Clinical aspects of type 2 diabetes

Transcription

1 Clinical aspects of type 2 diabetes Soria Moria 26 August 2009 Henning Beck-Nielsen Professor, MD, DMSc Odense University Hospital/ University of Southern Denmark

2 Extrapopulation models for prevalence of diabetes in Denmark Number of patients 700,000 Simple extrapopulation Freeze of incidence and mortality rates at 2008 level IDF estimate Reduction of incidence rate of 5 % per year from 2008 Ultimo year Anders Green

3 Aetiological forms of T2D 80% of multigenetic and multifactorial origin: 70% obese 10% normal weight 5% of specific genetic origin: Monogenetic (MODY) Mitochondrial diabetes (MIDD) 15% of late onset autoimmune diabetes (LADA)

4 Obesity-induced diabetes mellitus Overeating + leisure lifestyle + genetic predisposition Obesity Photo: Michael Krumphanzl, AP Politiken Sunday 7 April 2002 Abdominal obesity Big insulin resistant fat cells (hypertrophia) BMI around 30 kg/m 2 Increased plasma FFA Decreased plasma Adiponectin Subcutaneous obesity Small relative insulin sensitive fat cells (hyperplasia) BMI > 40 kg/m 2 Unchanged plasma FFA Unchanged plasma Adiponectin Type 2 Diabetes NGT

5 Maturity onset diabetes of the young (MODY) Monogenic form of diabetes Autosomal dominant mode of inheritance Diabetes appears at a low age Impaired insulin secretion is a major phenotypic trait Different subtypes due to mutations in different genes

6 Known MODY subtypes MODY subtype MODY1 MODY2 Mutated gene HNF-4α Glukokinase Severity of diabetes Severe (insulin deficiency, frequent complications) Mild (defect glucose sensing) MODY3 MODY4 HNF-1α IPF-1 Severe (insulin deficiency, frequent complications)? (insulin deficiency) MODY5 HNF-1β Severe (insulin deficiency, kidney abnormalities) MODY6 NeuroD Severe (insulin deficiency)

7 The A3243G Mutation may cause the Syndroms Maternally Inherited Diabetes and Deafness (MIDD) Other symptoms observed: Opthalmoplegia Occipital infarcts Basal-ganglia calcification Hypertrophic cardiomyopathy Inter-individual differences in time of debut, the severity and the combination of symptoms are observed

8 Putative type 2 diabetes susceptibility variants PPARG: peroxisome proliferator-activated receptor-γ KCNJ11: inwardly rectifying potassium channel PPARGC1A: PPAR-γ coactivator-1α HNF4A: hepatocyte nuclear factor-4α CAPN10: calpain-10 PTPN1: protein tyrosine phosphatase 1B ACDC: adiponectin IL6 and IL6R: interleukin-6 and its receptor SLC2A2: glucose transporter 2 LTA: lymphotoxin-α LIPC: hepatic lipase ENPP1/PC1:plasma cell glycoprotein-1 PYY: prepropeptide YY

9 New gene variants (2007) TCFL2 SLC30A8

10 LADA definition Anti-GAD positive subjects Onset after 35 years of age No initial ketoacidosis H. Beck-Nielsen et al, in preparation

11 The four musketeers and their contribution to T2D Liver VLDL FFA Adiponectin + Adipose tissue Glucose Beta-cells FFA + + Insulin (response) Muscle

12 Glucose turnover (mg/m 2 /min) Dose-response effect of insulin in DM2 T2D Obese controls Obese DM 2 * * * * Rd HGP Plasma insulin (mu/l) Staehr et al Diabetes 2001;50:1363

13 Glucose homeostasis The Sink Model Normal subjects T2D subjects R a R a Plasma glucose 12 mm 5 mm R d R d R a = Rate of glucose appearance Insulin resistance R d = Rate of glucose disappearance

14 Effect of Fasting Plasma Glucose Acute Insulin Response Relative acute insulin response (% increase) FPG (mg/dl) (n=24) (n=20) (n=7) (n=3) (n=12) Brunzell et al (1976) Time (minutes)

15 Can correction of the patophysiological defects normalise plasma glucose?

16 Effect of a High-Protein, Low Carbohydrate Diet on Blood Glucose Control in People With Type 2 Diabetes Mary C. Gannon and Frank Q. Nuttall Diabetes 2004;53:2375

