(Pre)Diabetes as Focus Disease – Inactivity and Low-Grade Inflammation

Table of Contents

1. Learning Objectives and Clinical Framing
2. Continuous Glucose Monitoring – Reading a 24-Hour Profile
3. Fact Sheets on Exercise, Insulin and GLUT4
4. Energy Balance and Obese Phenotypes
5. Anthropometric Diagnostics – Waist Circumference
6. Synthesis – Inactivity as a Driver of Prediabetes

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1 Learning Objectives and Clinical Framing

Learning Objectives (Lernziele)

By the end of this lecture, students will be able to:

1. Identify (pre)diabetes as a focus disease in contemporary sports medicine.
2. Explain how physical inactivity is a primary cause of prediabetes and low-grade inflammation.
3. Interpret a continuous glucose monitoring (CGM) profile in terms of hyper- and hypoglycaemia, the responsible counter-regulatory hormones, and the modifying effects of physical activity.
4. Distinguish obese phenotypes by anthropometric and metabolic criteria.
5. Place prediabetes within the broader frame of cardiometabolic disease.

Why Prediabetes Matters

Prediabetes — defined by elevated fasting glucose, impaired glucose tolerance or elevated HbA1c below the diabetes threshold — is not a benign waiting state. It is associated with elevated cardiovascular risk, accelerated micro- and macrovascular damage, and a high annual conversion rate to type 2 diabetes [1, 2]. Crucially, conversion is largely modifiable by physical activity, nutrition and weight loss [3, 4].

The lecture takes the position — following Stefan and colleagues [2] — that prediabetes warrants active management rather than expectant observation, particularly in the presence of additional cardiometabolic risk factors.

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2 Continuous Glucose Monitoring – Reading a 24-Hour Profile

A Practical Teaching Tool

Continuous glucose monitoring devices such as the FreeStyle Libre 3 produce a 14-day, near-continuous plasma-glucose surrogate. For teaching, a single 24-hour trace is sufficient to anchor four phenomena:

1. Post-prandial hyperglycaemic spikes following high-glycaemic-index meals.
2. Reactive hypoglycaemic troughs in some individuals following large insulin responses.
3. The exercise effect — an acute or post-acute reduction in glucose excursions following physical activity.
4. Diurnal patterns — typically lower glucose excursions in morning than evening (cf. Lecture 2).

Hormonal Regulation of Blood Glucose

Hormone	Source	Effect on glucose	Stimulus
Insulin	β-cells, pancreas	↓ blood glucose; promotes uptake and storage	Hyperglycaemia
Amylin	β-cells	↓ gastric emptying, ↓ glucagon	Postprandial
GLP-1	L-cells, gut	↑ insulin, ↓ glucagon, ↓ gastric emptying	Postprandial
GIP	K-cells, gut	↑ insulin	Postprandial
Glucagon	α-cells, pancreas	↑ blood glucose; glycogenolysis, gluconeogenesis	Hypoglycaemia
Cortisol	Adrenal cortex	↑ blood glucose; gluconeogenesis, insulin resistance	Stress, low glucose
Catecholamines	Adrenal medulla, SNS	↑ blood glucose; glycogenolysis	Acute stress, exercise
Somatostatin	δ-cells	↓ both insulin and glucagon	Local pancreatic

Table 1. Major hormones regulating blood glucose. Adapted from clinical physiology references and integrated with the Fact-Sheets used in the Planetary Health OSCE 2024 [5].

A Teaching Exercise

Using a CGM trace, students are asked to:

• annotate breakfast, lunch and dinner spikes;
• identify any reactive hypoglycaemia;
• mark the time and intensity of any documented physical activity;
• describe expected effects on insulin, glucagon, catecholamines and cortisol at each annotated time point.

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3 Fact Sheets on Exercise, Insulin and GLUT4

Fact Sheet 1 — Exercise, Insulin and GLUT4

Mechanism of GLUT4 activation. GLUT4 is the major insulin-responsive glucose transporter in skeletal muscle and adipose tissue. Its insertion into the plasma membrane is triggered by two independent signalling routes [6]:

1. Insulin-mediated: insulin → IRS-1 → PI3K → Akt → AS160 phosphorylation → GLUT4 vesicle exocytosis.
2. Contraction-mediated: muscle contraction → AMPK activation, calcium signalling, mechanical strain → GLUT4 vesicle exocytosis.

