Chapter 16 Diabetes type 2

AETIOLOGY

Diabetes type 2, in contrast to type 1, is a lifestyle disease. It has become a public health burden worldwide, leading to premature morbidity and mortality. Abdominal obesity with deranged glucose tolerance (where glucose tissue uptake is impaired) leads to insulin resistance, hyperinsulinaemia, diabetes type 2 and cardiovascular abnormalities such as hypertension, hypertriglyceridaemia, low high-density lipoproteins (HDL), microvascular lesions and atherosclerosis.^1,² It is also a risk factor for polycystic ovarian syndrome, sleep apnoea and some hormone-sensitive cancers.³ It has been aptly called the ‘hyperactive fork and hypoactive foot’, a ‘deadly duet’.⁴

Two commonly encountered mechanisms seem to underlie the development of insulin resistance, leading to metabolic syndrome: high cortisol levels and adiposity. Increases in serum cortisol, such as is seen in stress, lead to gluconeogenesis (often derived from protein, leading to progressive muscle wasting) and therefore increased glucose levels in blood.^5,⁶ The interconnection of cortisol and glucose could thus be the cause for the progressive nature of the disease.⁷ Up-regulation of cortisol due to stress (see also Chapter 15 on adrenal exhaustion) increases glucose and very low density lipoproteins VLDL secretion from the liver while inhibiting their reuptake, thus promoting hyperinsulinaemia, insulin resistance and storage of energy in the form of visceral fat.^8,⁹ Disturbances in the hypothalamic–pituitary–adrenal (HPA) axis not only increase cortisol levels but also enhance immune activation.¹⁰ These disturbances exert their influence on other steroid hormones. Assaying these may give a better understanding of underlying wider-ranging pathology; it may also give clues as to their possible treatment.¹¹

Increased inflammatory markers have been noted, linking the signs and symptoms of metabolic syndrome to an inflammatory process.¹² One study¹⁰ hypothesises that the pathoaetiology of metabolic syndrome results from pro-inflammatory cytokines (IL-1, IL-6, TNF-α), due to inflammatory processes or emotional stress, enhancing sympathetic nervous system (SNS) activity, leading to obesity from enhanced feeding activity and increased leptin levels due to neuropeptide Y. A further indicator of inflammation in insulin resistance is an elevation in C-reactive protein (CRP).¹³ Genetic links have also been suggested, with glucocorticoid receptor polymorphism.¹⁴ Research echoes all of the above.¹⁵

Chronic elevations in blood glucose result in glycosylation of red blood cells and other biological substances, leading to oxidative tissue damage. It is suggested that this is the underlying mechanism that results in the common, late complications of diabetes, such as microvascular damage in blood vessels, eyes and kidneys.^16,¹⁷ It has been suggested that oxidative stress could also be the cause, not just the result, of this syndrome.¹⁸

High dietary saturated fat intake, low omega-3 fatty acids and other polyunsaturated fatty acids, alcohol consumption, sedentary lifestyle and mental stress are all promoters of metabolic syndrome. Certain personality types have enhanced sympathetic nervous system activity, with increased secretion of catecholamines, cortisol and serotonin, which all appear to be involved in the pathogenesis of metabolic syndrome.^19,²⁰ It is estimated that approximately 40% of Europeans above the age of 60 years have metabolic syndrome, with rates in the US population climbing to approximately two-thirds.^1,²⁰ Figure 16.1 shows the interdependency of the variables described in the text above.²¹

Figure 16.1 Overview of diabetes type 2 aetiology

Source: Adapted from Gropper et al. 2009 ²¹

Metabolism of glucose uptake into the cells and the role of insulin

In most tissues, except hepatic tissue, glucose relies on a transport system called GLUT4 to be able to enter the cell. This system requires insulin for optimal uptake of glucose by muscle and adipose tissue, where insulin enhances the translocation of GLUT4 from the intracellular pool to the cell membrane.²² The putative metabolic cause for diabetes type 2 lies in suboptimal functioning of these glucose transporters due to insulin resistance.²¹

It has been found that insulin is more effective in the presence of chromium. The mechanism is not entirely elucidated, but it is suggested that chromium (Cr³⁺), bound to transferrin, enters the cells via transferrin receptors. Once inside the cell, chromium is released and four chromium ions bind with apochromodulin, forming holochromodulin (often simply called ‘chromodulin’). Chromodulin then binds to the insulin receptor, increasing receptor activity.²¹ Figures 16.2a and 16.2b illustrate the initial phase of insulin uptake (Figure 16.2a) and the resultant uptake of glucose into the cell (Figure 16.2b), and the role of chromodulin.

