Mednotes

L3 Metabolism Dysregulation of fuel metabolism in diabetes

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tagsmetabolism, lecture, diabetes
aliasesDysregulation of Fuel Metabolism in Diabetes

22 min read

Overview

This lecture covers the dysregulation of fuel metabolism in diabetes mellitus, moving from the two ends of the blood-glucose spectrum (hypoglycaemia and hyperglycaemia) through to diabetes diagnosis and classification (Type 1, Type 2, MODY), the tissue-level metabolic derangements that occur in the diabetic state, treatment approaches, the acute and chronic complications of diabetes, and finally the underlying biochemistry: how prolonged hyperglycaemia damages tissue (glycation/AGE-RAGE and the polyol pathway) and the molecular basis of insulin resistance (defects in insulin receptor signalling and AMPK). The parts fit together as a chain: glucose dysregulation → clinical presentation and diagnosis → complications → the biochemical mechanisms that explain those complications and that explain why insulin resistance develops and how exercise (via AMPK) counters it.

Hypoglycaemia

Hypoglycaemia is defined as glucose < 4.0 mmol/L, with a mild–moderate–severe paradigm of < 4.0 | < 3.1 | < 2.2 mmol/L. Clinical presentation is variable between individuals.

  • Initial symptoms: increased heart rate, sweating, trembling, weakness, intense hunger.
  • As it worsens, neuroglycopenia (low glucose in the brain) develops, causing confusion, tiredness, poor coordination, weakness, drowsiness, then seizure and coma.

Causes (Figure 20.9): exercise; fasting; excess of exogenous insulin; insulinoma (excess endogenous insulin); inhibition of endogenous glucose production, e.g. alcohol. A common cause of hypoglycaemia is the treatment of elevated blood sugar in diabetes itself.

Rarer causes: genetic enzyme deficiencies in glycogen storage and gluconeogenesis; side effects of medications (e.g. pentamidine); misuse of hypoglycaemic drugs.

Treatment:

  • Mild–moderate: oral glucose, 15 g candy or 200 mL orange juice, repeated if needed.
  • Severe: intramuscular or subcutaneous glucagon, intravenous glucose, or both.
  • Adult glucagon dose: 1 mg IM or subcutaneous; does not require IV access; kits are usable by trained non-medical individuals; effect within minutes.
  • If no immediate response to glucagon, pursue IV glucose — often a bolus of 50% glucose (20–50 mL) followed by a 5% glucose infusion (D5W).

Hyperglycaemia, Diabetes Terminology and Diagnosis

“Diabetes” derives from an ancient Greek word for siphon, referring to large volumes of fluid leaving the body as urine. There are two types of diabetes: diabetes mellitus and diabetes insipidus. Thomas Willis (1675) first added “mellitus” (sweet) because the urine of these patients tasted sweet (now known to be due to high urine sugar). Diabetes insipidus is the contrasting type in which the urine lacks this taste — this is also the origin of “insipid” for something not in good taste.

Hyperglycaemia symptoms:

  • Mild–moderate: commonly no acute symptoms, can vary.
  • More severe: glucosuria, osmotic diuresis, dry mouth, feelings of dehydration.
  • Hyperglycaemia can occur with ketosis (ketonemia and ketonuria); initially may have few signs (e.g. breath odour) but can progress to diabetic ketoacidosis (DKA), a medical emergency.
  • DKA symptoms: thirst, frequent urination, fatigue, hyperventilation, blurred vision; without treatment can progress to severe illness, coma, death.

Diagnosis of diabetes (Diabetes New Zealand, 2005), in people without symptoms:

  • Fasting glucose > 7.0 mmol/L, or random > 11.1 mmol/L, or
  • HbA1c ≥ 50 mmol/mol (6.7%), or
  • Glucose Tolerance Test (GTT): glucose > 11.1 mmol/L two hours after a 75 g glucose load.
  • These findings, if present on 2 occasions, allow a diabetes diagnosis.
  • In people with typical symptoms of hyperglycaemia/insulin deficiency, only one positive test result is needed (no repeat required).