The clinical importance of the second route cannot be overstated: in insulin-resistant muscle, the contraction-mediated pathway remains largely functional. This is the molecular basis for prescribing exercise in prediabetes and type 2 diabetes.

Fact Sheet 2 — Exercise and Insulin (Historical)

Lawrence (1926) first documented that exercise increases insulin action in diabetic patients [7]. The empirical observation predated the molecular explanation by seven decades. Modern data confirm:

• Acute exercise: insulin sensitivity rises for up to 48 hours after a single moderate-to-vigorous bout.
• Chronic exercise: a structured training programme increases peripheral insulin sensitivity and reduces HbA1c by clinically meaningful margins [3].

Fact Sheet 3 — Energy Balance

Total daily energy expenditure (TDEE) is the sum of:

• Basal metabolic rate (BMR),
• Thermic effect of food (TEF),
• Activity energy expenditure (AEE),
• Non-exercise activity thermogenesis (NEAT).

Of these, AEE and NEAT are the most modifiable. Habitually sedentary individuals can double daily AEE through modest behavioural changes — climbing stairs, walking meetings, and the “exercise snacks” addressed in Lecture 6.

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4 Energy Balance and Obese Phenotypes

Fact Sheet 4 / 5 — Obese Phenotypes and Energy Balance

Obesity is not a single condition. Metabolic obesity in people with normal body weight (MONW), metabolically healthy obesity (MHO), and metabolically unhealthy obesity (MUO) differ in clinically meaningful ways [8].

Phenotype	BMI	Visceral fat	Insulin sensitivity	Cardiometabolic risk
Lean, metabolically healthy	<25	Low	Preserved	Low
MONW (normal-weight obesity)	<25	Elevated	Reduced	Elevated
Metabolically healthy obesity (MHO)	≥30	Variable	Largely preserved	Intermediate
Metabolically unhealthy obesity (MUO)	≥30	High	Reduced	High

Table 2. Phenotypes of obesity by anthropometric and metabolic criteria. Adapted from Pluta et al. [8].

Clinical implication. Body mass alone is a poor proxy for cardiometabolic risk. Visceral adiposity, ectopic fat (especially hepatic, see Lecture 9), and physical fitness — particularly cardiorespiratory fitness (CRF) — together provide a more accurate stratification [3, 8].

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5 Anthropometric Diagnostics – Waist Circumference

Fact Sheet 6 — How to Measure Waist Circumference

A reproducible procedure is essential for clinical use [9]:

1. Stand upright with feet close together and arms at the side.
2. Locate the bottom of the last rib and the top of the iliac crest.
3. Place the tape measure midway between these two points and wrap it around the waist (typically just above the umbilicus).
4. Read at the end of normal expiration, with the tape parallel to the floor and not compressing the skin.

Fact Sheet 7 — Interpretation of Waist Measurement

Independent of weight, recommended waist circumference thresholds [9]:

Sex	Recommended	Substantially increased risk
Men	< 94 cm (37 in)	≥ 102 cm (40 in)
Women	< 80 cm (31.5 in)	≥ 88 cm (34.5 in)

Table 3. Waist circumference thresholds for cardiometabolic risk.

Practical insight. A 10-minute consultation that includes blood pressure, waist circumference, fasting glucose, HbA1c and a brief activity history captures the bulk of modifiable cardiometabolic risk in primary care. Cardiorespiratory fitness should be added wherever feasible (see Lecture 5) [3].

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6 Synthesis – Inactivity as a Driver of Prediabetes

The Causal Chain

1. Sedentary behaviour reduces daily AEE and NEAT.
2. Reduced muscle contraction lowers GLUT4 translocation through the contraction-mediated pathway.
3. Visceral adiposity accumulates, with chronic low-grade inflammation (adipose macrophage infiltration, ↑ TNF-α, ↑ IL-6 in pro-inflammatory mode).
4. Insulin sensitivity falls; fasting glucose and HbA1c drift upward.
5. The clinical state of prediabetes emerges, often without symptoms.

Each step is reversible by behavioural intervention, particularly by adding structured exercise and breaking up sedentary time [3, 4].

Bridging to the Next Lectures

• Lecture 5 — formalises the metabolic syndrome and explores cardiorespiratory fitness as a vital sign and the mechanisms of weight-loss-induced remission.
• Lecture 6 — develops “exercise snacks” as a practical entry point for the deconditioned, time-poor patient.
• Lecture 7 — translates these findings into the DDG-Praxisempfehlung framework for prescribing exercise in diabetes.

