Ketotic Diabetes Research Articles

MON-415 Pituitary Carcinoma With Sequential Hormone Hypersecretion And A Novel Renal Complication Of Hormone Excess

Background: Pituitary carcinoma is a rare diagnosis, occurring in <1% of pituitary tumours. Most are hormonally active and resistant to conventional treatment. We present a rare case of a malignant lactotroph tumour whose extreme and evolving secretory phenotype has induced an unprecedented form of nephropathy. Case: A 55 year old man presented to ophthalmology with painful right third nerve palsy. Subsequent imaging revealed a 24 x 26 mm sellar mass extending into the right cavernous sinus and encroaching upon the optic chiasm. Endocrine evaluation demonstrated prolactin (PRL) of 68,000 mIU/L and accompanying hypogonadism (testosterone 1.3 nmol/L, FSH 1.8 IU/L, LH 1.4 IU/L), hypoadrenalism (peak cortisol 272 nmol/L after 250 mcg synacthen) and hypothyroidism (TSH 2.9 mIU/L, T4 8 pmol/L). IGF1-1 was also at the lower end of the reference range (10 nmol/L). He made an initial good response to cabergoline with PRL falling to 1570 mIU/L, resolution of visual symptoms, tumour shrinkage to 7 x 16 mm and restoration of HPA axis function. Five years later he demonstrated escape from hormone control with PRL rising to 32,000 mIU/L and return of the ophthalmoplegia, despite escalation of cabergoline to 3.5mg weekly. Unexpectedly, he also developed acute ketotic diabetes mellitus secondary to new onset acromegaly (GH >100 ug/L, IGF-1 97 nmol/L). The tumour remnant had expanded into the cavernous sinus on MRI. Biopsy of the lesion showed a tumour with strong PRL staining, micro-vacuolation, sparse GH staining and Ki-67 of 15-20% suggesting an aggressive nature and potentially in keeping with the rare acidophilic stem cell tumour subtype. He underwent stereotactic pituitary radiotherapy and later commenced pegvisomant therapy after a failed octreotide trial. Following this, prolactin levels continued to rise. Unfortunately, subsequent investigations for back pain with bilateral hand paraesthesia (at first considered secondary to acromegaly) revealed metastatic lesions in spine, lung and stomach - the latter confirmed to be of PRL-secreting neuroendocrine origin on biopsy. There was no uptake on octreotide scan. In response to new renal dysfunction (creatinine 463 umol/L with microscopic haematuria and proteinuria), a renal biopsy was also performed and revealed changes compatible with interstitial nephritis with cast nephropathy. The tubular casts stained positive for PRL, and serum PRL at this time reached a peak of 3.7 million mIU/L. Temolozamide has been commenced, and the patient may later be considered for immunotherapy . Conclusion: This is the first documented case of prolactin cast nephropathy and a rare example of a changing tumour secretion pattern, with intractable acute on chronic hyperprolactinaemia and acute acromegaly, in a case of metastatic pituitary carcinoma.

Long-lasting remission of type 1 diabetes following treatment with topiramate for generalized seizures

We report a case of unusually long-lasting remission of type 1 diabetes (T1D). The patient, a Caucasian man, at the age of 43 years developed a ketotic diabetes, classified as type 1 based on clinical presentation and positivity for islet autoantibodies. Shortly after diabetes onset, oral topiramate was added to preexisting valproic acid for generalized seizures and maintained thereafter. Initial intensive insulin treatment was rapidly reduced to low doses (3 Units/day) maintained for a long time and then discontinued at month 55; fasting glucose and glycosylated hemoglobin were basically normalized at 58 months. An oral glucose tolerance test performed at month 53 showed an impaired fasting glucose (6.0 mmol/l) and a value slightly above the threshold for the diagnosis of diabetes at 2 h (11.2 mmol/l). We hypothesize that this unusually prolonged preservation of β-cell function might be ascribed to the concomitant therapy with topiramate, an antiepileptic agent with demonstrated efficacy as antidiabetic in type 2 diabetes (T2D). Topiramate should be further investigated as candidate agent for the preservation of β-cell function also in T1D.

