Diabetes Mellitus

Spec Mapping — OCR H420 Module 5.1.4 — Hormonal communication, content statements covering the causes of type 1 and type 2 diabetes mellitus, their treatments, the production of recombinant human insulin, and the ethical considerations of GM bacteria for therapeutic protein manufacture (refer to the official OCR H420 specification document for exact wording). Diabetes is the prime worked example for the entire hormonal-communication module — every concept (β-cell secretion, insulin action, blood-glucose homeostasis) is tested through its failure modes.

Diabetes mellitus is the commonest endocrine disorder in the world, affecting around 10% of UK adults in some form. It is a condition in which blood glucose becomes chronically elevated because insulin is either absent, deficient or ineffective. Understanding diabetes provides an excellent test of whether you have mastered the blood glucose control mechanisms covered in the previous lesson.

The historical lineage of diabetes research is rich. The ancient Egyptian Ebers Papyrus (c. 1500 BCE) describes "passing too much water"; the Greek physician Aretaeus of Cappadocia (c. 100 CE) coined the word "diabetes" (siphon) to describe the urine output. The "mellitus" (honeyed) suffix was added in the 17th century when Thomas Willis noted that diabetic urine tasted sweet. The pancreatic origin of the disease was demonstrated by Joseph von Mering and Oskar Minkowski (1889, paraphrase), who removed the pancreas from dogs and observed the development of fatal diabetes — flies were attracted to the glycosuric urine. Frederick Banting, Charles Best, James Collip, and J. J. R. Macleod (1921–22, paraphrase) isolated insulin from canine pancreatic islets and demonstrated its life-saving effect, transforming type 1 diabetes from a death sentence into a manageable chronic condition (paraphrase). Frederick Sanger (Nobel 1958, paraphrase) determined the complete amino acid sequence of bovine insulin, the first protein ever fully sequenced. Genentech (1978) produced the first recombinant human insulin (sold as Humulin from 1982) using E. coli, marking the beginning of the biotechnology industry. The recombinant-DNA revolution that diabetes care launched has gone on to give us recombinant growth hormone, erythropoietin, antibody therapeutics, and many more (paraphrase).

Key Definitions:

• Diabetes mellitus — a chronic condition characterised by hyperglycaemia due to insulin deficiency or insulin resistance.
• Type 1 diabetes — autoimmune destruction of β cells; no insulin produced.
• Type 2 diabetes — insulin resistance in target tissues, often with reduced insulin secretion.
• Hyperglycaemia — abnormally high blood glucose (>7 mmol dm⁻³ fasting or >11 mmol dm⁻³ random).
• Glycosuria — glucose in the urine; a classic sign of diabetes.

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Two Diseases with the Same Name

"Diabetes mellitus" is really an umbrella term for several conditions that all result in high blood glucose. Two are important for OCR (type 1 and type 2; gestational, MODY (maturity-onset diabetes of the young), LADA (latent autoimmune diabetes in adults), and secondary diabetes are real entities but are not required for A-Level):

Feature	Type 1	Type 2
Age of onset	Usually childhood/adolescence (but can be adult)	Usually middle age or later
Cause	Autoimmune destruction of β cells	Insulin resistance ± β cell dysfunction
Insulin production	None	Initially normal or high; later declines
Body weight	Often normal or thin	Often overweight or obese
Onset	Rapid (weeks)	Gradual (years)
% of cases	~10%	~90%
Main treatment	Insulin injections	Diet, exercise, oral medication; insulin in late stages
Ketoacidosis risk	High (classic acute presentation)	Low

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Type 1 Diabetes

Type 1 diabetes is an autoimmune disease. For reasons that are incompletely understood, the body's own immune system — T cells, especially — attacks and destroys the β cells of the pancreas, leaving the islets with α cells and δ cells but no insulin-producing cells. The loss is irreversible.

