Type II Diabetes

History

Patients with diabetes can present with:

• fatigue
• polyuria and polydipsia
• unexplained weakness

Physical Exam

skin problems

screening

Prediabetes (see below) describes a state of elevated blood glucose levels remaining below those of T2DM. It is best diagnosed with the glucose tolerance test, but can also be done using FPG.

In Canada, fasting blood glucose should be tested in everyone >40 every 3 years, or more frequently in people with any risk factors. Mass screening for T2DM is not recommended.

Urinalysis - glucose, ketones, protein

Children should be screened if they are >10 (or puberty) every 2 years using FPG if they have >1 risk factors:

• obesity
• high risk population or family history
• symptoms of insulin resistance
• IGT
• antipsychotics

Making the Diagnosis

Diabetes mellitus may be diagnosed in various ways:

one instance of:

• random blood glucose >11.1 mmol (200 mg/dL)

two of the following:

• fasting blood glucose >7.0 mmol/L (126 mg/dL)
• blood glucose 2 hours post 75g oral glucose tolerance test (OGTT) > 11.1 mmol/L
• HbA1c >6.5% (0.065)

OGTT: pancreatic stress test

Note: HbA1c can be skewed by recent blood transfusions.

Prediabetes is diagnosed with the following values:

Prediabetes: A1c 6.1-6.4%

Other Labs

Ketoacidosis is uncommon, presumably due to levels of portal vein insulin levels and sufficient fatty acid oxidation.

Hyperosmolar nonketotic coma can result from severe dehydration.

Macrovascular disease

Macrovascular disease results from problems with large- and medium-sized muscluar arteries, and causes accelerated atherosclerosis in people with diabetes. This can lead to increased risk for myocardial infarction, stroke, and gangrene inthe legs. MI is the most common cause of death in people with diabetes.

Biggest risk factor is age. Canadian guidelines suggest a 45 year-old man should be viewed as a 60 year-old when it comes to cardiovascular risk. In younger patients, risk for CAD is assessed based on other risk factors.

Up to 1/3 of MIs can be silent, occurring without recognized or typical symptoms.

Macrovascular disease appears meadiated primarily by increased levels of free fatty acids (FFAs), not hyperglycemia. Because of this, tight blood glucose control alone will not prevent the big guns, and lipid lowering agents need to be added.

Diabetes can also lead to hypertension, dyslipidemia, and platelet dysfunction.

• morbidity and mortality are increased in diabetes
• Type II DM is a CVD risk equivalent
• multiple risk factors coexist in TIIDM and metabolic syndrome
• diabetes enhances the impact of any risk factor on absolute risk: multiplicative effects, more than additive
• greater effect in women

Microvascular disease

Microvascular disease is caused by problems in capillary dysfunction in target organs unable to regulate a response to hyperglycemia, including endothelial cells (particularly those in the retina), mesangial cells in the kidney, and neurons and Schwann cells in peripheral nerves. Effects of tonic hyperglycemia thus include diabetic retinopathy, nephropathy, and neuropathy. The vasculature is affected by hypertension, dyslipidemia, inflammation, and impaired fibrinolysis

Microangiopathy involves thickening of the basement membranes, especially in the capillaries of the skin, muscle, retina, renal medulla, and glomeruli.

Diabetic nephropathy

Diabetic nephropathy (protein >300mg/day) is the most important cause of end-stage renal disease in the US and can lead to nephrotic syndrome.

It occurs due to glomerular lesions, renal vascular lesions, and pyelonephritis. Up to 30-40% of people with type I and about 20% of people with type II diabetes develop nephropathy, which is greatly influenced by genetics (Native Americans, blacks, and Hispanics have a greater risk).

Microalbuminuria is an early marker, almost inevitably to overt nephropathy within 5 years. It is associated with increased cardiovascular mortality.

Diffuse glomerulosclerosis is the most common lesion, with a uniform increase in mesangial matrix. Hyaline arteriosclerosis can affect afferent and efferent arterioles.

