Objective: Alterations in lipids in muscle and plasma have been documented in insulin-resistant people with obesity. Whether these lipid alterations are a reflection of insulin resistance or obesity remains unclear. Methods: Nondiabetic sedentary individuals not treated with lipid-lowering medications were studied (n 5 51). Subjects with body mass index (BMI) > 25 kg/m 2 (n 5 28) were stratified based on median glucose infusion rate during a hyperinsulinemic-euglycemic clamp into insulin-sensitive and insulin-resistant groups (above and below median, obesity/insulin-sensitive and obesity/insulin-resistant, respectively). Lean individuals (n 5 23) served as a reference group. Lipidomics was performed in muscle and plasma by liquid chromatography electrospray ionization-tandem mass spectrometry. Pathway analysis of gene array in muscle was performed in a subset (n 5 35).Results: In muscle, insulin resistance was characterized by higher levels of C18:0 sphingolipids, while in plasma, higher levels of diacylglycerol and cholesterol ester, and lower levels of lysophosphatidylcholine and lysoalkylphosphatidylcholine, indicated insulin resistance, irrespective of overweight/obesity. The sphingolipid metabolism gene pathway was upregulated in muscle in insulin resistance independent of obesity. An overweight/obesity lipidomic signature was only apparent in plasma, predominated by higher triacylglycerol and lower plasmalogen species. Conclusions: Muscle C18:0 sphingolipids may play a role in insulin resistance independent of excess adiposity.Obesity (2016) 24, 908-916.

We investigated the importance of glucagon in the development of diabetic ketoacidosis by withholding insulin from six patients with juvenile-type diabetes and four totally pancreatectomized subjects. Patients were fasting and had previously been maintained on intravenous insulin for 24 hours. In diabetic patients plasma glucagon concentrations rose sharply after withdrawal of insulin, and the increases were accompanied by a rise in blood ketone concentration of 4.1+/-0.7 (S.E.M.) and blood glucose concentration of 12.5+/-1.8 mmol per liter by 12 hours. In the pancreatectomized patients, despite the absence of measurable glucagon, blood ketones rose by 1.8+/-0.8 and blood glucose by 7.7+/-1.5 mmol per liter. Thus, glucagon is not essential for the development of ketoacidosis in diabetes, as has previously been suggested, but it may accelerate the onset of ketonemia and hyperglycemia in situations of insulin deficiency.

Previous studies of the pancreatic exocrine response to intraduodenal glucose administration have not demonstrated the release of secretin; consequently, the importance of secretin in the enteric insulin release mechanism has been questioned.In tbis study, serum levels of secretin were estimated by radioimmunoassay in three normal subjects after oral, intravenous or intraduodenal administration of glucose (1 gm per Kg). No secretin response was recorded during the intravenous study but sirnilar peak levels (12 to 18 ng per ml) were observed with the oral and intraduodenal routes of administratioIL The initial response was rapid in both instances, but the effect was more prolonged after intraduodenal administration. As secretin is known to potentiate the glycaemic release of insulin, it is postulated that this hormone is a major factor in the augmented insulin response observed during both oral and intraduodenal studies.Horm. Metab. Res. 3: 180·183 (1971) K e y -W 0 r d s: Secretin Release -Insulin Release -Glu· cose Administration -Radioimmunoassay

No abstract

The relative potency of porcine insulin and semisynthetic human insulin has been examined in humans using the euglycaemic glucose clamp technique. Three 90 minute consecutive infusions at 2.4, 4.8 and 7.2 units/hr were administered to 7 normal subjects. The rate of glucose infusion (mg/min, mean +/- SEM) required to maintain euglycaemia during the last 40 minutes of each insulin infusion for porcine (P) and human (H) insulin was not significantly different. However, when the glucose infusion rate was expressed as a function of the mean serum insulin level (mU/l) over the same period of time the values for P and H at 4.8 and 7.2 U/hr were not significantly different but H was greater than P (13.6 +/- 1.9, v 10.8 +/- 1.9, p less than .05) at 2.4 U/hr. Mean serum insulin levels did not differ significantly for human or porcine insulin infusion. This study confirms the similarity in potency between human and porcine insulin in the human. However, delivery at 2.4 U/hr, which would predominantly affect hepatic glucose output, suggests that semisynthetic human insulin is more potent than porcine insulin with respect to the liver.

