Claus Kühl

PANCREATIC SOMATOSTATINOMA: Clinical Features and Physiological Implications

The first case of a tumour producing somatostatin-like immunoreactivity and bioactivity is presented. The pancreatic tumour was composed of cells indistinguishable from islet D cells. Radioimmunoassay of blood-samples obtained by tumour-vein catheterisation revealed very high levels of somatostatin immunoreactivity. On gel chromatography tumour extracts were found to contain at least 4 different immunoreactive components, one of which eluted in the position of synthetic somatostatin. Extracts from the tumour were potent in inhibiting insulin and glucagon secretion from isolated perfused porcine pancreas. Clinical abnormalities included hypochlorhydria, steatorrhoea, and diabetic glucose tolerance. Conceivably some of these abnormalities may be related to somatostatin hypersecretion from the pancreatic tumour.

Predictive factors for the development of diabetes in women with previous gestational diabetes mellitus.

OBJECTIVES: The purpose of this study was to determine the incidence of diabetes in women with previous dietary-treated gestational diabetes mellitus and to identify predictive factors for development of diabetes. STUDY DESIGN: Two to 11 years post partum, glucose tolerance was investigated in 241 women with previous dietary-treated gestational diabetes mellitus and 57 women without previous gestational diabetes mellitus (control group). RESULTS: Diabetes developed in 42 (17.4%) women with previous gestational diabetes mellitus (3.7% insulin-dependent diabetes mellitus and 13.7% non—insulin-dependent diabetes mellitus). Diabetes did not develop in any of the controls. Predictive factors for diabetes development were fasting glucose level at diagnosis (high glucose, high risk), preterm delivery, and an oral glucose tolerance test result that showed diabetes 2 months post partum. In a subgroup of previous patients with gestational diabetes mellitus in whom plasma insulin was measured during an oral glucose tolerance test in late pregnancy a low insulin response at diagnosis was found to be an independent predictive factor for diabetes development. CONCLUSIONS: Women with previous dietary-treated gestational diabetes mellitus have a considerably increased risk of later having diabetes. Follow-up investigations are therefore important, especially in those women with previous gestational diabetes mellitus in whom the identified predictive factors are present.

Prevalence and predictive value of islet cell antibodies and insulin autoantibodies in women with gestational diabetes.

The objective of the present study was to investigate the predictive value of islet cell antibodies (ICA) and insulin autoantibodies (IAA) for development of diabetes in women with previous gestational diabetes (GDM). Two hundred and forty‐one previous diet‐treated GDM patients and 57 women without previous GDM were examined 2–11 years after the index pregnancy. In subgroups, plasma from the diagnostic OGTT during index pregnancy was analysed for ICA and IAA. Among the previous GDM patients, 3.7% had developed Type 1 diabetes and 13.7% Type 2 diabetes. Four (2.9%) of the 139 GDM patients tested for ICA were ICA‐positive and three of these had Type 1 diabetes at follow‐up, as well as three ICA‐negative patients. The sensitivity, specificity, and predictive value of ICA‐positivity for later development of diabetes were 50%, 99%, and 75%, respectively. None of the women was IAA‐positive during pregnancy. In conclusion, the majority of the patients with GDM did not show evidence of ongoing autoimmune destruction of the beta cells during the index pregnancy. However, ICA‐positive GDM patients had a high risk of developing Type 1 diabetes later in life.

C-peptide Metabolism and the Liver

It is generally assumed that C-peptide is not degraded in the liver to any significant extent. This assumption is, however, based on indirect evidence. We therefore measured the hepatic extraction ratio (R) of insulin and C-peptide in anesthetized pigs with simultaneous sampling of portal and hepatic venous blood. Blood samples were taken at one-minute intervals for 10 minutes during basal (unstimulated) experimental conditions as well as after intravenous injection of 1 mg. glucagon into four normal-weight and four obese pigs. The hepatic extraction ratio of insulin or C-peptide was calculated as the portal concentration minus the hepatic concentration divided by the portal concentration. The average pre- and poststimulatory molar ratios of C-peptide to insulin were 1.5 ± 0.11 (S.E.M.) and 1.2 ± 0.06 in portal blood and 3.4 ± 0.21 and 2.2 ± 0.08 in hepatic blood. For all pigs the mean Rc-peptide was 0.30 ± 0.03 and 0.33 ± 0.02 pre- and poststimulatory, respectively. The corresponding figures for Rinsulin (0.71 ± 0.02 and 0.61 ± 0.02) were both significantly higher (p < 0.01). The mean R-values for C-peptide and insulin were consistently higher in obese pigs than in normal-weight pigs (p < 0.01). Additional experiments in two normal-weight pigs showed that ligation of the hepatic artery elicited a significant fall of mean Rc-peptide, which, however, never became less than 0.12. These results suggest that besides the wellknown hepatic extraction of insulin, the livers of anesthetized pigs also extract significant amounts of endogenous C-peptide. Hepatic extraction of C-peptide is, however, about 50 per cent lower than that of insulin.

