Health-related Topics : Diabetes (overview)

Dr. James Manos (MD)

October 25, 2015

Overview of diabetes mellitus type 2

‘Prevention is better than cure’ (Hippocrates, ancient Greek doctor – the father of Western medicine, 460 – 370 B.C.).

Note: in this text, the writer expresses his point of view. Some advice is empirical, so you should consult your family doctor beforehand.

Overview

Diagnostic criteria for diabetes mellitus (DM)

· Fasting plasma glucose >_126 mg/dL (>_7 mmol/L)

· Symptoms of diabetes & random blood glucose >_ 200 mg/dL (>_ 11.1 mmol/L)

· 2 – hour plasma glucose >_200 mg/dL (>_11.1 mmol/L) during a 75 g (grams) oral (taken by mouth) glucose tolerance test

· Hemoglobin A1c (glycated hemoglobin, HbA1c) > 6.5%.

· The following are the results when HbA1C is being used to diagnose diabetes:

· Normal (no diabetes): Less than 5.7%

· Pre-diabetes: 5.7% to 6.4%

· Diabetes: 6.5% or higher

· The diagnosis of DM is accomplished by measuring venous plasma glucose. People with diabetes measure their blood glucose at home with a glucometer (glucose meter).

· DM is classified as type 1 (insulin-dependent diabetes mellitus (IDDM)), juvenile DM), treated with insulin, and type 2 (noninsulin-dependent diabetes mellitus (NIDDM), adult-onset DM), treated with oral hypoglycemic agents – antidiabetic drugs and sometimes also with insulin.

· Another type of DM is gestational diabetes, which occurs when pregnant women without a previous history of diabetes develop a high blood sugar level. It may cause obstetric problems such as shoulder dystocia from a large for gestational age (LGA) baby (because of DM).

Complications of diabetes mellitus (DM)

· Diabetes is a group of chronic diseases characterized by hyperglycemia (high blood glucose). Modern medical care uses a vast array of lifestyle and pharmaceutical interventions to prevent and control hyperglycemia. In addition to ensuring the adequate delivery of glucose to the tissues of the body, treatment of diabetes attempts to decrease the likelihood that the body's tissues are harmed by hyperglycemia. Generally, the injurious effects of hyperglycemia are separated into macrovascular (referring to the large vessels) complications [coronary artery disease (of the coronary arteries of the heart – it causes myocardial infarction (heart attack)), peripheral arterial disease (of the legs; causes intermittent claudication and ulcers that may lead to gangrene), and cerebrovascular disease (stroke)] and microvascular (referring to the small vessels) complications [diabetic nephropathy (kidney disease), neuropathy (peripheral nervous & autonomous nervous system disease), and retinopathy (eye disease)]. Physicians need to understand the relationship between diabetes and vascular disease because the prevalence of diabetes continues to increase in the United States, and the clinical armamentarium for primary and secondary prevention of these complications is also expanding.

· Diabetes Mellitus (DM) is a significant cause of premature atheromatosis (fat deposits on the inner wall of the vessels) that is responsible for coronary heart disease that may to myocardial infarction (MI) and also for cerebrovascular accident (CVA; stroke), renal (kidney) failure (microalbuminuria in diabetics is a premature indication for renal disease), retinal disease of the eye (diabetic retinopathy; it may cause blinding), diabetic neuropathy (nerve disease; mononeuropathy or polyneuropathy and also autonomic neuropathy and neurogenic bladder) and peripheral artery disease (PAD) that may be associated with ulcers/ gangrene on the legs & feet. All these are related to microvascular and macrovascular disease.

· DM may also be associated with heart failure, erectile dysfunction, gastroparesis (slowed emptying of the stomach), and poor wound healing.

· Patients with DM are prone to infections such as UTIs (Urinary tract Infections), mucormycosis (an infection involving the nose & sinuses infection; it may invade deeper in the brain!), ear infection (e.g., from Candida), necrotizing fasciitis, sepsis, and coma from diabetic ketoacidosis (DKA) on type 1 diabetes mellitus (DM), or hyperosmolar coma on type 2 DM.

Diabetes & diabetic nephropathy (kidney disease) –screening for microalbuminuria

Diabetic nephropathy is the leading cause of renal (kidney) failure in the USA. It is defined by proteinuria (urine protein) > 500 mg in 24 hours in the setting of diabetes, but this is preceded by lower degrees of proteinuria or ‘microalbuminuria.’ Microalbuminuria is defined as albumin excretion of 30 – 299 mg/24 hours. Without intervention, diabetic patients with microalbuminuria typically progress to proteinuria and overt diabetic nephropathy. This progression occurs in both type 1 and type 2 diabetes. As many as 7% of patients with type 2 diabetes may already have microalbuminuria when diagnosed with diabetes. In the European Diabetes Prospective Complications Study, the cumulative incidence of microalbuminuria in patients with type 1 diabetes was about 12% for 7 years. In the UKPDS, the prevalence of microalbuminuria was 2% per year in patients with type 2 diabetes, and the 10-year incidence after diagnosis was 25%.

Diabetes mellitus & obesity

Body mass index (BMI) & obesity

· Body mass index (BMI) (also known as Quetelet index) is a measure of relative size based on the mass (weight) and height of an individual.

· BMI=mass (Kg)/ (height (m))² or BMI=mass (lb)/ (height (in))² x 703

· BMI Prime, a simple modification of the BMI system, is the ratio of actual BMI to upper limit BMI (currently defined at BMI 25). As established, BMI Prime is also the body weight ratio to the upper body weight limit, calculated at BMI 25. Since it is the ratio of two separate BMI values, BMI Prime is a dimensionless number without associated units. For example, a person with a BMI of 34 has a BMI Prime of 34/25 = 1.36 and is 36% over his or her upper mass limit.

· Obesity is a significant health problem. Measuring BMI helps classify obesity.

· BMI is estimated by weight (Kg)/ [height (m)]2.

· BMI 18,5 – 24,9 is normal.

· BMI 25 – 29,9 is overweight.

