin-sensitive and insulin-resistant normal subjects [46]. In both sensitive and resistant subjects, acute exercise increased blood flow markedly but similarly in both groups and glucose extraction decreased significantly. However, in the resistant subjects glucose extraction and glucose uptake remained lower than in the sensitive subjects. These data demonstrate that while exercise stimulates glucose uptake by enhancing glucose delivery, differences in this response appear intact in non-diabetic and diabetic insulin-resistant subjects. In insulin-resistant patients such as those with type 2 diabetes, glucose uptake is determined under both resting and exercising conditions by the ability of skeletal muscle to extract glucose.

Regarding the cellular mechanisms contributing to glucose extraction, it is now clear that insulin and exercise stimulate this process by independent mechanisms. In normal subjects, physiologic hyper-insulinemia stimulates glucose uptake in skeletal muscle via the classic insulin signaling pathway, i.e. by stimulating insulin receptor and insulin receptor substrate 1 (IRS-i) tyrosine phosphorylation, association of the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase with IRS-i and glycogen synthase frac tional velocity [52]. In contrast, exercise has no effect on IRS-i tyrosine phosphorylation and even decreases tyrosine phosphorylation of the insulin receptor [52]. After one-legged acute exercise in normal men, insulin-stimulated glucose uptake is higher in the exercised than the rested leg but this is accompanied by no change in insulin receptor or IRS-i tyrosine phosphorylation [53,54], and by a decrease in IRS-i-associated PI 3-kinase activity [54]. In mice which lack insulin receptors selectively in skeletal muscle, insulin has no effect on muscle glucose uptake while the ability of exercise to stimulate glucose uptake is intact [55]. As in humans, acute exercise has no effect on insulin receptor tyrosine phosphorylation or PI3-kinase activity. Regarding the mechanism of contraction-stimulated glucose uptake, 5'-AMP-activated protein kinase (AMPK) is one candidate [56] (Fig. 4.4.3). AMPK, especially its a2 isoform, is activated by muscle contractions in human skeletal muscle. Activation of AMPK results in GLUT-4 translocation and an increase in glucose transport [57]. In animal studies, contractions but not insulin have been shown to increase AMPK activity [56]. The PI 3-kinase inhibitor wortmannin completely blocks insulin-stimulated glucose transport but has no effect on stimulation of glucose transport by contractions or an adenosine analog that stimulates AMPK [56]. On the other hand, in glycogen-loaded slow-twitch muscle, glucose transport increases sixfold by contractions despite an unchanged AMPK activity [58]. These data suggest that mechanisms other than AMPK may contribute to contraction-induced

Xk Microvesicles 0 0 with 0 0 V/y glut-4 \Q/

Glut-4 translocation

PI3 kinase +

CJRS-T)

Glut-4

-OOOtf woo-

Contraction

AMPK

Sarcoplasm

Sarcolemma

Insulin

Fig. 4.4.3 Exercise and insulin stimulate glucose uptake in skeletal muscle by distinct mechanisms. The classic insulin signaling molecules such as the insulin receptor (IR), the insulin receptor substrate i (IRS-i) and phosphatidylinositol 3-kinase (PI3-kinase) are necessary for insulin- but not contraction-stimulated glucose uptake. Contractions have been suggested to trigger glucose uptake by increasing the activity of an adenosine 5'-monophosphate-activated kinase (AMPK). Both insulin- and exercise-stimulated pathways result in recruitment of glucose transporters (GLUT-4) to the cell surface, which leads to glucose transport. Reproduced with permission from [97].

glucose transport under conditions where AMPK has been deactivated by increasing muscle glycogen content.

