Insulin secretory capacity and the regulation of glucagon secretion in diabetic and non-diabetic alcoholic cirrhotic patients.
OBJECTIVE
Insulin secretion is increased in cirrhotic patients without diabetes but decreased in cirrhotic patients with diabetes. Increased glucagon secretion is found in both groups. Our aim was to determine: 1) whether alterations in insulin secretion are due to changes in maximal secretory capacity or altered islet B-cell sensitivity to glucose, and 2) whether regulation of glucagon secretion by glucose is disturbed.


METHODS
Insulin, C-peptide and glucagon levels were measured basally and during 12, 19 and 28 mmol/l glucose clamps, and in response to 5 g intravenous arginine basally and after 35 min at a glucose of 12, 19 and 28 mmol/l in 6 non-diabetic alcoholic cirrhotic patients, six diabetic alcoholic cirrhotic patients and six normal controls.


RESULTS
Fasting insulin, and C-peptide levels were higher in cirrhotic patients than controls but not different between diabetic and non-diabetic patients. C-peptide levels at t=35 min of the clamp increased more with glucose concentration in non-diabetic cirrhotic patients than controls; there was little increase in diabetic cirrhotic patients. At a blood glucose of approximately 5 mmol/l the 2-5 min C-peptide response to arginine (CP[ARG]) was similar in all groups, but enhancement of this response by glucose was greater in non-diabetic cirrhotic patients and impaired in diabetic cirrhotic patients. Maximal insulin secretion (CP(ARG) at 28 mmol/l glucose) was 49% higher in the non-diabetic cirrhotic patients than controls (p<0.05); in diabetic cirrhotic patients it was 47% lower (p<0.05). The glucose level required for half-maximal potentiation of (CPARG) was not different in the three groups. Cirrhotic patients had higher fasting glucagon levels, and a greater 2-5-min glucagon response to arginine, which was enhanced by concomitant diabetes (p<0.001 vs controls). Suppression of plasma glucagon by hyperglycaemia was markedly impaired in diabetic cirrhotic patients (glucagon levels at 35 min of 28 mmol/l glucose clamp: diabetics, 139 x/divided by 1.25 ng/l, non-diabetic cirrhotic patients, 24 x/divided by 1.20, controls, 21 x/divided by 1.15, p<0.001). Suppression of arginine-stimulated glucagon secretion by glucose was also impaired in diabetic cirrhotic patients, and to a lesser extent in non-diabetic cirrhotic patients.


CONCLUSIONS
Insulin secretory abnormalities in diabetic and non-diabetic cirrhotic patients are due to changes in maximal secretory capacity rather than altered B-cell sensitivity to glucose. The exaggerated glucagon response to arginine in alcoholic cirrhotic patients is not abolished by hyperglycaemia/hyperinsulinaemia. In diabetic alcoholic cirrhotic patients, the inhibitory effect of glucose on basal glucagon secretion is also markedly impaired.
Kruszynska
Y T
YT
Department of Endocrinology and Metabolism, VA Medical Center, University of California San Diego, La Jolla 92093, USA.
Goulas
S
S
Wollen
N
N
McIntyre
N
N
D000328:Adult; D000368:Aged; D001120:Arginine / Q000494:pharmacology; D001481:Basal Metabolism; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000378:metabolism; D016022:Case-Control Studies; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D005934:Glucagon / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D006943:Hyperglycemia / Q000097:blood; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects*; D008104:Liver Cirrhosis, Alcoholic / Q000150:complications / Q000503:physiopathology*; D008875:Middle Aged; D012636:Secretory Rate / Q000187:drug effects
D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D005934:Glucagon; D001120:Arginine; D005947:Glucose