· BMI 30- 39,9 is considered obesity

· BMI equal to or more than 40 is morbid obesity.

· For your BMI, you may check the online calculator on http://www.cancer.org/healthy/toolsandcalculators/calculators/app/body-mass-calculator

· A BMI over 30 triples mortality!

· The target body mass index (BMI) should be twenty-five.

Central (visceral) obesity & waist circumference

· Europe: men>_ 94 cm, women >_ 80 cm

· South Asia: men >_90 cm, women >_80 cm

· China: men >_90 cm, women >_80 cm

· Japan: men >_85 cm, women >_90 cm

· South & Central America: use South Asian pro tem (for the time being)

· African & Middle East: use European pro tem.

· Waist circumference equal to or more than 94 cm (37 inches) for men and 80 cm (32 inches) for women increases the risk for coronary heart disease (CHD) and diabetes mellitus (DM).

Insulin resistance/ diabetes mellitus type 2 as part of the metabolic syndrome

· Metabolic syndrome is a widespread syndrome.

Prevalence & causes of metabolic syndrome

· Prevalence (the number of disease cases in a population at a particular time): 20% of the population.

· USA: 44% of population >50 years; women>men

· Causes: interaction of genes & sedentary overnutrition perpetuated by social norms

· Presence of mild inflammation (differentiation from simple obesity)

· There is a 2 –way interaction between depression & insulin resistance

Etiology – risk factors of metabolic syndrome

· Overweight/ obesity – especially central adiposity

· Sedentary lifestyle

· Increasing age

· Insulin resistance (key role)

· Lipodystrophy

Mechanisms of Metabolic Syndrome

· Excess adipose (fat) tissue leads to increased production of pro-inflammatory cytokines

· Increased intracellular fatty acid metabolites contribute to insulin resistance by impairing insulin signaling pathways and an accumulation of triglycerides in skeletal & cardiac muscle while stimulating hepatic glucose & triglyceride production.

Characteristics – diagnostic criteria of metabolic syndrome

· No specific symptoms. Endothelial dysfunction

· Diagnostic criteria: Central obesity or BMI (body mass index) > 30 plus any 2 of the following:

· Hypertension – ΒP> 130/85 mmHg or specific medication

· Hyperglycemia/ insulin resistance – Fasting glucose > 100 mg/dL (5.6 mmol/L) or previously diagnosed with type -2 diabetes mellitus (DM) or specific medication

· Dyslipidemia: increased triglycerides > 150 mg/dL or >1.7 mmol/L) or specific treatment for hypertriglyceridemia; decreased HDL (‘good’) - cholesterol < 40 mg/dL or <1.03 mmol/L in males and < 50 mg/dL or <1.29 mmol/L in females; or specific treatment.

Associated conditions with metabolic syndrome

· Cardiovascular disease

· Type 2 diabetes mellitus

· Non – alcoholic fatty liver disease (liver steatosis)

· Hyperuricemia/ gout

· Polycystic ovary syndrome (PCOS)

· Obstructive sleep apnea (snoring with episodes of apnea; relation with an increased neck mass and abdominal adiposity)

Insulin resistance & diabetes mellitus (DM)

· Hyperglycemia (high blood glucose)/ insulin resistance is defined as fasting glucose > 100 mg/dL (5.6 mmol/L) or previously diagnosed with type -2 diabetes mellitus (DM) or specific medication.

· Insulin resistance is a decreased ability of insulin to mediate the metabolic actions on glucose uptake, glucose production, and/or lipolysis.

· Prevalence of DM is increasing, parallel with the epidemic of obesity – it touches 8.4% of the USA population – but a significant percentage of the population is undiagnosed. It is the fifth leading cause of death!

Mechanisms of insulin resistance

· Obesity causes insulin resistance by increasing the release rate of non-esterified fatty acids, causing post-receptor defects in insulin’s action.

· Mutation of genes encoding insulin receptors.

· Circulating of autoantibodies to the extracellular domain of insulin receptor.

· Diabetes mellitus results when the beta pancreatic cell function is insufficient to overcome insulin resistance. In type 1 diabetes, the beta-cell function is destroyed. In type 2 diabetes, beta cell function cannot overcome insulin resistance.

· Young women with insulin-resistant polycystic ovary syndrome (PCOS) are as insulin-resistant as newly presenting middle-aged patients with type 2 diabetes. Still, they have high beta–cell activity and normal glucose homeostasis.

Increased insulin resistance –causes

· DM (diabetes mellitus type 2)

· Metabolic syndrome

· Obesity

· Asian race

· Tuberculosis (TB) drugs

· SSRIs (medications for depression)

· Pregnancy

· Acromegaly

· Cushing syndrome

· Renal failure

· Polycystic ovary syndrome (PCOS)

· Werner’s syndrome (progeria, precocious aging after puberty)

Medications that may cause insulin resistance

· Thiazides (diuretics)

· Beta-blockers

· Statins (!)

· Steroids

· Antipsychotics, including atypical

· Immunosuppressive medications (e.g., tacrolimus & cyclosporine)

· Protease inhibitors (for AIDS)

· Nicotinic acid (used as a lipid-lowering agent)

· Pentamidine (used to treat Pneumocystis jirovecii pneumonia, e.g., in AIDS).

Statin therapy & insulin resistance

Statins are evidence-based drugs to prevent cardiovascular disease. However, their benefits have been disputed by a statin-related increased risk of new-onset diabetes (NOD) in randomized controlled trials (RCTs) and meta-analyses. NOD risk seems to be more relevant with high–intensity rather than low–intensity statin treatment. Also, this risk is notably increased in patients at risk for developing diabetes (Reference: http://www.ncbi.nlm.nih.gov/pubmed/26437128 ).

