Clinical Aspects of Hypoglycemia in Diabetes – Consequences and Prevention

Approach to management of hyperglycemia Figure

Patient-Centered Approach to Type 2 Diabetes

Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

Glycemic Targets:

1. Target HbA1c < 7.0%

• In most patients to reduce the incidence of microvascular disease
• Mean plasma glucose of ~ 8.3-8.9 mmol/L
• Fasting and premeal glucose < 7.2mmol/L
• Postprandial glucose < 10 mmol/L

2. Target more stringent HbA1c (e.g., 6.0-6.5%)

• In selected patients such as short disease duration, long life expectancy, no significant cardiovascular disease (CVD) if this can be achieved without significant hypoglycemia or other adverse effects of treatment

 

3. Target less stringent HbA1c (e.g., 7.5-8.0% or even slightly higher)

• In patients with history of severe hypoglycemia, limited life expectancy, advanced complications, extensive comorbid conditions and those in whom the target is difficult to attain despite intensive self-managment education, repeated counseling, and effective doses of multiple gluocse-lowering agents, including insulin.

 

Reference:

1. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;25:1364-79

Exendin - A New Incretin?

ADA June 2012 Conference

Alpha cells and the origin of glucagon-like sequences and their receptors

David M. Irwin, Department of Laboratory Medicine and Pathobiology, University of Toronto

Summary of presentation:

Incretin Hormones – 2 known human incretin hormones

-          Glucagon-like peptide 1 (GLP-1)

-          Glucose-dependent insulinotropic peptide (GIP)

Other incretins = Exendin

-          Long acting GLP-1 analogue

o   Acts through the GLP-1 receptor

o   Have increased circulating half-life

o   Synthetic version marketed

-          From the venom of a lizard (Gila monster)

-          No known orthologs in vertebrates, not a product of the proglucagon gene

-          Anole Lizard Exendin – sequence of peptides are not similar to GLP-1 or GIP (human genome)

-          Other animals had similar exendin to lizard (chicken, turkey, duck, zebra finch, xenopus)

-          Exendin 1, 2, 3,and 4 sequences – exendin 3 and 4 are GLP-1 like in their sequence and function; exendin 1 and 2 similar to the are GIP-like in sequence and function

-          Expression of the exendin gene in the chicken and xenopus brain – who knows what it is duing there?

-          No exendin gene in human genome!

-          Exendin genes are found in birds, reptiles and frogs

-          No obvious candidate receptor for exendin; glucagon, GLP1, GLP2, and GIP act through related receptors

-          There are novel group of receptors present in fish, reptiles, birds that are NOT present in mammals – why do mammals not have this gene?

-          GLP1 receptors not found in fish

-          GCGR – duplicated in fish (glucagon receptors)

-          GLP2R – single copy in all species

-          GIPR – no intact gene found in birds

-          GRLR – not found in mammals (glucagon-receptor-like-receptors

Conclusion

o   Genomic data useful for identifying new genes

o   Continues to yield surprises

o   Hormone and receptor families are larger and more complex

-          Open questions

o   What does exendin do in other vertebrates?

o   Is GRLR the receptor for exendin?

o   Why do humans (all mammals) not have Exendin/GRLR?

o   What ligand/receptor has replace the function of Exendin/GRLR in mammals?

ADA 2012 Part 1

Omega-3 Fatty Acids & CV outcomes in patients with dysglycemia

Clinical Question
In patients at high risk for cardiovascular events and have impaired fasting glucose, impaired glucose tolerance, or diabetes, what are the benefits (death from cardiovascular causes) and risks (adverse effects) of 1-g n-3 fatty acids (containing at least 900mg of ethyl esters) compared to placebo at 6.2 years of therapy?

Answer
Efficacy Outcomes
In 12,536 patients (n=6281 in n-3 fatty acid group and n=6255 in placebo group), there was no statistical difference in the primary outcome of death from cardiovascular causes after a median follow-up of 6.2 years.  All secondary outcomes (mycoardial infarction, stroke, death from cardiovascular causes, death from any cause/arrhythmia, hospitalization for heart failure, revascularization procedure, angina, limb or digit amputation for ischemia, and hospitalization for any cardiovascular cause) were all non-significant.  By the end of the trial, patients in the group receiving n-3 fatty acids had a mean reduction in the triglyceride level of 0.16mmol/L as compared to placebo (p<0.001).  No significant between-group differences in the levels of other lipid fractions, plasma glucose levels, glycated hemoglobin levels, blood pressure, or heart rate.

Adverse Effects
The most commonly reported reasons for permanently stopping a study drug was abdominal discomfort (n=32 (0.51%) in the n-3 fatty acid group and 18 (0.29%) in the placebo group), lower gastrointestinal symptoms (n=14 in n-3 fatty acid group and 24 in the placebo group).  Bleeding was reported in 57 (0.91%) patients receiving n-3 fatty acids, as compared with 65 (1.04%) patients in the placebo group, with intracranial bleeding reported in 42 patients, and 51 patients, respectively.



Reference:  The ORIGIN Trial Investigators. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 2012.published on June 11, 2012.

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