If insulin resistance automatically caused hyperglycaemia, every person with obesity would have diabetes. This does not happen. ADA 2026 puts it firmly: the common denominator of T2DM appears to be insulin secretory deficiency and β-cell dysfunction, often against a background of resistance. The pathways to β-cell death or dysfunction are heterogeneous: genetic predisposition, epigenetic changes, inflammation, metabolic stress.
The β-cell is a pancreatic islet cell that secretes insulin. As long as it responds to resistance with greater secretion, glycaemia is held in check. When the secretory reserve falls below tissue demand, first postprandial and then fasting hyperglycaemia appears. This is not "a sudden breakdown on the day of diagnosis". ADA notes that glucose and HbA1c may rise long before clinical onset; for type 1 diabetes this has been described as a shift in fasting plasma glucose (FPG) and 2-hour plasma glucose (2-h PG) roughly 6 months before diagnosis in high-risk cohorts. For T2DM the duration of hidden hyperglycaemia is often measured in years — hence retinopathy already at the start.
The teaching morphological frame of this module is "atrophy, fibrosis and lipomatosis". In the current ADA 2026 and KDIGO 2022 recommendations and in the MoH RK 2022 protocol, these three words are not diagnostic criteria and do not change the HbA1c threshold. Their place is in understanding the substrate, not on the lab form.
In the kidney, in diabetic injury the pathologist describes thickening of the basement membranes, mesangial expansion, nodular glomerulosclerosis (Kimmelstiel–Wilson nodules), tubulointerstitial fibrosis and tubular atrophy. This is already a bridge to Module 3, where the albuminuria and GFR thresholds will appear. In adipose tissue and the liver, "lipomatosis" in the clinical sense is closer to ectopic lipid deposition that sustains resistance — again a mechanism, not a criterion. A separate diagnostic threshold of "pancreatic lipomatosis = T2DM" was not found in the course's three normative documents. If a teaching histology slide shows you fatty infiltration of the pancreas, it illustrates the metabolic background, not a substitute for plasma glucose.
What happens to secretion as the disease progresses. The early defect is the loss of the first phase of insulin secretion in response to glucose: the rapid peak flattens and postprandial glycaemia rises. Later the second phase also suffers. At the same time, glucagon secretion by α-cells may increase: the liver receives a signal to produce glucose even after a meal. The incretin response — glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) — is functionally weakened in T2DM. This is one of the reasons why GLP-1 receptor agonists work as a class at all, but the "incretin defect" itself does not prove the benefit of a specific molecule: benefit is proven by the cardiovascular and renal RCTs of Module 4.
Why this matters for differential diagnosis. In type 1 diabetes the leading mechanism is autoimmune destruction of β-cells, usually with absolute insulin deficiency. In T2DM there is often no absolute deficiency at onset: C-peptide is preserved or even elevated, and there are no autoantibodies. The MoH RK 2022 protocol summarises this in a differential diagnosis table: in type 2 — elevated immunoreactive insulin (IRI) and C-peptide, absence of antibodies to glutamic acid decarboxylase (GAD), islet tyrosine phosphatase (IA-2), islet cell cytoplasm (ICA) and zinc transporter 8 (ZnT8); in type 1 — the opposite. But ADA 2026 warns: an adult with new diabetes and a BMI of 27 kg/m² may still have an autoimmune process. Classification at onset is sometimes wrong.
The practical conclusion. Resistance explains why the tissues need more insulin. The diagnosis appears when the β-cell stops covering that need. Treatment that only "hits the sugar" and does not take into account preserved secretion, hypoglycaemic risk and comorbidity chooses its tool blindly.