Medicine chapters
Diabetes mellitus: diagnosis, types and treatment (oral agents, insulins, glucose monitoring incl. CGMS)
How diabetes is diagnosed, how to tell the types apart, and how the oral drugs, injectable agents and insulins are used, with home glucose testing, HbA1c and continuous glucose monitoring.
- Diabetes is diagnosed by fasting glucose ≥7.0 mmol/L, random or 2-hour OGTT glucose ≥11.1 mmol/L, or HbA1c ≥48 mmol/mol (6.5%); one result with symptoms, two without.
- Metformin is the first drug for type 2 diabetes; SGLT2 inhibitors or GLP-1 agonists are added early when there is heart, kidney or atherosclerotic disease.
- Type 1 diabetes needs basal–bolus insulin; CGM reads interstitial glucose with a 15–20 minute lag and helps people with troublesome hypoglycaemia.
On this page
Overview
Diabetes mellitus is a state of chronic hyperglycaemia caused by too little insulin, poor insulin action, or both. It is very common in Pakistan and often found by chance on a routine test. Making the diagnosis correctly, choosing the right drug for the right patient and checking control are core house-job skills and a steady source of PGET MCQs.
Diagnostic criteria
The WHO criteria use venous plasma glucose or HbA1c.
| Test | Diabetes (mmol/L; mg/dL) | Pre-diabetes range (mmol/L) | Normal (mmol/L) |
|---|---|---|---|
| Fasting | ≥7.0; ≥126 | Impaired fasting glycaemia (IFG): 6.1–6.9 | Below 6.1 |
| 2 hours after 75 g OGTT | ≥11.1; ≥200 | Impaired glucose tolerance (IGT): 7.8–11.0 | Below 7.8 |
| Random | ≥11.1; ≥200 | – | – |
| HbA1c | ≥48 mmol/mol (6.5%) | – | – |
- With classic symptoms (thirst, polyuria, weight loss): one abnormal result is enough.
- Without symptoms: you need two abnormal results (the same test repeated or two different tests).
- The OGTT uses 75 g glucose in water for adults (1.75 g/kg for children) with a fasting and a 2-hour sample. It is needed mainly when the result is borderline, and for gestational diabetes and cystic fibrosis-related diabetes.
- The American (ADA) threshold for IFG is lower, at 5.6 mmol/L (100 mg/dL).
- IFG and IGT mark people at high risk of diabetes and heart disease. People with IGT carry a heart risk close to that of frank diabetes but do not get microvascular disease.
Glycosuria cannot diagnose diabetes. The renal threshold varies (lower in pregnancy and familial renal glycosuria, higher in older people). Always confirm with blood.
A random glucose of 12 mmol/L in a patient without symptoms is not yet diabetes. Repeat a test (fasting glucose or HbA1c) before labelling.
When HbA1c misleads
HbA1c reflects the glucose exposure of red cells over roughly the previous 2–3 months, so anything that changes red cell lifespan changes the result.
| Falsely low HbA1c | Falsely high HbA1c |
|---|---|
| Haemolysis, recent blood loss or transfusion | Iron deficiency (older red cells) |
| Pregnancy | Some haemoglobin variants and assays |
| Some haemoglobin variants (e.g. HbS, high HbF) | Renal failure (assay-dependent) |
In these cases use plasma glucose, or fructosamine (glycated albumin), which reflects about the last 2–3 weeks.
Types of diabetes
| Feature | Type 1 | Type 2 |
|---|---|---|
| Cause | Autoimmune destruction of β cells | Insulin resistance plus failing β-cell secretion |
| Usual age | Children and young adults (any age) | Adults; now also obese young people |
| Body build | Often thin, weight loss | Usually overweight |
| Ketosis | Prone to DKA | Rare; HHS is the typical emergency |
| Antibodies | GAD, IA-2, insulin, ZnT8 | Absent |
| HLA | DR3 and/or DR4 in most | No link |
| C-peptide | Falls and disappears with time | Persists |
| Treatment | Insulin from diagnosis | Lifestyle, tablets, later injectables or insulin |
Other types to know
- LADA (latent autoimmune diabetes in adults): adults who look like type 2 but have islet antibodies and drift to insulin within a few years.
- Monogenic diabetes (MODY): autosomal dominant, diagnosed young, with a strong family history over generations. HNF-1α is the commonest form and responds very well to low-dose sulphonylurea. Glucokinase (GCK) MODY causes mild, stable fasting hyperglycaemia from birth and usually needs no treatment.
