Diabetes mellitus: pathophysiology and management

How the body controls blood sugar, why it fails in the different types of diabetes, how diabetes is diagnosed and how treatment is built up step by step.

Updated Nov 12, 2026

Diabetes is a group of diseases in which blood glucose stays too high because insulin is missing, works poorly, or both. This page links the physiology of the islets to diagnosis, complications, emergencies and the logic of combining drugs in type 2 diabetes. The individual drugs have their own class pages.

Key points

Beta cells release insulin when glucose enters them and raises ATP, closing K-ATP channels; glucagon from alpha cells does the opposite.
Type 1 diabetes is autoimmune destruction of beta cells and needs insulin for survival; type 2 combines insulin resistance with progressive beta-cell failure.
Diagnosis rests on HbA1c, fasting glucose, an oral glucose tolerance test or a random glucose with symptoms; an HbA1c of 6.5% or more is in the diabetes range.
Chronic high glucose damages small vessels (eye, kidney, nerve) and large vessels (heart attack, stroke).
In type 2 diabetes, metformin plus lifestyle is the usual start; further drugs are chosen by comorbidity, hypoglycaemia risk, weight, cost and the HbA1c goal.
Ketoacidosis and the hyperosmolar state are emergencies treated in hospital with fluids, insulin and close electrolyte control.

Glucose homeostasis and the islet

Between meals the liver keeps glucose up by releasing stored glycogen and making new glucose; after a meal insulin switches the body to storage. In the beta cell, glucose enters, is metabolised, and the rise in ATP closes ATP-sensitive potassium channels. The membrane depolarises, calcium enters and insulin granules are released. Gut hormones (the incretins GLP-1 and GIP) amplify this response after food. Alpha cells secrete glucagon, which raises glucose; in diabetes glucagon is often inappropriately high.

Insulin: promotes glucose uptake into muscle and fat, glycogen storage and fat storage; suppresses hepatic glucose output and ketone production.
Sulfonylureas close the K-ATP channel directly; incretin drugs amplify glucose-dependent secretion.

Diagnosis and screening

The same tests define diabetes and prediabetes. An HbA1c from 5.7% to 6.4% is the prediabetes range and 6.5% or above the diabetes range; fasting plasma glucose and a 2-hour oral glucose tolerance test have their own cut-offs, and a random glucose counts only with typical symptoms. A second test usually confirms the result. Screening targets adults with risk factors, including overweight, a family history, previous gestational diabetes and Hispanic/Latino ancestry, which matters for Latin American populations. Pregnancy uses different criteria.

Pathogenesis of the main types

Type 1: autoimmune destruction of beta cells; autoantibodies can appear years before glucose rises. Insulin is essential for life.
Type 2: by far the most common type. Insulin resistance (linked to excess weight, inactivity and genes) is first compensated by more insulin; when beta cells fail to keep up, glucose rises.
Monogenic diabetes (MODY): autosomal dominant, single-gene defects in beta-cell transcription factors or in glucokinase, the glucose sensor; onset is usually in youth and it is often mistaken for type 1 or 2.
Gestational diabetes and secondary forms (pancreatic disease, drugs such as glucocorticoids) complete the list.

Complications

Long-standing hyperglycaemia damages small vessels and nerves: retinopathy can cause blindness, nephropathy can progress to kidney failure, and neuropathy with poor circulation leads to foot ulcers and amputation. Large-vessel disease raises the risk of heart attack and stroke. Regular eye, kidney (urine albumin and filtration) and foot checks, blood-pressure control and statins are part of standard care.

Goals and non-drug measures

Targets are individualised: tighter where hypoglycaemia risk is low and life expectancy long, looser in frail older people or after severe hypoglycaemia. A healthy weight, regular physical activity, a diet low in added sugar and saturated fat, and not smoking are treatments in their own right and also prevent type 2 diabetes in people with prediabetes.

Building drug therapy in type 2 diabetes

Metformin is the consensus first drug and is started at diagnosis together with education on diet and activity. When the goal is not reached, a second or third agent is added; there is no single preferred order, and the choice weighs comorbidities, side effects, cost and the HbA1c goal. In people with atherosclerotic cardiovascular disease, heart failure or chronic kidney disease, SGLT2 inhibitors and GLP-1 receptor agonists are favoured because some members reduce cardiovascular events, heart-failure admissions or kidney decline, beyond lowering glucose. Insulin is added when other drugs are not enough, and is often needed in pregnancy and in hospital.

Low hypoglycaemia risk: metformin, SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, pioglitazone.
Higher hypoglycaemia risk: sulfonylureas and insulin.
Weight loss: GLP-1 receptor agonists and SGLT2 inhibitors; weight gain: sulfonylureas, pioglitazone, insulin.

Hospital care: DKA and the hyperosmolar state

In diabetic ketoacidosis insulin is so low that fat breakdown floods the blood with ketones and acid; it typically affects type 1 diabetes, can be its first sign, and is triggered by infection, missed insulin or surgery. The hyperosmolar hyperglycaemic state affects mainly older people with type 2 diabetes: glucose climbs very high, osmotic diuresis causes severe dehydration and confusion, with little ketosis. Both are treated with intravenous fluids, intravenous insulin, careful potassium replacement and a search for the trigger. SGLT2 inhibitors can cause ketoacidosis with near-normal glucose, especially during acute illness.

Test yourself

Think of the answer, then tap the question to see it.

Which HbA1c ranges define prediabetes and diabetes?

An HbA1c from 5.7% to 6.4% is the prediabetes range; 6.5% or more is in the diabetes range, usually confirmed with a second test.

How does glucose trigger insulin release from the beta cell?

Glucose metabolism raises ATP, which closes K-ATP channels; the cell depolarises, calcium enters and insulin granules are released.

Why are SGLT2 inhibitors or GLP-1 receptor agonists favoured in type 2 diabetes with heart or kidney disease?

Because members of these classes reduce cardiovascular events, heart-failure admissions or kidney decline, an effect beyond glucose lowering.

What distinguishes the hyperosmolar hyperglycaemic state from diabetic ketoacidosis?

It occurs mostly in older people with type 2 diabetes, with extreme glucose and dehydration but little ketosis; DKA is driven by ketone acid build-up.

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Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: Diabetes Tests & Diagnosis (National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 2026); Diabetes (World Health Organization, 2026); Diabetic ketoacidosis: MedlinePlus Medical Encyclopedia (MedlinePlus (U.S. National Library of Medicine), 2026).

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