Mednotes

L11 Clinical Pharmacology Hypoglycaemics 1

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tagsclinicalpharmacology, lecture, diabetes, insulin
aliasesManagement of Diabetes with Hypoglycaemic Agents (1)

20 min read

Hypoglycaemics

Overview

This lecture (part 1) covers the pharmacological management of diabetes mellitus. It begins with the physiology needed to understand the drugs: normal pancreatic hormones, the beta-cell insulin-secretion pathway, and how insulin acts and is cleared. It then defines the types of diabetes and the concept of insulin resistance, the complications of inadequate control, and how the disease is diagnosed and monitored (HbA1c and blood-glucose thresholds and targets). The bulk of the therapeutics is then developed in two blocks: insulin replacement (analogue engineering, pharmacokinetic classes, regimens, administration and adverse effects) and the oral first-line agent metformin (a biguanide), with sulphonylureas introduced at the end. The pieces fit a treatment logic that escalates from lifestyle change to metformin monotherapy to oral combinations to insulin, guided throughout by HbA1c.

Normal glucose regulation and insulin secretion

Pancreatic hormonal control of blood glucose:

  • Insulin lowers blood glucose by allowing glucose uptake by cells.
  • Glucagon raises blood glucose when needed.
  • Somatostatin can suppress both glucagon and insulin when needed.

Diabetes results from either a failure to produce insulin or a loss of sensitivity to insulin.

Beta-cell insulin secretion pathway (glucose-stimulated): glucose enters the beta cell via GLUT2 and is phosphorylated by glucokinase to glucose-6-phosphate. Mitochondrial metabolism (Krebs cycle) generates ATP, raising the ATP/ADP ratio. ATP closes the ATP-dependent (Kir6.2) K+ channel, causing membrane depolarisation, which opens voltage-gated Ca2+ channels; the resulting rise in intracellular [Ca2+] promotes release of insulin from vesicles. The sulphonylurea binding site is on this ATP-dependent K+ channel.

Autonomic and incretin modulation of insulin release:

  • alpha-adrenergic (alpha2) sympathetic stimulation inhibits insulin release.
  • beta-adrenergic sympathetic stimulation promotes insulin release (raises cAMP).
  • Muscarinic M2 receptor (parasympathetic) stimulation promotes insulin release.
  • Incretins act via GLP-1R and cAMP. cAMP/PKA/EPAC2 signalling and rising intracellular Ca2+ drive insulin granule exocytosis.
  • Insulin/IGF-1 signalling (via IRS-2, PI3K, PKB/Akt) increases beta-cell proliferation and decreases beta-cell apoptosis.

How insulin works and is cleared

  • Beta-cell-derived insulin is secreted into the portal circulation in response to elevated blood sugar.
  • Insulin is an agonist at insulin receptors (tyrosine kinase class); receptor activation induces glucose uptake by GLUT transporters on cells, an effect that can last several hours.
  • Insulin clearance is specifically mediated by cellular receptor trafficking and internalisation (predominantly of albumin-bound insulins, which are not filtered renally as easily as unbound “free” insulin).
  • The remainder is metabolised: insulinase (hepatic ~60%, renal ~40%) breaks down insulin, giving a of ~6 min for the free hormone. Insulin is also cleared renally by glomerular filtration and proximal tubule transport.
  • Lack of insulin causes low cellular glucose intake (metabolic issues) and residual high blood glucose (hyperglycaemia).

Types of diabetes and insulin resistance

Classification:

  • Type I: failure to produce insulin.
  • Type II (insulin resistance): loss of sensitivity to insulin combined with an insufficiency in insulin production.
  • Secondary DM: a consequence of another disease, e.g. pancreatitis or cystic fibrosis.
  • Gestational DM: generally type II diabetes arising during pregnancy.
  • Impaired glucose tolerance: an intermediate between normal and diabetes.

Cellular picture:

  • Type I: diminished insulin, so few insulin receptors are activated, Glut-4 transporters are not mobilised, and glucose uptake into fat/muscle cells is diminished.
  • Type II (NIDDM): insulin is present but there is a defect in signalling to Glut-4, so glucose uptake is again diminished.