Figure 16.2 (a) Cell activation for glucose uptake (b) Glucose uptake into the cell

Source: Adapted from Devlin ²² and Gropper et al. 2009²¹

Testing for diabetes type 2 and metabolic syndrome

In-house testing comprises blood glucose, urinalysis (dipstick), blood pressure and anthropometric measurements. The latter includes body mass index (BMI ^∗), waist circumference^† and body composition measured through skinfold thickness or bioimpedance.²

Metabolic syndrome is confirmed when there are abnormalities in three or more of the following:

• elevated fasting glucose

• elevated glucose tolerance test results

• elevated insulin

• increased waist circumference or BMI

• high blood pressure (> 130/85)

• high triglycerides

• low HDL.

Since multiple parameters are involved in diabetes type 2 and metabolic syndrome the combined results of in-house and pathology testing can give conclusive evidence. Table 16.1 shows information on each of the laboratory tests involved.

Table 16.1 Pathology tests recommended for suspected diabetes type 2 and metabolic syndrome ^23,²⁴

TEST	TISSUE	COMMENTS
Fasting glucose	Serum	Values > 6 mmol/L are indicative of diabetes type 2 or metabolic syndrome.
Fasting insulin	Serum	Normal values are 4–10 mU/L.
GTT (glucose tolerance test)	Serum	Commonly, the test is done over 2 hours, with blood samples taken pre-glucose loading and 2 hours after. Values > 7.8 mmol/L post-loading are indicative of DM2. However, this test will not show insulin and cortisol levels, nor the finer details of glucose control. Hence a 3-hour test with half-hourly measurements of glucose, insulin and cortisol is recommended. Insulin should not rise more than eightfold after glucose loading.
Glycosylated haemoglobin (HbA_1c)	Serum	HbA_1c measures long-term glucose control and is an indicator of how well diabetics are managing their disease. Non-diabetic: 2.2–4.8% Good diabetic control: 2.5–5.9% Fair diabetic control: 6–8% Poor diabetic control: > 8%
Cortisol	Serum Urine Saliva	Cortisol is subject to diurnal variations, being highest in the morning and lowest at night. The best time for measuring cortisol levels in serum are early morning and again around 4 p.m. Night-time or 24-hour urinary cortisol, or repeat salivary samples, may be even more advantageous.²⁵
Lipid studies	Serum	Triglycerides > 1.81 and 1.52 mmol/L and HDL < 0.75 and 0.91 in males and females, respectively, are indicative of diabetes type 2 or metabolic syndrome.
Liver profile	Serum	Elevations in alanine aminotransferase (ALT) have been found in insulin resistance and metabolic syndrome.²⁶
CRP, ESR (inflammatory markers)	Serum	The ideal range of CRP and ESR is < 1. Elevation, even if still within the normal range, is indicative of inflammation, with the level of these markers proportional of the degree of inflammation.
Homocysteine	Serum	Homocysteine is an inflammatory amino acid produced in the methylation cycle. It is commonly elevated in metabolic and heart diseases.²⁷ Ideal range is < 10.
Active B12	Serum	Active B12 or holotranscobalamin has been termed the best and earliest indicator of impending vitamin B12 deficiency.²⁸ It needs to be > 35 pmol/L.
Folate	RBC	Folate and vitamin B12 are both needed in the homocysteine-methionine (methylation) cycle. Values differ markedly between laboratories.
Vitamin D	Serum	Despite the high amount of sunshine, vitamin D deficiency is high in Australia. It is needed for insulin secretion and found to be low in people not receiving much sunlight on their skin.²⁹ Both the inactive (25-hydroxyvitamin D) and the active (1,25-dihydroxyvitamin D) forms can be measured. Ideal values for vitamins are in the upper half of the reference range.
TSH	Serum	Hypothyroidism is present when thyroid-stimulating hormone is elevated. It may explain some people’s inability to lose weight. However, subtle elevations (> 2.5 mIU/L) within the reference range (0.4–5.0 mIU/L) could indicate a ‘labouring’ thyroid or a pre-hypothyroid state.^30,³¹

RISK FACTORS

Stress, a diet high in refined and simple carbohydrates and human-modulated fats, and low in fibre, antioxidants and polyunsaturated fatty acids, especially omega-3, as well as lack of exercise, are the most outstanding contributors to obesity and metabolic syndrome.

