Diabetes Mellitus Overview PDF

Diabetes Mellitus Type 1  Definition Type 1 diabetes mellitus (T1DM) is a metabolic disorder characterised by hyperglycaemia due to an absolute deficiency of insulin. This is caused by an autoimmune destruction of beta cells of the pancreas.  Epidemiology o Typically manifes...

Diabetes Mellitus Type 1  Definition Type 1 diabetes mellitus (T1DM) is a metabolic disorder characterised by hyperglycaemia due to an absolute deficiency of insulin. This is caused by an autoimmune destruction of beta cells of the pancreas.  Epidemiology o Typically manifests in childhood, reaching a peak incidence around the time of puberty - but can present at any age o Usually younger - < 30yrs o Patient is usually lean o Increased in those of Northern European ancestry, especially in Finland o Incidence is increasing in most populations - particularly children  Aetiology o AUTOIMMUNE - Auto-antibodies forming against insulin and islet beta cells - INSULITIS o Idiopathic - Uncommon form that is characterised by absence of antibodies o Genetic susceptibility - HLA-DR3-DQ2 or HLA-DR4-DQ8 o Association found with enterovirus  Risk Factors o Northern European - especially Finnish o Family history - HLA-DR3-DQ2 or HLA-DR4-DQ8 in > 90% o Associated with other autoimmune disease:  Autoimmune thyroid  Coeliac disease  Addison’s disease (excess cortisol)  Pernicious anaemia o Environmental factors:  Dietary constituents  Enteroviruses such as Coxsackie B4  Vitamin D deficiency   Cleaner environment may increase type 1 susceptibility  Pathophysiology o Results from autoimmune destruction by autoantibodies of the pancreatic insulin-secreting Beta cells in the Islets of Langerhans o Causing insulin deficiency and thus the continued breakdown of liver glycogen (producing glucose and ketones) leading to glycosuria and ketonuria as more glucose is in the blood o In skeletal muscle and fats there is impaired glucose clearance:  Blood glucose is increased - when it reaches 10mmol/L, body can no longer absorb glucose - you become thirsty and get polyuria (as body attempts to remove excess glucose) o Patient MUST have INSULIN since they are prone to diabetic ketoacidosis:  This is due to reduced glucose supply to cells due to lack of insulin which drives the formation of ketone bodies for use as a form of energy. Ketone bodies are strong acids and lower the pH of the blood. This has many effects e.g. impairing Hb ability to bind O2, acute kidney injury etc o Eventual complete Beta cell destruction results in the absence of serum C- peptide o Present VERY LATE often with only 10% of beta cells remaining  Clinical manifestations o Key Presentations  Pt generally leaner than pt with T2DM o Signs  BMI typically < 25 kg/m2  Glycosuria  Ketonuria  Failure to thrive in children: dropping off height and weight centiles  Glove and stocking sensory loss  Reduced visual acuity  Diabetic retinopathy  Diabetic foot disease:  Reduced peripheral pulses  Calluses  Ulceration  Charcot join  o Symptoms  Polydypsia  Polyuria  Nocturia  Weight loss  Lethargy  Recurrent infections - e.g. pt complaining of balanitis or pruritis vulvae due to repeat candida infections  Evidence of complications: Blurred vision or parasthesia  Investigations o 1st line Primary investigations:  Random blood glucose: taken at any time of day and ≥11mmol/L is diagnostic  Fasting blood glucose: ≥7.0 mmol/L  For both tests one abnormal value is DIAGNOSTIC in symptomatic individuals  Two abnormal values are required in asymptomatic individuals For borderline cases  Oral glucose tolerance test: >11mmol/L two hours after a 75g oral glucose load. 7.8-11mmol/L suggests pre-diabetes.  HbA1C: measures amount of glycated haemoglobin. ≥48 mmol/mol suggests hyperglycaemia over the preceding 3 months o Other Investigations to consider:  C-peptide: NICE advise this should only be measured in atypical presentations, e.g. age > 50, or BMI > 25kg/m2.  Autoantibodies: only conducted if atypical features are present, and if positive, suggests autoimmune beta-cell destruction. Autoantibodies against the following may be found:  Glutamic-acid decarboxylase (GAD)  Insulin  Islet cell  Islet antigens  Zinc transporter (ZnT8)   VBG: if concerned about DKA, e.g. systemically unwell or vomiting, this will reveal a metabolic acidosis o Diagnostic criteria NICE guidelines stipulate a diagnosis should be made taking into account clinical features and evidence of hyperglycaemia, e.g. random glucose ≥ 11.1 mmol/L. Additionally, NICE state that type 1 diabetics will usually have one of the following:  Ketosis  Rapid weight loss  Age of onset < 50 years  BMI < 25 kg/m2  Personal and/or family history of autoimmune disease  Differential diagnosis o Monogenic diabetes: maturity onset diabetes of the young (MODY) - should be suspected in cases of diabetes in non-obese, young patients (adolescence or young adult) with family history of diabetes in two or more successive generations.  