Reference: New Mechanisms in Glucose control. First Edition, Anthony H. Barnett & Jenny Grice. 2011. Blackwell Publishing Ltd.

1. There are approximately 285 million people with diabetes all over the world as of 2010.

2. There are 3 mechanisms involved in the pathogenesis of Type 2 diabetes: insulin resistance leading to decreased uptake of glucose in muscle, liver and fat; increased glucose output by the liver; and, an insulin secretory defect in the pancreas. Of these three mechanisms, the first to appear in most people is insulin resistance. Obesity, particularly abdominal obesity, is strongly associated with insulin resistance. Insulin resistance leads to increased secretion of insulin which subsequently causes beta cell exhaustion and insulin secretory defects.

3. Insulin secretion by the pancreas is in 2 phases. First phase refers to the insulin secreted immediately after a meal and Second phase refers to the insulin secreted much later. It is the first phase of insulin secretion that becomes defective initially in Type 2 diabetes. This results in postprandial hyperglycemia. When the second phase also becomes defective, fasting hyperglycemia results.

4. The inevitable decline in insulin secretory function may be linked to factors like excessive stimulation of the beta cells, glucotoxicity and lipotoxicity. Those with Type 2 diabetes also have a lower than normal level of Glucagon-Like Peptide 1(GLP1). Since GLP 1 enables glucose-mediated insulin release, suppresses glucagon release and improves insulin sensitivity while also slowing gastric emptying, it is possible that this incretin hormone is also associated with the pathogenesis of Type 2 diabetes.

5. The prevalence of diabetes is higher in those belonging to a low socioeconomic class in England. On the contrary, in developing countries, there is increased prevalence of diabetes in higher socioeconomic groups.

6. People from the Indian subcontinent, Mexican Americans and African Americans are more likely to develop insulin resistance when they become obese or adopt a sedentary lifestyle when compared to Caucasians.

7. The ADVANCE study and the VADT study have raised doubts about the desirability of HbA1c values less than 7 percent in the elderly with long duration of diabetes while the ACCORD study showed that HbA1c values below 6 percent in this group of patients did not benefit them.

8. The UKPDS -80 trial which was a follow up of the original UKPDS trial showed that intensive glycemic control in newly diagnosed diabetics was beneficial by reducing microvascular complications and myocardial infarctions and that this benefit persisted even ten years after glycemic control was no longer so intensive.

9. There are now 8 classes of non-insulin antidiabetes therapies for type 2 diabetes: metformin, sulphonylureas, meglitinides, thiazolidinediones, alpha glucosidase inhibitors, amylin analogues, glucagon like peptide -1 receptor agonists and dipeptidyl peptidase 4 inhibitors.

10. Metformin can reduce HbA1c by a maximum of 1.5 percent as monotherapy. Sulphonylureas also do the same but much more quickly. Pioglitazone works slowly and reduces the HbA1c by a maximum of 1.5 percent as monotherapy but scores over Metformin and Sulphonylureas in that it preserves beta cell function and has non glycemic benefits in the lipid profile and inflammatory markers. It may however increase the risk of distal bone fractures.

11. The incretin system of peptides was detected by the observation that orally administered glucose stimulated a far greater release of insulin than the same amount of glucose given intravenously. The incretin system consists of two hormones: GLP 1 and GIP (Glucose dependent insulotropic polypeptide). GLP 1 also inhibits secretion of glucagons, reduces appetite and delays gastric emptying.

12. There are classes of drugs that utilize the incretin system for glycemic control – the incretin mimetics like exenatide and liraglutide and the DPP 4 inhibitors like sitagliptine and vildagliptine.

13. Exenatide must be injected twice daily; Liraglutide needs to be injected only once daily. Both can cause nausea but liraglutide causes less nausea than exenatide. These drugs can be considered in those diabetics not adequately controlled with diet and metformin or diet, metformin and sulphonylurea. They are particularly useful for those in whom the risk of hypoglycemia must be absolutely minimized and for those who are obese. They can also be considered for those who are averse to the frequent monitoring of blood sugar needed with insulin injections.

14. The DPP 4 inhibitors can be considered for those whose blood sugar is not controlled well with metformin or a sulphonylurea alone. Sitagliptine can also be given for those whose control is not good on both metformin and a sulphonylurea or for those on insulin. The DPP 4 inhibitors are particularly useful for the elderly because they are given orally, they do not cause weight gain and they have a low potential for hypoglycemia and drug-drug interactions.

15. Bariatric surgery – gastric banding and Roux-en-Y gastric bypass – is an effective treatment for obesity. It also appears to lead to normalization of blood sugar in a large number of those who have diabetes.

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