The Aetiologyof Type 2 Diabetes

Dr Rangan ChatterjeeMBChB, BSc(Hons) Immunology, MRCP, MRCGP

Part 2

Copyright© 2020 Prescribing Lifestyle Medicine

Learning Objectives

1. Identify the many different causes of insulin resistance

2. Overview of science on gut dysbiosis and role of Lipopolysaccharides

3. The contribution of non-dietary factors

4. The science on time restricted feeding

5. The four primary areas of lifestyle change and using The Personal Framework

6. Specific lifestyle interventions and how to personalise for individuals

7. Case studies to demonstrate concepts

Exercise

Sunlight

Genetics

Stress

Diet

Infections

Sleep

Environment

Type 2 DiabetesThe Symptom

Web

The gut microbiome is the term given to describe the vast collection of symbiotic microorganisms in the human gastrointestinal system and their collective interacting genomes. Recent studies have suggested that the gut microbiome performs numerous important biochemical functions for the host, and disorders of the microbiome are associated with many and diverse human disease processes.

Systems biology and omic technologies have established the importance of the gut microbiome in the disease pathogenesis for numerous systemic disease states, such as obesity and cardiovascular disease, and in intestinal conditions, such as inflammatory bowel disease.

The Gut Microbiome Kinross JM, et al.: Gut microbiome-host interactions in health and disease. Genome Medicine 2011, 3:14.

Diseases Influenced by Gut MicrobialMetabolism

• Gut-brain hypothesis

• Asthma/atopy

• Hypertension/ischemic heart disease

• Peripheral vascular disease

• Colon cancer

• Biliary disease

• Altered xenobiotic/drug metabolism

• Obesity/metabolic syndrome

• Inflammatory bowel disease

TAXONOMIC TREASURE TROVE: A survey of faecal microbiota of 43 subjects revealed a more varied mix of gut bacteria phyla among Hadzahunter-gatherers compared withurban Italians.

Gut microbiome of the hadza hunter-gatherers, by stephanie l.Schnorr et al., In nature communications, vol. 5,Article no. 3654; april 15, 2014;

The Hadza: Complexity of Microbiome vs Western Microbiome

The world has over 50 000 edible plants. Just three of them, rice, maize and wheat, provide 60 percent of the world's food energy intake.

"Seasonality in diet and lifestyle is a universal thing that modern societies dropped, the high fibre consumption is likely to have been universal, too. The same for the intimate relationship with environmental microbes."

Rapid environmental transition and modern lifestyles are likely driving changes in the biodiversity of the human gut microbiota. With clear effects on physiologic, immunologic, and metabolic processes in human health, aberrations in the gut microbiome and intestinal homeostasis have the capacity for multisystem effects. Changes in microbial composition are implicated in the increasing propensity for a broad range of inflammatory diseases, such as allergic disease, asthma, inflammatory bowel disease (IBD), obesity, and associated noncommunicable diseases (NCDs).

West CE, et al. The gut microbiota and inflammatory noncommunicable diseases: associations and potentials for gut microbiota therapies. J Allergy ClinImmunol. 2015 Jan;135(1):3-13.

Gut Microbiota Therapies

Gut Microbiome: The Peacekeepers.Nature 518, S3–S11 (26 February 2015)

The field of gut microbiome research has already moved from the idea of describing the core species to identifying the core ecological functions various microbes perform. Many potential species may fulfill any given role.

Now another concept may be emerging, which might be called the keystone relationship. “The interaction between fiber and microbes that consume it, is the fundamental keystone interaction that everything else is built on in the gut. It may lie at the heart of the symbiotic pact between microbes and humans.

The Peacekeepers

How Many?!

Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation. Seeking an inflammatory factor causative of the onset of insulin resistance, obesity and diabetes, we have identified bacterial lipopolysaccharide (LPS) as a triggering factor.

We conclude that the LPS/CD14 system sets the tone of insulin sensitivity and the onset of diabetes and obesity. Lowering plasma LPS concentration could be a potent strategy for the control of metabolic diseases.

Cani PD, et al.: Metabolic Endotoxemia Initiates Obesity and Insulin Resistence.Diabetes 56:1761-1772, 2007.

