Glucose Intolerance and Type II Diabetes

by Martin Krause (2009)

What is it and how do muscle contractions affect it?

• 26% of the population has glucose intolerance
• since the 1980's there has been an increased prevalence of type II insulin resistant diabetes from 5.3% to 8.2% (1976 ->2002) to 9.3% (2006) (Gregg et al 2004; Cowie et al 2006 in Gregg & Kriska 2008)
• many people do not know that they have diabetes let alone impaired glucose tolerance
• glucose intolerance and type II diabetes is occuring in ever younger populations
• abdominal fat (as opposed to subcutaneous fat) is a major determinant in the development of glucose intolerance
• two mechanisms for the development of type II diabetes from glucose intolerance are due tothe lack of translocation of the Glut 4 receptor from the centre of the cell and the increased ability of long chain fatty acids to cross the cell membrane (due translocation of subcellular FAT/CD36 to the sarcolemma). Rather than being used correctly as an energy substrate (Beta Hydroxylase cycle) the fat is stored inside the cell as triacylglycerol (TAG) depots
• the cells are clogged up by fats (increased TAG depots and reduced FAT/CD36 pool) analogous to a sticky date pudding
• physiological, biochemical, and molecular evidence has shown that fatty acid movement across the plasma membrane is regulated acutely by muscle contraction, AMPK activation and selected hormones (insuline, leptin, resistin) as well as chronically by altered muscle contraction (Bonen Chabowski Glatz & Luiken 2008)
• In insulin-resistant muscle, rates of long chain fatty acid (LCFA) transport are increased, which in turn leads to insulin resistance
• inflammatory - immune compromise may be an aspect in the development of type II diabetes
• obesity-linked type II diabetes is associated with cytokine acute phase/stress response (White & Marette 2008)
• levels of C-reactive Protein (CRP), a marker of low grade inflammation and acute phase protein response are elevated in children associated with higher adiposity (fat) (Cook et al 2000 in White & Marette 2008)
• elevated levels of interleukin -6 (IL-6) and Tumor Necrosis Factor aplha (TNF alpha) and overexpression of interferon gamma (IFN gamma) in tissues of humans and animals with obesity has been observed (Yudkin et al 1999, Hotamisligil et al 1993, Perreault & Marette 2001 in White & Marette 2008).
• muscles act as a sink for the action of insulin. Muscles acount for about 85% of insulin stimulated blood glucose clearance (DeFronzo et al 1981 in Cartee 2008)
• muscles are an important source of protein for the immune system

Marathon runners have a lower prevalence of hypertension, hypercholesterolemia, and diabetes. (Williams 2009, Med Sc Ex Sp, 41, 3, 523-529)

What can be done about glucose intolerance, type II diabetes and inflammation/immune function?

Exercise

• weight reduction through exercise (minimum of 700Kcals per day) and diet
• training must include 6-8 exercises of large muscle groups of moderate intensity (70%Vo2max; RPE 14-17), 3-6sets x 10-15reps
• must include abdominal girth reduction exercises
• ideally some form of exercise daily eg squats, push ups, pull ups, abdominal strengthening (5-10minutes)
• resistance training 1-2 x per week
• endurance training (40-60minutes) 2-3 x per week
• stress reduction stretching, meditation and/or yoga at least once per week