- Neonatal diabetes: diabetes before 6 months of age is almost never type 1. Mutations of KCNJ11 (Kir6.2 subunit of the K-ATP channel) keep the channel open; these babies can switch from insulin to sulphonylurea tablets.
- Secondary diabetes: pancreatic disease (chronic pancreatitis, pancreatectomy, haemochromatosis, cystic fibrosis, pancreatic cancer); hormone excess (Cushing syndrome, acromegaly, phaeochromocytoma, glucagonoma, thyrotoxicosis); drugs (glucocorticoids, thiazides, some antipsychotics).
- Wolfram (DIDMOAD) syndrome: optic atrophy and deafness together with both diabetes insipidus and diabetes mellitus.
- Gestational diabetes: see the chapter on complications and pregnancy.
C-peptide is made in equal amounts with insulin. Low C-peptide = the patient makes little insulin (type 1, or injected insulin). It is most useful when diabetes has lasted more than 5 years.
First steps in management
- Diet: regular meals, fewer refined sugars and saturated fats, more fibre; calorie reduction if overweight. Weight loss can put early type 2 diabetes into remission.
- Exercise improves insulin sensitivity. Muscle contraction moves GLUT4 transporters to the cell surface, so exercise can cause late hypoglycaemia in insulin users.
- Stop smoking; treat blood pressure and lipids (most adults with diabetes need a statin).
- Bariatric (metabolic) surgery can be offered to people with obesity and type 2 diabetes when other measures fail.
Glycaemic targets
- Most guidelines aim for an HbA1c of 48–58 mmol/mol (6.5–7.5%), set for each person.
- A common practical rule: about 48 mmol/mol (6.5%) if on lifestyle or metformin alone; about 53 mmol/mol (7%) if on drugs that can cause hypoglycaemia.
- Relax targets in the frail elderly, people with severe hypoglycaemia, short life expectancy or heavy co-morbidity.
Very tight control in long-standing type 2 diabetes with heart disease did not lower deaths in large studies and increased hypoglycaemia. Tight control mainly protects the small vessels (eyes, kidneys, nerves).
Oral and non-insulin drugs
| Drug class (examples) | How it works | Main advantages | Key side effects and cautions |
|---|---|---|---|
| Biguanide: metformin | Cuts hepatic gluconeogenesis (via AMPK); improves insulin sensitivity | First line; no weight gain, no hypoglycaemia alone; cheap; heart benefit in UKPDS | GI upset (10–20%), lactic acidosis, low B12; avoid in significant renal, liver or heart failure |
| Sulphonylureas (gliclazide, glimepiride, glibenclamide) | Bind the SUR receptor and close K-ATP channels in β cells → insulin release | Powerful, cheap | Hypoglycaemia (worst with long-acting glibenclamide, elderly, renal failure); weight gain 1–4 kg; no effect in type 1 |
| Meglitinides (repaglinide, nateglinide) | Same channel, short action | Taken with meals | Hypoglycaemia |
| Thiazolidinedione (pioglitazone) | PPAR-γ agonist; insulin sensitiser | No hypoglycaemia alone | Weight gain, fluid retention and heart failure, fractures |
| DPP-4 inhibitors (sitagliptin, linagliptin, vildagliptin) | Stop breakdown of GLP-1 and GIP | Weight neutral; no hypoglycaemia alone | Pancreatitis; saxagliptin linked to heart failure; linagliptin needs no renal dose change |
| SGLT2 inhibitors (empagliflozin, dapagliflozin) | Block glucose reabsorption in the proximal tubule → glycosuria | Weight loss 2–4 kg; protect heart and kidneys; lower BP | Genital candidiasis, dehydration, euglycaemic DKA, Fournier gangrene |
| GLP-1 receptor agonists (liraglutide, semaglutide, dulaglutide, exenatide) | Glucose-dependent insulin release, less glucagon, slower gastric emptying, less appetite | Weight loss; cardiovascular benefit | Nausea, vomiting, pancreatitis; mostly injected |
| α-glucosidase inhibitor (acarbose) | Slows carbohydrate digestion in the gut | Lowers post-meal glucose | Flatulence, bloating, diarrhoea |
Metformin in more detail
- Lowers fasting glucose by about 2–4 mmol/L and HbA1c by about 1–2%.
- Do not start if eGFR is below 45; stop if eGFR falls below 30 mL/min/1.73 m².
- Withhold before iodinated contrast; restart after 48 hours if kidney function is stable. Also hold it around surgery and acute illness (dehydration, sepsis, shock).
- Avoid in alcohol misuse. Check B12 in long-term users with neuropathy or macrocytosis.