Lipopolysaccharides

“About 75% off the food in the Western diet is of limited or no benefit to the microbiota in the lower gut. Most of it, comprised specifically of refined carbohydrates, is already absorbed in the

upper part of the GI tract, and what eventually reaches the large intestine is of limited value, as it contains only small amounts of

the minerals, vitamins and other nutrients necessary for maintenance of the microbiota”

Stig Bengmark

Bengmark, S. Nutrition of the Critically Ill — A 21st-Century Perspective. Nutrients 2013, 5, 162-207; doi: 10.3390/nu5010162

Food Choices

Gut Bugs

Immune System

Minimally processed wholefood diet

Highly processed modern diet

Healthy microbiome

Immune system balanced

Automatic regulation of body function

Good health

Disrupted microbiome

Immune system unbalanced

Low grade inflammation

Poor health

Chaix A et al. Time-Restricted Feeding Is a

Preventative and Therapeutic Intervention

against Diverse Nutritional Challenges. Cell

Metab. 2014 Dec 2;20(6):991-1005

• Time-restricted feeding (TRF) confines food access to 9–12 hrs during the active phase

• TRF is a therapeutic intervention against obesity without calorie restriction

• TRF protects against metabolic diseases even when briefly interrupted on weekends

• TRF is effective against high-fat, high-fructose, and high-sucrose diets

Time-Restricted Feeding

Chaix A, Zarrinpar A, Miu P, Panda S. Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges. Cell Metab. 2014 Dec 2;20(6):991-1005.

While subjects randomized to time-restricted feeding had meals at 1 pm, 4 pm, and 8 pm, those who were in the normal diet group had meals at 8 am, 1 pm, and 8 pm. At the end of 8 weeks of 16 hours of fasting, the time-restricted feeding group had a significant reduction in fat mass, leptin, triglyceride, total testosterone, insulin growth factor-1, and interleukin-1β levels and had a significant increase in adiponectin levels compared to the normal diet group.

Moro T, Tinsley G, Bianco A, Marcolin G, Pacelli QF,

Battaglia G, Palma A, Gentil P, Neri M, Paoli A. Effects of

eight weeks of time-restricted feeding (16/8) on basal

metabolism, maximal strength, body composition,

inflammation, and cardiovascular risk factors in

resistance-trained males. J Transl Med. 2016 Oct

13;14(1):290.

Based on the findings of studies conducted on human subjects, dawn-to-sunset fasting has the potential to be a cost-effective intervention for obesity, metabolic syndrome, and NAFLD.

Mindikoglu AL, Opekun AR, Gagan SK, Devaraj S.

Impact of Time-Restricted Feeding and Dawn-

to-Sunset Fasting on Circadian Rhythm,

Obesity, Metabolic Syndrome, and

Nonalcoholic Fatty Liver Disease. Gastroenterol

Res Pract. 2017;2017:3932491

Melatonin treatment inhibits insulin secretion

Tuomi et al., Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes, Cell Metabolism 23, 1067-1077, June 14, 2016

Melatonin Signaling

Exercise

Stress

Diet

Sleep Type 2 Diabetes

The Symptom Web

Global Health Risks: Mortality and Burden of Disease Attributable to Selected Major Risks. Geneva, World Health Organization, 2009.

Inactivity accounts for 5% of global mortality.

Inactivity is a greater health risk than being overweight or obese.

Muscle Mass and Insulin ResistancePreethi Srikanthan and Arun S. Karlamangla Relative Muscle Mass Is Inversely Associated with Insulin Resistance and Prediabetes. Findings from The Third National Health and Nutrition Examination Survey J Clin Endocrinol Metab. 2011 Sep;96(9):2898-903

Higher muscle mass is associated with better insulin sensitivity and lower risk of PDM.

Francois ME, et al. ‘Exercise snacks’ before meals: a novel strategy to improve glycaemic control in individuals with insulin resistance Diabetologia (2014) 57:1437-1445.

Dosing exercise as brief, intense ‘exercise snacks’ before main meals is a time-efficient and effective approach to improve glycaemic control in individuals with insulin resistance.

‘Exercise Snacks’

Bernard M. F. M. Duvivieret al. Breaking sitting with light activities vs structured exercise: a randomised crossover study demonstrating benefits for glycaemic control and insulin sensitivity in type 2 diabetes Diabetologia (2017) 60:490-498 doi: 10.1007/s00125-016-4161-7

Sitting vs Standing

Breaking sitting with standing and light-intensity walking effectively improved 24 h glucose levels and improved insulin sensitivity in individuals with type 2 diabetes to a greater extent than structured exercise. Thus our results suggest that breaking sitting and standing and light-intensity walking may be an alternative to structured exercise to promote glycaemic control in patients type 2 diabetes.