Insulin and glucagon ratio in the patho-physiology of diabetic ketoacidosis and hyperosmolar hyperglycemic non-ketotic diabetes.

To assess the role of insulin / glucagon ratio in pathophysiology of diabetic ketoacidosis and hyperosmolar hyperglycemic non-ketotic diabetes. Case control, analytical study. Military Hospital, Rawalpindi from September 2003 to August 2004. The study included 7 patients with diabetic ketoacidosis, 3 patients with hyperosmolar hyperglycemic non-ketotic diabetes, 8 patients with uncontrolled type 1 diabetes mellitus and 12 patients with uncontrolled type 2 diabetes mellitus. Twenty non-diabetic persons having blood glucose level less than 6 mmol/L were selected as control group. Patient s detailed history was taken and general physical examination was done. Plasma samples of all the patients and control subjects were assayed for plasma glucose, glycosylated hemoglobin, plasma insulin and glucagon levels. Presence or absence of ketone bodies in urine was also determined. Seven patients with diabetic ketoacidosis, 3 females and 4 males, were found to be hyperglycemic ( p<0.001 ), hypoinsulinemic ( p < 0.05) and hyperglucagonemic ( p < 0.001 ) as compared to control group. Three patients with hyperosmolar hyperglycemic non-ketotic diabetes, 1 male and 2 females, were hyperglycemic ( p < 0.001 ). Eight patients with uncontrolled type I diabetes mellitus, 6 males and 2 females, were having hyperglycemia (p< 0.001) along with hyperglucagonemia (p < 0.001). Twelve patients with uncontrolled type 2 diabetes mellitus, 6 males and 6 females, were found to be hyperglycemic ( p < 0.001 ) and hyperinsulinemic (p < 0.001) as compared to control group. The insulin / glucagon ratio was found to be 1 : 0.9 in diabetic ketoacidosis, 1: 0.15 in hyperosmolar hyperglycemic non-ketotic diabetes, 1: 0.24 in type 1 diabetics, 1: 0.08 in type 2 diabetics, and 1: 0.1 in the control group. It was concluded that if insulin / glucagon ratio in type 2 diabetics reduces to 1: 0.9 then these patients may develop ketoacidosis instead of hyperosmolar hyperglycemic non ketotic diabetes. Hence, it is the balance and interplay of insulin and glucagon which predicts the type of acute hyperglycemic emergencies (diabetic ketoacidosis and hyperosmolar hyperglycemic non-ketotic diabetes ) being observed in diabetic patients and not the type of diabetes mellitus.

Pancreatic exocrine and endocrine events occur concomitantly but independently during the course of fulminant type 1 diabetes

Although pancreatic exocrine enzymes are often elevated in patients with fulminant type 1 diabetes, the onset of this elevation and its significance in disease development remain unclear. We therefore investigated the significance of elevated serum enzyme concentrations and pancreatic swelling in the development of fulminant type 1 diabetes. Serum pancreatic exocrine enzymes, including amylase, elastase-I, lipase and trypsin, were measured during the course of the disease in 11 patients with fulminant type 1 diabetes (3 men and 8 women; a range of age 24–73 years, median 33 years; a range of HbA 1c at onset 4.5–6.7%, median 6.0%), all of whom developed ketotic diabetes requiring intensive insulin therapy within a month. At least one pancreatic exocrine enzyme was elevated in each patient during the course of the disease. The concentration of enzymes on admission could not be correlated with urinary excretion of C-peptide. The time course of increase in serum amylase varied in these patients. In conclusion, neither the level of serum amylase nor the swelling of pancreas was associated with the onset or severity of fulminant type 1 diabetes. The pancreatic exocrine and endocrine events may occur concomitantly but independently during the course of fulminant type 1 diabetes.

1H-MRS detected lipolysis in diabetic rat hearts requires neutral lipase.