Insulin resistance:

  • Blood insulin concentration is normally dependent on blood glucose. However, as blood insulin concentration rises, receptor response to insulin falls.
  • Associated with liver disease and reduced activity of insulin-degradation enzymes, among other factors.

Natural history: as a person progresses from insulin-sensitive to insulin-resistant/metabolic syndrome (MetS) to type 2 diabetes (T2D), postprandial and fasting blood glucose both rise over time and coronary artery disease develops across this span. Insulin resistance rises early and plateaus high; plasma insulin rises to a peak around diagnosis then declines; beta-cell function peaks before diagnosis then progressively falls.

Consequences of inadequate treatment

  • Elevated insulin (with insulin resistance) can raise triglycerides and cholesterol (related to low lipoprotein lipase) with storage in adipocytes and release of inflammatory factors in the endothelium, promoting atherosclerosis.
  • Unabated high circulating insulin may lead to diabetic retinopathy, hypertension, heart disease, kidney failure, peripheral vascular disease, and diabetic neuropathies leading to infections.
  • Early hyperglycaemic symptoms are often not detected, and hyperglycaemia sufficient to cause pathological and functional change may be present long before diagnosis.
  • Diabetes causes capillary basement membrane thickening; long-term complications include diabetic retinopathy and diabetic foot disease (peripheral vascular disease / neuropathy).

Diagnosis, monitoring and targets

Management requires patient education: adherence to prescribed diet and regular exercise; regular blood glucose and HbA1c monitoring; and compliance with prescribed medications. If glycaemic control is not achieved with lifestyle modification within 1-3 months, an oral anti-diabetic agent should be initiated. The threshold for inadequate control is HbA1c ≥50 mmol/mol, FPG >7.0 mmol/L, or an RPG >11.0 mmol/L.

Medication requirements may be complex: glucose-lowering drugs (oral or insulin) if a “green script” (lifestyle prescription of diet and exercise) alone is insufficient, plus antihypertensives and statins (because insulin enhances transcription of endothelial lipoprotein lipase, which mediates cellular uptake of lipoproteins in the vasculature).

HbA1c as a control indicator: the overall aim of glucose-lowering treatment is to reduce HbA1c and the risk of complications. HbA1c is expressed in new units (mmol/mol) or old units (%), and maps to mean blood glucose; higher values indicate poorer control. Reference points from the dial: 30 mmol/mol ~ 4.9% ~ 5.2 mmol/L glucose, rising through 50 mmol/mol ~ 6.7% ~ 8.1 mmol/L, up to 100 mmol/mol ~ 11.3% ~ 15.4 mmol/L.

Screening / confirming suspected type II DM, HbA1c pathway:

  • HbA1c <42 mmol/mol: T2D unlikely; no further screening unless the risk-factor profile changes.
  • HbA1c 42-47 mmol/mol: “impaired” or “pre-diabetes”; rescreen HbA1c annually; do not measure blood glucose.
  • HbA1c ≥48 mmol/mol: diagnostic of T2D; manage per type 2 guidelines.
  • No confirmatory test now required if HbA1c ≥53 mmol/mol; a confirmatory test is required as soon as practical if HbA1c 48-52 mmol/mol (e.g. repeat HbA1c, fasting glucose, or random glucose if symptomatic).

Screening, fasting blood glucose (FBG) pathway:

  • FBG <5.5 mmol/L: diabetes unlikely; retest in three years if indicated.
  • FBG 5.5-6.9 mmol/L: diabetes possible; perform OGTT.
  • FBG ≥7.0 mmol/L or RBG ≥11.1 mmol/L: diabetes likely; confirm with repeat FBG.

Aims of management: achieve near-normal glycaemia; short-term, prevent symptoms of hyperglycaemia and avert hypoglycaemia; long-term, prevent micro- and macro-vascular complications.

