Type 2 diabetes with hypoinsulinemia
A large body of clinical and experimental evidence documents that hyperinsulinemia and insulin resistance precede the onset of T2DM. Nonetheless, a number of studies have shown that absolute insulin deficiency, with or without impaired tissue insulin sensitivity, can lead to the development of T2DM. This scenario is best exemplified by patients with maturity onset diabetes of youth (MODY) [69–71]. This familial subtype of T2DM is characterized by early age of onset, autosomal dominant inheritance with high penetrance, mild-to-moderate fasting hyperglycemia, and impaired insulin secretion.
MODY originally was described by Fajans and subsequently it was demonstrated that MODY-1 resulted from a nonsense mutation in exon 7 of the hepatic nuclear factor (HNF4α) gene . It later was demonstrated that MODY in French families resulted from mutations in the glucokinase gene on chromosome 7p (MODY-2) . More than eight specific mutations in different genes have been implicated in the MODY profile including glucokinase and seven transcription factors [69–74]: MODY-1=HNF4α; MODY-2=glucokinase; MODY-3=HNF1α; MODY-4=insulin promoter factor 1; MODY-5=HNF1β;MODY-6=neurogenic differentiation 1/β- cell E-box transactivator 2; MODY-7=KLF11 or Kruppel-like factor 11 that regulates Pdx1 transcription in β cells; MODY-8=carboxyl-ester lipase gene. HNF1α, HNF1β, and HNF4α constitute part of a network of transcription factors that function collectively during embryonic development and during adulthood to regulate the expression of the insulin gene. The hallmark defect in MODY individuals is impaired insulin secretion in response to glucose and other secretagogues. However, peripheral tissue resistance to insulin and abnormalities in hepatic glucose metabolism have also been shown to play some role in the development of impaired glucose homeostasis .
Although glucokinase mutations are characteristic of MODY-2, genetic studies in typical older-onset type 2 diabetic individuals have shown that glucokinase mutations account for less than 1% of the common form of T2DM .
Cerasi, Luft, Hales, and coworkers [77–79] have championed the view that insulin deficiency represents the primary defect responsible for glucose intolerance in typical type 2 diabetic individuals who do not have glucokinase or other MODY mutations. According to these investigators, impaired early insulin secretion leads to an excessive rise in plasma glucose\ concentration and the resultant hyperglycemia is responsible for late hyperinsulinemia. Hales and colleagues  have demonstrated that many lean Caucasians with mild fasting hyperglycemia (<140mg dL−1, 7.8mmol L−1) are characterized by insulin deficiency at all time points during an OGTT. An impaired early insulin response has also been a characteristic finding in Japanese Americans who progress to T2DM . Unfortunately, none of these studies provided information about insulin sensitivity. In Caucasians several groups [80,81] have demonstrated normal insulin sensitivity in a minority of type 2 diabetic individuals and it has been suggested that up to 50% of African American type 2 diabetic patients who reside in New York City are characterized by severely impaired insulin secretion and normal insulin sensitivity . A similar defect in insulin secretion has been described in black African type 2 diabetic individuals living in Cameroon .
In summary, it is clear that impaired insulin secretion—in the absence of insulin resistance—can lead to the development of full-blown T2DM. However, it remains to be clarified how frequently a pure β-cell defect results in typical T2DM in the general population.