The effect of sulphonylurea therapy on skeletal muscle glycogen synthase activity and insulin secretion in newly presenting type 2 (non-insulin-dependent) diabetic patients.
Ten newly presenting, Type 2 (non-insulin-dependent), Caucasian diabetic patients were studied before and after 8 weeks treatment with the sulphonylurea gliclazide, and in parallel 13 similar patients were studied before and after 8 weeks treatment with diet alone. Eight non-diabetic subjects were also studied. Insulin action was assessed by measuring activation of skeletal muscle glycogen synthase (GS) prior to and during a 4-h hyperinsulinaemic euglycaemic clamp (100 mU kg-1 h-1). Fasting plasma glucose (+/- SE) and glycosylated haemoglobin decreased to a greater extent in the gliclazide treated patients (fall of 6.2 +/- 0.7 vs 2.1 +/- 0.5 mmol l-1, p less than 0.005 and 4.7 +/- 0.5 vs 2.1 +/- 0.5%, p less than 0.005). This was accompanied by an increase in fasting serum insulin concentrations in the gliclazide treated patients (7.0 +/- 1.3 to 10.1 +/- 1.1 mU l-1, p less than 0.005), but no change in the diet treated patients. Fractional GS activity did not increase during the clamp at presentation in either treatment group (change +2.9 +/- 1.8 and -1.5 +/- 1.9%, respectively) whereas it increased markedly in the control subjects (+16.4 +/- 3.4%, both p less than 0.001). After 8-week treatment there was a significant increase in GS activity during the clamp in the patients receiving gliclazide (+6.9 +/- 2.7%, p less than 0.05), but no change in GS activity in the patients on diet alone (+0.5 +/- 1.4%). The difference in post-treatment muscle insulin action was significant (p less than 0.05). There was no correlation between the degree of improvement in metabolic control and the improvement in response of GS to insulin in the gliclazide treated patients (r = -0.06), suggesting a possible direct drug effect on skeletal muscle. Glucose requirement during the clamp at presentation was markedly lower in both treatment groups than in the non-diabetic subjects (gliclazide 2.1 +/- 0.3, diet 2.0 +/- 0.6 vs 7.8 +/- 0.4 mg kg-1 min-1, both p less than 0.001), and despite a marked improvement in both groups after treatment (4.3 +/- 0.4 and 3.1 +/- 0.5 mg kg-1 min-1, both p less than 0.001) remained lower than in the non-diabetic subjects (p less than 0.001).(ABSTRACT TRUNCATED AT 400 WORDS)
Johnson
A B
AB
Department of Medicine, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
Argyraki
M
M
Thow
J C
JC
Jones
I R
IR
Broughton
D
D
Miller
M
M
Taylor
R
R
D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology*; D003927:Diet, Diabetic; D005215:Fasting; D005260:Female; D005907:Gliclazide / Q000627:therapeutic use*; D006442:Glycated Hemoglobin / Q000032:analysis; D006006:Glycogen Synthase / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D000078790:Insulin Secretion; D061389:Insulin, Regular, Pork; D008297:Male; D008875:Middle Aged; D009132:Muscles / Q000201:enzymology*; D011897:Random Allocation; D011994:Recombinant Proteins / Q000494:pharmacology
D001786:Blood Glucose; D002096:C-Peptide; D005907:Gliclazide; D006442:Glycated Hemoglobin; D006006:Glycogen Synthase; D007328:Insulin; D061389:Insulin, Regular, Pork; D011994:Recombinant Proteins; C000006:insulin, neutral