Specific Advice for Insulin Resistance

• Walk More and Sit Less

• Focus on Muscle Mass

• Exercise ‘Snacks’

• High Intensity Interval Training

Exercise

Stress

Diet

Sleep Type 2 Diabetes

The Symptom Web

Poroyko VA, et al. Chronic Sleep Disruption Alters Gut Microbiota, Induces Systemic and Adipose Tissue Inflammation and Insulin Resistance in Mice SCIENTIFIC REPORTS 6:35405, Oct (2016)

Chronic sleep deprivation causes:

• Increased gut permeability

• Increased inflammation

• Increased visceral fat

• Increased leptin levels

• Increased insulin resistance

Importance of Sleep

Donga E et al A Single Night of Partial Sleep Deprivation Induces Insulin Resistance in Multiple Metabolic Pathways in Healthy Subjects The Journal of Clinical Endocrinology & Metabolism, Volume 95, Issue 6, 1 June 2010, Pages 2963–2968

Sleep Deprivation

Partial sleep deprivation during only a single night induces insulin resistance in multiple metabolic pathways in healthy subjects. This physiological observation may be of relevance for variations in glucoregulation in patients with type 1 and type 2 diabetes.

Sleep DeprivationBriançon-Marjollet A, Weiszenstein M, Henri M, Thomas A, Godin-

Ribuot D, Polak J. The impact of sleep disorders on glucose metabolism: endocrine and molecular mechanisms. Diabetol Metab Syndr. 2015;7:25. Published 2015 Mar 24. doi:10.1186/s13098-015-0018-3

Karine Spiegel, Esra Tasali, Rachel Leproult, and Eve Van Cauter Effects of poor and short sleep on glucose metabolism and obesity risk Nat Rev Endocrinol. 2009 May ; 5(5): 253–261.

Sleep Deprivation in Healthy Individuals

• Participants who slept 4 hours per night for 6 nights, were 40% less effective at absorbing a standard dose of glucose compared to when they were fully rested

• Some would now be diagnosed as prediabetic

• Sleep deprivation causes insulin resistance• Chronic sleep deprivation is a major

contributor to the development of type 2 diabetes

Exercise

Stress

Diet

Sleep Type 2 Diabetes

The Symptom Web

In recent years, the roles of chronic stress and depression as an independent risk factor for decreased insulin sensitivity and the development of diabetes have been increasingly recognized.

We hypothesized that acute psychological stress may cause the development of insulin resistance, which may be a risk factor in developing type 2 diabetes.

Stress and Insulin Resistance

Li L1, Li X, Zhou W, Messina JL.Acute psychological stress results in the rapid development of insulin resistance. J Endocrinol. 2013 Apr15;217(2):175-84.

Stress and Insulin Resistance

• Glucose enters cells via GLUT-4 receptor

• Stress disables GLUT-4 – this is insulin resistance

• Oxidative stress possible mechanism

• We are well adapted to a SHORT term increase in cortisol and glucose

Sleep, Stress and Metabolism

Hirotsu C, Tufik S, Andersen ML. Interactions between sleep, stress, and metabolism: From physiological to pathological conditions. Sleep Sci. 2015;8(3):143-52.

• 10% of total UK NHS expenditure goes on treating diabetes (9 billion of which 1 billion spent on antidiabetes drugs)

• Medical costs are x2 to x3 greater than the average for people with diabetes

• Diabetes affects about 3.2 million to 5 million people in the UK

10%

“Diabetes management is beginning to focus on reversible underlying disease mechanisms rather than treating symptoms and subsequent multisystem pathological consequences”

“Recognising remission of diabetes can be a powerful motivator for patients to maintain weight loss.”

Type 2 Diabetes & Lifestyle MedicineMcCombie, et al. Beating type 2 diabetes into remission BMJ 2017;358:j4030 Sept (2017)

T2DM can now be understood to be a metabolic syndrome potentially reversible by substantial weight loss, and this is an important paradigm shift.

The observations carry profound implications for the health of individuals and for the economics of future health care.

