New developments in diabetes
- Hypoglycaemia
- Glucose-sensors, pumps
Bruce H.R. Wolffenbuttel, internist-endocrinologist University Medical Center Groningen
Dept. of Endocrinology: www.umcg.net Blog: www.gmed.nl
Twitter: @bhrw
1986
1
Hypoglycaemia pathophsyiology
Symptoms
Many definitions of hypoglycaemia ?
• Low plasma glucose causing neuroglycopaenia
• Clinical definition of hypoglycaemia:
• Mild: self-treated
• Severe: requiring help for recovery
• Biochemical definition of low plasma glucose:
• ≤3.9 mmol/L (prev. 3.1 mmol/L EMA)
• ≤3.9 mmol/L (ADA)
• 3.0 mmol/L is clinically important hypo !!
Hypoglycaemia related to diabetes type & duration
UK Hypoglycaemia Study Group. Diabetologia 2007;50:1140-7
Type 1 diabetes:
Diabetes Control & Complications Trial
Intensive therapy = better control =
fewer complications = higher chance of (severe) hypoglycaemia
Physiological responses preventing hypoglycaemia
Zammit and Frier. Diabetes Care 2005:28:2948–61 Courtesy of prof. S. Heller
Factors contributing to hypoglycaemia
• Failure to clear circulating insulin during hypoglycaemia (s.c. insulin depot, effect SU)
• Loss of normal pancreatic alpha cell responses (glucagon, usually after > 5 yrs of T1D)
• Lower glucose threshold for release of counterregulatory hormones
Amiel SA, et al. Diabetes 1988; McNeilly and McCrimmon. Diabetologia 2018 online
Counterregulatory failure in type 1 diabetes
No diabetes
Conventionally treated type 1 diabetes
Intensive insulin therapy
Suppressed counterregulatory hormonal
and symptomatic responses to hypoglycaemia
Impaired hypoglycaemia awareness
Zammit and Frier. Diabetes Care 2005:28:2948–61 Courtesy of prof. S. Heller
• Smoke detector
• Metal detector
• Carbon monoxide detector
• Glucose sensor
Hypo case: CGM with alarms may save brain cells
• 16 year young man, T1diabetes since age of 6, HbA1c 7.4%
• MiniMed CGMS (without real time data or alarm) during diabetes camp
• Nocturnal hypo < 2.4 mmol/l was present 4 hrs before
epileptic attack / seizure
Buckingham et al. Diabetes Care 2008; 31: 2110-2
Hypo case 2
• 12 yrs old, MiniMed CGMS- Gold monitor (without real time data or alarm).
• Type 1 diabetes since age of 8 yrs, HbA1c 9.0%
• Hypoglycemia since 22 hr, seizure at 2 a.m.
• All glucose values < 3.4 mmol/l
• First seizure, glucagon injection
Buckingham et al. Diabetes Care 2008; 31: 2110-2
Hypo case 3
• 16 year old girl, type 1 diabetes since age of 1 yrs
• Hypoglycaemia since 3 a.m., seizure around 7 a.m.
• ‘Original’ CGMS, without alarm
• HbA1c 8.8%
• This was first seizure; was treated with glucagon
Buckingham et al. Diabetes Care 2008; 31: 2110-2
Hypo case 4
• 17 yr old girl, type 1 diabetes since age of 7, MiniMed 722 Paradigm real-time continuous glucose monitor
• No prior serious hypoglycaemia
• Sensor sounded alarm during 2 hours before seizure /
epileptic attack occurred, slept under thick blanket which muted the alarm sounds of the sensor
• When entering the girls room, her parents did not hear the alarm either
Buckingham et al. Diabetes Care 2008; 31: 2110-2
Hypo case 4
Buckingham et al. Diabetes Care 2008; 31: 2110-2
Recognition of hypoglycaemia
• CGM suggest unrecognised hypoglycaemia is common in insulin-treated diabetes:
• 63% of pat’s with T1D and 47% with T2D had unrecognised hypoglycaemia measured by CGM (n=70), 3/4 occurred at night
• 83% of hypoglycaemic episodes detected by CGM were not detected by patients with T2D (n=31), 55% were nocturnal
Chico et al. Diabetes Care 2003;26:1153–7;
Weber et al. Exp Clin Endocrinol Diabetes 2007;115:491–4
Impaired awareness of hypoglycaemia (IAH)
• Hypoglycaemia is detected by integrated network of
specialised cells throughout the body, mainly in the brain
• People with diabetes have widespread defects in the physiological response to hypoglycaemia
• Recurrent prior hypoglycaemia leads to IAH development
• IAH affects 25% of T1D and 10% of insulin-treated T2D
Possible causes / factors adding to reduced hypoglycaemia unawareness
• Long duration of diabetes
• Tight glycaemic control
• Repeated / earlier hypoglycaemia
• Increasing age
• Sleep
• Exercise
• Drugs, f.i. nonselective beta-blockers
• Alcohol
ACCORD study in T2D showed high incidence of severe hypoglycaemia
intensive control arm stopped prematurely because of increased C.V. events
p<0.001
(HbA1c<6.5%)
Diabetes
hypoglycaemia
low grade inflammation
C.V. event
metabolic imbalances
acceleration of atherosclerosis upregulation HPA -axis/ GH↑
cardiac arrhythmia treatment
ischaemia
Genes?