In insulin-resistant patients with type 2 diabetes, the ability of insulin to stimulate tyrosine phosphorylation of the insulin receptor and of IRS-i, and to stimulate IRS-i-associated Pl3-kinase activity is blunted. Furthermore, the ability of insulin to translocate GLUT-4 [59], the insulin-sensitive glucose transporter, is subnormal [60]. Few data are available regarding the ability of acute exercise or physical training to reverse defects in insulin signaling. In the study of Cusi et al. [6i], type 2 diabetic patients had higher basal levels of tyrosine phosphorylation of the insulin receptor and IRS-i and blunted phosphoryla-tion responses to insulin. After acute exercise, the increased basal levels decreased, the insulin-stimulated levels remained unchanged but the fold-response to insulin increased. These changes were not accompanied by any change in insulin-stimulated glucose uptake [6i]. On the other hand, aerobic training in patients with type 2 diabetes, as in normal subjects, has been shown to significantly increase the content of GLUT-4 in skeletal muscle [62] (Fig. 4.4.4) and also to significantly increase the expression and activity of glycogen synthase [45] and the ability of insulin to increase PI3-kinase activity [63]. There are currently few data available regarding the integrity of the insulin-

independent exercise-stimulated glucose transport pathway in patients with type 2 diabetes. A single bout of acute exercise, in contrast to insulin, seems to induce normal translocation of GLUT-4 from an intra-cellular pool to the sarcolemma in patients with type 2 diabetes [64]. Taken together these data are encouraging as they suggest that signaling defects, which are important for insulin action, may be enhanced by aerobic training. The data also suggest that the signaling pathways via which exercise stimulates glucose uptake in patients with type 2 diabetes may be intact. This has the practical implication that the glycemic response to exercise is unlikely to be blunted by insulin resistance.

In contrast to aerobic training, resistive training does not increase capillary density [65] or activity of oxidative enzymes [66-68]. Absence of these changes may explain why glucose uptake per muscle mass is similar in untrained subjects and weight lifters [69,70]. In studies comparing weight lifters or non-steroid-using body builders to sedentary subjects, a critical question is how the sedentary group is matched with the resistive-trained athletes. If muscular subjects are compared to equally heavy adipose subjects, insulin concentrations after an oral glucose load are lower in the muscular subjects [i4,7i]. This result could be explained by obesity-associated insulin resistance rather than enhanced sensitivity in muscular subjects. How-

UT T Control

UT T Type 2 DM

i 200

I 180

g 160

g 140

E 120

I 80

i 40

UT T Control

UT T Type 2 DM

ff 40

UT T Control

UT T Type 2 DM

Fig. 4.4.4 Effect of io-weeks one-legged training program on skeletal muscle GLUT-4 protein (left), GLUT-4 mRNA (middle) and glycogen synthase (GS) mRNA (right) content in eight non-diabetic (control) and seven patients with type 2 diabetes mellitus (Type 2 DM). *Increased in trained (T) compared with untrained (UT) leg (P < 0.05). Reproduced with permission from Dela et al. [62].

Training group

Sedentary group

Tii-

-----Normal subjects

----Type 1 DM after training

-Type 1 DM before training

Fig. 4.4.5 Insulin sensitivity of glucose uptake in patients with type 1 diabetes before and after 6 weeks of bicycle exercise training (4 times/week 4 x 15 min at an intensity corresponding to 70% V02 max with a 5-min rest period between exercise periods). Two control groups were studied: a group of sedentary type 1 diabetic patients who had similar and good glycemic control during treatment with continuous subcutaneous insulin infusion therapy as did the exercise group; and a group of normal subjects. The sedentary control group with type 1 diabetes was studied at 0 and 6 weeks. Body weight and HbAlc remained unchanged in both type 1 diabetic groups. In the training group, Vo2 increased significantly by 8%. This was sufficient to normalize insulin sensitivity. Reproduced with permission from [77].

ever, even when muscular subjects are compared to normal-weight men with similar Vo2max, both glucose and insulin concentrations are still significantly lower in muscular than the normal-weight subjects [14]. In both comparisons, the muscular subjects have relatively less fat, which could itself enhance insulin sensitivity, e.g. via free fatty acids, but this remains speculative. If insulin sensitivity is quantified in muscular and normal-weight sedentary subjects, who are matched with respect to VO2 , insulin-stimulated rates of glucose uptake expressed per unit muscle weight are identical [69,70] (Fig. 4.4.5, Plates 2 and 3 facing p. 192). These data could mean that the lower glucose insulin responses during an oral glucose tolerance test (OGTT) [14] can be attributed to a larger muscle mass rather than to enhanced insulin sensitivity if defined as increased glucose uptake per unit muscle mass. Thus, both aerobic and resistive training enhance insulin sensitivity but via fundamentally different mechanisms.

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