Choosing the add-on drug in type 2 diabetes
- Metformin plus lifestyle for almost everyone.
- If there is established atherosclerotic disease, add an SGLT2 inhibitor or GLP-1 agonist with proven benefit.
- If there is heart failure or chronic kidney disease, an SGLT2 inhibitor is the drug of choice.
- If weight loss is the priority: GLP-1 agonist or SGLT2 inhibitor. If hypoglycaemia must be avoided: DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 agonist or pioglitazone.
- If cost is the main issue (common in Pakistan): a sulphonylurea or pioglitazone.
- Add basal insulin when HbA1c stays high despite tablets, or at once if the patient is very symptomatic, losing weight or ketotic.
Glucose-lowering drugs that do not cause hypoglycaemia on their own: metformin, pioglitazone, DPP-4 inhibitors, SGLT2 inhibitors, GLP-1 agonists, acarbose. Those that do: sulphonylureas, meglitinides and insulin.
In a patient on an SGLT2 inhibitor who is unwell, vomiting and acidotic, normal glucose does not exclude DKA. Check ketones.
Insulin
Types of insulin
| Type | Examples | Onset and pattern | Use |
|---|---|---|---|
| Rapid-acting analogue | Lispro, aspart, glulisine | Minutes; short action | Inject just before meals (bolus); pumps |
| Short-acting (soluble, regular) | Human soluble insulin | About 30 minutes; lasts longer | Inject 20–30 min before meals; IV infusions |
| Intermediate (isophane/NPH) | NPH insulin | Peak in the middle of the night if given at bedtime | Basal, cheap; must be re-suspended |
| Long-acting analogue | Glargine (precipitates at tissue pH), detemir, degludec (longest) | Flat profile, about 24 h or more | Basal once daily; less night-time hypoglycaemia |
| Premixed (biphasic) | e.g. 30% soluble with 70% NPH; analogue mixes | Two peaks | Twice daily before breakfast and evening meal |
- Standard strength is 100 units/mL; concentrated forms (e.g. glargine U300) must never be drawn from a pen into a syringe (overdose risk).
- Only soluble insulin (or a rapid analogue) is given intravenously.
Regimens
- Basal–bolus (multiple daily injections): long-acting basal once or twice daily plus rapid-acting insulin with each meal, matched to carbohydrate. Standard for type 1 diabetes.
- Twice-daily premixed: simpler; needs regular meals; common in type 2 diabetes.
- Basal insulin alone (often bedtime NPH or glargine) added to tablets in type 2 diabetes.
- Continuous subcutaneous insulin infusion (pump): rapid analogue delivered continuously; some pumps link to CGM and pause insulin when glucose is falling. Risk of rapid DKA if the line fails, because there is no depot of long-acting insulin.
Problems with insulin
- Hypoglycaemia (the main limit to tight control).
- Weight gain.
- Lipohypertrophy at overused sites, giving erratic absorption: rotate sites.
Morning hyperglycaemia: dawn versus Somogyi
| Pattern | What happens | 3 am glucose | Fix |
|---|---|---|---|
| Dawn phenomenon | Early-morning rise in GH and cortisol raises glucose | High or normal | Increase or move the evening basal insulin |
| Somogyi effect | Night-time hypoglycaemia from too much evening insulin, then rebound | Low | Reduce the bedtime insulin |
A patient whose fasting glucose stays high after repeated increases in bedtime NPH, and who wakes sweaty with nightmares, has night hypoglycaemia. Reduce the dose; do not increase it again.
Hypoglycaemia
- Alert level: any glucose under 4 mmol/L (about 70 mg/dL) needs treatment. Under 3 mmol/L (about 54 mg/dL) is clinically significant. Severe hypoglycaemia means the patient needs another person's help.
- Symptoms: autonomic (sweating, tremor, palpitations, hunger) usually come before neuroglycopenic ones (confusion, odd behaviour, fits, coma).
- Impaired awareness: with long diabetes or frequent episodes, warning symptoms are lost. Strict avoidance of lows for some weeks helps awareness return.
- Causes: insulin error, missed meals, exercise, alcohol, lipohypertrophy, renal failure, sulphonylureas (prolonged in the elderly and in renal failure).
Treatment
- Conscious and able to swallow: 15–20 g fast-acting glucose (glucose tablets, sugary drink). Recheck after 15 minutes; repeat if still below 4.0 mmol/L. Then give a longer-acting carbohydrate.
- Unconscious or unable to swallow: IM glucagon 1 mg (works by releasing liver glycogen; poor effect after a long fast or in alcohol excess) or IV glucose (e.g. 10% or 20% dextrose).