Leading cause of end-stage renal disease in Canada

Ocular involvment can include retinopathy, cataract formation, or glaucoma. Within 15-20 years of diagnosis, 60-80% of people with diabetes have some form of diabetic retinopathy, with neovascularization (probably attributable to VEGF) being very important.

Diabetic neuropathy clinically affects up to 50% of patients who have lived with DM for over 25 years. Neuropathies can be sensory, sensorimotor, or autonomic. Axonal neuropathy is prominent, with relative loss of small fibres. Arterioles are affected. It is not clear if ischemia or metabolic problems are most causative.

Symmetric peripheral neuropathies are the most common. Mononeuropathies involving a single peripheral or cranial nerve are possible, as are multiple mononeuropathies.

Neuropathic ulcers cause huge problems for people with diabetes.

Gastroperesis, sexual dysfunction

Erectile dysfunction

Skin Disorders

Approximately 30% of patients with diabetes mellitus develop a skin disorder sometime during the course of disease.

Foot ulcers                 

• The diabetic foot is characterized by slowly healing plantar ulcers that result from apparently insignificant trauma. Left untreated, superficial ulcers may penetrate to underlying tissues, leading to complications including cellulitis, abscess formation, joint sepsis, and osteomyelitis. Gangrene may occur, and amputation may be required in severe cases.
• About 15% of diabetic patients experience clinically significant foot ulceration. Risk factors for ulcer development include long-standing diabetes, poor glycemic control, and concurrent diabetic complications. Visual loss and severe obesity may also contribute to difficulties with self-care.

Intertrigo: Dermatitis (inflammation) soccurring between folds or juxtaposed surfaces of the skin and caused by sweat retention, moisture, warmth, and the overgrowth of resident microorganisms.

Onychomycosis: A fungal infection of the fingernails or toenails that results in thickening, flaking, roughness, and splitting of the nails. Usually caused by Trichophyton rubrum or T. mentagrophytes. Aka: tinea unguium.

Mycosis: A contagious fungal skin infection caused by a species of Trichophyton or Epidermophyton that usually affects the feet, especially the skin between the toes, and is characterized by itching, blisters, cracking, and scaling (aka Also called tinea pedis.)

Xanthoma: A benign lesion composed of lipid laden foam cells, which are histiocytes containing cytoplasmic lipid material.

Xanthelasma: Same as above, except usually sharply demarcated yellowish collection of cholesterol underneath the skin on or around the eyelids (above & below inner canthus)

Shin Spots (Diabetic Dermopathy or pigmented pretibial patches): These are found in other conditions, but are the most common cutaneous finding in diabetes. Characterized by bilateral multiple hyperpigmented macules on the pretibial areas. Due to the frequent location of the lesions over bony prominences, diabetic dermopathy may simply be a magnified response to trauma. In several studies, shin spots were produced in response to trauma with heat, cold, or blunt objects in persons with diabetes. Lesions may also appear on the forearm, the side of the foot, and the anterior surface of the lower thigh. Lesions are round or oval, reddish-brown, scaly papules and plaques, of various sizes. The lesions eventually evolve into the characteristic shallow pigmented scars typical of diabetic dermopathy.

Diabetic bullae

• Rare, but a distinct marker for diabetes. Bullae are blisters appearing from normal skin. They are usually >0.5cm, and contain a clear, sterile, viscous fluid. They are usually self-limiting, and other than local care to avoid blister eruption and secondary infection, no treatment is recommended.
• They appear spontaneously, usually on the feet and toes, but occasionally on the hands and fingers and are intraepidermal or subepidermal.
• Intraepidermal bullae are clear, sterile, nonhemorrhagic blisters that generally heal on their own in 2 to 5 weeks without scarring or atrophy. Most patients are men b/w 40 and 75yo with long-standing diabetes, peripheral neuropathy, and good circulation to the involved extremity.
• Subepidermal bullae are less common. Blisters are similar to the other type except they occasionally are hemorrhagic and may heal with scarring and atrophy. They are seen in the same type of patients.