Triphasic oral contraception: Metabolic effects in normal women and those with previous gestational diabetes

The effect of a low-dose triphasic oral contraceptive (ethinyl estradiol and levonorgestrel) on glucose tolerance, plasma insulin and glucagon responses to glucose, fasting plasma cortisol, triglycerides, free fatty acids, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and very--low-density lipoprotein cholesterol was investigated in 16 women with previous gestational diabetes and in 19 normal women. Investigations were performed prior to the hormonal intake and after treatment for 2 and 6 months. Before treatment, the women with previous gestational diabetes had significantly elevated fasting glucose (p less than 0.05) and impaired glucose tolerance (p less than 0.05) when compared to those of the healthy control subjects. The glucose, insulin, and glucagon responses to oral glucose remained unchanged during the treatment period. Plasma cortisol increased in both groups (p less than 0.05) whereas plasma triglycerides increased in the control subjects only (p less than 0.05). Plasma free fatty acids, lipoproteins, and high-density lipoprotein cholesterol/total cholesterol ratio remained unchanged in both groups. The results suggest that a low-dose triphasic oral contraceptive (ethinyl estradiol and levonorgestrel) is suitable as contraception even in women with a previous deterioration of glucose tolerance during pregnancy.

Hormonal polypeptides and amine metabolites in small cell carcinoma of the lung, with special reference to stage and subtypes.

To elucidate the ectopic hormonal pattern in patients with small cell carcinoma of the lung, plasma ACTH, serum calcitonin, serum gastrin, plasma glucagon, serum insulin, plasma secretin, plasma VIP, serum growth hormone, serum hCG/LH, the total of serum hCG and hCG‐β‐subunit, serum α‐subunit, serum human placental lactogen, urine ADH, urine 5‐HIAA, urine VMA, urine HVA, and urine hCG‐LH were measured prior to therapy in 75 patients. Twenty‐two patients (29%) had elevated plasma ACTH, and 18 of these had concomitant increased values of corticosteroids in a 24‐hour urine sample. Forty‐eight patients (64%) were found to have elevated serum calcitonin, and one‐third of the patients were diagnosed as having the ectopic ADH syndrome. Serum gastrin concentrations were increased in 20% of the patients, but the elevations were marginal in almost all cases. None of the remaining substances was found to be significantly elevated. Concentrations of plasma ACTH, serum calcitonin, and urine ADH were not found to be correlated with the stage of the disease, and no correlation of these substances with the histological subtypes of small cell carcinoma was disclosed.

A Longitudinal Study of Plasma Insulin and Glucagon in Women With Previous Gestational Diabetes

OBJECTIVE To investigate whether plasma insulin or glucagon predicts later development of diabetes in women with gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS The subjects studied were 91 women with diet-treated GDM and 33 healthy women. Plasma insulin and glucagon during a 50-g oral glucose tolerance test (OGTT) were measured during pregnancy, postpartum, and at follow-up 5-11 years later. At follow-up, the women were also examined with a 75-g OGTT or an intravenous glucagon test. RESULTS Twenty-seven (30%) of the women with previous GDM had abnormal glucose tolerance at follow-up (2 had insulin-dependent diabetes mellitus, 13 had non-insulin-dependent diabetes mellitus, and 12 had impaired glucose tolerance). Compared with the control subjects, women with previous GDM had relatively impaired insulin secretion (decreased insulinogenic index and delayed peak insulin response) at all time points investigated; this was also found when only nonobese glucose-tolerant women were examined. Low insulin secretion during pregnancy together with a high fasting plasma glucose level at the diagnostic OGTT in pregnancy and hyperglycemia during the postpartum OGTT were predictive for subsequent development of overt diabetes (logistic regression analysis). CONCLUSIONS Women who develop GDM have a relative insulin secretion deficiency, the severity of which is predictive for later development of diabetes. Furthermore, our data indicate that their relatively reduced β-cell function may be a significant pathogenic factor in relation to the high incidence of subsequent diabetes in women with GDM. This could be important in the design of follow-up programs for women with previous GDM.