Typical symptoms at diagnosis: weakness, blurred vision, weight loss, increased thirst, increased urine output, increased eating.

  • Classic Type 1 triad: “polydipsia, polyuria, polyphagia.”
  • Type 2 onset: symptoms can be quite variable.

A patient with typical hyperglycaemic symptoms needs only one positive diagnostic test result — no repeat test is required, unlike in the asymptomatic case.

Types of Diabetes

Type 1 diabetes (IDDM, insulin dependent diabetes mellitus)

  • Caused by autoimmune destruction of β cells in the pancreas.
  • Childhood onset frequent, but can occur in adults too.
  • Strong genetic component (many susceptibility loci).
  • Obesity not common.
  • Insulin dependence is the norm; non-responsive to other hypoglycaemic drugs besides insulin.
  • Ketoacidosis much more common than in Type 2.
  • Chronic complications are an important cause of morbidity.
  • Can be prone to other autoimmune diseases.

Type 2 diabetes (NIDDM)

  • Caused by impaired insulin secretion and insulin resistance.
  • Adult onset most common; strong genetic component.
  • Obesity is a major factor, often with dyslipidaemia and hypertension.
  • Often initially insulin independent; responsive to hypoglycaemic drugs.
  • Ketoacidosis uncommon.
  • Macrovascular complications: atherosclerosis leading to CVD, PVD, stroke.
  • Microvascular complications: microangiopathy, retinopathy, neuropathy, nephropathy, cataracts, etc.

Maturity Onset Diabetes of the Young (MODY)

  • Rare cause of diabetes (1–2% of cases; ~80 per 1,000,000).
  • Presents like Type 2 but at a younger age (teens to 40s).
  • First identified in 1975 (Tattersall and Fajans).
  • Caused by mutations in genes involved in glucose metabolism or insulin production, e.g. glucokinase, transcription factors, HNF1α.
  • Diagnosis matters because treatment can differ and it may run in relatives; often does not require insulin.

Epidemiology: Type 1 diabetes incidence is relatively flat and low across age groups at diagnosis (values by decade bin: 35, 73, 89, 73, 55, 28 per 100,000), whereas Type 2 diabetes incidence rises steeply with age, dominating in older age groups (rising to ~3450–3500 per 100,000 in the 51–60 bin). Type 1 incidence by single year of age peaks around puberty (~age 12–13, ~24–25 per 100,000/year), rising from ~6–7 at age 0, declining to ~10–11 by age 18–20, with a smaller secondary bump (~13–14) around age 21–24. Type 1 incidence in children under 15 varies markedly by country/population, highest in Nordic/Northern European populations (Finland highest, ~29 per 100,000) and lowest in East Asian populations (Japan lowest, ~2–3 per 100,000).

In a diabetic versus non-diabetic, plasma glucose after meals: a non-diabetic stays close to ~5 mM baseline with small transient post-meal spikes to ~6.5–7 mM, returning quickly to baseline; a person with non-insulin-dependent diabetes starts around ~12 mM, spikes to ~17.5–18 mM after each meal, and remains persistently elevated (12–18 mM) through the day without full return to baseline — illustrating poor glycaemic regulation in diabetes.

Metabolic Derangements in the Diabetic State

The diabetic-state diagram (liver, muscle, adipose tissue) shows the following fluxes:

  • Liver: glycogen breaks down; gluconeogenesis is stimulated, producing glucose from glycerol, lactate, alanine and pyruvate; pyruvate feeds acetyl-CoA/the TCA cycle; ketogenesis is stimulated, producing ketone bodies from acetyl-CoA for export; glucose export to blood occurs, while glucose uptake into muscle is blocked.
  • Muscle: pyruvate from glycolysis feeds the TCA cycle via acetyl-CoA; alanine (from pyruvate and amino acids released by protein breakdown) and lactate are exported to the liver; fatty acids from triacylglycerol undergo fatty acid oxidation feeding acetyl-CoA/the TCA cycle; glucose uptake into muscle is blocked.
  • Adipose tissue: lipolysis is stimulated, releasing fatty acids (exported to liver/muscle) and glycerol (exported to liver for gluconeogenesis); glucose uptake/glycolysis is inhibited; re-esterification of fatty acids to triacylglycerol is inhibited.