C peptide will be present, autoantibodies will be absent o Neonatal diabetes: diabetes diagnosed under 6 months of age.  Genetic testing with majority of mutations in the genes encoding the adenosine triphosphate-sensitive potassium channel and the insulin gene. o Latent autoimmune diabetes in adults (LADA): Typical age of onset of diabetes is over 30 years old. Patients are usually non-obese and respond initially to lifestyle modifications and oral agents. Production of insulin gradually decreases (between 6 months and 5 years), such that treatment with insulin is required.  Low to normal initial C-peptide level.  Can be positive for at least 1 of the 4 antibodies commonly found in type 1 diabetic patients. o Type 2 diabetes: Older age and slow onset, obesity, a strong family history, absence of ketoacidosis, and initial response to oral anti-hyperglycaemic drugs are typical of type 2 diabetes.  C peptide present, autoantibodies absent  Management o 1st line Multidisciplinary approach Lifestyle:  Educate patient on disease and risk   Maintain lean weight, stop smoking and take care of feet (to reduce gangrene risk)  Patients should be educated regarding carbohydrate counting. This is a technique which allows the insulin dose to be matched to intake  NICE recommend that dietary advice should be tailored to the patient’s personal needs and culture Insulin therapy (refer to other notes tab for types of insulin): Basal-bolus regimen: the first-line regimen of choice, whereby a long-acting insulin is given regularly (basal) and supplemented with a rapid-acting insulin before each meal (bolus)  Basal: Levemir (Detemir) is the first line basal insulin given twice- daily. Lantus (Glargine) once-daily is an alternative  Bolus: Humalog (Lispro) or Novorapid (Aspart) are examples o Adjuncts/ other  Mixed insulin regimen: a mixture of a short or rapid- acting and intermediate-acting insulin. It is given twice daily and used in those who cannot tolerate multiple injections as part of a basal- bolus regimen  Continuous insulin infusion: indicated if the patient has disabling hypoglycaemia or persistently hyperglycaemic (HbA1c >69mmol/mol) on multiple injection insulin therapy o Complications of insulin therapy  Hypoglycaemia - most common (also caused by SULFONYLUREA - antidiabetic drug)  Injection site - lipohypertrophy  Insulin resistance - mild and associated with obesity  Weight gain - insulin makes people feel hungry  Monitoring Patients require regular follow-up to monitor HbA1c levels and assess for complications of diabetes. o HbA1c: measure every 3-6 months with a target of ≤48 mmol/mol  NICE advises that the target can be tailored based on personal daily activities, aspirations, the likelihood of complications, comorbidities, occupation and history of hypoglycaemia o Self-monitoring: should be tested at least 4 times a day, including before meals and before bed; more frequent monitoring may be required during periods of illness. Targets are as follows:  On waking: 5–7 mmol/L   Other times of the day including before meals: 4–7 mmol/L  Bedtime: this target should be personalised and depends on the timing of the last meal On an annual basis (more frequently if required), patients should receive a diabetic review. This includes assessment of injection site problems, retinopathy, nephropathy, diabetic foot problems (e.g. neuropathic problems), cardiovascular risk factors and thyroid disease. o Retinopathy: annual screening o Nephropathy: renal function (eGFR) and albumin:creatinine ratio (ACR) o Diabetic foot problems: full examination including footwear, monofilament assessment of neuropathy, vascular assessment +/- dopplers. o Cardiovascular risk factors: primary/secondary prevention strategy with optimisation of blood pressure, lipids, weight, smoking and others o Thyroid disease: screening blood test  Complications o DKA o Hypoglycaemia - complication of insulin treatment, especially insulin doses without a meal. o Diabetic kidney disease - involves glomerular mesangial sclerosis leading to proteinuria and progressive decline in glomerular filtration. o Retinopathy o Peripheral or autonomic neuropathy o Cardiovascular disease - increased risk of atherosclerosis, hyaline arteriolosclerosis etc o Summary of micro- and macrovascular complications   Prognosis Overall, cardiovascular disease is the leading cause of death in these patients. With good control of blood glucose levels, the risk of complications can be reduced. Life-expectancy is reduced by 13 years but this is dependent on glucose control.  