In 2012, the United States Food & Drug Administration (FDA) released changes to the statin safety label to include that statins have been found to increase glycosylated hemoglobin and fasting serum glucose levels. Many studies on patients with cardiovascular (CV) disease risk factors have shown that statins have diabetogenic potential (i.e., predispose for the development of diabetes mellitus). The effect varies as per the dosage and the type used. Various mechanisms for this effect have been proposed, including the downregulation of the glucose transporters by the statins. The recommendations by the investigators are that though statins have a diabetogenic risk, they have longer-term benefits that can outweigh the risk. In elderly patients and those with metabolic syndrome, as the risk of diabetes increases, the statins should be used cautiously. Other than a subset of the population with a risk for diabetes, statins still have long-term survival benefits in most patients (Reference: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360430/ ).

In a study, the authors investigated the effects of statin treatment on blood glucose control and the risk for type 2 diabetes in 8,749 nondiabetic men 45 to 73 years old in a 6-year follow-up of the population-based metabolic syndrome in men trial, based in Kuopio, Finland. During the follow-up, 625 of the participants were diagnosed with diabetes. Indices derived from oral glucose tolerance tests assessed insulin sensitivity and secretion. A total of 2412 individuals were taking statins. The drugs were associated with an increased risk for type 2 diabetes even after adjustment for age, body mass index, waist circumference, physical activity, smoking, alcohol intake, a family history of diabetes, and beta-blocker and diuretic treatment, at a hazard ratio (HR) of 1.46. The risk was dose-dependent for simvastatin and atorvastatin, which 388 and 1409 participants took, respectively. High-dose simvastatin was associated with an HR of 1.44 for diabetes vs. 1.28 for low-dose therapy, whereas the HR for diabetes with high-dose atorvastatin was 1.37. Statin therapy was also associated with a significant increase in 2-hour glucose and the glucose area under the curve at follow-up, and a nominally substantial rise in fasting plasma glucose levels.
Moreover, individuals taking statins had a 24% decrease in insulin sensitivity and a 12% reduction in insulin secretion compared with those not receiving the drugs. These increases were again dose-dependent for atorvastatin and simvastatin. Although pravastatin, fluvastatin, and lovastatin were found to be less diabetogenic (that predisposes to diabetes mellitus) than atorvastatin and simvastatin, the number of participants taking these agents was too small to reliably estimate their individual effects on the risk for diabetes, the research team notes. In conclusion, statin therapy appears to increase the risk of type 2 diabetes by 46%, even after adjustment for confounding factors. This suggests a higher risk for diabetes with statins in the general population than has previously been reported, with a 10% to 22% increased risk (Reference (Retrieved: October 11, 2015): http://www.medscape.org/viewarticle/843980 ).

An overview of the published data about statin therapy (used as lipid-lowering agents) and its correlation with insulin showed that clinical evidence suggests a worsening effect of statins on insulin resistance and secretion. The overview concluded that although most of the clinical studies suggest a worsening of insulin resistance and secretion, the cardiovascular benefits of statin therapy outweigh the risk of developing insulin resistance; thus, the data indicate the need to treat dyslipidemia and to make patients aware of the possible risk of developing type 2 diabetes or, if they already are diabetic, of worsening their metabolic control (Reference: http://www.ncbi.nlm.nih.gov/pubmed/25208056 ).

Metabolic hyperglycemia

Metabolic hyperglycemia arises from a combination of a reduction in the efficiency with which the insulin can move glucose into tissues and a reduction in the number of functioning beta–cells in the pancreas. This results in a surplus of glucose in the bloodstream.

Obesity - the role of the hormone leptin

Leptin (the ‘satiety hormone’) is a hormone made by adipose cells (fat tissue cells) that helps to regulate energy balance by inhibiting hunger. Leptin is opposed by the actions of the hormone ghrelin (the ‘hunger hormone’). Both hormones act on receptors in the arcuate nucleus of the brain's hypothalamus to regulate appetite to achieve energy homeostasis (regulation). Obesity is characterized by a decreased sensitivity to leptin, resulting in an inability to detect satiety despite high energy stores. Although regulation of fat stores is deemed the primary function of leptin, it also plays a role in other physiological processes, as evidenced by its multiple sites of synthesis other than fat cells and the multiple cell types besides hypothalamic cells that have leptin receptors.

· Obesity, diabetes mellitus & resveratrol (a natural substance that increases longevity)

Resveratrol is a substance found in the skins of grapes and certain other plants, fruits, and seeds. It is made by various plants to help defend against invading fungi, stress, injury, infection, and too much sunlight. It is being studied in the prevention of cancer and heart disease. It is a type of antioxidant polyphenol. Evidence suggests that resveratrol (found in red wine, grapes, and olive oil) may be extremely potent. Lab studies have demonstrated that it increases cell survival and has been shown to increase the lifespan of worms and fruit flies (Reference: http://www.umm.edu/patiented/articles/what_phytochemicals_000039_3.htm )

Studies demonstrated a longevity gene called Sir2 (silent information regulator 2) in baker's yeast cells, a sirtuin. This gene expands lifespan by decreasing DNA instability. In mammals, a similar gene is known as SIRT1. Many researchers support the idea that the Sir2 gene is expressed on calorie restriction (CR; see the separate chapter). CR has an increased longevity lifespan of 30% – 40% in mice and rats. Similarly, in mammals, a CR diet ends up in the increased activity of the SIRT1 gene. Resveratrol is a substance found by Sinclair that activates Sir2/SIRT1 gene in yeast, nematode worms, drosophila (fruit flies), and mice with a high-calorie intake, thus expanding their lifespan. However, other research in Drosophila (a fruit fly), yeast, worms, and normal mice didn't ascertain this lifespan extension. However, Italian researchers found that resveratrol expands the lifespan in vertebrate fish by 59%.

