Amylin and Glucagon-Like Peptide-1 (GLP-1): Influence on Gastric Emptying, Appetite and Food Intake in Humans

The aim of this proposal is to dissect the mechanisms controlling gastric emptying, appetite and food intake in humans, and to obtain new knowledge to fight obesity on a pharmacological basis.

The objective of the present study is to elucidate the mechanisms behind the effects of glucagon-like peptide-1 (GLP-1) on gastric emptying, appetite and food intake. The first GLP-1 based anti-diabetic therapy was approved by the FDA in 2005 and is now on the market in the United States. The strong glucose-dependent insulinotropic property of GLP-1 is a highly attractive feature in the pursue of optimal glycaemic control in type 2 diabetes. Moreover, the potential of GLP-1 to reduce gastric emptying, appetite and food intake makes it an attractive tool in the fight against obesity, a pandemic condition that often leads to type 2 diabetes, and several companies are developing weight lowering drugs based on GLP-1. Interestingly, another peptide, amylin, exerts very similar effects on gastric emptying, appetite and food intake in humans. Amylin is found in insulin-rich granules in pancreatic beta-cells and is co-secreted with insulin upon insulinotropic stimuli. Currently, it is not known whether the inhibiting effects of GLP-1 on gastric emptying, appetite and food intake are directly mediated by GLP-1, or if the effects are secondary to the robust insulin responses, and thereby amylin responses, elicited by GLP-1. The objective of the present study is therefore to further elucidate the mechanisms of these effects in order to strengthen the development of anti-diabetic drugs with potential weight lowering capabilities.

Eligibility Criteria:
Inclusion Criteria:

* Patients with type 1 diabetes

  * Informed oral and written consent
  * Caucasians over the age of 18 years with type 1 diabetes (diagnosed according to the criteria of WHO) receiving long acting insulin
  * C-peptide negative glucagon test
  * Normal blood haemoglobin concentration
* Healthy control subjects

  * Informed oral and written consent
  * Caucasians over the age of 18 years
  * Normal 75 g- oral glucose tolerance test (OGTT) according to the criteria of WHO
  * Negative islet cell autoantibodies (ICA) and GAD-65 autoantibodies
  * No first-degree relatives with diabetes
  * Normal blood haemoglobin concentration

Exclusion Criteria:

* Patients with type 1 diabetes

  * Residual beta-cell function (evaluated with glucagon test)
  * Impaired hepatic function (aspartate aminotransferase (ASAT) and/or alanine aminotransferase (ALAT) \> 2 times upper normal limit)
  * Diabetic nephropathy (serum-creatinine \> 130 µM and/or albuminuria)
  * Diabetic neuropathy
  * Proliferative diabetic retinopathy
  * Pregnancy, breastfeeding or intention of becoming pregnant or judged to be using inadequate contraceptive measures
* Healthy control subjects

  * Impaired hepatic function (ASAT or ALAT \> 2 times upper normal limit)
  * Impaired renal function (serum-creatinine \> 130 μM and/or albuminuria)
  * First-degree relatives with diabetes
  * Pregnancy, breastfeeding or intention of becoming pregnant or judged to be using inadequate contraceptive measures