Other notes o Latent autoimmune diabetes in adults (LADA)  A ‘slow burning’ variant with slower progression to insulin deficiency occurs in later life  May be difficult to differentiate from type 2 diabetes (which also presents in later life) - clinical clues include; leaner build, rapid progression to insulin therapy following an initial response to other therapies and the presence of circulating islet autoantibodies o Insulin 3 main types: Short acting soluble insulins -  Start working within 30-60 minutes and last for 4-6 hours  Given 15-30 minutes before meals in patients on multiple dose regimens and by continuous IV infusion in labour, during medical emergencies, at the time of surgery and in patients using insulin pumps Short acting insulin analogues -   Human insulin analogues (insulin aspart, insulin lispro, insulin glulisine) have a faster onset and a shorter duration than the soluble insulin but overall DO NOT IMPROVE DIABETIC CONTROL  Have a reduced carry-over effect compared to soluble insulin and are used with the evening meal in patients who are prone to nocturnal hypoglycaemia Longer acting insulin -  Insulin premixed with retarding agents (either protamine or zinc) precipitate crystals  Can be intermediate (12-24 hrs) or long-acting (more than 24hrs) Type 2  Definition Type 2 diabetes mellitus (T2DM) is characterised by insulin resistance and less severe insulin deficiency.  Epidemiology o Common in all populations enjoying an affluent lifestyle - has increased in incidence due to the ageing population and increasing obesity in the Western world o Older - usually >30 yrs of age - but teenagers are starting to get it o Often overweight around the abdomen o More prevalent in South Asian, African and Caribbean ancestry o Middle eastern and Hispanic Americans also more at risk o M>F  Aetiology o Decreased insulin secretion +/- increased insulin resistance o Associated with obesity, lack of exercise, calorie and alcohol excess o No immune disturbance o No HLA disturbance but there is a stronger genetic link o Polygenic disorder  Risk Factors o Family history - genetics. 75% risk if both parents have T2DM o Increasing age o Obesity and poor exercise - can trigger DMT2 in genetically susceptible individuals o Ethnicity - Middle Eastern, South-east Asian and Western pacific  o Obesity o Hypertension o Dyslipidemia - especially with low high-density lipoprotein (HDL) and/or high triglycerides o Gestational Diabetes o Polycystic ovary syndrome o Drugs: corticosteroids, thiazide diuretics  Pathophysiology o Type 2 diabetes is associated with central obesity, hypertension, hypertriglyceridaemia, decreased high-density lipoprotein (HDL) cholesterol, disturbed homeostatic variables and modest increases in a number of pro- inflammatory markers o Insulin binds normally to its receptor on the surface of cells in DMT2 just like in healthy people - thus insulin resistance develops post-receptor i.e. not caused by a problem with insulin binding to receptor o Circulating insulin levels are typically higher than in non-diabetics following diagnosis and tend to rise further, only to decline again after months or years due to eventual secretory failure - phenomenon is known as the Starling curve of the pancreas.  Initial compensatory mechanism is hyperplasia and hypertrophy of beta cells to secrete more insulin. This is then exhausted and leads to hypoplasia and hypotrophy. o At the time of diagnosis the Beta cell mass is reduced to about 50% of normal o Almost all patient show amyloid deposition in the islets of the pancreas at autopsy derived from a peptide known as amyloid or islet amyloid polypeptide which is co-secreted with insulin by beta cells. When beta cells hypertrophy and undergo hyperplasia to release more insulin as a compensatory mechanism, they also secrete more amylin. o Abnormalities of insulin secretion manifest early in the course of DMT2 o An early sign is loss of the first phase of the normal biphasic response to insulin o Circulating insulin levels are higher than in healthy controls - but are still inadequate to restore glucose homeostasis o Hyperglycaemia and lipid excess are toxic to beta cells (glucotoxicity) and this is thought to result in further beta cell loss and further deterioration or glucose homeostasis o Don’t tend to develop diabetic ketoacidosis as even a small amount of insulin can halt the breakdown of fat & muscle into ketones  Clinical manifestations o Key Presentations Pt generally overweight compared to pt's with T1DM o Signs  Acanthosis nigricans - characterised by blackish pigmentation at the nape of the neck and in the axillae  Glove and stocking sensory loss  Reduced visual acuity  Diabetic retinopathy  Diabetic foot disease  Reduced peripheral pulses  Calluses  Ulceration  Charcot joint o Symptoms  Weight loss  Polyuria  Polydypsia  Lethargy  Recurrent infections  Evidence of complications e.g. blurred vision or paresthesia  Investigations o 1st line Primary investigations:  Random blood glucose: taken at any time of day and ≥11mmol/L is diagnostic  Fasting blood glucose: ≥7.0 mmol/L  For both tests one abnormal value is DIAGNOSTIC in symptomatic individuals  Two abnormal values are required in asymptomatic individuals For borderline cases  Oral glucose tolerance test: >11mmol/L two hours after a 75g oral glucose load. 7.8-11mmol/L suggests pre-diabetes.  