An Unusual Form of Type 1 Diabetes With an Elevated Proinsulin Level

Introduction: Diabetes is one of the most prevalent diseases in the world. We recognize the three most common types of diabetes: type1, type2 and gestational diabetes. It is estimated that around 425 million of people worldwide have diabetes and about 90% of those represent type 2 diabetes. The most common types of diabetes are polygenic -- they are caused by a defect in multiple genes. Monogenic diabetes is caused by a mutation in a single gene. We currently have over 10 different types of monogenic diabetes called MODY (Maturity Onset Diabetes of the Young). Sun et al. states that over the past few years, 30 different insulin gene mutations were reported to cause a new syndrome called MIDY (Mutant INS-gene-induced Diabetes of Youth). Most of these mutations lead to proinsulin misfolding in the endoplasmic reticulum. We present a rare case of a young obese female with an elevated proinsulin level and low C-peptide level diagnosed with type 1 diabetes requiring therapy with insulin. Case Description: A 21 year old female with past medical history of chronic diarrhea initially presented with a complaint of dry mouth, dizziness, excessive urination, and thirst. She was found to have hyperglycemia of 203 mg/dL, A1C 8.3, and negative ketones. Patient had a strong family history of diabetes. She had a family history of: father with type 1 diabetes; mother with a past medical history of gestational diabetes who became diabetic postpartum; and three of the patient’s grandparents with a history of diabetes. Patient was started on the oral hypoglycemic agents metformin and glipizide, but she only had partial response to these medications. Because of her strong family history and incomplete response to oral hypoglycemic agents, additional testing was performed. Patient was found to have a low C-peptide level (1.6 ng/mL), elevated proinsulin (72.9 pmol/L), positive GAD antibody (10.3 units/mL) and negative islet cell autoantibody. Patient had a very good response to insulin and subsequently became insulin dependent. She is currently on an insulin pump. Conclusion: Sun et al. reports that proinsulin misfolding causes beta cell failure. Increased misfolding occurs under certain pathological conditions that are currently unknown. We think that there might be some increased proinsulin misfolding abnormality that might be occurring in this patient. There are most likely many epigenetic modifiers that would trigger certain individuals to be more prone to this phenomena of misfolded proinsulin. Future research in diabetes may one day yield antibodies that would specifically recognize misfolded proinsulin in the plasma. Further research is required to elucidate how defective proinsulin folding may lead to beta cell dysfunction and subsequent evolution of diabetes mellitus.

A rare pancreatic neuroendocrine tumor with proinsulin-secreting activity

This paper presents a clinical case describing hypoglycemic condition with atypical symptoms in a young patient in the early postpartum period. Abdominal ultrasound revealed a large formation in the hook region of the pancreas, which was subsequently confirmed according to endoscopic ultrasound, CT and MRI. The idea of insulinoma was formed according to the presence of pancreatic formation, documented Whipple’s triad, and data on hyperinsulinism at the outpatient stage. However, the 72-hour fasting test showed no significant increase in insulin and C-peptide levels. After excluding other causes of hypoglycemia, the patient was suspected of having proinsulinoma, which was confirmed by increased blood proinsulin level. Gastropancreatoduodenal resection was performed. We detected a highly differentiated neuroendocrine pancreatic tumor with the expression of CD56, NSE, synaptophysin and chromogranin A, with a Ki-67 index of about 1%. After surgical treatment, hypoglycemic conditions were not observed.