Overall: increased hepatic gluconeogenesis and ketogenesis, increased adipose lipolysis, increased muscle proteolysis with alanine/lactate export, and blocked glucose uptake into muscle and adipose tissue — the metabolic picture of insulin-deficient/insulin-resistant diabetes.

The insulin resistance fed/fasted diagram contrasts three states:

  1. Fasted: liver increases glucose output via glycogenolysis and gluconeogenesis (fed by amino acids/lactate from muscle) and releases glucose to blood; adipose tissue increases lipolysis, releasing fatty acid and glycerol to blood/liver.
  2. Fed/insulin: muscle increases glucose uptake and glycogen synthesis; liver increases glycogen synthesis and de novo lipogenesis while decreasing glucose output (insulin-driven); adipose tissue increases glucose uptake and de novo lipogenesis while decreasing lipolysis, with increased lipid storage.
  3. Insulin resistance: muscle glucose uptake is decreased (insulin action blocked); liver shows increased glucose output, increased de novo lipogenesis and increased glycogen synthesis with insulin action on the liver blocked; adipose tissue shows increased lipolysis, increased fat mass (obesity), decreased glucose uptake, with increased lipogenesis.

In insulin resistance, insulin fails to suppress hepatic glucose output and adipose lipolysis and fails to promote muscle/adipose glucose uptake — the liver and adipose tissue behave as if fasted even when insulin is present, while lipogenesis in liver/adipose stays increased, contributing to hyperglycaemia and dyslipidaemia.

Treatment of Diabetes

Type 1 diabetes:

  • Daily insulin injections; intermittent injection versus pump (pump now common); sophisticated pumps with intelligent features; both user-intervention and “closed-loop” systems available.
  • Glucose monitoring with active blood-sugar management.
  • β cell transplants being studied.
  • Other care: lifestyle interventions (diet, exercise); regular exams, labs, glucose and HbA1c monitoring to prevent/delay complications; a comprehensive programme with family/whānau involvement is helpful for best outcomes; emergency treatment for acute conditions like ketoacidosis is rare in modern healthcare settings.

Type 2 diabetes:

  • Dietary intervention, physical exercise.
  • Oral medications: metformin, DPP-4 inhibitors, GLP-1 agonists, SGLT2 inhibitors; other possible meds: thiazolidinediones (PPAR agonists), sulfonylureas.
  • Insulin may be needed, often later in the disease course.
  • Monitor by regular exams, labs, glucose and HbA1c measurements.
  • Comprehensive programme with family/whānau involvement needed for best outcomes.

Long-term care and follow-up: establishing a programme (medications, diet, health programme, family, support); regular follow-up; regular HbA1c monitoring; monitoring for complications and related conditions; engagement with specialists as needed (ophthalmology, neurology, renal, cardiology, orthopaedics, podiatry) alongside GP care.

Complications of Diabetes

Acute complications (Table 1): fatigue, polyuria, blurry vision, polydipsia; infection(s); diabetic ketoacidosis (DKA); hyperglycaemic, hyperosmolar, non-ketotic coma (HHNKC). Acute complications, other than infection, are more common in Type 1.

Chronic complications: retinopathy/blindness; neuropathy/gastroparesis; coronary artery disease; cerebrovascular disease; peripheral vascular disease; infection/amputation. Chronic complications occur in both types.

Major chronic complications by site (body diagram): cataracts (eyes); retinopathy — visual impairment and blindness; autonomic neuropathy — diarrhoea, impotence; macroangiopathy — coronary heart disease, peripheral vascular disease; diabetic foot — peripheral neuropathy and ischaemia, foot ulcers, amputations; nephropathy — renal failure. Assessment of a diabetic patient includes: blood glucose and HbA1c, eye examination, serum creatinine, urine protein, microalbuminuria, neurologic examination, ECG, serum lipid levels.