Previous research demonstrated that resveratrol possesses promising properties for preventing obesity. Endoplasmic reticulum (ER) stress was proposed to be involved in the pathophysiology of both obesity and hepatic (liver) steatosis (‘fatty liver’). In a study, the authors hypothesized that resveratrol could protect against high-fat diet (HFD)-induced hepatic steatosis and ER stress and regulate the expression of genes related to hepatic steatosis. Rats were fed either a control diet or HFD for 12 weeks. After 4 weeks, HFD-fed rats were treated with either resveratrol or a vehicle for 8 weeks. The results showed that resveratrol prevented dyslipidemia (high blood lipids, i.e., fats, such as cholesterol & triglycerides) and hepatic steatosis induced by HFD. Resveratrol significantly decreased activating transcription factor 4, C/EBP-homologous protein, and immunoglobulin binding protein levels, which were elevated by the HFD. Resveratrol also decreased PKR-like ER kinase phosphorylation, although it was not affected by HFD. Moreover, resveratrol increased the expression of peroxisome proliferator-activated receptor delta while decreasing the expression of ATP citrate lyase, suppressor of cytokine signaling-3, and interleukin-1β. In conclusion, this data suggests that resveratrol can prevent hepatic ER stress and regulate the expression of peroxisome proliferator-activated receptor delta, ATP citrate lyase, suppressor of cytokine signaling-3, tumor necrosis factor-alpha, and interleukin-1beta in diet-induced obese rats, and these effects likely contribute to resveratrol's protective function against excessive accumulation of fat in the liver (Reference: http://www.ncbi.nlm.nih.gov/pubmed/26055348 ).

Resveratrol is a natural polyphenolic compound that activates nicotinamide adenosine dinucleotide-dependent deacetylase SIRT1. Resveratrol has recently been shown to exert potent antidiabetic actions when orally delivered to animal models of type 2 diabetes. However, the tissue(s) mediating these beneficial effects is unknown. Because SIRT1 is expressed in the central nervous system (CNS) neurons known to control glucose and insulin homeostasis, scientists have hypothesized that resveratrol antidiabetic effects are mediated by the brain. A study reported that long-term intracerebroventricular infusion of resveratrol normalizes hyperglycemia (high blood glucose) and dramatically improves hyperinsulinemia (high blood insulin) in diet-induced obese and diabetic mice. These effects are independent of changes in body weight, food intake, and circulating leptin levels. Also, CNS resveratrol delivery improves hypothalamic nuclear factor-kappaB inflammatory signaling. In conclusion, these results unveiled a previously unrecognized key role for the CNS (central nervous system) in mediating the anti-diabetic actions of resveratrol (Reference: http://www.ncbi.nlm.nih.gov/pubmed/19819963 ).

Glycated hemoglobin (HbA1c)

· Glycated hemoglobin (hemoglobin A1c, HbA_1c, A1C, or Hb_1c, HbA1c, or HGBA1C) is a form of hemoglobin measured primarily to identify the average plasma glucose concentration over prolonged periods of time. It is formed in a non-enzymatic glycation pathway by hemoglobin's exposure to plasma glucose. Normal levels of glucose produce a normal amount of glycated hemoglobin. As the average amount of plasma glucose increases, the fraction of glycated hemoglobin increases predictably. This is a marker for average blood glucose levels over the previous 3 months before the measurement, as this is the half-life of red blood cells (RBCs).

· Glycated Hemoglobin (HbA1c) is a helpful biochemistry measurement of blood sugar control over the previous 3 months and should be measured at least every 2 – 6 months.

· People with diabetes should have this test every 3 months to determine whether their blood sugars have reached the target level of control. Those with diabetes under good control may be able to wait longer between the blood tests, but experts recommend checking at least 2 times a year (Reference: (Retrieved: October 12, 2015): http://www.webmd.com/diabetes/guide/glycated-hemoglobin-test-hba1c ).

· In 2010, the American Diabetes Association Standards of Medical Care in Diabetes added the HbA_1c ≥ 48 mmol/mol (≥6.5 DCCT %) as another criterion for diagnosing diabetes.

· (Normal) reference range for HbA1c is 4 – 5.9%.

· The following are the results when HbA1C is being used to diagnose diabetes:

· Normal (no diabetes): Less than 5.7%

· Pre-diabetes: 5.7% to 6.4%

· Diabetes: 6.5% or higher

(Reference: (Retrieved: October 11, 2015): https://www.nlm.nih.gov/medlineplus/ency/article/003640.htm ).

Target Glycated hemoglobin (HbA1c) in diabetics

· Patients with Type 2 Diabetes should normally have their HbA1c maintained between 48 mmol/mol (6.5%) and 58 mmol/mol (7.5%). Clinicians should aim to involve people in decisions about their individual HbA1c target level, which may, in some cases, be above that of 48-58 mmol/mol set for people with Type 2 Diabetes in general. Target HbA1c level should be informed by some factors, including duration of diabetes, life expectancy, comorbidities, established vascular complications, and available support. Tighter targets (6.0 – 6.5% or 42 – 48 mmol/mol) may apply to younger, healthier diabetics, while looser targets (7.5 – 8.0%+/ 53 – 60+ mmol/mol) may apply to older diabetics, with comorbidities, prone to hypoglycemia, etc. The doctor should encourage the diabetic to maintain his/her individual target unless the resulting side effects (including hypoglycemia) or their efforts to achieve this impair their quality of life. The doctor should offer therapy (lifestyle and medication) to help achieve and maintain the HbA1c target level and inform a person with a higher HbA1c that any reduction in HbA1c towards the agreed target is advantageous to future health. However, the doctor should avoid pursuing highly intensive management, particularly in elderly and frail patients with a high risk of hypoglycemia.

· According to NICE (National Institute for Health & Care Excellence), the HbA1c target level for blood glucose control in children with diabetes should be 48mmol/mol (6.5%) and below (Reference (Retrieved: October 11, 2015): http://www.nursingtimes.net/nursing-practice/specialisms/diabetes/nice-pushes-down-hba1c-target-for-children-with-diabetes/5089904.article )

· According to NICE, adults with type 1 diabetes should aim for a target HbA1c level of 48 mmol/mol (6.5%) or lower (Reference (Retrieved: October 11, 2015): https://www.nice.org.uk/news/article/stricter-blood-glucose-targets-for-people-with-diabetes ).

· The International Diabetes Federation and the American College of Endocrinology recommend HbA_1c values below 48 mmol/mol (6.5 DCCT %), while the American Heart Association recommends HbA_1c be below 53 mmol/mol (7.0 DCCT %) for most patients. A review of the UKPDS ACCORD, ADVANCE, and VADT trials estimated that the risks of the main complications of diabetes (retinopathy, nephropathy, neuropathy, and macrovascular disease) decreased by approximately 3% for every 1 mmol/mol decrease in HbA_1c.

