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Related Subjects: Type 1 DM |Introduction to Type 2 Diabetes |Management of Type 2 Diabetes |Diabetes in Pregnancy |HbA1c |Diabetic Ketoacidosis (DKA) Adults |Hyperglycaemic Hyperosmolar State (HHS) |Diabetic Nephropathy |Diabetic Retinopathy |Diabetic Neuropathy |Diabetic Amyotrophy |Maturity Onset Diabetes of the Young (MODY) |Diabetes: Complications

Insulin resistance means that higher doses need to be given for the same physiological activity.

International definitions

• Normal Fasting sugar < 6.1 mmol [110 mg/dl] and 2 hr < 7.8 mmol/l [140 mg/dl]
• Diabetes: Fasting Blood sugar > 7.0 mmol [126 mg/dl]
• Impaired Glucose tolerance OGTT 2 hr Glucose > 7.8-11 mmol/l [140-199 mg/dl]
• Diabetes : Random > 11.1 mmol/l [200 mg/dl] + symptoms (if not repeat another day)

About

• Chronic disease featured by hyperglycaemia
• Mixed Insulin deficiency and Insulin resistance
• Long term vascular risks.
• A minority will need Insulin.
• Do not develop significant ketosis except in rare cases

Aetiology

• Strong polygenic factors with 90% concordance in identical twins
• Usually homeostasis keeps the blood glucose between 3.5-8.0 mmol/L
• There is partial beta-cell loss in the Islets of Langerhans
• Increased Insulin resistance
• Islet cell amyloid at postmortem rather than beta cell destruction

Criteria for Diagnosis

• Symptomatic patient with one Fasting plasma glucose >= 7.0 mmol/L
• Fasting plasma glucose >= 7.0 mmol/L
• Random plasma glucose >= 11.1 mmol/L
• If there are no symptoms then you need two separate readings on different days

Physiology

• The liver is the key organ in glucose management
• Converts glucose to glycogen and stores it or then releases it
• Liver also produces Glucose from metabolic intermediates
• Insulin allows glucose to enter fat cells and muscle

Secondary causes

• Endocrine - Acromegaly, Cushing's syndrome, Taking steroids
• Pancreatic destruction - Chronic Pancreatitis, Cystic fibrosis, Haemochromatosis, Pancreatic cancer (Rare), Fibrocalculous pancreatopathy seen in tropical countries "Malnutrition related diabetes"
• Genetic - Insulin resistance (defects Insulin receptor or Insulin actions) e.g. Type A Insulin resistance - Young Women Acanthosis nigricans and Acromegalic features seen but not obese. Type B Insulin resistance - autoantibodies to Insulin receptor.

Clinical

• Polyuria, Polydipsia but weight loss less common
• Hyperglycaemia often picked up on urinalysis or blood test
• Eye problems
• Stroke, Myocardial infarction/IHD, Peripheral vascular disease
• Impotence, Foot ulcers, Obesity
• Candida Balanitis, Vulvitis

Investigations

• FBC, U&E, Creatinine clearance, urinalysis for proteinuria
• Blood glucose elevated (plasma and capillary levels are lower and whole blood higher)
• Lipids
• HbA1C Aim to maintain HbA1C less than 7%. After an alteration in therapy one should wait 2 months before repeating the Hba1c which is half the half-life of a red cell which is 120 days.

Management

• Weight loss, dietary advice, risk factor assessment, smoking cessation, exercise
• One should aim for a systolic BP < 135 mmHg. The importance of good BP control is possibly more important than glycaemic control in terms of later complications. ACE inhibitors or AT2 blockers are the drugs of choice
• Glycaemic control is important using the HbA1c as a marker of glycaemic control. One should wait 2 months before checking Hba1c to reevaluate new therapy. Oral agents are described below. In those where oral agents do not suffice Insulin may be added. Longer-acting once-daily doses are increasingly being used.
• Patients are commenced on Insulin if diet and oral drug measures are failing to control blood glucose and provide a satisfactory HbA1C
• Aspirin 75 mg od
• Statin e.g. Simvastatin
• Blood pressure control - ACE Inhibitor or ATII inhibitor
• Smoking cessation