• Cellular stress and eccentric contractions activate MAP kinase signalling which affect MSK 1, p90rsk and p38. The latter durectly affects Nuclear Respiratory Factors (NRF)1/2 which influences Mitochondrial biogenesis and the electron transport chain, Estrogen related receptor (ERR) alpha and the fatty acid uptake and oxidation as well as affecting Peroxismoe Proliferator-Activated Receptors (PPARs) and High Density Lipoprotein (HDL) synthesis
• Motor nerve activity affects Calcium-dependent signalling, Ca-calmodulin which affects Myocyte Enhancer Factor (MEF) 2, activating Myosine Heavy Chains (MHC) and Glut 4 expression.
• Energy status affects AMP-dependent signalling increasing AMP or decreasing ATP, AMPK and the expression of PGC1 (Peroxisome Proliferator-activated receptor gamma coactivator 1) which influences PPARs and HDL synthesis (Kraemer & Krook 2008)
• Exercise leads to an insulin independent translocation of GLUT4 to the cell surface and an increase in glucose transport (Douen et al 1990; Lund et al 1995 in Kraemer & Krook 2008). Transgenic mice which over-express GLUT4 in adipose and skeletal muscle exhibit improved oral glucose tolerance and insulin-stimulated glucose disposal (Deems et al 1994; Liu et al 1993; Ren et al 1995 in Kraemer & Krook 2008). MEF2 and GLUT4 Enhancer Factor (GEF) have been implicated in this process via possibly AMPK and p38 MAPK (Kraemer & Krook 2008)
• Endurance exercise has been shown to be of greater benefit than strength training in treating type 2 diabetes due to improved oxidative capacity through increased mitochondrial density.
• PPARs are activated by dietry lipids and are therefore considered to be nutritional lipid sensors and to control lipid homeostasis (Smith & Muscat 2005). PPARs have also been implicated in mechanisms that release anti-inflammatory factors or repress the inflammatory response (Lee et al 2003, Pascual et al 2005 in Kraemer & Krook 2008)
• PPARdelta has been shown to increase significantly in patients with type II diabetes following a 4month low intensity exercise program (Fritz et al 2006 in Kraemer & Krook 2008). This also correlated with improvements in other key clinical parameters.

see : Exercise and Sarcopenia

Polycystic Ovary Syndrome (PCOS)

PCOS is associated with increased risk of several metabolic complications including insulin resistance, type II diabetes, dyslipideamia, and possibly cardiovascular disease. The increased incidence was thought to be the result of small, dense LDL. In other populations with cardiovascular disease and insulin resistnace, similar sublcass annomalies have been found, as well as increased concentrations of large VLDL and small LDL particles and decreased numbers of large HDL particles. Larger VLDL size and smaller HDL size were also shown to be strongly associated with the development of type II diabetes.

Investigations prior to 2009 which did not use nuclear magnetic resonance (NMR) found little correlation between exercise and improved blood particle outcome. However, investigations using a protocol of Studies Targeted Risk Reduction Interventions through Defined Exercise (STRRIDE) with NMR. Brown et al (2009) used an 8-12 weeek ramp-up protocol followed by 12 weeks of moderate intensity (calorific equivalent to walking 12miles/wk) in 8 premenopausal women. Their results demonistrated significant reductions in concentrations of large VLDL/chylomicrons and medium/small HDL and increased large HDL and average HDL size in the exercise group compared with controls. These results represent a good investment for the 3h24min per wek needed for this intervention.

Brown et al (2009) Med Sci Sp Ex, 41, 3, 497-504S

Fine tuning the body with exercise and diet

1 calorie = 4.184 joules

• Insulin sensitivity can be incresed after a single bout of exercise which is not attributable to reduced body fat
• Reduced muscle triglyceride concentration is not essential for improved insulin sensitivity with dietry or exericise intervention strategies. In fact with endurance exercise the intramuscular triglyceride concentrations can increase.
• Calorific restriction neither activates AMPK nor does it trigger GLUT4 abundance, in contradistinction to what occurs with exercise training (Zheng et al 2001; Cartee et al 1994; Gazdag et al 2000 in Cartee 2008)
• Insulin and exercise use distinctly different pathways to induce GLUT4 translocation from the cytoplasm to the cell surface (Hooloszy & Hansen 1996 in Cartee 2008). Contraction dependent GLUT4 translocation appears to require elevated Calcium and elevated AMPK levels (Mu et al 2001; Wright et al 2004 in Cartee 2008)
• After 7days of Calorific Restriction (CR) (consuming 800kcal/day) participants lost 2.2kg (17% of total weight) but they achieved 45% in insulin sensitivity measured at 3months of CR (Kelley et al 1993 in Cartee 2008). CR in obese humans with type 2 diabetes demonstrated weight loss of only 3.5% but this was accompanied by a 35% increase in glucose disposal rate during a hyperglycemic clamp (Aciero et al 1999 in Cartee 2008). Clearly, modest weight loss can be accompanied by marked improvement in glucose tolerance
• GLUT4 abundance is not affected by CR (Cartee 2008) suggesting that CR may enhance glucose transport by acting specifically on the insulin signaling pathway
• As of 2008, the results of combined exercise and CR on insulin sensitivity and hence glucose tolerance have yet to be determined.