Type 2 Diabetes & VLCDsStevens S et al. Very Low-Calorie Diet and 6 Months of Weight Stability in Type 2 Diabetes: Pathophysiological Changes in Responders and Nonresponders. Diabetes Care 2016 May;39(5):808-15

Unwin D et al. Low carbohydrate diet to achieve weight loss and improve HbA1c in type 2 diabetes and pre-diabetes: experience from one general practicePRACTICAL DIABETES VOL. 31 NO. 2 (2014)

Remission of Type 2 Diabetes

It could be said that starchy foods such as bread, pasta or rice are just concentrated sugar, and as such may represent a block to good diabetic control; even wholemeal bread has a higher glycaemic index (71) than table sugar itself (GI index 68). This is the basis for the low carbohydrate diet currently gaining popularity via the internet

A low carbohydrate diet was trialled in a primary care setting for 19 diabetic or pre-diabetic patients, bringing about improvements in health markers over an eight month period. Blood glucose control improved…..

Patients reported the diet was surprisingly easy to comply with and also noticed increasing energy levels. Seven patients were able to come off medication of one form or another

Type 2 Diabetes Remission

• Roy Taylor’s work

• 1g fat loss in pancreas

• Multiple methods

• Low Calorie

• Low Fat

• Low Carb

• Patients need choices!

Case Studies

• Rachel, 36 year old female

• Andrew, 55 year old executive

Case Study – Rachel

• 36 year old female

• Weight - 19st 10lbs

• Struggling to lose weight

• Lacking motivation and mood often low

• Mother had T2DM

• HbA1C – 7.3%

• Joint pains

• Fatigue

Exercise(Minimal)

Sunlight(vitamin D – deficient

Indoors a lot)

Genetics(positive family history)

Stress(Not much interaction at home. Eating in front of TV whilst scrolling social

media)

Diet(Highly processed)

Infections

Sleep(disturbed every night, wakes up tired every day)

Environment

Rachel

Symptom Web

4 Pillars

Rachel’s Lifestyle Prescription

• FOOD Cut out all refined and processed carbs, focus on wholefoods

• MOVEMENT 5 minute strength training in her kitchen, 2-3 times per week

• SLEEP No specific advice initially

• RELAXATION Sit around table to eat evening meal with family

• Vitamin D (found to be deficient and had joint pains)

5 Minute Kitchen Workout

After 1 week

• Within 3 days no more ankle pain

• More energy

• Sleep improving

• Managing to stick to 5 minutes strength training 2 times per week

30 days later

• Weight 17st 8lbs (was 19st 10lbs)

• HbA1C – 5.8% (was HbA1C –7.3%)

• Energy and sleep continuing to improve

Rachel’s results short term

3 months later

• Starting to cycle

• Walking more

• Mood improved

Changes have induced a feed forward cycle because Rachel is feeling better

2 years later

• HbA1c – 5.3%

• All managed herself

• She has been empowered

• She goes off-track but then self corrects

• Kitchen workout 5 times per week has become a habit

• Eat around a table

Rachel’s results long term

Case Study - Andrew• 55 year old executive

• 2 years Hx DM

• On Metformin 500mg BD

• HbA1c initially 8.0 - tried a ‘low carb’ diet and HbA1c came down to 7.0. Tired restricting carbs further, but HbA1c remained at 7.0

• Frustrated by lack of improvement

• Gym twice per week - cardio

• Working hard professionally and NO off time

• No relaxation

• Sleep impacted

Exercise(Strenuous cardio twice per week)

Sunlight(Indoors a lot)

Genetics

Stress(Busy executive AND

stressed re: blood sugars!)

Diet(Fantastic – Possibly being too aggressive

on low carb)

Infections

Sleep(Poor and work emails in bed)

Environment(Metformin 500mg)

Andrew

Symptom Web

Andrew’s Lifestyle Prescription

• FOOD Less aggressive on carb restriction

• MOVEMENT Stop cardio work outs and advised yoga instead

• SLEEP No work email after 8pm

• RELAXATION 10 minutes daily meditation app

2 months later

• Eating more carbs AND HbA1c 5.9

• Still on Metformin

• Sleep improved

• Enjoying Yoga and feeling benefit

Treat the system as a whole - body is interconnected

Andrew’s Results

2 years later

• Stopped Metformin

• HbA1c 5.5

• Feels in control of his health

• “I used to think it was just what I ate but now I understand how other aspects of lifestyle affect my blood sugar”

Conclusions: Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk.

The lifestyle intervention was more effective than metformin.

Lifestyle Intervention or Metformin?

Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002 Feb 7;346(6):393-403.