Causes

• Genetic predisposition — certain HLA (human leukocyte antigen) types increase risk.
• Environmental triggers — possibly viral infections (Coxsackie B, mumps, rubella); early cow's milk exposure has been investigated. The exact trigger is debated.
• Not caused by diet or obesity.

Symptoms

The classic "polys" develop rapidly as glucose rises:

• Polyuria — passing large volumes of urine. Glucose in the filtrate exceeds the tubular maximum for reabsorption, so it remains in the filtrate, raising its solute concentration and reducing water reabsorption by osmosis.
• Polydipsia — excessive thirst, caused by the dehydration that follows polyuria.
• Polyphagia — increased hunger, as cells are unable to take up glucose.
• Weight loss — because fat and muscle are broken down for energy as an alternative.
• Fatigue — poor glucose use.
• Ketoacidosis — without insulin, fatty acids are broken down into acidic ketone bodies, lowering blood pH. Untreated, this is fatal within days.

Treatment

Type 1 diabetes is managed with:

• Insulin injections or insulin pumps — several times a day, matched to meals and activity. Modern regimens use rapid-acting insulin analogues with meals and a long-acting basal insulin.
• Blood glucose monitoring — traditionally with finger-prick meters; increasingly with continuous glucose monitors.
• Carbohydrate counting — matching insulin doses to food intake.
• Islet cell or pancreas transplantation — for selected patients.

There is no cure, but tight control of blood glucose greatly reduces long-term complications.

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Type 2 Diabetes

Type 2 diabetes is a different disease altogether. Here, the β cells still produce insulin (at least initially) but the target tissues — liver, muscle and fat — fail to respond adequately. This is called insulin resistance. Over time, the β cells exhaust themselves trying to overcome the resistance by producing more insulin, and eventually insulin secretion falls below what the body needs.

Causes

• Obesity — especially visceral (abdominal) fat, which releases adipokines that impair insulin signalling.
• Physical inactivity — sedentary lifestyles promote insulin resistance.
• Diet — high in refined carbohydrates and sugars.
• Age — risk rises steeply after 45.
• Genetic predisposition — some populations (e.g. South Asian) are at greater risk for any given BMI.
• Pregnancy — gestational diabetes in pregnancy is often a precursor.

Symptoms

Symptoms are often milder and develop more slowly. They include:

• Polyuria, polydipsia — similar mechanism to type 1.
• Fatigue.
• Blurred vision.
• Frequent infections (e.g. thrush) because glucose in tissues promotes fungal growth.
• Slow wound healing.
• Numbness in hands and feet (neuropathy, from chronic nerve damage).

Many people have type 2 diabetes for years before diagnosis. It is often picked up incidentally on a blood test, or only after complications have developed.

Treatment

Type 2 diabetes is initially treated without insulin:

• Diet and exercise — weight loss can reverse the condition in early cases. Recent evidence shows that very low-calorie diets can achieve remission.
• Metformin — the first-line oral medication; reduces gluconeogenesis in the liver and improves insulin sensitivity.
• Other oral drugs — sulphonylureas (stimulate β cells to release more insulin), SGLT2 inhibitors (increase urinary glucose excretion), GLP-1 mimetics (slow gastric emptying and increase insulin release).
• Insulin — used in advanced cases when β cells no longer cope.

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Recombinant Human Insulin

Before the 1980s, insulin for injection was extracted from the pancreases of cattle and pigs. This bovine and porcine insulin worked but was slightly different from human insulin and caused allergic reactions in some patients. Today, virtually all insulin is recombinant human insulin — produced by genetically modified bacteria (Escherichia coli) or yeast (Saccharomyces cerevisiae).