Prevention of macrovascular disease is of prime importance in long-term management of noninsulin dependent diabetes s mellitus > (NIDDM). The optimization of cholesterol levels is a major factor in reducing atherogenesis; dietary modification is the prime means of achieving this goal. In this study. we compared the impact of a nomvatunal approach to diet education on lipid> with a traditional program representative of current Australian practice. NIDDM subjects in poor metabolic control with unsatisfactory diet were studied (glycosylated hemoglobin > 9.5 % , normal 6 %-9 % ; body mass index I BMI >?5; fat >35% of diet). Sixty-five subjects (28 women. 37 men: mean age 59 years, range 44-75 years, lion diet, 39 on tablets, 24 on insulin therapy) were randomly assigned to two groups. Two baaeline samples for total, high density lipoprotein (HDL) chulesterol and triglyceride levels were collected. After keeping a four-day food record, subjects were given dietary instruction within an educational program. In the motivational group, no rcference was made to saturation or source of fat: the simplitied message was to reduce all fat with a view to better blood sugar control. Weight reduction was not emphasized but recognized as a possible result of diet change. In the conventional group, weight loss and a tow-saturated fat diet were recommended. Four weks after the finish. blood samples and diet records were collected. ResultsThe gruup's mean BMI was 31+1 1 (mean±SEM). Mean initial chulesterol was 6.3±0.2 mmul/L (244±7.7 mg/dL) in the cunventional group and 7.6±0.2 mnu~l/L 12y~±7.7 mg/dl) in the motivationat The initial mean HDL levels were not different ( 1.2 mnwI/L 146 mg/dLJ in buth); the initial &dquo;risk ratius&dquo; were 5.8 and 7.5 mmot/L (224 and 290 mg/dLl, respectl%-eiv. The plasma triglvceride levels did not differ (2.3 and 2.-~'iiiiiiol/L l202 and 193 mg/ dLi, respectively). The initial fat consumptions were 42~c' and ~5''~~ of diet. The initial mean cholesterol, saturated and polyunsaturated fat intakes did not differ significantly.At ti~lluw-up, the mean fall in cholesteml was signiticantly greater in the motiBationat group l-ll.y r +I).I 1 iiiiiiol/L [-35 n +4 mg/dLI. P < .0001 ). The mean HDL level did not change aignitirantly in either, the cholesterol risk ratio thus decreased aignrticantly in the motivationat group (the change heing -l .S v +0.2 mmo)/L [-58 n +8 mg/dLI, P < .002). The triglyceride levels were not signiticantl) altered in other. The fat make in both declined ar'~nrti~antl_v, the mutivatrunal group droppIng to 30'~' of diet, while the traditional group fell to 35%: -, the change was greater in the motivational group 1-16 l~ r-7~.P < .l)001 ).The fall,, m chotcstcro) and unsaturated fat intake did not ~lrffer, %%hile saturates fat tell more in the motivationat group (-20g r-8g. P <.003).Although the nuWvatrunal program was longer < viccklj< for I weeks t' threẽ iaya), the change described were significantly better in the experimental group exaiiiined 1I11mcdiatcl) after the dict intervent...

In order to determine whether glucagon levels of diabetic subjects are suppressible, alpha cell responsiveness to acute insulin administration (0.1 units/kg intravenously) was determined in fourteen juvenile onset, healthy diabetic and eight control subjects. In the diabetics, insulin produced a significant but slow fall in blood glucose over 60 min (P less than 0.01). On the other hand, glucagon levels fell dramatically in all diabetics to undetectable levels (P less than 0.001). Only one diabetic became hypoglycaemic and he alone showed a rebound rise of glucagon at 60 min. The rate of fall of blood glucose in the diabetic subjects was not influenced by the basal glucagon level (r=0.13) or the rate of fall of plasma glucagon (r=0.04). The glucose and glucagon responses of control subjects to insulin administration were in sharp contrast to the diabetics: blood glucose levels fell rapidly to hypoglycaemic levels and were associated with a major rise in glucagon levels (mean rise 116 pmol/1, P less than 0.001). We conclude that alpha cell hyperfunction in human diabetes can be completely suppressed by insulin administration and is therefore not autonomous, and that the slow rate of fall of blood glucose following insulin administration in diabetics is not secondary to glucagon excess.

No abstract