· Glycated Hemoglobin (HbA1c), for a single blood sample, provides far more revealing information on glycemic behavior than a fasting blood sugar value. However, fasting blood sugar tests are crucial in making treatment decisions. The American Diabetes Association guidelines advise that the glycated hemoglobin test be performed at least two times a year in patients with diabetes who are meeting treatment goals (and who have stable glycemic control) and quarterly in patients with diabetes whose therapy has changed or who are not achieving glycemic goals.

Oral glucose tolerance test (OGTT) for diagnosing diabetes mellitus

The glucose tolerance test is a medical test in which glucose (dextrose) is given orally. Blood samples for plasma glucose are taken afterward to determine how quickly it is cleared from the blood.

·         The test is usually used to test for insulin resistance, diabetes mellitus, and impaired beta-cell function of the pancreas (that secrete insulin) and sometimes for reactive hypoglycemia, acromegaly, and rarer disorders of carbohydrate metabolism.

·         In the most common version of the test, an oral glucose tolerance test (OGTT), a standard dose of glucose is ingested by mouth, and glucose blood levels are checked two hours later. Many variations of the GTT have been devised over the years for various purposes. The WHO recommends a 75g oral dose of glucose in all adults. The dose is adjusted for weight only in children. The dose should be drunk within 5 minutes.

·         Blood is drawn at intervals to measure glucose (blood sugar) and sometimes insulin levels. The intervals and number of samples vary according to the test's purpose. For simple diabetes screening, the most important sample is the 2-hour sample, and the 0 and 2-hour samples may be the only ones collected. A laboratory may continue to collect blood for up to 6 hours, depending on the protocol requested by the physician.

·         A variant is often used in pregnancy to screen for gestational diabetes with a screening test of plasma glucose over 1 hour after the oral administration of 50 grams of glucose. If elevated, this is followed by a test in which one hundred grams of glucose are administered, and the plasma glucose is checked over three hours.

·         Usually, the OGTT is performed in the morning as glucose tolerance can exhibit a diurnal rhythm variation with a significant decrease in the afternoon. The patient is instructed to fast for 8 – 12 hours before the tests.

Impaired fasting glycemia (IFG) and impaired glucose tolerance (IGT)

·         Impaired fasting glycemia (IFG): fasting plasma glucose level 100 – 125 mg/dL (5.6 – 6.9 mg/dL) (American Diabetes Association ADA) or 110 – 125 mg/dL (6.1 – 6.9 mg/dL) (WHO); or 2-hour glucose <140mg/dL (<7.8 mmol/L) on the 75 g oral glucose tolerance test

·         Impaired glucose tolerance (IGT): 2–hour glucose levels 140 – 199 mg/dL (7.8 – 11.1 mmol/L) on the 75 g oral glucose tolerance test. Prevalence: 10 – 15% of adults in the USA

·         People with IFG or IGT do not have DM but are at substantial risk of developing type 2 DM and cardiovascular disease in the future!



Advanced glycation end products (AGEs) and diabetes mellitus (DM)

· Advanced glycation end products (AGEs) can be a factor in developing or worsening many degenerative diseases such as diabetes mellitus, atherosclerosis, chronic kidney failure, and Alzheimer's disease. They also contribute to aging!

·         They are also believed to play a causative role in the blood-vessel complications of DM. AGEs are seen speeding up oxidative damage to cells and altering their normal behavior.

·         AGEs are formed both outside and inside the body. Specifically, they stem from the glycation reaction, which refers to adding a carbohydrate to a protein without the involvement of an enzyme. Glucose can bind with proteins in glycation, making cells stiffer, less pliable, and more subject to damage and premature aging.

·         AGEs have a range of pathological effects, such as increased vascular permeability, increasing arterial stiffness, inhibiting vascular dilation by interfering with nitric oxide (NO), oxidizing LDL, binding to various cells (including macrophage, endothelial and mesangial (in the kidney) cells) to induce the secretion of a variety of cytokines; and enhancing oxidative stress.

·         The advanced – glycation end products (AGEs) responsible for the vascular complications of diabetes mellitus. AGEs are the products of non-enzymatic glycation and oxidation of proteins and lipids. AGEs, by stimulating processes linked to inflammation, are implicated in many diseases, such as diabetes, inflammation, neurodegeneration (including dementia), and aging.

·         Dietary AGEs can be present in foods such as meat and butter and can form during frying, roasting, and baking, but less in boiling, stewing, steaming, and microwaving.

·         Barbecue foods are high in AGEs. Also, food, when cooked in carbon smoke, becomes carcinogenic. Additionally, cold cuts & cured meat contain nitrates (carcinogenic preservatives that may cause cancer, such as stomach cancer).

Treatment of diabetes mellitus (DM)

· Diabetics should have a special healthy diet for DM prescribed by a dietician or nutritionist.

· They should exercise regularly with aerobic exercise (e.g., jogging, treadmill, elliptical machine, and other ‘cardio’ exercises – the elderly may walk fast or do cycling),

· People with DM must stop smoking and should wear an alert bracelet with the indication of DM in case of hyperglycemic crisis or hypoglycemia.

· They should also have annual influenza (flu) and a pneumococcal vaccine (for pneumococcal pneumonia; it may also protect from some serotypes of pneumococcal meningitis).

· People with DM should have regular foot care from a podiatrist (doctor)/ podologist (foot expert), including prevention & treatment of leg ulcers and fungal infections.

· They should also notify the DVLA (Driver & Vehicle Licensing Agency) (especially) if DM is brittle, non-regulated, and there is a risk of hyperglycemia or hypoglycemia. They should have a kit with a prepared glucagon injection for hypoglycemia.

· Patients with DM should frequently check their blood sugar with a blood finger stick glucometer (glucose meter).