Granuloma annulare

• Annular or arciform plaques that begin as flesh-colored, red, or reddish-brown papules symmetrically spread across the upper trunk, neck, arms, and occasionally the legs.
• The generalized form (aka: disseminated) is the most type prevalent in diabetes. Etiology unknown, but often treated with corticosteroids.

Acanthosis nigricans (AN)

• Characterized by rough, velvety, dark patches of skin on the back of the neck Common in insulin resistance syndromes.
• Once considered a cutaneous marker for internal malignancy like adenocarcinoma of the gastrointestinal tract. Now excepted to be a close association exists between AN, obesity, and insulin resistance. It’s a risk factor for T2DM.
• Most likely is caused by factors that stimulate epidermal keratinocyte and dermal fibroblast proliferation. In the benign form of AN, the factor is probably insulin or an insulinlike growth factor that incites the epidermal cell propagation.

Ketoacidosis

Ketoacidosis results from periods of increased adipocyte breakdown of fatty acids and hepatic conversion of fatty acids acetylCoA into ketone bodies for use as fuel by tissues such as brain, heart, and muscle.

Dyslipidemia

Diabetes in adults is associated with a high risk of vascular disease (2- to 4-fold greater than that of individuals without diabetes), with CVD the primary cause of death among people with type 1 or type 2 diabetes. Aggressive management of all CV risk factors, including dyslipidemia, is therefore generally necessary. The most common lipid pattern in type 2 diabetes consists of hypertriglyceridemia (hyper-TG), low high-density lipoprotein cholesterol (HDL-C) and normal plasma concentrations of low-density lipoprotein cholesterol (LDL-C). However, in the presence of even mild hyper-TG, LDL-C particles are typically small and dense and may be more susceptible to oxidation. Chronic hyperglycemia promotes the glycation of LDL-C and both these processes are believed to increase the atherogenicity of LDL-C. In those with type 1 diabetes, plasma lipid and lipoprotein concentrations may be normal, but there may be oxidation and glycation of the lipoproteins, which may impair their function and/or enhance their atherogenicity.

Increased Atherosclerosis:

• hyperinsulinemia/insulin resistance
• dyslipidemia
• HT
• hemostatic abnormalities
• hyperglycemia
• advanced glycation end products (AGEs)

Other Complications

Diabetes can increase the risk of preinatal depression (Kozhimannil et al, 2009).

Anxiety in 40%

Depression in 15%

Diabetic osteopathy can be caused by bone demineralization and resorption.

Higher post-op mortality (increased infection, CV events).

Lifstyle Modifications

Gillies et al, 2007 published a meta-analysis showing that lifestyle interventions appear at least as effective as treatment with glitzazones in preventing type II diabetes, with both reducing progression of glucose intolerance by 50% or more. The authors warn of turning healthy people into patients unnecessarily.

This entails adopting healthy eating habits, achieving and maintaining a healthy weight, engaging in regular physical activity and smoking cessation.

Lifestyle should be the first treatment, unless A1C is 9% or higher. If targets are not reached within 2-3 months, medications should be strongly considered.

Lifestyle is incredibly difficult, as it requires total lifestyle change, predominantly of the family.

Lifestyle intervention continues to be protective against diabetes after studies have ended, as Lindstrom et al, 2006 found.

People sually eat what they like to eat, and are used to eating.

Use blood glucose to provide feedback to patients re: what their meals are doing to them.

A 5-10% reduction in weight has significant improvement in diabetes control.

Quitting smoking.

Bariatric surgery

Bariatric surgery increases incretins for up to 20 years

someone said it can resolve diabetes in over 80% of people.

Hypoglycemic Medications

Medications should be used to reach target A1C levels within 6-12 months.

Oral hypoglycemics are the initial mainstay for managing TII DM.