17 Energy (kcal) Protein (g) Carbohydrate (g) Fat (g) Cholesterol (mg) Dietary fiber (g) Composition of diets of T2D patients Monosaccharides (g) Disaccharides Monounsaturated (g) Polyunsaturated (g) Saturated (g) Control 2, (15%) 388 (55%) (30%) LoBAG 2, (30%) 142 (20%) (50%) MC Gannon Diabetes 2004;53:2375

18 A: Mean plasma glucose concentration before ( ) and after (o) 5 weeks on the control diet. Side graph: Net and total 24-h integrated glucose area response. Area response was not significantly different. B: Mean plasma glucose concentration before ( ) and after ( ) 5 weeks on the LoBAG diet. Side graph: Net and total 24-h integrated glucose area response. *Both the net and the total area responses were significantly lower after the LoBAG diet (P 0.05). MC Gannon Diabetes 2004;53:2375

19 A: Mean serum insulin concentration before ( ) and after ( ) 5 weeks on the control diet. Side graph: Net and total 24-h integrated insulin area response. Area response was not significantly different. B: Mean serum insulin concentration before ( ) and after ( ) 5 weeks on the LoBAG diet. Side graph: Net and total 24-h integrated insulin area response. *Both the net and the total area responses were significantly lower after the LoBAG diet (P 0.05). MC Gannon Diabetes 2004;53:2375

20 The combined effect of Insulin Aspart, Metformin and Rosiglitazone in the Treatment of Type 2 Diabetes Mellitus Patients. A Randomized Control Group Controlled Study Mikael Kjær r Poulsen, Jan Erik Henriksen and Henning Beck-Nielsen Department of Endocrinology Odense University Hospital

21 At randomization 17 patients were block randomized with 8 and 9 patients in the control and intervention group respectively. The control group (8 patients): continue their usual antidiabetic insulin treatment The intervention group (9 patients): Tabl. Glucophage (Metformin) 1 gram x 2 (at breakfast and at dinner). Tabl. Avandia (Rosiglitazone) 8 mg x 1, (at breakfast). Insulin NovoRapid just before every main meal (at breakfast, lunch and dinner).

22 Profiles after 6 months of treatment Mean blood glucose conc. after 6 months of treatment Control Intervention 16,0 B-glucose conc. / mmol/l 14,0 12,0 10,0 8,0 6,0 4,0 2,0 0,0 08:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 00:00 02:00 04:00 06:00 08:00 Time / am-pm.

23 HbA1c HbA1c / % 11,0 10,5 10,0 9,5 9,0 8,5 8,0 7,5 7,0 6,5 HbA1c (mean) (Normale range: %) 6,0 Inclusion Rand. 2 months 4 months 6 months Time / months Control Intervention

24 Conclusion Hyperglycaemia in T2D subjects can be normalised, but it often requires a combination therapy of all four patophysiological components. The long term effect of this correction of dysmetabolism into normo-metabolism is awaited.

25 Can normalisation of blood glucose values prevent cardiovascular disease?

26 UKPDS - optimal glucose control reduces the risk of complications! Complications micro / macrovascular 600 Any improvement of control is beneficial! 500 % ,0 7,0 8,0 9,0 10,0 HbA 1c

27 ACCORD: Treatment effects on glucose control Standard therapy A1C (%) Intensive therapy Time (years) 6 ACCORD Study Group. N Engl J Med. 2008;358:

28 ACCORD: Treatment effect on primary outcome 25 Patients with events (%) HR 0.90 ( ) P = 0.16 Standard therapy 5 Intensive therapy Time (years) ACCORD Study Group. N Engl J Med. 2008;358:

29 ACCORD: Treatment effect on all-cause mortality Patients with events (%) HR 1.22 ( ) P = 0.04 Intensive therapy Time (years) Standard therapy ACCORD Study Group. N Engl J Med. 2008;358:

30 ACCORD : Hypoglycemia

31 UKPDS 25 years follow up Insulin, SU Metformin

32 UKPDS 25 years follow up

33 UKPDS 25 years follow up

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35 Type 2 Diabetes Treatment Priorities Glucose control as near to normal as reasonably possible Treat Microvascular disease Macrovascular disease Insulin resistance, Hyperinsulinaemia, Obesity, Glucose intolerance, Dyslipidaemia, Hypertension, Pro-coagulant state, Atherosclerosis

36 modest Very good

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38 Algorithm for the metabolic management of type 2 diabetes Diabetologia 2009; 52: 17