Diabetes

It is well recognised that at lower ranges of HbA1c (~7%), postprandial sugars contribute significantly to the HbA1c levels,  Diabetes Care. 2003 Mar;26(3):881-5 such that targeting post-meal values are likely to pay most dividends with regard to improved HbA1c levels. Postprandial sugars have also been shown to significantly correlate with cardiovascular outcomes in numerous studies. Lancet. 1999 Aug 21;354(9179):617-21;     Diabetes Care. 1999 Feb;22(2):233-40.   Yet, tight postprandial control of blood sugars remains underachieved in many diabetics despite the availability of alpha glucosidase inhibitors, sulphonylureas,  non-sulphonylurea secretagogues as nateglinide and repaglinide, and even the short acting insulin analogues.  In this context GLP-1, an incretin,  may have a significant beneficial role in improving post prandial insulin secretion.

Impaired GLP 1 secretion post prandially has been demonstrated  in the obese, Gut. 1996 Jun;38(6):916-9,  patients with impaired glucose tolerance test and type 2 diabetics Diabetes. 2001;50:609-613. Patients with IGT have GLP-1 responses intermediate between normals and type 2 diabetics.   GLP-1 clearance seems to be normal in type 2 diabetics and controls,  J Clin Endocrinol Metab. 2003 Jan;88(1):220-4. The cause for the decreased GLP-1 release in obese or diabetic patients  is not clear. Reversal of obesity with bypass surgery has resulted in improved GLP-1 and other gut hormone secretion up to 31 years post surgery,    Int J Obes Relat Metab Disord. 1997 May;21(5):387-92     although the effect of the surgery itself altering the bowel motility with resultant increased GLP-1 response remains a possibility.   Ann Surg. 1990 Jun;211(6):763-70   

It has also been shown that type 2 diabetic patients are less sensitive to GLP-1  relative to non-diabetic individuals. Diabetes. 2003;52:380-386.  The efficacy of GLP-1 to stimulate insulin secretion in type 2 diabetics was 71%,    J Clin Invest. 1993 Jan;91(1):301-7,  but better than that of GIP (46%).  It seems that the early phase response of insulin to GLP-1 might be decreased in type 2 diabetics while the late phase is relatively preserved.  Diabetologia. 2002 Aug;45(8):1111-9.

A polymorphism of the GLP-1 receptor involving a methionine substitution of a threonine residue at position 149 has been described in a type 2 diabetic patient.   Regul Pept. 2005 Aug 15;130(1-2):1-6.   Although expression of the variant GLP-1R was similar to the wild type receptor, it showed 60 times lower affinity for GLP-1  and five times lower affinity for Exendin-4.  While this polymorphism results in loss of function, further investigation is needed as to its possible screening and predictive value for type 2 diabetes. 
In 1992, GLP-1 infusion was shown to be effective in type 2 diabetics.  N Engl J Med. 1992 May 14;326(20):1316-22  The incretin role of GLP-1 suggests that it would be most effective in correcting postprandial hyperglycaemia. However, exogenous administration of GLP-1 ([7-37] or [7-36 amide]) in doses elevating plasma concentrations to approximately 3-4 fold physiological postprandial levels fully normalizes fasting hyperglycaemia in Type 2-diabetic patients   Diabetologia. 1993;36:741-744   and is attributable to its extra-pancreatic actions in the form of glucagon suppression and slowing of gastric emptying. Overnight intravenous GLP-1 infusion improves fasting blood sugars as well as both the first and second phases of insulin secretory responses to a further intravenous glucose challenge in type 2 diabetics,  Diabetes. 1996 Nov;45(11):1524-30. with improved beta cell function demonstrable on HOMA measurements.  In the same study, type 2 diabetic patients treated with intravenous insulin did not produce the improvement in insulin secretory capacity seen with GLP-1 infusion.

The glucose dependency of GLP-1 action is preserved in type 2 diabetic patients with no stimulation of insulin at blood sugar levels below 4.3 mmol/L (80 mg/dl). J Clin Endocrinol Metab. 2002 Mar;87(3):1239-46.  An intravenous GLP dose of 0.4-1.2 pmol/kg/min or a subcutaneous infusion at double the dose (2.4-4.8 pmol/kg/min) achieves GLP-1 concentrations in the blood in the range of 120 pmol/L of total GLP-1 [i.e. intact + inactive GLP-1]  or 20 pmol/L of intact GLP-1[GLP-1 (7-36) + GLP-1(7-37)]. These levels which are 3-4 times higher than normal postprandial levels can produce normalisation of blood glucose without significant nausea. Nausea seems to happen at much higher blood levels of total GLP-1 (~500pmol/L) or intact GLP-1 (100 pmol/L)  Diabetes. 1995 Sep;44(9):1126-31  with the advantage of a broad therapeutic range.

Is GLP-1 effective in all stages of diabetes? GLP-1 glucose-dependently stimulates insulin secretion in diet- and sulfonylurea-treated Type 2-diabetic patients and also in patients under insulin therapy long after secondary failure of Sulfonylureas with improved glycaemia.   Diabetes Care. 1998 Nov;21(11):1925-31.   Although intravenous GLP-1 in standard doses (1- 1.2 pmol/L) normalises fasting glucose fairly consistently, continuous subcutaneous administration with 2-3 times higher doses decrease but do not normalise fasting glucose levels, despite achieving similar amounts of [presently measured] bioactive intact GLP-1 concentrations.  Diabetes Care. 1999 Jul;22(7):1137-43.  Further clarification is needed on the modifications happening to the GLP-1 molecule during its transit through the adipose tissue with suitable assays to detect them!  In Nondiabetic and Type 2 diabetic human subjects, exogenous GLP-1 reduces hunger, caloric intake and body weight. Exogenous administration of GLP-1 seems to produce a negative feedback loop with a decrease in endogenous GLP-1 levels as determined by studies using administration of glycine extended GLP-1 (7-37 ) Diabetes Care. 1999 Jul;22(7):1137-43.

Studies of GLP-1 secretion in type I diabetes are few, but reduced GLP-1 secretion has been described in newly diagnosed type I diabetics. J Clin Endocrinol Metab. 1983 Jun;56(6):1306-12.  The improvement in glycaemia mediated through halving of glucagon secretion in type I diabetics  Diabetes Care. 1996 Jun;19(6):580-6.    seems to be effective only if fasting glycaemia is high. The effects on gastric emptying and resultant improved post prandial glycaemia could contribute further to overall glycaemic control.  Demonstration of decreased islet cell apoptosis and increased beta cell mass in vivo with GLP-1 therapy as has been demonstrated in rodents  is difficult in humans   with the presently available techniques.

So are the beneficial effects of GLP-1 sustainable? The effect of GLP-1 has been demonstrated to be maintained over 6 weeks suggesting that tachyphylaxis to GLP-1 did not occur. Improvement in HbA1c by 1.3% and a 1.9 kg reduction in bodyweight has been demonstrated with 6 weeks GLP 1 treatment. Lancet. 2002;359:824-830     GLP-1 as infusions do not seem to be an option as a long term treatment in diabetics despite the demonstration of its effectiveness by subcutaneous pump therapy,  Lancet. 2002 Mar 9;359(9309):824-30    but they might be useful in the control of hyperglycaemia in diabetics in the short term as in the settings of myocardial infarction, post surgery, Crit Care Med. 2004 Mar;32(3):848-51   or during total parenteral nutrition.  Regul Pept. 2004 Apr 15;118(1-2):89-97.

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    This page was last updated on: 07/03/2007

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