Triacylglycerol (TAG) lipolysis increases in diabetic hearts. However, it is not known which pathway for lipolysis catalyzes this process. Thus, using 1H-magnetic resonance spectroscopy (MRS), we determined whether TAG lipolysis in diabetic rat hearts requires acid lipase or neutral lipase activity. Rats were given IP injections of 110 mg streptozotocin (STZ)/kg. Forty-eight to 72 h after this treatment, all rats exhibited ketotic diabetes. The hearts of these ketotic rats were isolated, perfused isovolumically, and analyzed using 1H-MRS. The content of methylene protons (CH2)n--and otherfatty acid protons, measured using 1H-MRS, increased in hearts isolatedfrom STZ-treated compared to untreated rats. This increase in heart--(CH2)n--was directly related to the chemical content of heart TAGs. If isolated diabetic hearts were perfused with either glucose or glucose plus the acid lipase inhibitor methylamine, then heart content of TAG, measured as (CH2)n, decreased at rates of approximately 130 nmol TAG/gdw/min throughout a 55-min perfusion. If diabetic hearts were pretreated with the neutral lipase inhibitor diethyl-p-nitro-phenylphosphate (DNPP) and perfused with glucose, then heart TAG content, measured as (CH2)n, did not change during perfusion. 1H-MRS can detect the TAG and the net lipolysis of TAG in diabetic rat hearts. Net TAG lipolysis in diabetic rat hearts requires neutral lipase.

Exaggerated stress-induced release of nonesterified fatty acids in JCR:LA-corpulent rats

Studies were performed to test the hypothesis that the stress response is exaggerated in obesity and to identify which component of the response is modified. Chronically cannulated lean (+/+) and obese ( cp cp ) JCR:LA rats were subjected to mild restraint stress for 15 minutes. Blood pressure and serum glucose, insulin, and corticosterone responses did not differ significantly between genotypes before, during, or after restraint. Lean rats had a significantly greater plasma epinephrine (EPI) response but a similar norepinephrine (NE) response compared with obese rats. Serum nonesterified fatty acid (NEFA) concentrations were unchanged in lean rats, but increased from 0.86 to a mean of 1.48 mmol/L in obese rats within 10 minutes of restraint. All animals recovered to prestress values by 45 minutes postrestraint. In obese rats, handling increased NEFAs to greater than 2 mmol/L before or at 165 minutes after restraint. In lean rats, NEFAs increased when handling occurred at 165 minutes after restraint, but there was no significant NEFA response at the prerestraint point. The sensitivity of adipose tissue to NE-induced lipolysis was not significantly different between genotypes. It is concluded that the exaggerated accumulation of NEFAs in the blood of obese rats results from increased adipose tissue mass. These increases in NEFAs in obese rats resulting from mild stress reached levels normally associated with gross pathology such as ketotic diabetes.

Pathogenesis of cerebral edema after treatment of diabetic ketoacidosis

We studied the roles of acidosis, plasma osmolality, and organic osmolytes in the pathogenesis of cerebral edema in an animal model of diabetes mellitus. Normonatremic rats with streptozotocin-induced non-ketotic (NKD) and ketotic (DKA) diabetes were sacrificed before or after treatment with hypotonic saline and insulin. Brains were analyzed for water, electrolyte, and organic osmolyte content. Brain water decreased by 2% in untreated DKA and NKD despite a 12% increase in plasma osmolality due to hyperglycemia. After treatment of both NKD and DKA, brain water increased equivalently by 8%. The cerebral edema that occurred after treatment was associated with decreased brain sodium content and no change in total major brain organic osmolytes in both NKD and DKA. However, brain content of the individual osmolytes glutamine and taurine increased after treatment of DKA. In a separate study, brain water and solute content of rats with DKA were compared after treatment with either hypotonic or isotonic fluid. Animals treated with isotonic fluid had significantly less cerebral edema and higher brain sodium content than those treated with hypotonic fluid. In our studies, brain swelling after treatment of DKA and NKD was primarily due to a rapid reduction of plasma glucose and osmolality, and was not caused by sodium movement into the brain. Acidosis did not appear to play a major role in the pathogenesis of cerebral edema after treatment of DKA.