  • Cataract is lens opacification (clouded lens, blocking light reaching the retina), distinct from retinopathy, which is retinal damage.
  • Diabetic foot ulcer: example shown is a severely ulcerated, infected great toe with necrotic tissue — illustrates the diabetic foot complication.

Hemoglobin A1c (HbA1c) gives a time-averaged assessment of glycaemia: hyperglycaemia causes excess HbA1c to form, and because it persists over the lifespan of the affected red blood cells, HbA1c can remain elevated even after plasma glucose has been brought back to normal (e.g. a patient’s high glucose and HbA1c 8% at a first visit prompts an insulin dose increase; at a second visit glucose is normal but HbA1c is still elevated at 7.5%, because it reflects glycation accumulated over the red cell’s lifespan, not just recent glucose).

Diabetic ketoacidosis (DKA) is a severe acute complication and a medical emergency requiring multiple factors to develop, from a starting point of insulin lack, via two parallel cascades:

  1. Increased gluconeogenesis and decreased glucose uptake → hyperglycaemia → glycosuria → osmotic diuresis → dehydration.
  2. Increased lipolysis → increased ketogenesis → ketonemia → ketonuria → (converges with osmotic diuresis) → acidosis → compensatory hyperventilation.

DKA requires urgent, complex therapy including: intravenous fluid to correct hypovolaemia; insulin (often continuous infusion) to correct the insulin deficit; careful electrolyte management; monitoring and treatment of acidosis; close monitoring, often in intensive care; frequent labs (pH, glucose, electrolytes).

Biochemical Basis of Diabetic Complications

Much of the cause of long-term diabetes complications is felt to be prolonged elevated glucose, with flow-on effects: non-enzymic glycation of proteins, increased polyol formation, and increased mitochondrial oxidation products. Over time these lead to long-term complications and to insulin resistance (IR).

Polyol pathway: glucose → sorbitol → fructose, leading to decreased NADPH, decreased glutathione, decreased nitric oxide, and increased AGE formation; affects kidney, retina, and nervous tissue. The broader flowchart: hyperglycaemia branches into (a) the polyol pathway (↑ sorbitol accumulation → cataracts, nerve conduction defects) and (b) ↑ AGE/↑ ROS (mutually reinforcing, also fed by ↑ mitochondrial oxidations from ↑NADH), which drive endothelial damage, NF-κB pathway activation, and insulin resistance. NF-κB activation causes a low-grade inflammatory reaction in the vessel wall, feeding back into endothelial damage and microangiopathy. Insulin resistance also drives dyslipidaemia → atherosclerosis. Endothelial damage additionally contributes to microangiopathy.

Non-enzymic glycation (AGE and RAGE):

  • Occurs at a rate proportional to glucose concentration (this is how glycated haemoglobin, HbA1c, forms).
  • Can damage crucial structural proteins by glycation and generation of Advanced Glycation Endproducts (AGEs).
  • Reaction steps: glucose (open-chain aldehyde) + the valine amine of haemoglobin → Schiff base → (via Amadori rearrangement) → stable ketoamine product (glycated haemoglobin, HbA1c).
  • AGEs are produced by non-enzymatic glycation of protein side chains, further oxidised to reactive aldehydes, and form cross-links (collagen, elastin).
  • AGEs bind to their receptor, RAGE, triggering multiple signals (inflammatory response, reactive oxygen species).
  • Adverse effects on endothelial cells, smooth muscle cells, monocytes.
  • Contribute to both microvascular and macrovascular disease; a very important cause of both chronic diabetic complications and insulin resistance.