- Sulphonylurea overdose can cause hypoglycaemia lasting a day or more: admit and give a continuous glucose infusion.
"15-15 rule": 15 g sugar, check again in 15 minutes.
Glucose monitoring
- Capillary (finger-prick) testing: essential for insulin users, especially type 1, to adjust doses and confirm lows; of little use on metformin alone unless the result changes action.
- HbA1c every 3–6 months for long-term control; fructosamine for the last few weeks.
Continuous glucose monitoring (CGMS)
- A small sensor under the skin measures interstitial fluid glucose every few minutes. A transmitter sends readings to a reader or phone. Sensors last up to about 14 days.
- Real-time CGM: shows the current value and trend arrows, with alarms for high and low glucose; can link to pumps.
- Retrospective (professional or blinded) CGM: data are downloaded later to look for patterns, such as unrecognised night lows.
- Intermittently scanned (flash) monitoring: the user scans the sensor to see the reading.
- Main limitation: a lag of about 15–20 minutes behind blood glucose. If symptoms suggest a low but CGM looks normal, check a finger-prick glucose.
- Who benefits: type 1 diabetes with recurrent severe or unrecognised hypoglycaemia, fear of hypoglycaemia, or persistently high glucose despite frequent testing; also pregnancy with type 1 diabetes.
- CGM gives time in range (commonly 3.9–10 mmol/L), with a usual aim of more than 70% of the day in range.
CGM lowers HbA1c and reduces glucose swings and hypoglycaemia in type 1 diabetes.
IFCC (mmol/mol) = (DCCT % − 2.15) × 10.929
6.5% → (6.5 − 2.15) × 10.929 = 47.5 → about 48 mmol/mol (diagnostic cut-off)
7.0% → (7.0 − 2.15) × 10.929 = 53 mmol/mol
Expect: the fasting, random, OGTT and HbA1c cut-offs and when one versus two results are needed; IFG and IGT ranges; conditions that make HbA1c unreliable; features separating type 1, type 2, LADA and MODY (HNF-1α responds to sulphonylurea; KCNJ11 neonatal diabetes); mechanism and side effects of each drug class (metformin and lactic acidosis/B12, sulphonylurea hypoglycaemia, pioglitazone heart failure, SGLT2 thrush and euglycaemic DKA, GLP-1 pancreatitis); metformin eGFR limits and contrast rule; which drug to add in heart failure or CKD; insulin types and regimens; dawn versus Somogyi; hypoglycaemia treatment; and how CGM works and its lag.
Quick revision
- Diabetes: FPG ≥7.0, random or 2-h ≥11.1, HbA1c ≥48 (6.5%); two results if no symptoms.
- IFG 6.1–6.9 (WHO); IGT 2-h 7.8–11.0.
- HbA1c low in haemolysis, blood loss, pregnancy; high in iron deficiency.
- Type 1: autoimmune, C-peptide disappears, DKA-prone; MODY HNF-1α → sulphonylurea.
- Metformin first; not if eGFR <45 to start, stop <30; hold for contrast and surgery.
- SGLT2 inhibitor for heart failure or CKD; GLP-1 agonist for weight and atherosclerotic disease.
- Sulphonylureas and insulin cause hypoglycaemia; glibenclamide worst in elderly.
- Type 1: basal–bolus insulin; glargine, detemir, degludec are long-acting analogues.
- Hypoglycaemia: 15–20 g glucose, recheck in 15 min; unconscious → IM glucagon 1 mg or IV dextrose.
- CGM measures interstitial glucose with a 15–20 minute lag.
Written by The House Job from standard references (Kumar and Clark's Clinical Medicine).
FAQ
Can HbA1c alone diagnose diabetes?
Yes. An HbA1c of 48 mmol/mol (6.5%) or more diagnoses diabetes, but in a patient without symptoms it should be confirmed by a second abnormal test, and it should not be used where red cell turnover is abnormal.
Why is metformin stopped before a contrast CT?
Contrast can injure the kidneys, and if metformin then builds up it can cause lactic acidosis. It is restarted after 48 hours if kidney function has not worsened.
Which diabetes drugs protect the heart and kidneys?
SGLT2 inhibitors reduce heart failure admissions and slow kidney decline, and several GLP-1 receptor agonists reduce heart attacks and strokes in people with established vascular disease.
What is the main drawback of continuous glucose monitoring?
It measures interstitial rather than blood glucose, so it lags about 15–20 minutes behind; a finger-prick test should be done if symptoms do not match the reading.