Insulin-like growth factor I levels decrease in the development of diabetes inMacaca nigra

Members of the monkey speciesMacaca nigra spontaneously develop impairments in insulin secretion and glucose clearance, and eventually become overtly diabetic. Changes in certain metabolic signals such as clearance of glucose and insulin increment secreted in an intravenous glucose tolerance test have allowed the identification of four stages in the progression from non-diabetes to diabetes in monkeys — non-diabetic, hormonally impaired, borderline diabetic, and diabetic. Recently, another metabolic stage, hyperinsulinemic, was also identified in these animals. In recent years, other factors besides those listed above have been implicated to be correlated with the metabolic progression from a nondiabetic to a diabetic state. One of these factors, is insulin like growth factor I (IGF-I). In diabetic humans who are in poor metabolic control, and in rats with streptozotocin induced ketotic diabetes, serum levels of IGF-I are lowered by as much as 40–50% of control non-diabetics. If indeed decreased IGF-I levels are correlated with the onset of diabetes then changes in IGF-I concentrations prior to the clinically diagnosed disease state would be expected. Using serum samples collected from different animals in a colony ofMacaca nigra in a variety of metabolic states, we have found that IGF-I and insulin levels decrease in each defined metabolic state as the animals progress from nondiabetic to diabetic. Since IGF-I and insulin levels decrease in a similar fashion in the progression of this disease then this maybe indicative of the coordinate expression of these two factors.

Effects of Diabetes on the Activity and Content of the Branched-Chain α-Ketoacid Dehydrogenase Complex in Liver

Severe ketotic diabetes induced in rats by streptozotocin resulted in a reduction in activity of the hepatic branched-chain α-ketoacid dehydrogenase complex, regardless of whether activity was expressed on the basis of liver wet weight, total liver, liver protein, or liver DNA. A decrease in enzyme specific activity (units of enzyme activity per mg of enzyme protein) was found responsible for the reduction in measurable enzyme activity of the complex. Insulin treatment reversed the decrease in enzyme specific activity. Treatment of tissue extracts with phosphoprotein phosphatase had no effect, indicating that activity of the complex was decreased by some mechanism other than reversible phosphorylation. Specific protein components of the complex were also not found reduced by the diabetic state. Induction of severe ketotic diabetes in rats previously fed a low-protein diet resulted in activation of the enzyme as a cortsequence of dephosphorylation. Nevertheless, the specific activity of the dephosphorylated enzyme of diabetic, low-protein-fed rats was decreased relative to that of control, low-protein-fed animals. Reconstitution studies with tissue extracts fortified with the purified E1 component indicate that severe diabetes induces a defect in this component of the hepatic branched-chain α-ketoacid dehydrogenase complex.

Effects of Ketoacidosis and Puberty on Basal and TRH-Stimulated Thyroid Hormones and TSH in Children with Diabetes Mellitus

Basal and TRH-stimulated thyroid hormones and TSH were evaluated in two groups of prepubertal and pubertal diabetics: group B - 45 children without ketoacidosis; group C - 16 children with ketoacidosis. The diabetic patients showed no signs of diabetic microangiopathy. Fifty-three healthy subjects served as controls (group A). T4, T3, FT4 and FT3 serum levels were reduced in diabetics, particularly in ketotic ones; T4 and T3 values were lower in pubertal than in prepubertal non-ketotic diabetics and in pubertal than in prepubertal controls, while no significant difference was observed between pubertal and prepubertal ketotic patients. Moreover, no difference in rT3 serum concentrations was found between group A, B and C, but non-ketotic and ketotic pubertals showed a significant rT3 reduction if compared with non-ketotic and ketotic prepubertals and with healthy pubertals. TBG was lower in group B and group C diabetics than in controls. After TRH stimulus, T3 levels showed a significant increase both in controls and in non-ketotic diabetics, while no variation was observed in ketotic children; furthermore, at 120 minutes T3 values were lower in diabetic than in healthy children, particularly in ketotic ones. Basal TSH serum concentrations were reduced in ketotic diabetics, while no difference was found between nonketotic and control subjects. After TRH stimulus, TSH peak was higher in pubertal non-ketotic diabetics than in pubertal controls, while no difference was found between prepubertal and pubertal diabetics, both in non-ketotic and in ketotic status.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatic carnitine palmitoyltransferase turnover and translation rates in fed, starved, streptozotocin-diabetic and diethylhexyl phthalate-treated rats.