· They should also aim to lower their total cholesterol and LDL – cholesterol (also known as ‘bad’ cholesterol) with a low–lipid (fat) diet and lipid-lowering agents such as the cholesterol-lowering drugs ‘statins.’ The omega-3 fatty acids contained in fish oil of fatty fish may decrease triglyceride levels.

Target Glycated hemoglobin (HbA1c) in diabetics

· Patients with Type 2 Diabetes should normally have their HbA1c maintained between 48 mmol/mol (6.5%) and 58 mmol/mol (7.5%). Clinicians should aim to involve people in decisions about their individual HbA1c target level, which may, in some cases, be above that of 48-58 mmol/mol set for people with Type 2 Diabetes in general. Target HbA1c level should be informed by many factors, including duration of diabetes, life expectancy, comorbidities, established vascular complications, and available support. Tighter targets (6.0 – 6.5% or 42 – 48 mmol/mol) may apply to younger, healthier diabetics, while looser targets (7.5 – 8.0%+/ 53 – 60+ mmol/mol) may apply to older diabetics, with comorbidities, prone to hypoglycemia, etc. The doctor should encourage the diabetic to maintain his/her individual target unless the resulting side effects (including hypoglycemia) or their efforts to achieve this impair their quality of life. The doctor should offer therapy (lifestyle and medication) to help achieve and maintain the HbA1c target level and inform a person with a higher HbA1c that any reduction in HbA1c towards the agreed target is advantageous to future health. However, the doctor should avoid pursuing highly intensive management, particularly in elderly and frail patients with an elevated risk of hypoglycemia.

Diabetes mellitus & treating obesity

Body mass index (BMI) & obesity

· Body mass index (BMI) (also known as Quetelet index) is a measure of relative size based on the mass (weight) and height of an individual.

Obesity is a significant health problem. Measuring BMI helps classify obesity.

· BMI is estimated by weight (Kg)/ [height (m)]2.

· BMI 18,5 – 24,9 is normal.

· BMI 25 – 29,9 is overweight.

· BMI 30- 39,9 is considered obesity

· BMI equal to or more than 40 is morbid obesity.

For your BMI, you may check the online calculator on http://www.cancer.org/healthy/toolsandcalculators/calculators/app/body-mass-calculator

· The BMI over 30 triples mortality!

· The target body mass index (BMI) should be 25.

Central (visceral) obesity & waist circumference

· Europe: men>_ 94 cm, women >_ 80 cm

· South Asia: men >_90 cm, women >_80 cm

· China: men >_90 cm, women >_80 cm

· Japan: men >_85 cm, women >_90 cm

· South & Central America: use South Asian pro tem (for the time being)

· African & Middle East: use European pro tem.

· Waist circumference equal to or more than 94 cm (37 inches) for men and 80 cm (32 inches) for women increases the risk for coronary heart disease (CHD) and diabetes mellitus (DM).

· The main stem for treating obesity is diet and exercise.

Low-calorie diet for treating obesity

· To lose weight, you should follow a low-calorie diet (there are specific calorie books, and all food products mention the calories on the label) with a target of losing 0.5 – 1 kg (1 – 2 lb.) weekly. This is achievable by a low–calorie diet, but these should not be less than 1500 calories daily.

· You may check online calorie calculators such as

· http://www.calculator.net/calorie-calculator.html?ctype=standard&cage=38&csex=m&cheightfeet=5&cheightinch=9&cpound=191&cheightmeter=180&ckg=60&cactivity=1.55&printit=0&x=83&y=9

· http://www.freedieting.com/tools/calorie_calculator.htm

· To maintain your weight, you can consult the online calculator on http://www.cancer.org/healthy/toolsandcalculators/calculators/app/calorie-counter-calculator

· For converting pounds (lbs.) to kilograms (Kg) and vice versa, you may check the converter on http://www.metric-conversions.org/weight/pounds-to-kilograms.htmwww.metric-conversions.org/weight/kilograms-to-pounds.htm

· For converting height from centimeters to feet & inches and vice versa, you can use the online converter on http://www.height-converter.com/

· To lose 1 pound a week, you must cut five hundred calories daily. You can do this by eating less, exercising more, or both.

· To cut five hundred calories per day, you may, for example, cut 250 calories from your daily diet and burn an extra 250 calories through physical activity. For a 150 lb. (68 Kg) person to lose 250 calories, he/she may do about 30 minutes of singles tennis or 45 minutes of brisk walking.

Exercise for treating obesity

· Regular aerobic exercise helps in losing weight.

· About how many calories you can lose with exercise, you can visit the online calculator at http://www.cancer.org/healthy/toolsandcalculators/calculators/app/exercise-counts-calculator

· Right after you stop exercising, take your pulse: place the tips of your first two fingers lightly over one of the blood vessels on your neck, just to the left or right of your Adam's apple. You may also try the pulse spot inside your wrist just below the base of your thumb. For calculating the pulses per minute, count your pulse for 10 seconds and multiply the number by 6 (as 1 minute is 60 sec). Check your pulse periodically to see if you exercise within your target zone. As you get in better shape, try exercising within the upper range of your target zone.

· To lose 1 pound a week, you need to cut 500 calories per day. You can do this by eating less, exercising more, or both.

· To cut 500 calories per day, you may, for example, cut 250 calories from your daily diet and burn an extra 250 calories through physical activity. For a 150 lb. (68 Kg) person to lose 250 calories, he/she may do about 30 minutes of singles tennis or 45 minutes of brisk walking.

· On exercising, the heart rate (HR) should not reach the maximum (220 – age) but within the target zone of 50 – 85% of the average (related to age) maximum heart rate. During the first few weeks of working out, aim for the lower range of your target zone (50%) and gradually build up to the higher range (85%). After six months or more, you may exercise comfortably at up to 85 percent of your maximum heart rate (Reference (Retrieved October 7, 2015): http://www.heart.org/HEARTORG/GettingHealthy/PhysicalActivity/FitnessBasics/Target-Heart-Rates_UCM_434341_Article.jsp and http://www.cancer.org/healthy/toolsandcalculators/calculators/app/target-heart-rate-calculator ).