Antidiabetic drug classes (overview)

Oral agents:

  • Biguanides (metformin): decrease hepatic glucose production and improve insulin response.
  • DPP-IV inhibitors (sitagliptin, vildagliptin): reduce GLP-1 (incretin) breakdown.
  • SGLT-2 inhibitors (empagliflozin). [printed “SLGT-2” on the slide]
  • Sulphonylureas (gliclazide): stimulate pancreatic beta-cells to release more insulin (insulin secretagogues).

Not covered in this lecture: meglitinides (repaglinide, stimulate beta-cell insulin release like sulphonylureas); thiazolidinediones (pioglitazone, increase muscle insulin sensitivity and reduce hepatic glucose production); alpha-glucosidase inhibitors (acarbose, block intestinal breakdown of starches and some sugars).

Subcutaneous agents: human and human-analogue insulins; GLP-1 receptor agonists (dulaglutide, liraglutide, exenatide).

Insulin replacement therapy

Indications: type I and ultimately many type 2 diabetics can become markedly insulinopaenic, and insulin therapy corrects this. Insulin is mainly given subcutaneously. Most type 2 patients are insulin resistant but to a variable degree, so insulin therapy must be individualised; it can be combined with oral hypoglycaemics such as metformin.

Historical milestones (selected from the 1893-2024 timeline): 1922 first insulin treatment in a human; 1923 insulin commercially available; 1955 amino-acid sequence determined; 1982 rDNA (recombinant) human insulin; 1996 fast-acting insulin lispro; 2010-2020 rapid- and longer-acting and inhaled insulins (aspart, glulisine, glargine, degludec, lispro); 2024 weekly insulin icodec, with efsitora alfa in development.

Analogue engineering: insulin is composed of two peptide chains (alpha and beta), linked by two disulphide bonds. Protein engineering modifies human insulin; substitution/modification of amino acids on the beta-chain alters absorption and dispersal rates (a pharmacokinetic modification) with no effect on receptor binding.

Absorption as the rate-limiting step: subcutaneously injected insulin exists in equilibrium as hexamers, dimers and monomers. Larger aggregates diffuse slowly from the depot (hexamer = slow, dimer = medium, monomer = rapid). Because absorption of subcutaneous insulin into blood is the rate-limiting step of insulin activity, short-acting insulins are designed to favour monomer formation.

Short-acting (rapid) analogues, insulin aspart (Novorapid) and insulin lispro (Humalog): less tendency to aggregate than standard insulin, with more rapid onset and offset.

  • Lispro: the lysine-proline sequence is reversed at the end of the beta-chain, creating steric hindrance and reduced self-association.
  • Aspart: a proline-to-aspartate substitution creates charge repulsion and steric hindrance; onset ~15 min and clearance within 2-5 hours.

Long-acting analogues:

  • Insulin glargine (Lantus): two extra arginine residues at the end of the beta-chain raise the isoelectric point, reducing solubility at neutral body pH and reducing clearance; microprecipitates form at the injection site and are slowly released.
  • Insulin detemir (Levemir): fatty-acid acylation of the amino group of lysine B29 promotes reversible binding to albumin, delaying subcutaneous absorption. Dissociated detemir re-binds albumin in the circulation, further delaying distribution; insulin levels rise slowly to a plateau within 6-8 hours and remain steady for up to 24 hours, suitable for once-daily dosing.

Pharmacokinetic classes (onset/peak):

  • Rapid acting (lispro, aspart, glulisine): starts 5-10 min, peaks 30-90 min.
  • Short acting (regular insulin): starts 30 min-1 hr, peaks 2-3 hr.
  • Intermediate acting (NPH / isophane): starts 1-3 hr, peaks 4-12 hr.
  • Long acting (detemir, glargine): starts 1-2 hr, no peak (low flat profile up to ~24 hr).

Regimens: a basal/bolus regimen uses basal long-acting insulin (glargine) in the evening plus multiple pre-meal doses of a short-acting analogue (e.g. lispro), overlaid to approximate non-diabetic insulin secretion. Bolus doses may be flexible based on carbohydrate count.