Hepatic carnitine palmitoyltransferase (CPT) turnover was studied in control and in non-ketotic hyperglycaemic streptozotocin-diabetic rats. The degradation constant (kd) and half-life (t1/2) did not appear to be altered by mild diabetes. The hepatic CPT (micrograms/g of liver) was not increased by the mild, non-ketotic, diabetes. However, the total hepatic CPT (micrograms/liver) was 37% greater in the diabetic animals, owing to the increased liver weight. This resulted from a 40% increase in the synthesis constant (ks). Hepatic CPT activity (total detergent-solubilized) and translation rates were measured in fed, starved (48 h), non-ketotic diabetic, ketotic diabetic and diethylhexyl phthalate (DEHP)-treated rats. CPT activity (m units/mg of mitochondrial protein) was not significantly increased with non-ketotic diabetes (44% increase, but non-significant), but was increased approx. 2-fold with starvation and ketotic diabetes, and 3.5-fold with DEHP treatment. CPT expressed as units/liver was increased non-significantly (23%) in non-ketotic and starved rats, similar to the turnover study, but was significantly increased with ketotic diabetes and with DEHP treatment. mRNA-translation activity for CPT was elevated in all states to a somewhat greater extent than was activity. It was concluded that protein synthesis as a product of increased CPT-mRNA translation activity is a major means of long-term regulation.

Effects of diabetes on fructose 2,6-P 2, glucose 1,6-P 2 and 6-phosphofructo 2-kinase in rat liver

The levels of fructose 2,6-P 2 and 6-phosphofructo 2-kinase have been found to be decreased in the liver of both ketotic and non-ketotic diabetic rats, a good correlation between fall of hepatic fructose 2,6-P 2, ketonemia and glycemia being observed. The “total” 6-phosphofructo 2-kinase activity and the “active” (non-phosphorylated) form of the enzyme were decreased to a different extent, resulting in a fall of the “active”/“total” activity ratio. Hepatic levels of glucose 1,6-P 2 were lowered only in ketotic diabetes. Insulin treatment normalized all the values studied. Insulin administration to control rats decreased the hepatic levels of fructose 2,6-P 2 and did not affect glucose 1,6-P 2 levels. It also decreased the “active” form of 6-phosphofructo 2-kinase, without significantly altering the “total” activity.

Sulfur amino acid metabolism in juvenile-onset nonketotic and ketotic diabetic patients

Sulfur amino acid metabolism was studied in non-fasting nonketotic and ketotic juvenile-onset diabetic children and the results were compared to age-matched healthy children on an ordinary diet. An increased excretion of total sulfur and inorganic sulfate was found in diabetic children, probably a result of a decreased protein-serum synthesis and/or increased endogenous protein catabolism, although as a result of hyperglycemia a decreased tubular reabsorption may also have contributed. All diabetics showed a normal excretion of methionine. For cyst(e)ine and taurine an increased excretion was seen in ketotic diabetics, probably also a consequence of an increased endogenous protein degradation. As a sign of the latter, an increased output of 3-methylhistidine was also observed, a confirmation of earlier reports. The increased output of mercaptolactate and mercaptoacetate found in ketotic patients, was probably also a result of enhanced endogenous protein degradation. An increased urinary excretion of N-acetylcysteine was seen in diabetic children, which may reflect an enhanced availability to acetyl coenzyme A.

Decreases in hepatic fructose-2,6-bisphosphate level and fructose-6-phosphate,2-kinase activity in diabetic mice: A close relationship to the development of ketosis

Hyperglycemic mice with streptozotocin diabetes were divided into two groups according to the presence or absence of ketosis. No difference in blood glucose level between two groups was observed in this experiment. However, hepatic fructose-2,6-P 2 level and fructose-6-P,2-kinase activity were decreased only in ketotic diabetic mice. Similar decreases in those indices were observed in 48-h starved normal mice. In ketotic diabetes, insulinization for 24 h was required to normalize fructose-2,6-P 2 level and fructose-6-P,2-kinase activity, while glucose administration normalized altered fructose-2,6-P 2 metabolism in starvation only in 30 min. Hepatic cyclic AMP was increased neither in ketotic nor in non-ketotic diabetic mice. These results indicate that the decrease in hepatic fructose-2,6-P 2 level in diabetes is apparently related to the occurrence of ketosis, but not to hyperglycemia. The mechanisms of the decrease in fructose-6-P,2-kinase activity in ketotic diabetes and starvation are discussed.