This disease process brings with it a number of other risk factors, notably in cardiovascular health. Hypertension and dyslipidaemia are commonly encountered and in fact are part of metabolic syndrome. The derangement of steroid hormones, including sex hormones and dehydroepiandrosterone (see Figure 15.3 in Chapter 15 on adrenal exhaustion) can lead to lack of libido, erectile dysfunction and prostate problems in men, and menstrual irregularities, infertility and exacerbation of hormonal symptoms in females.

Due to the reduced life quality that accompanies any chronic health problem and possibly the decreased feelings of self-worth from being overweight, depression and anxiety should also be considered. Depression may also play a role in the aetiology of stress and metabolic syndrome (see also Chapter 12 on depression).

CONVENTIONAL TREATMENT

It is now commonly accepted that diet and lifestyle need to be considered in order to control this disease.³⁰ A number of diets have been recommended, with no clear answers as yet (see the discussion below).

In addition, medical treatment aims at regulating blood sugar to gain control of diabetes type 2. The drugs mentioned here are suitable only if there is some function left in the pancreatic β-cells; otherwise insulin needs to be given.

In the first instance, biguanides (such as metformin) will be prescribed. The supposed mechanisms include reduced gluconeogenesis and increased insulin sensitivity. A possible side effect of this drug is pernicious anaemia. Therefore, vitamin B12 should be measured regularly and, if found to decline or be low, vitamin B12 treatment via monthly intramuscular injections should be initiated.³³

Sulfonylureas are recommended to enhance the secretion of insulin in response to blood glucose. However, care needs to be taken in patients with liver or kidney disease. They also promote weight gain and are therefore not ideal in metabolic syndrome.

Another treatment option is α-glucosidase inhibitors. This class of drugs reduces the breakdown of carbohydrates in the intestines by inhibiting the enzymes involved in this process, thus reducing the rise in blood sugar levels following a meal. They are therefore useful in obesity. However, the remaining carbohydrates are likely to be fermented in the gastrointestinal tract, leading to unwelcome side effects such as bloating and flatulence.

The glitazones (thiazolidinediones) reduce insulin, but have no direct effect on glucose. Their beneficial action in diabetes type 2 may be the lowering of free fatty acids, thus increasing muscular glucose usage.

Various combinations of these drugs, notably metformin with sulfonylureas, are currently used, particularly when good glucose control (as assessed by HbA_1c levels) is not achieved by one drug alone. Only as a last resort will insulin be used for diabetes type 2.

Cardiovascular risk factors are commonly controlled by blood pressure and lipid-lowering medication (see Section 3 on the cardiovascular system).

KEY TREATMENT PROTOCOLS

This needs to be a multi-pronged approach, including stress management, dietary and lifestyle changes, exercise, and nutritional and herbal supplements.

Modify lifestyle and diet

Fat loss, even if it is small, is paramount and has resulted in greater insulin sensitivity, lower blood pressure and improved lipid profile, thus reducing risk factors for both diabetes type 2 and heart disease.¹ A hypocaloric diet rather than a total fast has been advocated, together with physical exercise and reduction in alcohol consumption. These lifestyle changes, although superior to drug treatment, are sometimes difficult to achieve and an extensive health-care program needs to be initiated to prevent relapse.²⁰ A slow reduction in weight seems to be better to rapid weight-loss diets for lasting success as the weight is more likely to stay off. Protein needs to be emphasised as there is often a reduction in lean body mass due to the gluconeogenic effects of raised cortisol.