However, continued compliance over time seems to be a major issue when it comes to exercise regimes

High intensity exercise (RPE 15.4) versus low intensity exercise (RPE 11.1) for a 16 week walking programm was shown to reduced regional body fat by 47 vs 11cm2 and abdominal visceral fat content by 24 vs 7cm2 (Irving et al 2008) . Further reductions in visceral fat were reported by the same authors with 8 months of vigorous jogging (~20miles/week). This is significant as visceral fat is directly correlated with the progression of glucose intolerance to type II insulin resistant diabetes. Interestingly, moderate intensity exercise (500Kcal) energy expenditure was shown to improve postprandial dyslipidemia in people diagnosed with metabolic syndrome (Mestek et al 2008). This finding wasn't found in healthy subjects, suggesting that even moderate amounts of activity can have large impacts on a critical risk factor for morbidity.

See : Exercise Training and Weight Loss

Diet

• Fish Oil (omega 3) - 1000mg daily
• Cold pressed Flaxseed oil (omega-3, 6, 9) - good fats versus bad fats
• Magnesium (esp if there is a blood pressure problem) - 300mg daily
• Co-enzyme Q10 - for mitochondrial energy transfer
• Vitamen B for the liver - energy power house of the body and hence metaboliser of glucose and producer of glycogen; Vit B6 50-100mg, Vit B3 500mg for one month and then 250mg daily
• Vitamen C (1-2g) and Vitamen E (400-800IU) to prevent glycosylation
• Chromium 250-500mcg daily
• Curcumin - immune enhancer and anti-inflammatory derived from tumeric powder (Curcuminoids)

Stress and Allostasis

Stress affects blood sugar levels both directly and indirectly. Stress can cause an overproduction of hormones such as adrenaline and cortisol, which makes blood suger rise. In addition, people under stress tend to adopt unhealthy lifestyles, such as poor eating habits, smoking and alcohol which all have a negative impact on blood sugar. Cognitive behavioural approaches to stress managment, guided imagery, as well as yoga and meditation can all be used to eleviate stress.

Exercise and heart rate recovery has been demonstrated to be as sensitive marker to the balance between sympathetic and parasympathetic nervous system activity. Vagal tone and smpathetic-parasympatheic balance have long been associated as a fitness marker through reduced blood pressure and resting heart rate. Specifically, the initial post exercise plateau seen in fit individuals remains elevated in low fitness individuals despite low rates of oxygen consumption (HR/VO2plat). Yeckel et al (2009) concluded that heart rate recovery after exercise was a sensitive marker of this balance. Additionally, they concluded that this exercise recovery indiex for sympathetic overactivity was linked to insulin resistance.

Yeckel et al (2009) Med Sc Ex Sci, 41, 3, 505-515

Clinical reasoning, the neuro-matrix and allostasis in explaining the role of musculoskeletal physiotherapy in health and disease

Macrophages are necessary for skeletal muscle regeneration. Pro-inflammatory macrophages stimulate myoblast proliferation, whereas anti-inflammatory macrophages stimulate their differentiation. Macrophages that invade skeletal muscle soon after injury present a specific phenotype, characterized by high expression of TNF-alpha, interleukin-1beta and secretory leukocyte protease inhibitor (SLPI). Non-phlogistic phagocytosis of the apoptotic and necrotic debris switches the phenotype of pro-inflammatory macrophages into anti-inflammatory macrophages. Consequently, there is a high expression of Transforming Growth Factor- Beta (TGF-beta), interleukin - 10 (IL-10), and peroxisome proliferator-activated receptor - gamma (PPAR-gamma) which have been shown to be associated with the resolution of inflammation and tissue repair (Chazaud et al 2009)

Cognitive Behavioural Therapy for exercise prescription

see : Neuro-immune and Cognitive Behavioural Response to Exercise