Exogenous insulin PK: exogenous insulins avoid first-pass metabolism and undergo renal clearance (~80%). Severe renal dysfunction (GFR <50 mL/min) reduces clearance and prolongs the PK profile; dose reduction to 75% or 50% of normal may be considered to prevent hypoglycaemia, particularly with long-acting insulins (of uncertain value). Altered PK/PD in diabetic nephropathy can produce an unstable metabolic situation with more frequent and severe hypoglycaemic episodes.

Administration sites: abdomen, thighs, upper buttocks and arms; rotate the site. Absorption is faster from abdomen and arm than from thigh and buttock. Peripheral subcutaneous administration bypasses effects on hepatic metabolic processes and does not mimic the rapid rise and fall of the endogenous insulin response to glucose.

Adverse effects of insulin (mainly hypoglycaemia, often transient):

  • Hypoglycaemia from insulin overdose, missed meals, or other drug combinations affecting caloric intake.
  • Weight gain.
  • Rarely oedema (extravasation of fluid to subcutaneous tissue, renal Na+ retention).
  • Lipoatrophy or lipohypertrophy.
  • Transient deterioration in retinopathy, microvascular injury and atherosclerosis.
  • Local cutaneous allergy or even IgG-mediated insulin resistance, with a burning sensation at the injection site (particularly with premixed insulin).

Management of type 2 diabetes

Type II (NIDDM) is the most common form, nearing epidemic proportions. It is often characterised by insulin resistance and associated with obesity, lack of exercise, disease and poor diet; roughly 50% of men and 70% of women are obese at diagnosis. It may require insulin supplementation; consider insulin at diagnosis if the initial HbA1c is >90 mmol/mol.

Treatment algorithm (stepwise escalation): diagnosis, then therapeutic lifestyle change, then oral monotherapy with metformin (started when HbA1c >50 mmol/mol; if HbA1c >64 mmol/mol consider a second oral agent), then oral combination therapy (add empagliflozin or vildagliptin, or dulaglutide subcutaneously), then oral drugs with insulin.

Adding insulin in T2D (ADA/EASD Consensus 2022): consider immediate insulin for severe hyperglycaemia, acute glycaemic dysregulation, or when type 1 is suspected. When personalised HbA1c targets are not met, start basal insulin (10 U or 0.1-0.2 U/kg per day) at bedtime, titrate to the FPG target while avoiding over-basalisation, and if FPG is on target but HbA1c/time-in-range is not, add mealtime insulin (basal-plus, MDI, or premixed) and consider a GLP-1 RA if not already used. Maintain cardiorenal-protective agents (SGLT2 inhibitor, GLP-1 RA) and intensify healthy behaviour and nutrition at each step.

Oral first-line therapy: in type 2 patients, initiate metformin as soon as possible unless contraindicated.

  • SGLT2 inhibitors, DPP-4 inhibitors, GLP-1R agonists and sulphonylureas are acceptable alternatives if metformin-intolerant.
  • SGLT2 and DPP-IV inhibitors are recommended for patients with cardiovascular risk.
  • Avoid sulphonylureas in obese patients.
  • Caution in diabetic kidney disease (DKD).
  • Use insulin if HbA1c is uncontrolled >80 mmol/mol [printed “>80mol/mol” on the slide], and consider insulin at diagnosis if initial HbA1c >90 mmol/mol.

Biguanides (metformin)

Metformin is the preferred initial agent for monotherapy in type II and a standard part of combination treatments.

  • Increases sensitivity to insulin (can be used in type I to improve response to injected insulin).
  • Most effective in overweight/obese people; does not promote further weight gain (gives modest weight loss).
  • Must be taken with food to reduce stomach and bowel adverse effects.
  • Does not cause hypos, but do not initiate dosing at high therapeutic levels.

Mechanisms of action:

  • Inhibits mitochondrial respiration and increases the AMP/ATP ratio, activating hepatic and muscle AMP-activated protein kinase (AMPK), a cellular signal of increased energy requirement.
  • Inhibits hepatic gluconeogenesis and increases insulin-mediated peripheral glucose uptake in muscle and fat.
  • Increases enterocyte glucose utilisation.
  • Lactate handling: normally glucose metabolism produces pyruvate for the Krebs cycle; increased AMPK raises cytosolic NADH, stimulating conversion of pyruvate to lactate and causing lactate accumulation, an effect exaggerated in renal injury (metformin is retained at high doses in renal failure).