There has been much debate regarding the best diet for this condition: high complex-carbohydrate/low-fat (HC/LF) or high-protein/low-carbohydrate diet (HP/LC), or anything in between.^44,⁴⁵ It is feared that the HP/LC diet may be too high in saturated fats due to its high meat content and hence contribute to increased calorie consumption. Although weight loss after 1 year seems to be the same on either diet, the HC/LF dieters tends to have a better LDL profile. However, the HP/LC diet has led to greater fat loss and improved triglyceride and HDL values.^44,⁴⁶

Further, there is evidence that animal fat (in dairy and meat), particularly conjugated linoleic acid, can have a protective effect against obesity, diabetes, heart disease and cancer.⁴⁷^–⁵⁰ With the low-fat diet recommendations, apparently people now consume less than half the amount of conjugated linoleic acid needed to reap the benefits.⁵¹ And the beneficial effects of fish consumption, especially those with high omega-3 content, are well known. Another advantage of a low-carbohydrate diet lies in its reduced insulin requirements.

Care needs to be taken, too, with low-fat products, as the fat is often replaced with carbohydrates such as olestra or a similar ‘fat substitute’. Believing that this is a low-fat (healthy) food, people may tend to eat more, thus making up the calories. Besides, these

DIABETIC FOOT CARE ^43,³⁴

‘Diabetic foot’ is the umbrella term for the numerous foot problems in diabetics that arise from arterial complications and peripheral neuropathy. This combination can lead in turn to poor circulation; poor wound healing and eventual ulcer development. Therapies such as corrective footwear, diabetic socks and regular podiatrist review are encouraged, as well as hyperbaric oxygen and various wound management techniques when or if ulceration does occur. However, one of the best patient recommendations may simply be that of increased vigilance—studies suggest that increasing awareness of the issue is effective in reducing serious lesions. Simple tips such as testing shoe tightness with fingers to reduce pressure—which many patients may not be aware of, due to neuropathy—may stave off serious issues in the future. Improving circulation may also reduce the possibility of ulcer formation by improving wound-healing ability. Considering that 10–15% of diabetic patients can expect complications, that over half of diabetic hospital admissions are related to foot complications and that diabetes is the most common reason for medical amputation, these recommendations need to be an integral part of diabetic patient management.

fat replacers also have calories. Carroll claims that this substitution has contributed markedly to the current obesity epidemic.⁵² In addition, olestra has been shown to reduce the absorption of fat-soluble vitamins, thus depriving the body further of essential nutrients.⁵³

In order to achieve a feeling of satiety without overindulging in calorie-rich foods, fibre needs to be an essential dietary constituent of every person attempting to lose weight.⁴⁵ Fibre will bind fats and lower the absorption of glucose through delaying gastric emptying. Studies with psyllium hulls (Plantago psyllium) have shown significant reductions in fasting plasma glucose, cholesterol, LDL and triglycerides, and elevations in HDL.⁵⁴ However, care needs to be taken as too much of it will reduce nutrient absorption and can lead to flatulence.

Increase exercise

The positive influence of exercise on glucose control cannot be overemphasised,²⁰ as a plethora of literature on this topic testifies. It facilitates the uptake of glucose into the cells and lowers insulin resistance, apart from the beneficial effect on body composition. Even small daily tasks, such as getting up to change the TV channel or taking the stairs rather than the lift, will be beneficial.⁵⁵

In insulin resistance and diabetes type 2, high levels of fatty acids are stored in skeletal muscle, with exercise being able to reduce this through β-oxidation (fat burning), thus lowering triglycerides and improving glucose control.⁵⁶ For people with impaired fasting glucose, before the development of diabetes type 2, even greater benefits can be achieved, as seen in improvements in glycolysis, aerobic metabolism, β-oxidation and mitochondrial biogenesis.⁵⁷

In particular, strength training maximises fat loss and minimises the loss of lean body mass which usually accompanies weight loss diets.² Sarcopenia is common in diabetics, particularly in the elderly.⁵⁸ Since it is the muscles that use glucose to produce energy, lack of muscle mass further promotes the disease process.