Metformin is the first-line agent for use used if blood glucose levels are not restored by diet and exercise in 2-4 months. If patients' initial A1C is above 9%, combination therapy or insulin should be considered as initial treatment.

Second-line -A lengthy list of agents can be selected according to specific patient situation. This includes any of the oral hypoglycemics, as well as insulin.

Guidelines include:

• Canadian Diabetes Association
• American Diabetes Association

In seniors, the biggest risk is low blood sugar. Metformin is the ideal choice. Insulin should be avoided, especially in sliding scales. Aim for 6-14.

Complicating factors include:

• irregular meals
• weight loss
• medication adherence
• cognitive impairment
• renal impairment
• vision problems
• support issues

The following medications should be held when patients are sick and become dehydrated

• Sulfonylureas
• ACEis
• Dieuretics
• Metformin
• ARBs
• NSAIDs
  

Insulin

Other Indicators

A number of elements should be present to assist with vascular protection, and the number of medications taken usually increases with duration of disease.

• most people should be on 12 meds, according to some

Blood Pressure and Kidney Protection

ACE inhibitors or angiotensin receptor blockers (ARBs) are very useful for blood pressure control and to reduce levels of proteinuria. The medications that have been shown to be protective include ramipril, perindopril, and telmasartan.

However, most patients will require multiple drugs for adequate blood pressure control.

Current targets are for a BP of <130/80, though there is increasing evidence that this tight control does not result in improved outcomes.

ACEi and ARBs should be used in all patients with:

• microvascular or macrovascular disease
• age >55 year old

Note: these drugs should not be used if pregnancy is present, or is being considered, given the teratogenic effects they can have.

Cholesterol

Statins should be used in the following groups:

• meets treatment criteria according to lipid guidelines
• age >40
• macrovascular or microvascular disease
• DM >15 years, and age >30

Note: statins should not be used if pregnancy is present, or is being considered, given the teratogenic effects they can have.

Adults at high risk of vascular disease should be treated with a statin to achieve an LDL-C ≤2.0 mmol/L. Clinical judgement should be used as to whether additional LDL-C lowering is required for adults with an on-treatment LDL-C of 2.0 to 2.5 mmol/L. The primary target is LDL, and the secondary is ratio.

If the TC/HDL-C ratio is ≥4.0, consider strategies to achieve a TC/HDL-C ratio <4.0, such as improved glycemic control, intensification of lifestyle (weight loss, physical activity, smoking cessation) and, if necessary, pharmacologic interventions.

In adults with serum TG >10.0 mmol/L despite best efforts at optimal glycemic control and other lifestyle interventions (e.g. weight loss, restriction of refined carbohydrates and alcohol), a fibrate should be prescribed to reduce the risk of pancreatitis.

For those with moderate hyper-TG (4.5 to 10.0 mmol/L), either a statin or a fibrate can be attempted as first-line therapy, with the addition of a second lipid-lowering agent of a different class if target lipid levels are not achieved after 4 to 6 months on monotherapy.

For adult patients not at target(s), despite optimally dosed first-line therapy as described above, combination therapy can be considered. Options include:

• statin plus ezetimibe
• statin plus fibrate
• statin plus niacin

Anticoagulation

Anticoagulation, with ASA or clopidogrel, should be used when macrovascular disease is present.

Peripheral neuropathy

There are many treatments that are used for neuropathy (main article)

• anticonvulsants: pregabalin, gabapentin, valproate
• antidepressants: amitriptyline, duloextine, venlafaxine
• opioid analgesics
• topical nitrate spray

Retinopathy

Retinopathy can be slowed through good sugar control, as well as the addition of fibrates.

Opthalmologic treatments can include laser photocoagulation, intra-ocular injections, or retinal surgery

Good foot care

There are a number of points that should be made to patients (CDA, 2013):

Prevention

Impaired glucose tolerance (IGT) diagnosis is a critical period to offer lifestyle support.

Medications, especially metformin, can prevent progression.