A regular meal and insulin infusion regimen: its use in the treatment of acute-onset ketotic diabetes and in stabilization of poorly controlled established diabetic subjects.

A simple regimen, consisting of a constant intravenous insulin infusion at either a basal, nocturnal rate or at a daytime rate matched by seven small, isocaloric meals taken every 2 h, has been applied to two clinical situations requiring optimal blood glucose control. In eight poorly controlled established diabetic subjects, quantitative estimates of daily insulin requirements were possible, with consequent improved control upon reinstitution of twice-daily subcutaneous insulin. In five acute-onset, ketotic diabetic subjects first treated by intravenous saline and low-dose intramuscular insulin, the regimen was used to achieve and maintain basal and postprandial normoglycemia. Ketonuria was abolished quickly in these patients, and falling insulin requirements and large doses of insulin were handled easily. In both clinical situations, subsequent subcutaneous insulin doses required little adjustment. The regimen is cheap, convenient to use, and widely applicable.

Erroneous C-Peptide Values Given?

To the Editor. —A letter regarding permanent remission of ketotic diabetes with subsequent normal C-peptide secretion was published in theArchives(1981;141:960-961) by Harstine and co-workers. Their data for C-peptide in their table and their contention that the patient had subsequent normal values for this polypeptide are probably erroneous if the serum used for the C-peptide tests was not first cleared of insulin antibodies that, no doubt, would have arisen from the patient's previous insulin therapy. Since these antibodies would cause retention of proinsulin in the patient's plasma, cross-reactivity in the C-peptide assay would, therefore, accrue, with elevated levels of C-peptide ultimately being detected. 1 Normal basal C-peptide levels are usually 0.75 ng/mL, or thereabouts, and the elevated basal levels noted in their patient bespeak some technical problem, if not an abnormality, in insulin secretion. Their comment on this point would be greatly appreciated and would help clarify what is

Permanent remission of ketotic diabetes with subsequent normal C-peptide secretion

Permanent remission of ketotic diabetes with subsequent normal C-peptide secretion

Permanent Remission of Ketotic Diabetes With Subsequent Normal C-Peptide Secretion

<h3>To the Editor.</h3> —Juvenile diabetics is initially seen with fatigue, weight loss, increased thirst, frequent urination, and glycosuria-ketonuria with or without ketoacidosis. Initially, the insulin secretory function is minimal despite hyperglycemia. Many diabetics enter a transient period of remission (the honeymoon period) within several months, but their conditions eventually deteriorate to a state of total insulin deficiency. A young man examined for remission showed evidence of a diabetes cure. <h3>Report of a Case.</h3> —An 18-year-old man was seen initially at the Joslin Clinic on June 29, 1973, for evaluation of diabetes mellitus. He had polyuria, polydipsia, fatigue, leg cramps, and had had a 23-kg weight loss from 108 kg. He had been hospitalized at another hospital for three weeks, with an admission blood glucose level of 441 mg/dL associated with glycosuria (4 + ) and ketonuria. Serum electrolyte levels were normal. He received a 2,400-calorie/day diet, and his condition was regulated with

Changes in thyroid hormone levels during the treatment of ketotic diabetes.

Changes in thyroid hormone levels during the treatment of ketotic diabetes.

PHYSICAL EXERCISE AND JUVENILE DIABETES—SUMMARY AND CONCLUSIONS

The various metabolic effects of physical exercise in ketotic diabetics, non-ketotic diabetics and non-diabetics are summarized. A favorable metabolic effect is only observed during optimal insulin administration, while in ketotic diabetics exercise may aggravate the metabolic situation. The use of exercise as a tool in the routine treatment of young diabetics is described. Activity-produced hypoglycemia should be prevented through an adequate food intake and through patient education. Regular exercise may postpone the appearance of diabetic microangiopathy.