dietary factors?
metabolic syndrome
adverse effect on vasculature which is already damaged in diabetes
Hazard ratios for all-cause mortality by HbA1c deciles
oral combination insulin-based therapies
Currie CJ, et al. Lancet 2010; 375: 481–89
Primary care database on diabetes treatment in England:
1. Those on insulin had more c.v. disease & renal insufficiency 2. With very low HbA1c, we observe an increase in mortality
Severe hypoglycaemia is associated with high costs
• Drivers of costs:
• Assistance from medical personnel, G.P., or hospital admission
• Additional clinical appointments, telephone contacts
• Increasing number of BG measurements
• Productivity costs, sick leave
• Estimated total costs of severe hypoglycaemia:
• T1DM: € 552; T2DM: € 1036.
De Groot S, et al. BMJ Open 2018;8:e019864
Avoiding hypoglycaemia restores awareness
• Intervention: total avoidance of hypo for 4 mo’s
• Result: improvement of adrenalin response;
improvement of symptom response
• Even 3 weeks of hypo avoidance improves awareness
Cranston, Lancet, 1994; Dagogo-Jack S. Diabetes 1994
The ‘hypo dog’
Los et al, Journal of Diabetes Science and Technology, 2017.
• Woman, 48 yrs, cystic fibrosis, lung transplantation
• Immunosuppressive therapy, chronic antibiotics
• Insulin-treated diabetes (CF-related)
• Repeated infections with Pseudomonas & other
• Severe recurrent hypoglycaemia with (car) accidents
• 2012 Islet-cell transplantation
• 2018 still insulin-INDEPENDENT, no hypoglycaemia, no severe infections
2
Sensor technology to the rescue ………?
Het is niet alles goud dat er blinkt ……
FreeStyle Libre
Vergoed voor:
Type 1 diabetes met HbA1c > 8.0%
Kinderen
Zwangerschap(swens)
FreeStyle Libre – stoorfactoren (1)
FreeStyle Libre in a ‘normoglycaemic’ individual
FreeStyle Libre – example chart
Developments of measuring glucose
Most critical: measurement in low BG area
RT-CGM sensors anno 2018
Most critical: measurement in low BG area
Setting alarms
Parental supervision
The technology to prevent hypo is here
The technology to prevent hypo is here
The technology to prevent hypo is here
The technology to prevent hypo is here
The technology to prevent hypo is here
Dazed and confused …….
3
Kijk mama, met losse handen
Concept of the artificial pancreas (AP)
Device development in AP
Summary
• Hypoglycaemia in diabetes
• longer-term diabetes
• strict glycaemic control
• high costs and consequences
• Sensor technology helpful in early detection and prevention
• alarm when BG drops too fast
• insulin pump stops when hypo is imminent
• artificial pancrease development ongoing
For more information
• DEXCOM: https://www.dexcom .com
• Medtronic:
http://www.professional.medtronicdiabetes.com/minimed- 670g-insulin-pump-system
• Abbott: https://www.freestylelibre.nl/
• Endocrinologie UMCG: https://umcg.net/