Decreased gluconeogenesis (hepatic mechanism): oral metformin reaches the liver via the portal circulation and enters hepatocytes via OCT1 (organic cation transporter 1). It inhibits mitochondrial electron transport Complex 1, lowering ATP and raising ADP then AMP; increased AMP activates AMPK. AMPK inhibits mitochondrial glycerol-3-phosphate dehydrogenase (mGPD), raising NADH so that (via LDH) pyruvate is converted to lactate (pyruvate falls, lactate rises), and AMPK phosphorylation of the CBP and CRTC2 transcription factors decreases gluconeogenic gene expression. The net effect is decreased hepatic glucose production; mGPD inhibition raises NADH and causes lactate build-up in overdose.

AMPK roles and effects: AMPK is a cellular signal for increased energy requirements, normally activated by AMP accumulation from ATP metabolism. AMPK activation inhibits acetyl-CoA carboxylase (ACC) to promote fatty-acid oxidation; decreases expression of the transcription factor SREBP-1 (sterol-regulatory-element-binding-protein-1, implicated in insulin resistance, dyslipidaemia and diabetes); inhibits hepatic glucose production and promotes skeletal-muscle glucose uptake; and boosts intestinal glucose absorption within enterocytes, increases GLP-1 secretion and has pleiotropic effects. In liver, reduced ACC activity and SREBP-1 expression lower lipogenic-enzyme gene expression, increasing fatty-acid oxidation and reducing VLDL synthesis (less fatty liver, greater hepatic insulin sensitivity) alongside reduced gluconeogenesis; in muscle, glucose uptake increases.

Pleiotropic effects across tissues:

  • Liver: decreased gluconeogenesis (inhibited gene transcription, reduced enzyme activity, fewer substrates, inhibited mitochondrial respiratory chain); inhibited lipogenesis; increased fatty-acid oxidation.
  • Immune system: inhibits the NF-kB pathway; reduces inflammatory cytokines; reduces neutrophil-to-lymphocyte ratio; inhibits monocyte-to-macrophage differentiation.
  • Adipose tissue: increased glucose uptake and fatty-acid oxidation; reduced adipogenesis; increased brown-adipose-tissue thermogenesis.
  • Gastrointestinal tract: reduced glucose absorption; increased glucose transport from blood into the gut lumen; increased glucose utilisation by intestinal cells; increased GLP-1 secretion; modulation of gut microbiota.
  • Skeletal muscle: increased glucose uptake and fatty-acid oxidation; reduced muscle inflammation.

Skeletal-muscle glucose uptake (mechanism): metformin enters the muscle cell via OCT1 (SLC22A3, a facilitated organic cation/monoamine transporter) and activates AMPK, which increases translocation of GLUT-4 to the membrane, increasing glucose uptake.

Pharmacokinetics: metformin has its greatest effect in the GI tract and liver.

  • Efficacy: decreases FPG by 1-4 mmol/L and HbA1c by 5-10 mmol/mol.
  • Oral absorption: take with food (food decreases the extent and slightly delays absorption, reducing GI adverse effects).
  • High concentrations at the GI tract and liver lower glucose on enterocytes and reduce hepatic glucose production; systemic plasma concentrations are low.
  • No plasma protein binding.
  • Plasma ~4-6 h.
  • No hepatic metabolism in humans; excreted renally unchanged via OCT-1 and OCT-2 on proximal tubules (can be affected by other drugs).
  • Caution in severe renal injury.

Clearance stages: absorption, metformin enters enterocytes via PMAT, OCT3 and OCT1 and passes to the portal vein (40-70 microM). Uptake, in hepatocytes it is taken up by OCT1/3 with some eliminated in bile via MATE1, then enters the systemic circulation (10-40 microM). Elimination, in renal epithelial cells it is taken up by OCT2 and secreted via MATE1/2, cleared at the proximal tubule.