Improving glycaemic control Oral agents

• Lifestyle modifications, Diet, weight control, exercise
• Monotherapy: Start with standard release metformin
• HbA1C > 58mmol/mol, consider 2 agents : Metformin plus
  • DPP4 inhibitor (eg sitagliptin)
  • Pioglitazone
  • Sulphonylurea (SU)
  • SGLT-2i (glifazon)
• If still HbA1C > 58mmol/mol, consider 3 agents Metformin plus
  • DPP4 inhibitor (e.g. sitagliptin) + Sulphonylurea
  • Pioglitazone + Sulphonylurea
  • Sulphonylurea OR Pioglitazone + SGLT-2i (glifazon)
  • Insulin therapy

Hypoglycaemia seen with Insulin, Sulphonylureas and Glitazones

Notes on Oral agents

• Metformin 500 mg - 1 g bd: Increases sensitivity to Insulin. It reduces hepatic gluconeogenesis and reduces Insulin resistance. It is useful in the obese as it contributes to weight loss. Usually stopped when creatinine over 150
• Sulphonylureas (Secretagogues) stimulate Insulin release by closing ATP-sensitive potassium channels. This leads to Calcium influx which stimulates Insulin release. They can cause weight gain and hypoglycaemia. They are also heavily protein-bound with interactions. Most nowadays use short-acting agents such as Gliclazide 40 mg OD and up titrating. They require the presence of some pancreatic Insulin excretion. Can increase weight.
• Glitazones: increase sensitivity to Insulin by interaction with peroxisome proliferators activated receptor gamma (PPAR-gamma). Hypoglycaemia. They cause fluid retention and weight gain and anaemia. Do not use if CCF.
• Meglitinides act in a similar way to Sulphonylureas as described above. They too cause closure of ATP-sensitive K channels and increase Insulin release.
• Alpha-glucosidase inhibitors such as Acarbose cause carbohydrate malabsorption which leads to bloating, flatulence and diarrhoea and are rarely used nowadays.
• Lipase inhibitors such as Orlistat cause fat malabsorption and can aid weight loss but with similar side effects
• Gliptins (DPP4 inhibitors) e.g. Sitgliptin inhibits the breakdown of Glucagon-like peptide-1 (GLP-1). They produce moderate falls in HbA1c and are weight neutral. GLP-1 analogues mimic the action of natural GLP-1 and reduce appetite at a brain level, delay gastric emptying and synchronise Insulin release with meals. They cause weight loss and significant falls in HbA1c
• SGLT-2 Inhibitors: These oral drugs block renal glucose reabsorption resulting in ~ 600Kcal extra glucose being excreted daily. They produce significant falls in HbA1c and weight.

Management in the Elderly

• Focus is to maintain quality of life and minimise the risks associated with achieving stringent glycaemic targets, e.g. hypoglycaemia, while also avoiding the symptoms and adverse consequences of hyperglycaemia
• The benefits of intensive glycaemic control for the prevention of microvascular complications are less clear as a person’s health status becomes more complex and their life expectancy is reduced
• Most randomised clinical trials including middle-aged and older people with longstanding type 2 diabetes have not shown any benefit of intensive glycaemic control for the prevention of CVD-related or all-cause mortality
• Less stringent HbA1c targets, e.g. 58–64 mmol/mol or higher, are recommended for older people with diabetes; higher targets, e.g. 70 mmol/mol, are likely to be appropriate for those with very poor health, e.g. due to co-morbidities or frailty, those who have limited life expectancy or experience severe or recurrent hypoglycaemia
• Continue to recommend lifestyle interventions, i.e. diet and exercise, to help manage diabetes in all patients, particularly those who are overweight, but goals should be tailored to the individual’s physical capabilities and fitness level

NICE and other Algorithm

References

• NICE guidance on T2DM