Tai chi has shown to significantly improve glycaemic control and lower triglyceride levels in Chinese diabetic women.⁵⁹ In a 6-month trial in Korea those people adhering to the activity schedule experienced much better glucose control and quality of life.⁶⁰

As exercise usually has a glucose-lowering effect, blood glucose needs to be monitored carefully regarding possible hypoglycaemia, and medication may need to be adjusted (see also Chapter 19 on Endometriosis).⁵⁸

Increase insulin release and receptor sensitivity, and reduce hyperinsulinaemia

The precursor to diabetes type 2 is insulin resistance and compensatory hyperinsulinaemia. Although insulin is overproduced and secreted by the pancreas it is not facilitating glucose uptake into the cell. Fat loss results in increased insulin sensitivity and should be pursued.⁶¹ Certain nutrients and herbs can aid insulin sensitivity, thus reducing hyperinsulinaemia.

Nutritional interventions

A whole range of vitamins, minerals, amino acids and bioactive substances have been explored in the treatment of diabetes type 2 and insulin resistance. Nutrients which have shown a positive effect include vitamins A, B₁, B₃ and biotin, the minerals calcium, potassium, zinc and manganese and fructo-oligosaccharides. Some amino acids, such as taurine (needed for liver detoxification pathways and control of heart rhythm and blood pressure) and L-arginine (for nitric oxide production to maintain endothelial function) may also help.^3,^4,^21,^38,⁴⁵ However, there are nutrients that are very specific for diabetes type 2, as demonstrated below.

Most animals produce their own vitamin C from glucose. The two molecules are therefore structurally similar, and competition for cellular uptake between vitamin C and glucose has been suggested as a possible mechanism by which this vitamin exerts its positive influence on glucose metabolism. Further, vitamin C is needed to stimulate the release of insulin following glucose ingestion. As little as 500 mg/day has been shown to be effective. Vitamin C also acts as an antioxidant, reduces blood pressure and protects blood vessels.⁴

Chromium is needed to facilitate the entry of glucose into the cells by stimulating insulin uptake and enhancing its activity (Figure 16.2).²¹ Supplementation has had a beneficial effect on metabolic syndrome by lowering fasting blood glucose (FBG), postprandial glucose (PPG) and corresponding insulin levels, and by improving insulin sensitivity, HbA_1c values and lipid profiles. The recommended dosage is 200–1000 μg/day. Increased benefits have been noted with higher doses.^45,⁶² Another possible effect of chromium is its action on down-regulating pancreatic β-cell activity, thus increasing glucagon levels.⁶³

Magnesium is essential for all reactions requiring energy as it is needed to stabilise ATP. Low levels have been found in cardiovascular disease and diabetes, and in people with high alcohol intake. Normalisation through supplementation up to 400 mg/day has enhanced insulin sensitivity, reduced fasting glucose and improved HbA_1c.^21,^45,⁶⁴ Trials with small amounts of magnesium have yielded mixed results. However, reductions in FBG and HbA_1c, and increases in postprandial insulin, in glucose uptake and in glucose oxidation have been noted.⁶²

Enhanced insulin sensitivity with reductions in FBG, HbA_1c and hepatic glucose production, and better insulin-mediated glucose uptake, have been found with vanadium.⁶² The usual dose is 100 μg/day. Vanadium mimics the action of insulin, as seen by its similar effects on the translocation of GLUT4 to the cell membrane.²¹

Coenzyme Q10 has been shown to reduce blood glucose, hyperinsulinaemia, high blood pressure, triglycerides and lipid peroxidation.⁴ Dosage range is 30–120 mg/day. It is particularly important for people on statin drugs as some of these have a depleting effect on this nutrient.⁶⁵

N-acetyl carnitine, made from lysine by methylation, is instrumental in the transport of fatty acids across the mitochondrial membrane for β-oxidation. It is therefore essential for energy production from fat burning.³⁸ Administration of this nutrient has enhanced glucose uptake, storage and utilisation, and insulin sensitivity.⁶² A relatively high amount, ≥ 3 g/day, is needed to achieve these effects.

Vitamin E tends to decrease HbA_1c, FBG and PPG.⁶²

The bioactive nutrient α-lipoic acid is both water and fat soluble and has been shown to enhance cellular glucose uptake and utilisation. The daily amount is up to 1200 mg/day. In conjunction with exercise, this nutrient has shown to enhance glucose transport and insulin signalling in skeletal muscle cells.⁶⁶