HbA1C: measures amount of glycated hemoglobin. ≥48 mmol/mol suggests hyperglycaemia over the preceding 3 months o Other   Fasting lipids: patients with diabetes often have dyslipidaemia  U&Es: reduced eGFR may be seen due to diabetic nephropathy  Urine albumin:creatinine ratio: diabetic nephropathy leads to protein leaking through the glomerular basement membrane o Diagnostic Criteria Diagnosing T2DM requires an elevated plasma glucose sample and/or HbA1c on one occasion if symptomatic or two occasions if asymptomatic**.** The WHO diagnostic criteria also contain a pre-diabetic phase which comprises impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Both of these confer an increased risk of developing diabetes mellitus.  Patients with IFG: raised fasting glucose and normal OGTT  Patients with IGT: raised OGTT, and may or may not have a raised fasting glucose  Differential diagnosis o Pre-diabetes o T1DM o LADA - can be mistaken due to late onset o Monogenic diabetes - MODY o Ketosis-prone diabetes - idiopathic diabetes. Unprovoked ketosis or ketoacidosis. Some patients may have type 2 presentation. o Gestational diabetes  Management o 1st line Lifestyle: Target HbA1c with lifestyle management is 48 mmol/mol (6.5%). Metformin should be commenced if HbA1c rises above this.  High fibre, low glycaemic index sources of carbohydrates  Include low-fat dairy products and oily fish  Control intake of trans and saturated fats, and limit sucrose-containing foods  Discourage the use of foods marketed specifically for people with diabetes  Aim for an initial weight loss of 5-10% Anti-diabetic medications: There are a number of choices with metformin used first line.   Metformin  First-line agent and target HbA1c with metformin is 48 mmol/mol (6.5%). If level rises above this, the dose should be increased  Dual therapy (with a second anti-diabetic drug) should be commenced if HbA1C rises above 58 mmol/mol (7.5%) despite maximal dose (1g BD)  If not tolerated, monotherapy with an alternative anti-diabetic should be used and then further anti-diabetic agents added in as the HbA1c rises above 58mmol/mol (7.5%) o Adjuncts/ other Triple therapy and insulin:  If the HbA1C is >58 mmol/mol (7.5%) despite dual therapy, either triple therapy can be commenced, or insulin treatment can be considered  If triple therapy fails, metformin with a sulfonylurea and GLP-1 mimetic may be used if any of the following apply:  BMI ≥ 35 kg/m2 and specific psychological or other medical problems associated with obesity  BMI < 35 kg/m2 for whom insulin therapy would have significant occupational implications  BMI < 35 kg/m2 and weight loss would benefit other significant obesity-related comorbidities  NICE suggest commencing an intermediate-acting insulin with metformin, with the need for all other anti-diabetic agents to be reviewed. A long-acting insulin may be used as an alternative. Controlling other factors:  Ramipril for BP control  Statins for hyperlipidaemia control  Orlistat - to promote weight loss in pt's who are obese o Summary of treatment  o Complication of treatment  Hypoglycaemia - due to insulin or antidiabetic drugs such as sulfonylurea  Injection site - lipohypertrophy  Side effects of metformin: anorexia, diarrhoea, nausea, abdominal pain o Examples of anti-diabetics  Metformin  Reduces rate of gluconeogenesis in the liver  Increases cells sensitivity to insulin  Helps with weight issues  Reduces CVS risk in diabetes  Sulfonylureas  Promotes insulin secretion  These are ineffective in patients without a functional beta-cell mass  Avoided in pregnancy  Effect wears off as beta-cell mass declines  Dipeptidyl peptidase-4 inhibitor (DPP-4i)  Pioglitazone  Sodium–glucose cotransporter 2 inhibitor (SGLT-2i)  Monitoring  o HbA1c: measure every 3-6 months until the HbA1c is stable on unchanging therapy, after which it can be measured 6 monthly. The targets are dependent on the treatment and summarised below, however, NICE states that these can be tailored on a case by case basis o Self-monitoring: not routine and only indicated in the following circumstances:  On insulin therapy  Evidence of hypoglycaemic episodes  At risk of hypoglycaemia whilst operating machinery or driving  Pregnant or planning pregnancy  Complications   Prognosis Survival depends on glucose control and management of cardiovascular risk factors. Adults with type 2 diabetes are twice as likely to die of stroke or myocardial infarction compared to those without diabetes.