· For an online calculator of the target heart rate on an exercise, you may visit the site http://www.cancer.org/healthy/toolsandcalculators/calculators/app/target-heart-rate-calculator

· Losing fast weight, faster than 1 kg (2 lb.) weekly, may cause health problems, such as vitamin & mineral deficiency, electrolyte disturbance, metabolic disorders such as hypoglycemia (low blood sugar), anemia by lack of iron and/or vitamin B12 & folic acid, dehydration, sexual dysfunction (such as in the anorectic women who lose their menstrual cycles), etc. Fast losing weight may also cause the skin to become loose and hang!

Blood pressure (BP) and the prevention of hypertension in diabetics

According to NICE (National Institute for Health & Care Excellence) in the UK, for people with diabetes mellitus, the target blood pressure is < 130/80 mmHg for patients with kidney, eye, or cardiovascular damage. For others, the target blood pressure is < 140/80 mmHg.

· Three leading groups of heart experts have issued updated guidelines that set blood pressure goals for people with heart disease. The guidelines reinforce a target blood pressure of less than 140/90 mm Hg for those at risk for heart attack and stroke. The guidelines also set a goal of 130/80 mm Hg for those with heart disease who have already had a heart attack, stroke, or a mini-stroke (TIA; transient ischemic attack) or who have had a narrowing of their leg arteries or an abdominal aortic aneurysm (Reference: http://www.newsmax.com/Health/Health-News/blood-pressure-guidelines-heart/2015/03/31/id/635609/ ).

· The American Heart Association (AHA), American College of Cardiology (ACC), and American Society of Hypertension (ASH) issued new recommendations for treating hypertension in patients with coronary artery disease (CAD). The AHA/ACC/ASH guidelines recommend a target BP <130/80 mm Hg in some patients with CAD. However, lowering diastolic blood pressure (DBP) <60 mm Hg is not recommended in patients with CAD, especially those aged older than 60 years, due to the potential for increasing cardiovascular (CV) risk.

Avoidance of salt for the prevention of hypertension

· Diabetics should prevent hypertension (high blood pressure), another risk factor for cardiovascular & cerebrovascular disease.

· They should eat about less than half a teaspoon of salt daily. However, diabetics should keep in mind that sugar (and salt) is added to processed & restaurant food.

· The American Heart Association recommends consuming less than 1,500 mg of sodium daily. 1/4 teaspoon of salt has 575 mg sodium; 1/2 teaspoon salt contains 1,150 mg sodium; 3/4 teaspoon salt contains 1,725 mg sodium, and 1 teaspoon salt has 2,300 mg sodium.

· You can find the amount of sodium in packaged food sold in stores by looking at the Nutrition Facts label.

· 90% of American adults are expected to develop high blood pressure in their lifetimes, and overeating sodium is strongly linked to the development of high blood pressure.

· For tracking the sodium in food, you may check the articles of the American Heart Association (AHA): http://www.heart.org/HEARTORG/GettingHealthy/NutritionCenter/HealthyEating/How-to-Track-Your-Sodium_UCM_449547_Article.jsp and http://www.heart.org/HEARTORG/GettingHealthy/NutritionCenter/HealthyEating/About-Sodium-Salt_UCM_463416_Article.jsp

· The recommendation for less than 1,500 mg of sodium daily does not apply to people who lose significant amounts of sodium in sweat, such as competitive athletes and workers exposed to extreme heat stress (for example, foundry workers and firefighters), or to those directed otherwise by their healthcare provider.

· Salt also has iodine as an additive necessary for the thyroid gland. Its deficiency in children may cause cretinism, a severe mental disease.

Dietary advice for the prevention of diabetes mellitus

· Avoid sugar. Keep in mind that salt & sugar are added to many processed foods (e.g., cereals, snacks, etc.), so always check the ingredients.

· High carbohydrate diets are unhealthy, as they predispose to diabetes and coronary heart disease accelerated by hyperglycemia (high blood sugar).

· Excess carbohydrates (‘carbs’) are the primary cause of a high-calorie diet, and their contribution to obesity is major for most people.

· Do not add sugar or honey to fresh fruit juices, as they already have many carbohydrates.

· Avoid artificial sweeteners, such as saccharin, cyclamate acid, and aspartame, which have been suspicious for cancer.

· Stevia is a herb that is a natural sweetener, but I don’t prefer it as it is bitter.

· In a study in 1990, 33 upper-trimester chiropractic students volunteered for oral glucose tolerance testing comparing sucrose, fructose, and honey during successive weeks. A 75-gm carbohydrate load in 250 ml of water was ingested, and blood sugar readings were taken at 0, 30, 60, 90, 120, and 240 minutes. Fructose showed minimal changes in blood sugar levels, consistent with other studies. Sucrose gave higher blood sugar readings than honey at every measurement, producing significantly (p less than .05) greater glucose intolerance. Honey provided the fewest subjective symptoms of discomfort. Given that honey has a gentler effect on blood sugar levels per gram basis and tastes sweeter than sucrose so that fewer grams would be consumed, it would seem prudent to recommend honey over sucrose (Reference: http://www.ncbi.nlm.nih.gov/pubmed/2394949 ).

· High-heat food cooking induces the formation of advanced glycation end products (AGEs), which are thought to impair glucose metabolism in type 2 diabetic patients. High intake of fructose might additionally affect the endogenous formation of AGEs. A study in 2014 investigated whether adding fructose or cooking methods influencing the AGE content of food affects insulin sensitivity in overweight individuals. Seventy-four overweight women were randomized to follow either a high- or low-AGE diet for 4 weeks and consume either fructose or glucose drinks. Glucose and insulin concentrations after fasting and 2 hours after an oral glucose tolerance test were measured before and after the intervention. The results showed that the low-AGE diet decreased urinary AGEs, fasting insulin concentrations, and homeostasis (regulation) model assessment of insulin resistance (HOMA-IR), compared with the high-AGE diet. The addition of fructose did not affect any outcomes. The study concluded that diets with high AGE content may increase the development of insulin resistance. AGEs can be reduced by modulation of cooking methods but are unaffected by moderate fructose intake (Reference: http://www.ncbi.nlm.nih.gov/pubmed/23959566 ). A study in rabbits in 2005 concluded that fructose worsened the atheromatous lesions caused by cholesterol feeding. The mechanism is most likely through lipid peroxidation, which was increased by cholesterol-feeding-induced hyperlipidemia and the formation of AGEs (Reference: http://www.ncbi.nlm.nih.gov/pubmed/16205022 ).