Oral contraceptives in diabetic women: metabolic effects of four compounds with different estrogen/progestogen profiles *

The metabolic effects of four oral contraceptives with different estrogen/progestogen profiles (monophasic nonalkylated estrogen/norethindrone, low-dose monophasic ethinyl estradiol (EE2)/norethindrone, progestogen only treatment with norethindrone, and triphasic EE2/levonorgestrel) were examined in insulin-dependent diabetic women. During the 6-month study period, no differences were found in fasting plasma glucose, 24-hour insulin requirements, glycated hemoglobin, free fatty acids, low-density lipoprotein cholesterol concentrations, or high-density lipoprotein cholesterol/total cholesterol ratio between the patients in each treatment group. Compared with the nonalkylated estrogen/norethindrone and the triphasic EE2/levonorgestrel formulations, the low-dose EE2/norethindrone combination resulted in small but significant increases in plasma triglyceride and very low-density lipoprotein cholesterol levels (P less than 0.01), which seemed unfavorable from a clinical point of view. Norethindrone-only treatment appeared to be an appropriate alternative to both the nonalkylated estrogen/norethindrone combination and the triphasic EE2/levonorgestrel formulations.

Comparison of Continuous Subcutaneous Insulin Infusion with Multiple Insulin Injections Using the NovoPen

Twenty‐one patients with insulin‐dependent diabetes mellitus (IDDM) participated in a 20‐week randomized cross‐over comparison of continuous subcutaneous insulin infusion (CSII) with intensified conventional treatment (ICT) using the NovoPen, The Medix or the Auto‐Syringe pumps were used for CSII and, during ICT with NovoPen, conventional plastic syringes were used for injections of intermediate‐acting insulin at bedtime. At entry HbA10 was 8.7±0.4% (mean ±SE) in CSII patients and 8.8±0.5% in the ICF group. HbA10 declined significantly in both groups (ICT 7.6±0.2%; CSII 7.6±0.2%) though there was no significant difference between the responses. Overall mean blood glucose was slightly but significantly lower during CSII than during ICT (CSII: 7.6±0.2 mmol/l; ICT: 8.7±0.4 mmol/l, p<0.05). The number of hypoglycaemic episodes did not differ significantly between patients treated with NovoPen and CSII. At the end of the study, a questionnaire revealed that all but one patient preferred ICT with NovoPen to conventional therapy. Given the choice for future treatment, 6 patients chose CSII, 12 patients preferred ICT with NovoPen and 1 was unsure.

Review: Etiology and Pathophysiology of Gestational Diabetes Mellitus

In pregnancy, several physiologic changes take place, the sum of which tends to reset the glucose homeostasis in the direction of diabetes. About 1–2% of all pregnant women develop an abnormal glucose tolerance in pregnancy, but most often glucose tolerance returns to normal postpartum. This condition is called gestational diabetes mellitus (GDM). The possibility that glucose tolerance deteriorates in pregnancy because of diabetes-like changes in the secretory function of the endocrine pancreas has been investigated in healthy controls and in normal-weight gestational diabetic subjects. The insulin responses to oral glucose and mixed meals are equally large in these two groups, but the insulin response per unit of glycemic stimulus is significantly lower in the gestational diabetic subjects than in the controls. Diabetes-like changes in glucagon secretion are not observed in either group. Insulin degradation is unaffected by human pregnancy and the proinsulin share of the total plasma insulin immunoreactivity does not increase in pregnancy. Insulin receptor binding to monocytes from normal pregnant women is increased in midpregnancy but is significantly decreased in late pregnancy. No difference in insulin binding (at tracer insulin concentration) to monocytes from healthy pregnant controls and gestational diabetic subjects is found. The insulin concentration necessary to reduce tracer insulin binding by 50% (ID50) is lower in the gestational diabetic subjects diagnosed in late pregnancy than in the pregnant controls. Together, these findings indicate that the number of insulin receptors on monocytes is decreased in GDM at this stage of pregnancy. Thus, the cause of GDM could be a decreased insulin receptor binding to target cells combined with a relative lack of circulating insulin, but the possibility of postreceptor defects does also exist.