Serum Proinsulin in Bangladeshi Subjects with Impaired Glucose Tolerance

Hyperproinsulinemia is commonly present in subjects with impaired glucose tolerance. The present study was undertaken to investigate the proinsulin level in Bangladeshi IGT subjects and to explore its association with insulin resistance. This observational study was conducted under a case-control design with IGT subjects (n=50) and controls (n=44). IGT was diagnosed following the WHO Study Group Criteria. Serum glucose was measured by glucose-oxidase method, serum lipid profile by enzymatic method and serum insulin and serum proinsulin were measured by ELISA method. Insulin secretory capacity (HOMA%B) and insulin sensitivity (HOMA%S) were calculated from fasting serum glucose and fasting serum insulin by homeostasis model assessment. The study subjects were age- and BMI- matched. Mean (±SD) age (yrs) of the control and IGT subjects were 40±6 and 40±5 respectively (p=0.853). Mean (±SD) BMI of the control and IGT subjects were 23±3 and 22±2 respectively (p=0.123). Fasting glucose was not significantly higher in IGT subjects, but serum glucose 2 hours after 75 gm glucose load was significantly higher in IGT subjects. Median (Range) value of fasting serum glucose (mmol/l) of control and IGT subjects were 5.3 (3.8-6) and 5.2 (4-12) respectively; (p=0.297). Median (Range) value of serum glucose (mmol/l) 2 hours after 75 gm glucose load of control and IGT subjects were 6.1 (3-7.8) and 7.9 (5- 21) respectively; (p=0.001). Fasting TG was significantly higher in IGT subjects and LDL-c was significantly lower in IGT subjects. Serum Total cholesterol and HDL-c were not significantly different between the IGT and control subjects. Median (Range) value of fasting serum TG (mg/dl) of control and IGT subjects were 119 (51-474) and 178 (82-540) respectively; (p=0.001). Median (Range) value of fasting serum T chol (mg/dl) of control and IGT subjects were 180 (65-272) and 186 (140-400) respectively; (p=0.191). Median (Range) value of fasting serum HDL-C (mg/dl) of control and IGT subjects were 29 (19-45) and 31 (15-78) respectively; (p=0.914). Median (Range) value of fasting serum LDL-C (mg/dl) of control and IGT subjects were 117(29-201) and 111(41- 320) respectively; (p=0.001). Fasting serum proinsulin was significantly higher in IGT subjects. Median (Range) value of fasting serum proinsulin (pmol/l) of control and IGT subjects were 9.2(1.8-156) and 17(3-51) respectively; (p=0.001). Insulin secretory capacity (HOMA%B) was higher but insulin sensitivity (HOMA%S) was significantly lower in case of IGT subjects. Median (Range) value of HOMA%B of control and IGT subjects were 97(46-498) and 164(17-300) respectively; (p=0.001). Median (Range) value of HOMA%S of control and IGT subjects were 68(19-270) and 39(15-110) respectively (p=0.001). In multiple regression analysis a significant negative association was found between fasting proinsulin and insulin sensitivity (p=0.037). The data led to the following conclusions: a) Insulin resistance is the predominant defect in Bangladeshi IGT subjects. b) Basal proinsulin level is significantly increased in IGT subjects. c) Insulin resistance is negatively associated with serum proinsulin in IGT subjects. DOI: http://dx.doi.org/10.3329/bjmb.v7i2.22411 Bangladesh J Med Biochem 2014; 7(2): 41-46

Proinsulin level as a predictor of metabolic syndrome in the romanian population

Background and Aims: The aim of the present study was to determine discriminating values of proinsulin (FPP), proinsulin to insulin ratio (PIR), proinsulin to C-peptide ratio (PCPR) and Homeostasis model of assessment of insulin resistance (HOMA-IR) for the metabolic syndrome (MetS) as well as discovering sex-specific cutoff points of these parameters in the Romanian population. Material and Methods: We analyzed data from 224 patients. Circulating levels of fasting plasma glucose (FPG), fasting plasma insulin (FPI), FPP, fasting plasma C-peptide, HbA1c, and lipid profile were measured. Results: Among the 224 patients (87 males) MetS was diagnosed in 97 patients (43.3%) according to International Diabetes Federation (IDF) criteria. After stratification by gender, 43 men (49.4%) and 54 women (39.4%) had MetS. There were statistically significant differences between sexes for body mass index (BMI), % body fat, FPG, FPP, PIR, PCPR (all p<0.05). On multivariate logistic regression analysis, only age, BMI, FPP, and HOMA-IR were the independent factors associated with the presence of MetS. Conclusions: The present study showed that FPP and HOMA-IR were the best predictors for MetS in this sample of the Romanian population. Our results suggest that, regardless of gender, HOMA-IR and FPP could be the preferred parameters for predicting MetS.

The proinsulin level in the blood of children with type 1 diabetes mellitus of various duration

Proinsulin content was measured in the serum of 82 children (aged from 3 to 14 years) with type 1 diabetes mellitus of various duration. Three groups of patients characterized by low (54%), normal (42%) and high (4%) levels of this prohormone were recognized. No dependence the proinsulin level on the disease term was found. The serum proinsulin level may be used as a parameter specifying the pathogenesis of type 1 diabetes mellitus.