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.

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

Patients with type 1 diabetes and matched healthy control subjects