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References

• [1] International Diabetes Federation. IDF Diabetes Atlas, 10th Edition. 2021. https://diabetesatlas.org/idfawp/resource-files/2021/07/IDF_Atlas_10th_Edition_2021.pdf
• [2] Stefan N. Fragwürdige Erkrankung oder auf der Schwelle zum Diabetes — Ist Prädiabetes behandlungsbedürftig? CARDIOVASC. 2022;22(3).
• [3] Ross R, Blair SN, Arena R, et al.; American Heart Association. Importance of assessing cardiorespiratory fitness in clinical practice: a case for fitness as a clinical vital sign — a Scientific Statement from the American Heart Association. Circulation. 2016;134(24):e653–e699.
• [4] Sandforth A, von Schwartzenberg RJ, Arreola EV, et al. Mechanisms of weight loss-induced remission in people with prediabetes: a post-hoc analysis of the randomised, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS). Lancet Diabetes & Endocrinology. 2023;11(11):798–810.
• [5] Planetary Health OSCE 2024. Sportmedizin Exercise Nutrition Immune Function — Fact Sheets. Friedrich-Schiller-University Jena.
• [6] Richter EA, Hargreaves M. Exercise, GLUT4, and skeletal muscle glucose uptake. Physiological Reviews. 2013;93(3):993–1017. doi:10.1152/physrev.00038.2012.
• [7] Lawrence RD. The effect of exercise on insulin action in diabetes. British Medical Journal. 1926;1(3406):648–650. doi:10.1136/bmj.1.3406.648.
• [8] Pluta W, Dudzińska W, Lubkowska A. Metabolic obesity in people with normal body weight (MONW) — review of diagnostic criteria. International Journal of Environmental Research and Public Health. 2022;19:624. doi:10.3390/ijerph19020624.
• [9] World Health Organization. Waist Circumference and Waist–Hip Ratio: Report of a WHO Expert Consultation. Geneva; 2008.

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One-Minute-Paper Topics

1. Define prediabetes by the three accepted biochemical criteria. Why is the diagnosis often missed in primary care?
2. Describe two independent signalling routes to GLUT4 translocation. Why does insulin resistance leave one of them largely intact?
3. List the four components of TDEE and rank them by modifiability.
4. Reproduce Table 1: name three glucose-lowering and three glucose-raising hormones with their sources.
5. Walk through a 24-hour CGM trace and predict where exercise should be timed to flatten the largest excursion. Justify your timing with hormonal reasoning.
6. Lawrence (1926) showed exercise increases insulin action. What was the molecular explanation, and how long did it take to emerge?
7. Distinguish the four obese phenotypes in Table 2 by BMI, visceral fat, insulin sensitivity and risk profile.
8. Why is BMI alone an inadequate measure of cardiometabolic risk? Provide two empirical examples.
9. Describe the four steps of waist measurement. Where are the most common procedural errors?
10. State the WHO-recommended waist thresholds for men and women and the thresholds for substantially increased risk.
11. Name three lifestyle interventions that have been shown to reduce conversion from prediabetes to type 2 diabetes.
12. Explain how visceral adiposity drives chronic low-grade inflammation. Which exerkines and cytokines are most directly involved (cf. Lecture 3)?
13. What is MONW, and why is it clinically important? How would you screen for it?
14. Why is cardiorespiratory fitness called a “clinical vital sign”? Which test would you use in routine practice?
15. Sketch the five-step causal chain “sedentary behaviour → prediabetes” from Section 6 in five sentences.
16. After an acute bout of moderate-intensity exercise, insulin sensitivity is elevated for how long? What is the practical implication for medication timing in type 2 diabetes?
17. A patient presents with BMI 27, waist 102 cm, fasting glucose 102 mg/dL, and a sedentary office job. Outline a four-component lifestyle prescription.
18. How would you operationalise “breaking up sedentary time” in a working day? Refer forward to the exercise-snacks concept (Lecture 6).
19. Discuss the position of Stefan (2022) that prediabetes warrants active management. What are the strongest counter-arguments?
20. Design a 12-week prevention programme for prediabetes that integrates nutrition, structured exercise and continuous glucose monitoring feedback.