How It Is Made

OCR expects you to describe the outline of the process:

1. Identify the human insulin gene. The gene can be extracted from human cells (using mRNA + reverse transcriptase to make cDNA — the intron-free version is what is needed because E. coli cannot splice introns) or synthesised chemically from the known amino-acid sequence determined by Sanger.
2. Insert it into a vector. The gene is cut using a restriction enzyme (e.g. EcoRI), which produces complementary sticky ends. A bacterial plasmid is cut with the same restriction enzyme. DNA ligase joins the insulin gene into the plasmid by reforming the sugar-phosphate backbone — the recombinant plasmid now carries the human insulin gene.
3. Transform the host. The recombinant plasmid is introduced into E. coli (or yeast) using heat shock (CaCl₂ + 42°C briefly) or electroporation.
4. Grow the bacteria in fermenters. Only bacteria containing the plasmid grow on selective media (selection with antibiotic resistance markers also carried by the plasmid; non-transformants die on ampicillin or kanamycin plates). Industrial fermenters of thousands of litres are used.
5. Induce expression. The insulin gene is transcribed and translated using a strong inducible promoter (e.g. lac, tac), producing human proinsulin (or the A and B chains separately depending on manufacturer).
6. Purify the insulin. The protein is extracted from the bacteria (cell lysis), purified by ion-exchange and reverse-phase chromatography, and the C-peptide is enzymatically excised to yield mature human insulin. Quality-control assays (HPLC, mass spectrometry, biological activity) confirm purity and identity before release.

Advantages Over Animal Insulin

Feature	Human recombinant insulin	Animal insulin
Immune reactions	Rare	More common
Supply	Unlimited, scalable	Limited by animal supply
Cost (long term)	Lower	Higher
Ethical issues	Fewer (no animals)	Religious/ethical objections for some patients
Sequence match	Identical to human	Slightly different (1–3 amino acids)

Insulin Analogues

Modern diabetes care often uses insulin analogues — recombinant insulins with small amino acid changes that alter their absorption profile. Some are absorbed very rapidly for use at mealtimes (e.g. insulin lispro, where Lys-Pro in the B-chain is swapped for Pro-Lys; this disrupts the dimer/hexamer association that normally slows absorption, giving onset in ~15 minutes), others are slow-release for basal control (e.g. insulin glargine, modified to precipitate at neutral pH so it forms a depot in subcutaneous tissue, giving 24-hour duration). These give patients better control and more flexibility. OCR does not require you to name specific analogues, but knowing the principle is useful — small molecular changes can produce large pharmacokinetic changes, exemplifying structure-function relationships in protein engineering.

Ethical considerations

The use of GM bacteria for therapeutic protein production raises several ethical considerations that OCR-style discussion questions may ask about:

• Risks of GM organism escape into the environment — addressed by using laboratory-domesticated E. coli strains that cannot survive outside fermenter conditions, plus physical containment.
• Religious or cultural objections — some patients prefer non-animal-derived insulin for religious reasons (pork-free); recombinant human insulin satisfies these constraints.
• Patenting of living organisms — the patenting of genetically modified bacteria for biotechnology has been controversial; legal frameworks have evolved (e.g. the Diamond v Chakrabarty US Supreme Court decision, 1980).
• Access and cost — although recombinant insulin is cheaper than animal insulin in the long term, modern analogues are expensive and access disparities persist globally.

These ethical considerations are part of "How Science Works" (AO3) and may appear in extended-prose questions.

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Long-term Complications of Poorly Controlled Diabetes

Both types of diabetes, if poorly controlled, cause the same long-term complications because they share the common feature of chronic hyperglycaemia:

• Macrovascular — atherosclerosis (large-vessel disease), myocardial infarction, ischaemic stroke, peripheral vascular disease. Diabetes is one of the strongest risk factors for cardiovascular death.
• Microvascular — retinopathy (capillary damage in the retina, leading to blindness; preventable by laser photocoagulation if detected early), nephropathy (kidney capillary basement membrane thickening, leading to proteinuria, hypertension, end-stage renal failure; the leading cause of dialysis in the UK), neuropathy (nerve damage, often "stocking-and-glove" sensory loss in the feet, with risk of unnoticed injury and ulceration).
• Infections — impaired neutrophil function in hyperglycaemia, impaired wound healing, foot ulcers, amputations (diabetic foot syndrome accounts for around 6,000 lower-limb amputations per year in the UK).