Extracellular/intracellular effects of AGEs (endothelial cell schematic):

  • Extracellular: AGE cross-links elastin (increases vascular stiffness) and cross-links collagen/laminin/lipid components of the matrix.
  • AGE (including CML-AGE) binds RAGE and also the TGFβ receptor.
  • Intracellular signalling from RAGE activation: NAD(P)H oxidase → ROS; p21 RAS, CDC42, MAP kinases (ERK1/2, p38), RAC → converge on nuclear transcription factors (e.g. NF-κB), driving transcription of endothelin-1, ICAM-1, E-selectin, VCAM-1, tissue factor, VEGF, IL-1α, IL-6, TNF-α, and RAGE itself (positive feedback), plus increased cell growth.
  • eNOS activity is decreased and NO inactivation increased, so NO decreases overall.
  • A monocyte/macrophage AGE receptor and Ox-LDL/scavenger receptors (class A, CD36) feed into foam cell formation.
  • Overall: AGE–RAGE binding triggers intracellular signalling causing inflammatory gene transcription, decreased NO/endothelial dysfunction, matrix cross-linking/stiffening, and macrophage foam cell formation — the mechanistic basis of AGE-driven vascular damage.

This diagram (extracellular/intracellular effects of AGEs) is dense with many abbreviations; it was transcribed only to the extent legible at the rendered resolution.

Molecular Basis of Insulin Resistance

The full insulin receptor signalling pathway: insulin binds the insulin receptor (IR) at the plasma membrane, triggering phosphorylation of IR and of adaptor proteins.

  • Growth branch: Shc, Grb2, Sos, Raf1/Ras → MEK → MAPK → Myc/Jun/Fos and p90rsk → DNA/RNA/protein synthesis → cellular growth and differentiation.
  • Metabolic branch: IRS proteins (phosphorylated) recruit SHP-2 and Fyn and activate PI3K → PDK1, which branches to: mTOR ↔ S6 kinase → S6 (protein synthesis); and PKB/Akt → GSK3β (glycogen synthesis) and AS160 (glucose transport); also PKCζ/PKCλ (glucose transport).
  • CAP/Cbl pathway: APS/Cbl, CAP, CrkII, C3G, TC10, acting via lipid rafts/caveolae, also feeds into glucose transport.
  • Outputs: DNA/RNA/protein synthesis → cellular growth and differentiation; glycogen synthesis and glucose transport → metabolism.

This multi-branch structure means any of several points in the pathway could be disrupted to cause insulin resistance. Documented mechanisms of impairment:

  • Altered phosphorylation of IRS proteins: stress/inflammatory kinases (PKC, ERK, Akt, JNK, p38, IKK) drive inhibitory serine phosphorylation of IRS proteins (alongside normal tyrosine phosphorylation).
  • SOCS (suppressor of cytokine signalling) inhibition of the insulin receptor itself, driven by free fatty acid (FFA) influx, inflammation, and cytokine excess.
  • PTPase-mediated dephosphorylation of IRS proteins (inactivating them).
  • Altered activity of PI3K.

A highlighted branch of the pathway — PKB/Akt → AS160 → glucose transport — is emphasised as a key site of insulin-resistance-related disruption. Supporting evidence (Karlsson et al. 2005): AS160 protein expression was similar in muscle biopsies from 9 control subjects and 10 patients with type 2 diabetes, but phosphorylation of AS160 in response to physiologic hyperinsulinaemia was reduced 39% (p < 0.05) in the diabetic samples, caused by aberrant Akt signalling. Karlsson et al. concluded that defects in insulin action on AS160 may impair GLUT4 trafficking in type 2 diabetes.

Insulin resistance due to AMPK inhibition (mitochondrial over-activation model): in obesity, lipids induce mitochondrial over-activation by boosting fatty-acid β-oxidation to enhance energy disposal (especially in muscle, liver, brown fat). This generates a large amount of ATP; if the extra energy cannot be released as heat, ATP levels exceed a threshold and trigger negative feedback that attenuates mitochondrial function: ATP inactivates AMPK to reduce insulin-induced glucose uptake and so decrease ATP production. In this model, insulin resistance is a cellular protective mechanism aimed at controlling the ATP stress response in muscle and liver. Insulin-sensitising agents (metformin, thiazolidinediones, berberine, resveratrol, curcumin, quercetin, oestrogen, HDAC inhibitors) rescue tissue from insulin resistance by inhibiting mitochondrial β-oxidation. Cascade: lipotoxicity → mitochondrial over-activation → ATP ↑ → AMPK ↓ → glucose oxidation ↓ / glucose uptake ↓ → insulin sensitivity ↓.