Other beneficial effects: in UKPDS, for equivalent HbA1c reduction, metformin patients had less hypoglycaemia and weight gain than those on sulphonylureas. Metformin gives a small (~15%) decrease in LDL cholesterol and triglycerides, can reduce macrovascular events, and reduced the risk of MI (UKPDS, borne out in animal trials); use with caution in cardiorenal injury.

Adverse effects:

  • Diarrhoea and abdominal discomfort (mechanism unclear, possibly lactic-acid build-up in enterocytes or increased bile presentation in the colon); reduced by taking metformin with food.
  • Vitamin B12 malabsorption (17% of the population).
  • Currently contraindicated in severely impaired renal function, hepatic failure and cardiac failure; dose reduction required in renal failure.
  • Lactic acidosis, very rarely associated (3.3 per 100,000 patients), though diabetic patients may already be predisposed.

Sulphonylureas

Insulin secretagogues. Second generation: gliclazide (short acting), glibenclamide (long acting).

  • Stimulate insulin secretion from pancreatic beta-cells (act at the sulphonylurea site on the ATP-dependent K+ channel).
  • Ineffective if pancreatic beta-cell function is reduced, and of debatable value in an insulin-resistant state.
  • Other attributed effects such as somatostatin induction, which suppresses glucagon.
  • Ineffective in insulin resistance and may be ineffective in obesity.
  • Hypos may occur.

Slides skipped as non-informational: title (1), objectives/study links (2-3), section-divider and lifestyle cartoons (13, 47), and the closing slide (48).

Self-test

  1. Name the three pancreatic hormones described and state each one’s effect on blood glucose.
  2. Describe, in order, the steps of glucose-stimulated insulin secretion in the beta cell.
  3. Explain how sympathetic alpha-adrenergic, sympathetic beta-adrenergic and parasympathetic muscarinic (M2) stimulation each affect insulin release.
  4. Describe how insulin is cleared and metabolised, including the half-life of free insulin.
  5. Distinguish the cellular defect in type I diabetes from that in type II (NIDDM).
  6. List the categories of diabetes given in the lecture, with one distinguishing feature of each.
  7. Explain what happens to plasma insulin, insulin resistance and beta-cell function as a patient progresses from insulin-sensitive through MetS to T2D.
  8. State the thresholds (HbA1c, FPG, RPG) that define inadequate glycaemic control warranting an oral agent after 1-3 months of lifestyle change.
  9. Describe the HbA1c pathway for screening/confirming suspected type II DM, including the three key thresholds and the actions at each.
  10. List the four pharmacokinetic classes of insulin with their onset and peak times.
  11. Explain why short-acting insulin analogues are engineered to favour monomer formation.
  12. Distinguish the molecular modifications and effects of insulin glargine from those of insulin detemir.
  13. Describe metformin’s mechanism for decreasing hepatic gluconeogenesis, from cellular entry to reduced glucose output.
  14. List the tissues/systems in which metformin has pleiotropic effects and give one action in each.
  15. Describe metformin’s pharmacokinetics, including protein binding, half-life, metabolism and route of elimination.
  16. List the adverse effects and contraindications of metformin.
  17. Explain why sulphonylureas are ineffective when beta-cell function is reduced or in an insulin-resistant state.
  18. Outline the stepwise treatment algorithm for type 2 diabetes, including the HbA1c thresholds that trigger each escalation.
  19. A newly diagnosed type 2 patient is obese with cardiovascular risk. Which first-line and alternative oral agents are favoured or avoided, and why, and at what HbA1c would you consider insulin at diagnosis?
  20. A patient with diabetic nephropathy (GFR <50 mL/min) is on a long-acting insulin. Predict how this affects insulin handling and what dose adjustment may be considered, and why.
  21. Integrative: link the beta-cell secretion pathway to the mechanism of sulphonylureas and explain why metformin, by contrast, does not cause hypoglycaemia.

Answers

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