About fructose

· Many people prefer fructose as a sweetener (it has only 12 calories a teaspoon; sugar has 20; its benefits are debated) or honey.

· Commercially, fructose is frequently derived from sugar cane, sugar beets, and corn. Fructose is often recommended for diabetics because it does not trigger insulin production by pancreatic beta–cells. However, the net effect for both diabetics and non-diabetics is debated. Fructose has a very low glycemic index of 19 ± 2, compared with 100 for glucose and 68 ± 5 for sucrose (refined sucrose is the table sugar). Fructose is also 73% sweeter than sucrose. Studies show that fructose consumed before a meal may even lessen the glycemic response of the meal. Excessive fructose consumption may contribute to the development of fatty liver (liver steatosis). A 2008 study found a substantial risk of gout associated with fructose consumption. A meta-analysis in 2012 concluded that the isocaloric exchange of fructose for another carbohydrate improves long-term glycemic control, as assessed by glycated blood proteins, without affecting insulin in people with diabetes (Reference: http://care.diabetesjournals.org/content/35/7/1611.abstract ).

Is fructose harmful?

Fructose is also called fruit sugar, while refined sugar, called sucrose, is half glucose and half fructose. Refined sugars are used to make breakfast cereals, pastries, sodas, fruit drinks, and other sweet foods and beverages. The breakdown of fructose in the liver may lead to the buildup of fat there, causing what is called nonalcoholic fatty liver disease. It also elevates triglycerides, increases LDL-cholesterol (also called ''bad'' cholesterol), promotes the buildup of fat around organs (visceral fat), raises blood pressure, makes tissues insulin-resistant, predisposes to diabetes, and increases the production of free radicals that can damage DNA and cells. (Reference (Retrieved: August 16, 2018): https://www.health.harvard.edu/heart-health/abundance-of-fructose-not-good-for-the-liver-heart )

Excessive accumulation of triglycerides (TG) in the liver, without significant alcohol consumption, causes nonalcoholic fatty liver disease (NAFLD). NAFLD is a significant risk factor for developing cirrhosis and an independent predictor of cardiovascular disease. High fructose corn syrup (HFCS)-containing beverages were associated with metabolic abnormalities and contributed to the development of NAFLD in human trials. Ingested carbohydrates constitute a significant stimulus for hepatic de novo lipogenesis (DNL) and are more likely to directly contribute to NAFLD than dietary fat. Substrates used to synthesize newly made fatty acids by DNL are primarily glucose, fructose, and amino acids. Epidemiological studies linked HFCS consumption to the severity of liver fibrosis in patients with NAFLD. (Reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405421/ )

Advanced – glycation end products (AGEs)

· The advanced – glycation end products (AGEs) responsible for the vascular complications of diabetes mellitus. AGEs are the products of non-enzymatic glycation and oxidation of proteins and lipids. AGEs, by stimulating processes linked to inflammation, are implicated in many diseases, such as diabetes, inflammation, neurodegeneration (including dementia), and aging.

· Dietary AGEs can be present in foods such as meat and butter and can form during frying, roasting, and baking, but less in boiling, stewing, steaming, and microwaving.

Glycaemic index (GI)

· Foods with a low glycemic index should be preferred.

· The glycemic index (GI) is a number associated with a particular type of food that indicates the food’s effect on a person’s blood glucose. The number typically ranges between 50 and 100, where 100 represents the standard, an equivalent amount of pure glucose. We all need to choose foods with a low glycemic index (GI), as foods with a high glycemic index may predispose us to diabetes and cardiovascular disease. Common foods such as bananas have a high glycemic index, so we should eat them moderately or less. For a calculator of the glycemic index on foods, see http://www.glycemicindex.com/foodSearch.php

Medications for diabetes (hypoglycemic agents – antidiabetic drugs)

Metformin

· Acts on the liver to reduce gluconeogenesis and causes a decrease in insulin resistance via increasing AMPK (5' AMP-activated protein kinase) signaling.

· It has a low risk of hypoglycemia as compared to alternative hypoglycemic drugs

· Good effect on LDL-cholesterol and decreases triglycerides.

· Adverse effects include gastrointestinal problems.

Sulfonylureas (e.g., glyburide, glipizide & glimepiride)

· They stimulate insulin release by pancreatic beta cells by inhibiting the K⁺ /ATP channel.

· They have an increased risk for hypoglycemia.

· They do not influence LDL-cholesterol.

· They have a lower risk of gastrointestinal (GI) problems than with metformin

Thiazolidinediones (TZDs, e.g., pioglitazone & rosiglitazone)

· Reduce insulin resistance by activating PPAR - gamma receptor in fat and muscle.

· Have a lower risk for hypoglycemia and slightly increase the HDL ('good'')-cholesterol.

· Their adverse effects are the increased risk of heart failure, weight gain, higher risk of edema & anemia, increased LDL (''bad'' )-cholesterol, and hepatotoxicity (liver toxicity).

Inhibitors of dipeptidyl peptidase 4 (DPP-4 inhibitors or gliptins such as sitagliptin and vildagliptin)

· Inhibitors of dipeptidyl peptidase 4 (DPP-4 inhibitors or gliptins) are oral hypoglycemic agents that block the DPP-4 and are used to treat diabetes mellitus type 2. Adverse effects include nasopharyngitis, headache, nausea, heart failure, hypersensitivity, skin reactions, and severe joint pain. A recent meta-analysis found no favorable or harmful effect of DPPIV inhibitors on all-cause mortality, cardiovascular mortality, or stroke but a marginally statistically significant increase in heart failure.

Thanks for reading!

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