AMPK’s normal (beneficial) role, blocked when AMPK activity falls: increased AMP/ATP ratio, exercise, and cellular stress activate AMPKK (also activated by adiponectin and metformin, inhibited by PP2C), which activates AMPK. Adiponectin is increased by exercise, particularly aerobic exercise, and feeds into AMPK activation in muscle. Active AMPK drives:

  1. Increased glycolysis and glucose uptake in muscle (via HK, GLUT4, UCP3).
  2. Decreased SREBP-1 → decreased lipogenic gene expression.
  3. Inhibition of HMG-CoA reductase (phosphorylated) → decreased cholesterol synthesis.
  4. Inhibition of ACC (phosphorylated) → decreased fatty acid synthesis → increased fat oxidation.
  5. Phosphorylation of MCD.

AMPK activation (via exercise, adiponectin, or metformin) increases glucose uptake and fat oxidation while decreasing lipogenesis and cholesterol/fatty-acid synthesis — this is the biochemical basis for why exercise helps in diabetes. In insulin resistance, reduced AMPK activity blocks all of these beneficial effects.

Self-test

  1. Define hypoglycaemia and give the mild/moderate/severe glucose thresholds.
  2. List the causes of hypoglycaemia shown in the lecture, and name one rare cause.
  3. Describe the treatment options for mild-to-moderate versus severe hypoglycaemia, including the adult glucagon dose and route.
  4. Explain the origin of the terms “diabetes mellitus” and “diabetes insipidus.”
  5. State the diagnostic criteria for diabetes in a person without symptoms, and explain why a person with typical hyperglycaemic symptoms needs only one positive test.
  6. Distinguish Type 1 diabetes from Type 2 diabetes in terms of cause, typical age of onset, obesity association, insulin dependence, and frequency of ketoacidosis.
  7. What is MODY, and why is correctly diagnosing it clinically important?
  8. Describe how the age-at-diagnosis pattern differs between Type 1 and Type 2 diabetes.
  9. Describe the metabolic changes occurring in liver, muscle, and adipose tissue in the diabetic (insulin-deficient) state.
  10. Explain how insulin resistance alters the fed/fasted metabolic paradigm in the liver and adipose tissue.
  11. List the main components of Type 1 and Type 2 diabetes management.
  12. Distinguish the acute complications of diabetes from the chronic complications, and state which type of diabetes acute complications are more common in.
  13. Describe the two parallel biochemical cascades that lead to diabetic ketoacidosis, starting from insulin lack.
  14. List the components of urgent DKA therapy.
  15. Explain why HbA1c can remain elevated even after plasma glucose has returned to normal.
  16. Describe the steps of non-enzymic glycation that form HbA1c, and define AGE and RAGE.
  17. Describe the polyol pathway and its downstream effects on the kidney, retina, and nervous tissue.
  18. List four distinct molecular mechanisms by which insulin signalling can be impaired, per the SOCS/IRS diagram.
  19. Describe the evidence from Karlsson et al. (2005) implicating AS160 in type 2 diabetes insulin resistance.
  20. Describe the mitochondrial over-activation model of AMPK-mediated insulin resistance in obesity, and name two agents that counter it.
  21. Explain why exercise helps in diabetes, in terms of AMPK.
  22. A patient presents with thirst, frequent urination, fatigue, hyperventilation and blurred vision. What is this presentation, what two biochemical processes underlie it, and what is the immediate treatment priority?
  23. A person is found with intense hunger, sweating, and a fast heart rate, progressing towards confusion. Explain what is happening physiologically as this worsens, and state the appropriate treatment given the severity.
  24. Integrative: trace how chronic hyperglycaemia can lead to both a chronic vascular complication (e.g. microangiopathy) and to insulin resistance itself, linking the polyol pathway and AGE/RAGE/ROS pathway.

Answers

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